JPH0446951B2 - - Google Patents

Description

[Detailed description of the invention]

"Industrial Application Field" The present invention relates to 1-acyl-2,3-dihydro-4
Regarding (1H)-quinolinone-4-oxime derivatives, their production methods, and therapeutic agents containing them, in more detail, the general formula (): (In the formula, R ¹ is a straight chain or branched alkyl group having 1 to 8 carbon atoms,
Straight-chain or branched halogenated alkyl group, C3-C6 cycloalkyl group, lower alkoxy group, methoxymethyl group, methoxycarbonylethyl group, benzyl group, styryl group, naphthyl group, pyridyl group, thienyl group group, pyrazinyl group,
One or more of the same or different types selected from the group consisting of a phenyl group, or a linear or branched alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a nitro group, a lower alkoxy group, a trifluoromethyl group, and a halogen atom. Represents a phenyl group substituted at any position with 5 substituents, R ² and R ³
are the same or different and represent a hydrogen atom or a methyl group, R ⁴ is a carboxymethyl group, a sulfo group,
Represents a methanesulfonyl group or a methoxyphospho group, and R ⁵ and R ⁶ are the same or different, hydrogen atom, halogen atom, hydroxyl group, methylthio group, methylsulfinyl group, methanesulfonyl group, N,N
- represents a dimethylamino group, a nitro group, 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. )
1-acyl-2,3-dihydro-4 represented by
(1H)-quinolinone-4-oxime derivatives, salts, solvates and solvates of salts thereof, or methods for producing these compounds, diuretic, antihypertensive, antiedema and ascites removal agents containing them as main ingredients; relates to its synthetic intermediates. ``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, Helen's loop, 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(1H)-quinolinone-4-oxime derivatives,
Especially 1-acyl-2,3-dihydro-4
It has been found that (1H)-quinolinone-4-oxime-O-sulfonic acid derivatives, their 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 of the present invention
The (1H)-quinolinone-4-oxime derivative is a new compound and can generally be synthesized by the following steps. That is, 2,3-dihydro-4(1H)-quinolinone derivatives, which are compounds known per se, such as 7-chloro-2,3-dihydro7
-4(1H)-quinolinone, 5-chloro-2,3-
Dihydro-4(1H)-quinolinone (French patent 1514280), 6-chloro-2,3-dihydro-4
(1H) - Quinolinone (The Journal of the American Chemical Society, Vol. 71, pp. 1901-1904, 1949, and U.S. Pat.
2558211, 8-chloro-2,3-dihydro-4
(1H)-quinolinone (French patent 1514280)
Alternatively, a known mono- or di-substituted aniline is reacted with γ-butyrolactone or acrylic acid according to a conventional method, and the resulting N-carboxyethyl form of the mono- or di-substituted aniline is subjected to Friedel-Crafts reaction. Upon condensation, the resulting novel 2,3-dihydro-4(1H)-quinolinone derivatives as described in Table 18 and Example 14, step 1, such as 6-chloro-7-fluoro-2,3-
Dihydro-4(1H)-quinolinone, 7-chloro-
6-fluoro-2,3-dihydro-4(1H)-quinolinone, 6,7-difluoro-2,3-dihydro-4(1H)-quinolinone, etc., and a reactive derivative of a carboxylic acid to be introduced as an acyl group, In particular, the intermediate 1-acyl-2,3-dihydro-4 can be prepared by reacting with an acid chloride in an organic solvent, if desired in the presence of a base as a deoxidizing agent.
A (1H)-quinolinone derivative is obtained. Examples of organic solvents that can be used in this reaction include chloroform, methylene chloride, ether, tetrahydrofuran, dioxane, benzene, and ethyl acetate. Examples of bases that can be used as deoxidizers include organic solvents such as pyridine, triethylamine, and N,N-dimethylaniline. Bases, inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, etc. can be used. As acid chlorides, acid chlorides corresponding to R ¹ in general formula (),
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-
The corresponding 1-acyl-
2,3-dihydro-4(1H)-quinolinone-4-
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 by reacting it with a base such as n-butyllithium, sodium hydride, phenyllithium, etc. By reacting a halogenated phosphoric acid ester such as dichlorophosphoric acid methyl ester, or by reacting 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. The corresponding 1-acyl-2,3-dihydro-4(1H)-quinolinone- 4-oxime-O-sulfonic acid derivative, or 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-phosphoric acid monomethyl ester derivative, or 1-acyl-2,3-
Dihydro-4(1H)-quinolinone-4-oxime-O-acetic acid derivative, or 1-acyl-2,3
-dihydro-4(1H)-quinolinone-4-oxime-O-methanesulfonyl derivative is obtained. Also, 1-acyl-2,3-dihydro-4
(1H)-quinolinone derivatives, such as pyridine, N,N-
Organic bases such as dimethylaniline and potassium acetate,
1-Acyl-2,3-dihydro-4(1H)- is reacted with hydroxylamine-O-sulfonic acid in the presence of an inorganic base such as potassium carbonate or sodium carbonate.
A quinolinone-4-oxime-O-sulfonic acid derivative can be obtained. 1-acyl-2,3 produced in this way
Representative examples of -dihydro-4(1H)-quinolinone-4-oxime derivatives are shown in Table 1.

【table】

[Table] It can be used as salt.
Next, the effectiveness, toxicity, usage, dosage, etc. of representative compounds included in the present invention will be explained using experimental examples. Experimental example 1 Diuretic effect in dogs A mongrel dog weighing 7 to 15 kg was fasted for a day, artificial respiration,
The patient was fixed in a supine position under anesthesia with 30 mg/Kg of pentobarbital intravenously injected, and physiological saline was continuously infused at a rate of 0.15 ml/Kg/min through a catheter inserted into the femoral vein. After laparotomy, a catheter was inserted into the left ureter and urine was collected every 10 minutes to measure urine volume.
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 3)] Urine volume increase rate (%) = (Increase in urine volume due to test compound)
÷ (increase in urine volume due to furosemide) x 100 The results are shown in Table 2.

[Table] It was done.
Experimental example 2 Rat carrageenan paw edema inhibitory effect Wistar rats weighing approximately 120 g were administered in groups of 3 to 3.
Five animals were used. One hour after the oral administration of the test compound and phenylbutazone, 0.1 ml of a 1% carrageenan saline solution as an inflammatory agent was subcutaneously injected into the right hind paw pad of the rat, which had been thinned in advance. The volume of the right leg was measured before and 3 hours after the administration of the inflammatory agent, and the edema rate was determined by multiplying the difference by the leg volume before administration. Furthermore, the suppression rate of each compound administration group was determined by setting the edema rate of the target group as 100, and the suppression rate was 30%.
The capacity showing this was calculated and expressed as ED ₃₀ (mg/Kg). The results are shown in Table 3.

[Table] Remarkable anti-edema effects were observed for all compounds.
Experimental example 3 Antihypertensive effect in spontaneously hypertensive rats (SHR) Males weighing approximately 250-300g and blood pressure 170-190mmHg
SHR was used in groups of 3 to 5 animals. The test compound was administered every day for 7 days, and the blood pressure before and after the start of administration was measured using a plethysmograph. The results are shown in Table 4.

[Table] A significant hypotensive effect was observed for all compounds.
Experimental Example 4 Ascites removal effect in tumor-bearing mice 106 mouse leukemia cells P388 were intraperitoneally transplanted into 6-7 week old BDF ₁ mice, and 2 days later, the test compound was administered to ⁶ mice per group. After intravenous administration, 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] Ascites removal effect was observed.
Experimental Example 5 Acute Toxicity Experiment A test compound was intraperitoneally administered to a group of 5 ICR mice weighing approximately 20 g, and the mortality rate was measured 7 days later. The results are shown in Table 6.

[Table] Since the doses in the above experiments were all sufficiently large compared to the values showing pharmacological effects, these compounds are highly safe. As is clear from the above experimental examples, all of these compounds have remarkable diuretic, anti-edema, antihypertensive, and ascites-removing effects, and are also extremely safe at doses that produce these pharmacological effects. It's safe enough. Therefore, these compounds are very useful in the treatment of edema, congestive heart failure, hypertension, cancerous ascites, etc. caused by liver and renal dysfunction. The compound of the present invention represented by the general formula () is
It can be in the form of pharmaceutically acceptable salts. Examples of salts include 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, and diethylamine salts;
and salts with amino acids such as arginine salts and lysine salts. These compounds are usually administered orally or intravenously, but can also be administered subcutaneously, intradermally, or intramuscularly, and can also be made into inhalants, external preparations, or suppositories. The therapeutic dose for adults is 1-5000mg/
The dosage is preferably 10 to 1000 mg/day, but may 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, tween
80, a suspension using a gum arabic solution, an ointment for external use, and a spray for inhalation are preferred. Next, examples of the present invention will be shown, but the present invention is not limited to the following examples. Example 1 Synthesis of 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4-(1H)-quinolinone 20 g of 6-chloro-2,3-dihydro-4
(1H)-quinolinone, 26 g of pyridine (200 ml) and dioxane (200 ml) were mixed, and 30 g of 2,4-dichlorobenzoyl chloride was added dropwise to the mixture while stirring and maintaining the temperature at 0°C to 5°C. After the addition was completed, the reaction was allowed to proceed 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. 100 ml of the organic layer was washed once with 1N hydrochloric acid, twice with 200 ml of water, and once with saturated saline, 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-chlorobenzoyl)-2,3-dihydro-4
35 g of (1H)-quinolinone was obtained. Melting point: 176.8-177.8℃ IR (KBr, cm ^-1 ): 1700, 1670, 1480, 1390 NMR (CDCl ₃ , ppm): 2.87 (2H, t) 4.22 (2H, t) 7.07-8.04 (6H, m, aromatic) Example 2 Synthesis of 8-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4-(1H)-quinolinone (a) 30 g of 8-chloro-2,3-dihydro- 4
(1H)-quinolinone, 52 g of pyridine and 400 ml of dioxane were mixed at room temperature under stirring at 100 °C.
g of 2,4-dichlorobenzoyl chloride was added dropwise. After dropping, the reaction was continued for 5 hours under reflux. After cooling, the same treatment as in Example 1 was performed to obtain white crystals of 8-chloro-1-(2,4-dichlorobenzoyl)-4-[(2,4-dichlorobenzoyl).
61 g of oxy]-1,2-dihydroquinoline were obtained. (b) 61 g of the above compound was dissolved in 4000 ml of ethanol, and 4.5 g of sodium hydroxide was added over about 30 minutes while stirring and maintaining the temperature at 0°C to 5°C. After the addition was completed, the reaction was allowed to proceed at room temperature for 1 hour. reactant
It was poured into 1 liter of water, and 2 liters of dichloromethane was added to separate the liquid. The organic layer was washed twice with 300 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 dichloromethane-n-
Recrystallize with a mixed solvent of hexane to produce white crystals 8-
Chloro-1-(2,4-dichlorobenzoyl)-
2,3-dihydro-4(1H)-quinolinone 32g
I got it. Melting point: 157.0-159.4℃ IR (KBr, cm ^-1 ): 1700, 1680, 1440, 1280 NMR (CDCl ₃ , ppm): 2.73 (2H, t) 3.97 (2H, t) 6.73-7.84 (6H, m) Example 3 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-3-methyl-4(1H)
-Synthesis of quinolinone Mix 4.7 g of diisopropylamine and 100 ml of anhydrous tetrahydrofuran, maintain the temperature between -20°C and -15°C in a nitrogen stream with stirring, and prepare 29 ml of 1.6N
-Butyllithium hexane solution was added dropwise over 30 minutes. After dropping, raise the temperature to 0℃, and at the same temperature.
After stirring for 30 minutes, the reaction solution was cooled to -75°C with acetone-dry ice and maintained at the same temperature to give 6-chloro-1-(2,4-
dichlorobenzoyl)-2,3-dihydro-4
15 g of (1H)-quinolinone was dissolved in 150 ml of anhydrous tetrahydrofuran, and the solution was added dropwise over about 1 hour. After the dropwise addition was completed, the reaction was carried out at -75°C for 1 hour, and then 18g of methyl iodide was added dropwise over about 30 minutes while maintaining the same temperature. After dropping, the temperature was raised to 0℃ over about 2 hours.
After making the mixture weakly acidic by adding 2N hydrochloric acid while cooling, the reaction mixture was poured into 300 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/hexane:ethyl acetate (4:1) to give white crystals 6-
Chloro-1-(2,4-dichlorobenzoyl)-
7.8 g of 2,3-dihydro-3-methyl-4(1H)-quinolinone was obtained. Melting point: 156.7−159.4℃ IR (KBr, cm ^-1 ): 1690, 1650, 1740, 1385 NMR (CDCl ₃ , ppm): 1.35 (3H, d) 3.61 (1H, m) 4.38 (2H, d) 6.89− 7.95 (6H, m) Example 4 Synthesis of 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone 25 g of 7-chloro-2,3-dihydro- 4
(1H)-quinolinone, 32 g of pyridine, and 200 ml of dioxane were mixed, and 37 g of 2,4-dichlorobenzoyl chloride was added dropwise to the mixture while stirring and maintaining the temperature at 0°C to 5°C. After the dropwise addition was completed, the reaction was carried out at room temperature for 3 hours, and then treated in the same manner as in Example 1 to obtain white crystals 7-
Chloro-1-(2,4-dichlorobenzoyl)-
43 g of 2,3-dihydro-4(1H)-quinolinone was obtained. Melting point: 159.0-162.9℃ IR (KBr, cm ^-1 ): 1695, 1660, 1395, 1195 NMR (CDCl ₃ , ppm): 2.78 (2H, d) 4.08 (1H, m) 7.03-7.95 (6H, m) Example 5 Synthesis of potassium 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-sulfonate (compound 11) In Example 4 Obtained 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)
- 14.5 g of quinolinone, 200 ml of methanol and
200 ml of dichloromethane were mixed and 4.6 g of hydroxylamine-O-sulfonic acid was added under stirring at room temperature. After reacting for 30 minutes at room temperature, 5.6g
An aqueous solution 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). Then, recrystallization from a mixed solvent of methanol and carbon tetrachloride gave white crystals of 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-
10.0 g of potassium 4-oxime-O-sulfonate was obtained. Melting point: 217.5℃ (decomposition) IR (KBr, cm ^-1 ): 1660, 1395, 1240 NMR (DMSO-d ₆ , ppm): 2.80 (2H, t) 3.59 (2H, t) 7.12-7.93 (6H, m , aromatic) Example 6 Synthesis of sodium 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-sulfonate (compound 11) Implementation 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H) obtained in Example 4
- 14.5 g of quinolinone, 200 ml of methanol and
200 ml of dichloromethane were mixed and 4.6 g of hydroxylamine-O-sulfonic acid was added under stirring at room temperature. After reacting for 30 minutes at room temperature, 4.3g
An aqueous solution of sodium 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). Then, recrystallization from a mixed solvent of methanol and carbon tetrachloride gave white crystals of 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-
8.0 g of potassium 4-oxime-O-sulfonate was obtained. Melting point: 176.5℃ (decomposition) IR (KBr, cm ^-1 ): 1670, 1395, 1235 NMR (DMSO-d ₆ , ppm): 3.05 (2H, t) 3.90 (2H, t) 7.25-9.15 (6H, m , aromatic) Example 7 Synthesis of potassium 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-sulfonate (compound 11) ( Step 1) 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H) obtained in Example 4
- Dissolve 14.5 g of quinolinone in 250 ml of ethanol and add 7 g of hydroxylamine hydrochloride to this.
8.5 g of pyridine was added and the mixture was reacted under reflux for 1.5 hours. Pour the reaction product into 1 l of water, filter, wash with water,
After drying, recrystallize with ethanol to obtain white crystals 7.
-Chloro-1-(2,4-dichlorobenzoyl)-
2,3-dihydro-4(1H)-quinolinone-4-
16 g of oxime was obtained. Melting point: 230.7-232.3℃ IR (KBr, cm ^-1 ): 3250, 1635, 1420, 945 NMR (CDCl ₃ , ppm): 2.72 (2H, t) 3.72 (2H, t) 3.57 (2H, t) 7.05- 7.94 (6H, m) (Step 2) Dissolve 16 g of the above compound in 250 ml of dichloromethane, add 7 g of sulfur trioxide pyridine complex salt, react at room temperature for 24 hours, and remove about 150 ml of the solvent dichloromethane under reduced pressure. Removed below. 200 for residual liquid
ml of methanol was added, and to this was added at once an aqueous solution of 6 g of potassium carbonate dissolved in 10 ml of water. dichlorobenzoyl)-2,3
13 g of potassium -dihydro-4(1H)-quinolinone-4-oxime-O-sulfonate was obtained. The obtained product had completely identical IR, NMR spectra, and melting point to the product obtained in Example 5. Example 8 Synthesis of 6-chloro-2,3-dihydro-1-(1-oxopropyl)-4(1H)-quinolinone-4-oxime-O-acetic acid (compound 14) 7.7 g of bromoacetic acid and 6.5 g of potassium hydroxide and 60 ml of water, 6-chloro-2,3-
12.7 g of dihydro-1-oxopropyl-4(1H)-quinolinone-4-oxime was added in portions.
After reacting at room temperature for 24 hours, the pH was adjusted to 3 with 2N hydrochloric acid under ice cooling. Pour the reaction mixture into 150ml of water,
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/dichloroethane:methanol (9:1) to give white crystals of 6-chloro-2,3-dihydro-1-(1 10.5 g of -oxopropyl)-4(1H)-quinolinone-4-oxime O-acetic acid was obtained. Melting point: 142.8−144.0℃ IR (KBr, cm ^-1 ): 3300−2800, 1740, 1650,
1480, 1390 NMR (DMSO-d ₆ , 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 , aromatic) Example 9 Synthesis of 6-chloro-2,3-dihydro-1-(1-oxopropyl)-4(1H)-quinolinone-4-oxime-O-phosphate monomethyl ester (compound 15) 7.5 g 6-6-chloro-2,3-dihydro-
To a solution of 1-(1-oxopropyl)-4(1H)-quinolinone-4-oxime dissolved in 150 ml of anhydrous tetrahydrofuran was added - under stirring in a nitrogen stream.
While maintaining the temperature at 50°C, 21 ml of 1.6N n-butyllithium hexane solution was added dropwise over 30 minutes. After the addition was completed, the mixture was stirred at the same temperature for 30 minutes, and then 4.9 g of methyl dichlorophosphate was added dropwise over 30 minutes. After dropping, react at -70 to -60℃ for 2 hours,
The temperature was raised, and the pH was adjusted to 2 with 1N hydrochloric acid water while cooling on ice. After reacting at room temperature for 5 hours, the reaction mixture was poured into 200 ml of water, and 500 ml of ethyl acid 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 (19:1) to give white crystals of 6-chloro-2,3.
-dihydro-1-(1-oxopropyl)-4
7.2 g of (1H)-quinolinone-4-oxime-O-phosphoric acid monomethyl ester was obtained. Melting point: 71.0-75.0℃ IR (KBr, cm ^-1 ): 3420, 2950, 1680, 1395,
1195 NMR (DMSO-d ₆ , ppm): 1.01 (3H, t) 2.50 (2H, q) 2.58 (2H, t) 3.62 (3H, d) 3.78 (2H, t) 7.22-7.85 (3H, m, aromatic ) Example 10 Synthesis of 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime mesylate 10 g of 6-chloro-1-(2, 4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime, 4.1 g of triethylamine, and 150 ml of dichloromethane were mixed, and under stirring, -
While maintaining the temperature at 20°C, 3.5 g of methanesulfonyl chloride was added dropwise. After the dropwise addition was completed, the mixture was allowed to react at the same temperature for 30 minutes, then 300 ml of dichloromethane was added, and the mixture was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate, and then saturated brine. After washing, the mixture was dried over anhydrous sodium sulfate.
The solvent dichloromethane was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of ether-n-hexane to give white crystals of 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4. 11 g of (1H)-quinolinone-4-oxime mesylate was obtained. Melting point: 197.4-198.1℃ IR (KBr, cm ^-1 ): 1660, 1365, 1180 NMR (DMSO-d ₆ , ppm): 3.03 (2H, t) 3.38 (3H, t) 3.38 (2H, t) 3.72 ( 2H, t) 7.12-7.92 (6H, m, aromatic) Example 11 Synthesis of 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 20 g of 7-chloro- 2,3-dihydro-4
(1H)-quinolinone and 26 g of pyridine were mixed in 200 ml of dichloromethane and 26 g of 2-
Methylbenzoyl chloride was added dropwise. After the dropwise addition was completed, the mixture was heated under reflux for 4 hours. The reaction product was poured into 500 ml of water, and 1 liter of dichloromethane was added to separate the layers. The organic layer was diluted with 100ml of 1N hydrochloric acid once for 200ml.
The mixture was washed twice with 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 crystallized from diethyl ether to give white crystals of 7-chloro-2,3.
-dihydro-1-(2-methylbenzoyl)-4
28 g of (1H)-quinolinone was obtained. Melting point: 106.5-108.1℃ IR (KBr, cm ^-1 ): 1695, 1655, 1405, 1380 NMR (CDCl ₃ , ppm): 2.34 (3H, s) 2.80 (2H, t) 4.16 (2H, t) 7.00- 8.00 (7H, m) Example 12 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-
Synthesis of potassium oxime-O-sulfonate (compound 6) 7-chloro2,3-dihydro- obtained in Example 11
10 g of 1-(2-methylbenzoyl)-4(1H)-quinolinone, 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 30 minutes at room temperature, 14 g of potassium carbonate was added to
An aqueous solution dissolved in 20 ml of water was added all at once. After stirring at room temperature for 2 hours, the solvents methanol and dichloromethane were distilled off under reduced pressure, and the residue was dissolved in silica gel/dichloromethane.
Column chromatography was performed using dichloromethane:methanol (5:1), and then recrystallization was performed using a mixed solvent of methanol and carbon tetrachloride to obtain white crystals of 7-chloro-2,3-dihydro-1-(2-
Methylbenzoyl)-4(1H)-quinolinone-4-
12.0 g of potassium oxime-O-sulfonate was obtained. Melting point: 189.5℃ (decomposition) IR (KBr, cm ^-1 ): 1660, 1380, 1240 NMR (DMSO-d ₆ , ppm): 2.22 (3H, s) 2.81 (2H, t) 3.73 (2H, t) 6.90 -7.95 (7H, m) Example 13 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)4(1H)-quinolinone-4-
Synthesis of potassium oxime-O-sulfonate (compound 6) (Step 1) 14.9 g of 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone obtained in Example 11 was dissolved in 250 ml of ethanol, 7 g of hydroxylamine hydrochloride and 8.5 g of pyridine were added thereto, and the mixture was reacted under reflux for 1.5 hours.
The reaction product was poured into 1 l of water, filtered, washed with water, dried, and then recrystallized with ethanol to give white crystals 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)- Quinolinone-4-oxime 13.6
I got g. Melting point: 166.0-168.4℃ IR (KBr, cm ^-1 ): 3330, 1635, 1400 NMR (DMSO ₆ , ppm): 2.20 (3H, s) 2.81 (2H, t) 3.77 (2H, t) 87.05-7.98 ( 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, react at room temperature for 24 hours, and then dissolve about 150 ml of the solvent dichloromethane under reduced pressure. It was removed. to residual liquid
After adding 200 ml of methanol and adding thereto an aqueous solution of 6 g of potassium carbonate dissolved in 10 ml of water at once, the process was carried out in the same manner as in Example 12 to obtain white crystals 7-
13 g of potassium chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-oxime-O-sulfonate was obtained. The obtained product has IR, NMR spectra, and melting point as shown in Example
The product was completely consistent with the product obtained in 12. Example 14 Synthesis of potassium 7-chloro-6-fluoro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-oxime-O-sulfonate (compound 18) (step 1) Using 3-chloro-4-fluoroaniline and acrylic acid or methyl acrylate as raw materials, D. S. Johnsson et al. (Journal of the American Chemical Society,
71, p. 1901, 1949), 38 g of 3-(3-chloro-4-fluorophenylamino)propionic acid was replaced with 600 g of polyphosphoric acid,
The mixture was stirred for 70 minutes while maintaining the temperature at 110°C. The reaction product was poured into 1.51 g of ice water, and 1.51 g of dichloromethane was added to separate the layers. 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 give pale yellow crystals of 7-chloro-6-fluoro-2,3-dihydro- 20 g of 4(1H)-quinolinone was obtained. Melting point: 192.0-194.0℃ IR (KBr, cm ^-1 ): 3350, 1645, 1250, 1160 NMR (DMSO-d ₆ + CDCl ₃ ppm): 2.61 (2H, t) 3.52 (2H, t) 6.83 (1H, d ) 7.43 (1H, d) (Step 2) Using 15 g of the compound obtained in Step 1, 17 g of 2-methylbenzoyl chloride, 12 g of pyridine and 200 ml of dichloromethane, a reaction was carried out in the same manner as in Example 11 to obtain 7-chloro- 6-Fluoro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)
-21 g of quinolinone were obtained. Melting point: 84.9-88.7℃ IR (KBr, cm ^-1 ): 1700, 1665, 1480, 1370 NMR (CDCl ₃ , 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, 3.6 g of hydroxylamine-O-sulfonic acid, 4.4 g of potassium carbonate
7-chloro-6-fluoro-2,3-
Dihydro-1-(2-methylbenzoyl)-4
4 g of potassium (1H)-quinolinone-4-oxime-O-sulfonate was obtained. Melting point: 204.1℃ (decomposition) IR (KBr, cm ^-1 ): 1650, 1375, 1210 NMR (DMSO-d ₆ , 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 have melting points or
IR and NMR data (data marked with * are
Measured at 60MHz, other data measured at 90MHz. ) and are summarized in Tables 8 to 18. Synthesis methods for these compounds are classified into five types shown in Table 7.

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[Table] Examples of formulations containing the compounds of the present invention are shown below. Example A Capsule Compound 6 40g Lactose 645g Magnesium stearate 15g The above components were each weighed and mixed uniformly. Fill 350mg of the mixed powder into No. 1 hard capsules to make capsules. Example B Tablet Compound 11 50g Lactose 800g Potato starch 120g Polyvinyl alcohol 15g Magnesium stearate 15g After weighing each of the above ingredients, compound 11,
Mix lactose and potato starch evenly. 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 6 100g Lactose 890g Magnesium stearate 10g The above components were each weighed and mixed uniformly to form a 10% powder. Example D Suppository Compound 4 100g Polyethylene glycol 1500 180g Polyethylene glycol 4000 720g Compound 4 was ground well in a mortar to form a fine powder, and then made into a rectal suppository by a melting method. Example E Compound 7 for injection 1 g Sterile distilled water for injection 200 ml After weighing Compound 7, dissolve it in sterile distilled water for injection, filter sterilize it, dispense 2 ml into 5 ml ampoules, and seal them to form an injection. do.

Claims (1)

[Claims] 1 General formula (): (In the formula, R ¹ is a straight chain or branched alkyl group having 1 to 8 carbon atoms,
Straight-chain or branched halogenated alkyl group, C3-C6 cycloalkyl group, lower alkoxy group, methoxymethyl group, methoxycarbonylethyl group, benzyl group, styryl group, naphthyl group, pyridyl group, thienyl group group, pyrazinyl group,
One or more of the same or different types selected from the group consisting of a phenyl group, or a linear or branched alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a nitro group, a lower alkoxy group, a trifluoromethyl group, and a halogen atom. Represents a phenyl group substituted at any position with 5 substituents, R ² and R ³
are the same or different and represent a hydrogen atom or a methyl group, R ⁴ is a carboxymethyl group, a sulfo group,
Represents a methanesulfonyl group or a methoxyphospho group, and R ⁵ and R ⁶ are the same or different, hydrogen atom, halogen atom, hydroxyl group, methylthio group, methylsulfinyl group, methanesulfonyl group, N,N
- represents a dimethylamino group, a nitro group, 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. )
1-acyl-2,3-dihydro-4 represented by
(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 7-position halogen atom. 4 Claim 3 in which R ¹ is a phenyl group
Compounds described in Section. 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 R1 is a 2-methoxyphenyl group. 10. The compound according to claim 3, wherein ^R1 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 (): (In the formula, R ¹ is a straight chain or branched alkyl group having 1 to 8 carbon atoms,
Straight-chain or branched halogenated alkyl group, C3-C6 cycloalkyl group, lower alkoxy group, methoxymethyl group, methoxycarbonylethyl group, benzyl group, styryl group, naphthyl group, pyridyl group, thienyl group group, pyrazinyl group,
One or more of the same or different types selected from the group consisting of a phenyl group, or a linear or branched alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a nitro group, a lower alkoxy group, a trifluoromethyl group, and a halogen atom. Represents a phenyl group substituted at any position with 5 substituents, R ² and R ³
are the same or different and represent a hydrogen atom or a methyl group, R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a methylthio group,
Methylsulfinyl group, methanesulfonyl group,
Represents an N,N-dimethylamino group, nitro group, acetyl group, methyl group, trifluoromethyl group, methoxycarbonyl group or methoxy group. ) 1-acyl-2,3-dihydro-4(1H)-
By reacting a quinolinone derivative with hydroxylamine, the corresponding 1-acyl-2,3-dihydro-4
(1H)-Quinolinone-4-oxime is obtained, and this is reacted with a complex compound of sulfur trioxide, a halogenated phosphoric acid ester, a halogenated acetic acid or its ester, or methanesulfonyl halide, and then hydrolyzed if desired. A general formula () characterized by: (In the formula, R ¹ is a straight chain or branched alkyl group having 1 to 8 carbon atoms,
Straight-chain or branched halogenated alkyl group, C3-C6 cycloalkyl group, lower alkoxy group, methoxymethyl group, methoxycarbonylethyl group, benzyl group, styryl group, naphthyl group, pyridyl group, thienyl group group, pyrazinyl group,
One or more of the same or different types selected from the group consisting of a phenyl group, or a linear or branched alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a nitro group, a lower alkoxy group, a trifluoromethyl group, and a halogen atom. Represents a phenyl group substituted at any position with 5 substituents, R ² and R ³
are the same or different and represent a hydrogen atom or a methyl group, R ⁴ is a carboxymethyl group, a sulfo group,
Represents a methanesulfonyl group or a methoxyphospho group, and R ⁵ and R ⁶ are the same or different, hydrogen atom, halogen atom, hydroxyl group, methylthio group, methylsulfinyl group, methanesulfonyl group, N,N
- represents a dimethylamino group, a nitro group, 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. )
1-acyl-2,3-dihydro-4 represented by
A method for producing a (1H)-quinolinone-4-oxime derivative, a salt, a solvate thereof, and a solvate of the salt. 21 General formula (): 1-acyl-2, represented by (wherein R ¹ , R ² , R ³ , R ⁵ and R ⁶ have the same meanings as above)
Reaction of 3-dihydro-4(1H)-quinolinone derivative with hydroxylamine-O-sulfonic acid 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. General formula () characterized by: (In the formula, R ¹ is a straight chain or branched alkyl group having 1 to 8 carbon atoms,
Straight-chain or branched halogenated alkyl group, C3-C6 cycloalkyl group, lower alkoxy group, methoxymethyl group, methoxycarbonylethyl group, benzyl group, styryl group, naphthyl group, pyridyl group, thienyl group group, pyrazinyl group,
One or more of the same or different types selected from the group consisting of a phenyl group, or a linear or branched alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a nitro group, a lower alkoxy group, a trifluoromethyl group, and a halogen atom. Represents a phenyl group substituted at any position with 5 substituents, R ² and R ³
are the same or different and represent a hydrogen atom or a methyl group, R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a methylthio group,
Methylsulfinyl group, methanesulfonyl group,
It represents an N,N-dimethylamino group, a nitro group, 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 (): (In the formula, R ¹ is a straight chain or branched alkyl group having 1 to 8 carbon atoms,
Straight-chain or branched halogenated alkyl group, C3-C6 cycloalkyl group, lower alkoxy group, methoxymethyl group, methoxycarbonylethyl group, benzyl group, styryl group, naphthyl group, pyridyl group, thienyl group group, pyrazinyl group,
One or more of the same or different types selected from the group consisting of a phenyl group, or a linear or branched alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a nitro group, a lower alkoxy group, a trifluoromethyl group, and a halogen atom. Represents a phenyl group substituted at any position with 5 substituents, R ² and R ³
are the same or different and represent a hydrogen atom or a methyl group, R ⁴ is a carboxymethyl group, a sulfo group,
Represents a methanesulfonyl group or a methoxyphospho group, and R ⁵ and R ⁶ are the same or different, hydrogen atom, halogen atom, hydroxyl group, methylthio group, methylsulfinyl group, methanesulfonyl group, N,N
- represents a dimethylamino group, a nitro group, 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. )
1-acyl-2,3-dihydro-4 represented by
A diuretic, antihypertensive, antiedema and ascites removing agent characterized by containing as an active ingredient at least one of a (1H)-quinolinone-4-oxime derivative, its salt, solvate and solvate of the salt. . 23 Claim 2 in which R ⁴ is a sulfo group
The diuretic, antihypertensive, antiedema and ascites removing agent according to item 2. 24. The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 23, wherein at least one of R ⁵ and R ⁶ is a 7-position halogen atom. 25. The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R ¹ is a phenyl group. 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 a 2-ethylphenyl group. 29. The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein R ¹ is a 2-trifluoromethylphenyl group. The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein 30 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. The diuretic, antihypertensive, antiedema and ascites removing agent according to claim 24, wherein 36 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 according to claim 24, wherein R ¹ is a 2-chloro-1,1-dimethylethyl group;
Antihypertensive, anti-edema and ascites-removal agent. 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.