JPH08812B2 - 1-acyl-2,3-dihydro-4 (1H) -quinolinone derivative - Google Patents

Description

Detailed Description of the Invention

The present invention provides a novel 1-acyl-2,3-di
More specifically, it relates to a hydro-4 (1H) -quinolinone derivative , and more specifically, it has a general formula (I) having diuretic, antihypertensive, anti-edema and ascites removing activity:

[0002]

Embedded image (In the formula, R ¹ is a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched halogenated alkyl group having 1 to 4 carbon atoms, or 3 to 6 carbon atoms.
Cycloalkyl group, lower alkoxy group, methoxymethyl group, methoxycarbonylethyl group, benzyl group, styryl group, naphthyl group, pyridyl group, thienyl group, pyrazinyl group, phenyl group, or a straight chain having 1 to 4 carbon atoms or Phenyl substituted at any position with the same or different 1 to 5 substituents selected from the group consisting of branched chain alkyl groups, hydroxyl groups, nitro groups, lower alkoxy groups, trifluoromethyl groups and halogen atoms. Represents a group, R ² and R ³ are the same or different and represent a hydrogen atom or a methyl group, R ⁴ represents a carboxymethyl group,
Represents a sulfo group, a methanesulfonyl group or a methoxyphospho group, and R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a methylthio group, a methylsulfinyl group, a methanesulfonyl group, an N, N-dimethylamino group. , Nitro group, acetyl group, methyl group, trifluoromethyl group, methoxycarbonyl group or methoxy group, and the wavy line is syn (syn) type or anti (ant)
i) represents a type bond. 1-acyl-2,3 represented by
It is a compound useful as a synthetic intermediate for a dihydro-4 (1H) -quinolinone-4-oxime derivative.

[0003]

2. Description of the Related Art Conventionally, in the treatment of hypertension, blood pressure has been increased by acting on distal renal tubules of the kidney, loops of Henle, etc. to increase the excretion of electrolytes and water. Thiazide diuretics and loop diuretics that lower the blood pressure have been widely used. However, many of these antihypertensive diuretics are known to have common side effects such as hypokalemia, hyperuricemia, decreased glucose tolerance, and abnormal lipid metabolism.

Diuretics have also been used for the purpose of removing edema caused by accumulation of water and electrolytes due to functional deterioration of kidneys and heart and disorders of substance metabolism.
These diuretics also cannot be expected to have a great therapeutic effect on ascites accumulation caused by abdominal tumor, liver cirrhosis and the like.

It is well known that many of these thiazide type diuretics and loop diuretics have similar chemical structures, but the present inventors have solved the above-mentioned problems common to diuretics. In order to achieve this, we believe that a compound with a completely new chemical structure is required, and among the newly synthesized compounds, it is effective in treating hypertension, and more useful in treating edema and removing ascites. To find something,
I have been studying for many years.

[0006]

SUMMARY OF THE INVENTION The present inventors have developed 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4.
-Oxime derivatives, especially 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonic acid derivatives, their salts, solvates and solvates of salts have strong antihypertensive and antihypertensive properties. It has been found that the compound has an edema, diuretic and ascites removing effect and is useful for the production of the above derivative. The present invention has been completed based on the above findings.

1-acyl-2 represented by the above formula (I),
3- dihydro -4 (1H) - New-normalized Gobutsu of the present invention useful for the manufacture of quinolinone-4-oxime derivative has the formula (I
V) :

[0008]

[Chemical 3] (In the formula, R ¹ is a linear or branched alkyl group having 3 to 8 carbon atoms, a linear or branched halogenated alkyl group having 2 to 4 carbon atoms, or 3 to 6 carbon atoms.
Cycloalkyl groups, main Tokishimechiru group, a methoxycarbonylethyl group, a benzyl group, a styryl group, a naphthyl group, a pyridyl group, a thienyl group, a pyrazinyl group, a phenyl group or a linear or branched C1 -C4, Alkyl group, hydroxyl group, nitro group, lower alkoxy group,
A phenyl group substituted with 1 to 5 substituents of the same or different type selected from the group consisting of a trifluoromethyl group and a halogen atom at any position, R ² and R ³ being the same or different, each being hydrogen; Represents an atom or a methyl group, and R ⁵ represents 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, an acetyl group, a methyl group, a trifluoromethyl group. represents a methoxycarbonyl group or a methoxy group, R ⁶ is a halogen atom, a hydroxyl group, a methylthio group, methylsulfinyl group, a methanesulfonyl group, N, N-dimethylamino group, a nitro group, an acetyl group, a methyl group, a trifluoromethyl group Represents a methoxycarbonyl group or a methoxy group. ).

[0009] Final compound obtained new-normalized compounds of the present invention as an intermediate 1-acyl-2,3-dihydro-4 (1
The H) -quinolinone-4-oxime derivative is a novel compound and can be generally synthesized by the following steps.
First, 2,3-dihydro- which is a compound known per se
4 (1H) -quinolinone derivatives such as 7-chloro-
2,3-Dihydro-4 (1H) -quinolinone, 5-chloro-2,3-dihydro-4 (1H) -quinolinone (French Patent 1,514,280), 6-chloro-2,3.
-Dihydro-4 (1H) -quinolinone (The Journal of American Chemical Society, Vol. 71,
1901 to 1904, 1949, and US Pat. No. 2,558,211), 8-chloro-2,3-dihydro-4 (1H) -quinolinone (French Patent 1,
514, 280) or the like, or a mono- or di-substituted aniline known per se, is reacted with γ-butyrolactone or acrylic acid according to a conventional method, and then the obtained N-carboxyethyl derivative of the mono- or di-substituted aniline is subjected to Friedel-Crafts reaction. To give the novel 2,3-dihydro-4 (1 compound described in Table 18 and Step 1 of Example 11
H) -quinolinone derivative is obtained. For example 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-
By reacting dihydro-4 (1H) -quinolinone or the like with a reactive derivative of a carboxylic acid 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 (1H) -quinolinone derivative is obtained. Organic solvents that can be used in this reaction include chloroform, methylene chloride, ether, tetrahydrofuran,
Dioxane, benzene, ethyl acetate and the like, and as the base used as a deoxidizing agent, 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, R of the general formula (I) is used.
An acid chloride corresponding to ¹ , for example, 2-methylbenzoyl chloride, 2,4-dichlorobenzoyl chloride, 2-bromobenzoyl chloride, 4-chlorobenzoyl chloride, 2,2-dimethylpropionyl chloride, propionyl chloride and the like can be used.

The intermediate 1-acyl-2,3-dihydro-4 (1H) -quinolinone derivative thus obtained is treated with hydroxylamine in a solvent such as methanol, ethanol, tetrahydrofuran or dimethylformamide. Corresponding 1-acyl-2,3-dihydro-4
A (1H) -quinolinone-4-oxime derivative is obtained, and a sulfonation reagent such as a sulfur trioxide / pyridine complex or a sulfur trioxide / dimethylformamide complex is allowed to act thereon, or for example, n-butyllithium or sodium hydride. , Halogenated acetic acid such as bromoacetic acid or its ester by reacting a halogenated phosphoric acid ester such as dichlorophosphoric acid methyl ester in the presence of a base such as phenyllithium, or in the presence of a base such as 40% potassium hydroxide. By reacting or by reacting a methanesulfonyl halide such as methanesulfonyl chloride in the presence of a base such as triethylamine, and if desired, after the reaction is hydrolyzed, 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, 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-acetic acid derivative, or 1-
Acyl-2,3-dihydro-4 (1H) -quinolinone-
A 4-oxime-O-methanesulfonyl derivative is obtained.

Further, 1-acyl-2,3-dihydro-4
(1H) -quinolinone derivative in an organic solvent such as methanol, ethanol, tetrahydrofuran or dimethylformamide 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. Hydroxylamine-O
It is possible to obtain a 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonic acid derivative by reacting with -sulfonic acid.

1-acyl-prepared in this way
Table 1 shows typical examples of 2,3-dihydro-4 (1H) -quinolinone-4-oxime derivatives.

[0013]

[Table 1]

[0014]

[Table 2]

[0015]

[Table 3]

[0016]

[Table 4] Next, the efficacy, toxicity, usage and dose of the representative compounds in Table 1 will be described by way of experimental examples.

Experimental Example 1. Diuretic activity in dogs Fasting a miscellaneous dog with a body weight of 7 to 15 kg for one day, fixing it in a dorsal position under anesthesia by artificial respiration and pentobarbital 30 mg / kg IV, and through a catheter inserted into the femoral vein, 0.15 ml
Physiological saline was continuously infused at a rate of / kg / min. After laparotomy, a catheter was inserted into the left ureter and urine was collected for 10 minutes, and the urine volume was measured. The test compound was administered intravenously, and the rate of increase in urine volume was calculated by the following formula. Increase in urine volume = [Urine volume in 90 minutes after administration- (Urine volume in 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) × 100 The results are shown in Table 2.

[0018]

[Table 5] A marked diuretic effect was observed for all compounds.

Experimental Example 2 Rat Carrageenin Paw Edema Suppressing Effect Wistar rats having a body weight of about 120 g were used as one group of 3 to 5 rats. One hour after oral administration of the test compound and phenylbutazone, 0.1 ml of a 1% carrageenin physiological saline solution as an inflammatory agent was subcutaneously injected into the right hind footpad of a previously hair-removed rat. The right hind paw volume was measured before and 3 hours after the administration of the inflammatory agent, and the difference was divided by the paw volume before administration to obtain the edema rate. Furthermore, the edema rate of the control group was set to 100, and the inhibition rate of each compound-administered group was calculated.
The dose showing 0% was calculated and expressed as ED30 (mg / kg). The results are shown in Table 3.

[0020]

[Table 6] A remarkable anti-edema effect was observed for all the compounds.

Experimental Example 3 Spontaneously hypertensive rats (SH
R) antihypertensive body weight about 250-300 g, blood pressure 170-190 mmHg
Male SHR of 3 were used as one group of 3 to 5 animals. The test compound was administered every day for 7 days, and the blood pressure before and after the administration was measured using a plethysmograph. The results are shown in Table 4.

[0022]

[Table 7] A remarkable antihypertensive effect was observed for all compounds.

Experimental Example 4 Removal of ascites from cancer-bearing mice 6 to 7-week-old BDF1 mice were treated with mouse leukemia cell P3.
88 were implanted into one animal per 10 ⁶ intraperitoneal, 1 to 2 days later
The test compound was intravenously administered as 6 groups, and the amount of ascites after 5 hours was measured, and the ascites removal rate was calculated in comparison with the control group. The results are shown in Table 5.

[0024]

[Table 8] Each compound was found to have a stronger ascites removing effect than furosemide.

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

[0026]

[Table 9] Since the doses in the above-mentioned experiments are sufficiently large as compared with the values showing the pharmacological action, 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 all have extremely high safety and their pharmacological actions. It is sufficiently safe at the doses that develop. Therefore, these compounds are very useful for the treatment of edema, congestive heart failure, hypertension and cancerous ascites retention due to impaired liver function and renal function.

The compound represented by the above formula (I) can be in the form of a pharmaceutically acceptable salt. Salts include, for example, sodium salts, alkali metal salts such as potassium salts, alkaline earth metal salts such as calcium salts, salts with organic bases such as ammonium salts, benzylamine salts, diethylamine salts, and arginine salts, lysine And salts with amino acids such as salts. These compounds are usually administered orally or intravenously, but can also be administered subcutaneously, intradermally or intramuscularly, and can be in the form of inhalants, external preparations or suppositories. The therapeutic dose for adults is 1 to 5,
The dose is 000 mg / day, preferably 10 to 1,000 mg / day, but it may be increased or decreased as appropriate according to the symptoms or administration route.

The above formula (I) obtained from the compounds of the present invention
The compound represented by any of the following, a conventional pharmaceutical carrier, base,
Alternatively, it can be prepared into a pharmaceutical preparation by a conventional method together with an excipient.

Capsules, tablets, granules, fine granules, powders or oral liquid preparations for oral administration, rectal suppositories for rectal administration, and aqueous solutions or pharmaceutically acceptable dispersions for injections. It is preferable to use an auxiliary agent such as Tween 80, a suspension using a gum arabic solution, an ointment as an external preparation, and a spray as a dosage form for inhalation.

[0031]

EXAMPLES Next, examples of the present invention will be shown, but the present invention is not limited to the following examples. In addition, Example 5
7, 9 and 10 are examples of use of the intermediate compound of the present invention, and Reference Examples 1 to 3 are examples of producing final compounds from the compounds obtained in these examples of use.

Example 1 6-chloro-1- (2,4-dichlorobenzoyl)-
Synthesis of 2,3-dihydro-4 (1H) -quinolinone 20 g of 6-chloro-2,3-dihydro-4 (1H)-
Quinolinone, 26 g of pyridine and 200 ml of dioxane were mixed, and 30 g of 2,4-dichlorobenzoyl chloride was added dropwise while stirring at 0 ° C to 5 ° C. After the dropping was completed, the reaction was carried out at room temperature for 3 hours.

The reaction product was poured into 500 ml of water, and 1 l of dichloromethane was added thereto for partitioning. The organic layer was washed successively with 100 ml of 1N hydrochloric acid once, 200 ml of water twice, and saturated saline once, and then dried over anhydrous sodium sulfate. The solvent dichloromethane was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of dichloromethane-n-hexane to give white crystals 6-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4. (1H) -quinolinone 3
5 g was obtained. Melting point: 176.8-177.8 ° C IR (KBr, cm-1): 1700, 1670, 148
0.1390 NMR (CDCl3, ppm): 2.87 (2H, t),
4.22 (2H, t), 7.07-8.04 (6
H, m, aromatic)

Example 2 8-Chloro-1- (2,4-dichlorobenzoyl)-
Synthesis of 2,3-dihydro-4 (1H) -quinolinone

A) 30 g of 8-chloro-2,3-dihydro-4 (1H) -quinolinone, 52 g of pyridine and 40
After mixing with 0 ml of dioxane, 100 g of 2,4-dichlorobenzoyl chloride was added dropwise at room temperature with stirring. After completion of the dropping, the mixture was reacted under reflux for 5 hours. After cooling, Example 1
White crystal 8-chloro-1- (2,4-
61 g of dichlorobenzoyl) -4-[(2,4-dichlorobenzoyl) oxy] -1,2-dihydroquinoline were 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 maintaining the temperature at 0 ° C to 5 ° C with stirring. After the addition was completed, the reaction was carried out at room temperature for 1 hour. The reaction product was poured into 1 liter of water and 2 liter of dichloromethane was added to separate the layers.
The organic layer was washed twice with 300 ml of water and once with a saturated saline solution, washed, and then dried over anhydrous sodium sulfate. The solvent dichloromethane was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of dichloromethane-n-hexane to give white crystals 8-
Chloro-1- (2,4-dichlorobenzoyl) -2,3
32 g of dihydro-4 (1H) -quinolinone was obtained. Melting point: 157.0-159.4 ° C IR (KBr, cm-1): 1700, 1680, 144
0,1280 NMR (CDCl3, ppm): 2.73 (2H,
t), 3.97 (2H, t), 6.73-7.84.
(6H, m)

Example 3 6-chloro-1- (2,4-dichlorobenzoyl)-
Synthesis of 2,3-dihydro-3-methyl-4 (1H) -quinolinone 4.7 g of diisopropylamine and 100 ml of anhydrous tetrahydrofuran were mixed and stirred in a nitrogen stream under stirring.
Maintaining 20 ° C to -15 ° C, 29 ml of 1.6 normal n-
Butyllithium hexane solution was added dropwise over 30 minutes. After the dropping was completed, the temperature was raised to 0 ° C., the mixture was stirred at the same temperature for 30 minutes, and then the reaction solution was cooled to −75 ° C. with acetone-dry ice and kept at the same temperature. -Chloro-1- (2,4-dichlorobenzoyl)-
15 g of 2,3-dihydro-4 (1H) -quinolinone was added to 1
A solution dissolved in 50 ml of anhydrous tetrahydrofuran was added dropwise over about 1 hour. After completion of the dropping, the reaction was carried out at -75 ° C for 1 hour, and then 18 g of methyl iodide was added dropwise over about 30 minutes while maintaining the same temperature.

After completion of the dropping, the temperature was raised to 0 ° C. over about 2 hours, and 2N hydrochloric acid water was added under cooling to make it weakly acidic. The reaction product was poured into 300 ml of water and 500 ml of ethyl acetate was added. Was added to separate the layers. The organic layer was washed with saturated saline, washed 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)- 2,3-dihydro-3-methyl-4 (1
H) -quinolinone 7.8 g was obtained. Melting point: 156.7-159.4 ° C IR (KBr, cm-1): 1690, 1650, 147
0.1385 NMR (CDCl3, ppm): 1.35 (3H, d),
3.61 (1H, 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 (1H) -quinolinone 25 g of 7-chloro-2,3-dihydro-4 (1H)-
Quinoline, 32 g of pyridine and 200 ml of dioxane were mixed, and 37 g of 2,4-dichlorobenzoyl chloride was added dropwise while stirring at 0 ° C to 5 ° C. After completion of the dropwise addition, the mixture was reacted at room temperature for 3 hours and then treated in the same manner as in Example 1 to give white crystals of 7-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H)-. 43 g of quinolinone was obtained. Melting point: 159.0-162.9 ° C IR (KBr, cm-1): 1695, 1660, 139
5,1195 NMR (CDCl3, ppm): 2.78 (2H,
t), 4.08 (2H, t), 7.03-7.95.
(6H, m)

Example 5 7-chloro-1- (2,4-dichlorobenzoyl)-
Synthesis of potassium 2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonate (Compound 11) 7-chloro-1- (2,4-dichlorobenzoyl) -2 obtained in Example 4 , 3-Dihydro-4 (1H) -quinolinone (14.5 g), 200 ml of methanol and 200 ml of dichloromethane were mixed, and 4.6 g of hydroxylamine-O-sulfonic acid was added with stirring at room temperature. After reacting for 30 minutes at room temperature, 5.6 g of potassium carbonate was added to 10
An aqueous solution dissolved in ml water was added at once.

After stirring at room temperature for 2 hours, the precipitated crystals were filtered off, the solvents methanol and dichloromethane were distilled off under reduced pressure from the filtrate, and the residue was washed with silica gel / dichloromethane: methanol (10: 1). Column chromatography was carried out, followed by recrystallization with a mixed solvent of methanol-carbon tetrachloride, and white crystals of 7-chloro-1- (2,
4-dichlorobenzoyl) -2,3-dihydro-4 (1
H) -Quinolinone-4-oxime-O-potassium potassium salt 10.0 g was obtained. Melting point: 217.5 ° C (decomposition) IR (KBr, cm-1): 1660, 1395, 124
0 NMR (DMSO-d6, ppm): 2.80 (2H,
t), 3.59 (2H, t), 7.12-7.93.
(6H, m, aromatic)

Example 6 7-chloro-1- (2,4-dichlorobenzoyl)-
Synthesis of sodium 2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonate (Compound 11) 7-chloro-1- (2,4-dichlorobenzoyl) -2 obtained in Example 4 , 3-Dihydro-4 (1H) -quinolinone (14.5 g), 200 ml of methanol and 200 ml of dichloromethane were mixed, and 4.6 g of hydroxylamine-O-sulfonic acid was added with stirring at room temperature. After reacting for 30 minutes at room temperature, 4.3 g of sodium carbonate was added to 1
An aqueous solution dissolved in 0 ml water was added at once.

After stirring at room temperature for 2 hours, the precipitated crystals were filtered off, the solvent methanol and dichloromethane were distilled off under reduced pressure from the filtrate, and the residue was washed with silica gel / dichloromethane: methanol (10: 1). Column chromatography was carried out, followed by recrystallization with a mixed solvent of methanol-carbon tetrachloride, and white crystals of 7-chloro-1- (2,
4-dichlorobenzoyl) -2,3-dihydro-4 (1
H) -Quinolinone-4-oxime-O-sodium sulfonate 8.0 g was obtained. Melting point: 176.5 ° C (decomposition) IR (KBr, cm-1): 1670, 1395, 123
5 NMR (DMSO-d6, ppm): 3.05 (2H,
t), 3.90 (2H, t), 7.25-8.15.
(6H, m, aromatic)

Example 7 7-Chloro-1- (2,4-dichlorobenzoyl)-
Synthesis of potassium 2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonate (Compound 11) Step 1) 7-chloro-1- (2,4-dichlorobenzoyl) obtained in Example 4 ) -2,3-Dihydro-4 (1H)-
17.5 g of quinolinone was dissolved in 250 ml of ethanol, to which 7 g of hydroxylamine hydrochloride and 8.5 g were dissolved.
Pyridine was added and the mixture was reacted under reflux for 1.5 hours. The reaction product was poured into 1 liter of water, filtered, washed with water, dried and recrystallized from ethanol to give white crystals 7-chloro-1-
(2,4-Dichlorobenzoyl) -2,3-dihydro-
16 g of 4 (1H) -quinolinone-4-oxime was obtained. Melting point: 230.7-232.3 ° C IR (KBr, cm -1): 3251635, 142
0.945 NMR (DMSO-d6, ppm): 2.72 (2H,
t), 3.57 (2H, t), 7.05-7.94 (6
H, m)

Step 2) 16 g of the above compound was dissolved in 250 ml of dichloromethane, 7 g of sulfur trioxide pyridine complex salt was added thereto, and the mixture was reacted at room temperature for 24 hours, and then the solvent dichloromethane was distilled off under reduced pressure of about 150 ml. did. To the residual liquid was added 200 ml of methanol, and then an aqueous solution prepared by dissolving 6 g of potassium carbonate in 10 ml of water was added all at once.
Treated as in Example 5, white crystals 7-chloro-1-
(2,4-Dichlorobenzoyl) -2,3-dihydro-
13 g of potassium 4 (1H) -quinolinone-4-oxime-O-sulfonate was obtained. The product obtained is IR, N
The MR spectrum and melting point were completely in agreement with those of the product obtained in Example 5.

Reference Example 1 6-chloro-2,3-dihydro-1- (1-oxopropyl) -4 (1H) -quinolinone-4-oxime-O-
Synthesis of acetic acid (compound 14) 7.7 g of bromoacetic acid, 6.5 g of potassium hydroxide and 60 ml of water were mixed, and 6-chloro-2,3-dihydro-1-oxopropyl-4 (1H was added under ice cooling. ) -Quinolinone-4
-12.7 g of oxime were added in small portions. After reacting for 24 hours at room temperature, the pH was adjusted to 3 with 2N hydrochloric acid water under ice 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 saline, washed 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 6-chloro-2,3-dihydro-1- (1-oxo. 10.5 g of propyl) -4 (1H) -quinolinone-4-oxime-O-acetic acid was obtained. Melting point: 142.8-144.0 ° C IR (KBr, cm-1): 3300-2800, 174
0,1650,1480,1390 NMR (DMSO-d6, 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)

Reference Example 2 6-chloro-2,3-dihydro-1- (1-oxopropyl) -4 (1H) -quinolinone-4-oxime-O-
Synthesis of phosphoric acid monomethyl ester (Compound 15) 7.5 g of 6-chloro-2,3-dihydro-1- (1-
Oxopropyl) -4 (1H) -quinolinone-4-oxime was dissolved in 150 ml of anhydrous tetrahydrofuran to a solution of 21 ml under nitrogen stream with stirring at -75 ° C.
1.6 N-butyllithium hexane solution of was added dropwise over 30 minutes. After the dropping 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 the dropping, 2 at -70 to -60 ° C
After reacting for a period of time, the temperature is raised and p-ionized with 1N hydrochloric acid water under ice cooling.
H2. After reacting at room temperature for 5 hours, the reaction product was added to 20
The mixture was poured into 0 ml of water and 500 ml of ethyl acetate was added to separate the layers. The organic layer was washed with saturated saline, washed 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 6-chloro-2,3-dihydro-1- (1-
7.2 g of oxopropyl) -4 (1H) -quinolinone-4-oxime-O-phosphoric acid monomethyl ester was obtained. Melting point: 71.0-75.0 ° CIR (KBr, cm-1):
3420, 2950, 1680, 1395, 1195 NMR (DMSO-d6, ppm): 1.01 (3H,
t), 2.50 (2H, q), 2.88 (2H, t),
3.62 (3H, d), 3.78 (2H, t),
7.22-7.85 (3H, m, aromatic)

Reference Example 3 6-chloro-1- (2,4-dichlorobenzoyl)-
Synthesis of 2,3-dihydro-4 (1H) -quinolinone-4-oxime mesylate 10 g 6-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone- Four
-Oxime, 4.1 g of triethylamine and 150 ml of dichloromethane were mixed, and 3.5 g of methanesulfonyl chloride was added dropwise while stirring and maintaining the temperature at -20 ° C. After completion of dropping, the mixture was reacted at the same temperature for 30 minutes, 300 ml of dichloromethane was added, and the mixture was washed successively with 1N hydrochloric acid water, saturated aqueous sodium hydrogen carbonate and saturated brine, washed, and dried over anhydrous sodium sulfate. The solvent dichloromethane was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of ether-n-hexane to give white crystals 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 ° C IR (KBr, cm-1): 1660, 1365, 118
0 NMR (DMSO-d6, ppm): 3.03 (2H,
t), 3.38 (3H, s), 3.72 (2H, t),
7.12-7.92 (6H, m, aromatic)

Example 8 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 at room temperature with stirring. After completion of the dropping, the mixture was heated to reflux for 4 hours. Pour the reaction into 500 ml of water, 1
l of dichloromethane was added to separate the layers. 100 organic layers
It was washed once with 1 ml of 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,
The residue was crystallized from diethyl ether to give white crystals 7-chloro-2,3-dihydro-1- (2-methylbenzoyl).
28 g of -4 (1H) -quinolinone was obtained. Melting point: 106.5-108.1 ° C IR (KBr, cm-1): 1695, 1655, 140
5,1380 NMR (CDCl3, ppm): 2.34 (3H,
s), 2.80 (2H, t), 4.16 (2H, t),
7.00-8.00 (7H, m)

Example 9 7-Chloro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone-4-oxime-O
-Synthesis of potassium sulfonate (Compound 6) 7-chloro-2,3-dihydro-1-obtained in Example 8
(2 Methylbenzoyl) -4 (1H) -quinolinone 10
g, 150 ml of methanol and 100 ml of dichloromethane were mixed, and 11 g of hydroxylamine-O-sulfonic acid was added with stirring at room temperature. After reacting for 30 minutes at room temperature, an aqueous solution prepared by dissolving 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 residue was subjected to column chromatography using silica gel / dichloromethane: methanol (5: 1), followed by mixing methanol-carbon tetrachloride. Recrystallize with solvent to give white crystals 7-chloro-2,3-dihydro-1- (2
-Methylbenzoyl) -4 (1H) -quinolinone-4-
12.0 g of potassium oxime-O-sulfonate was obtained. Melting point: 189.0 ° C (decomposition) IR (KBr, cm-1): 1660, 1380, 12
40 NMR (DMSO-d6, ppm): 2.22 (3H,
s), 2.81 (2H, t), 3.73 (2H, t),
6.90-7.95 (7H, m)

Example 10 7-Chloro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone-4-oxime-O
-Synthesis of potassium sulfonate (Compound 6) Step 1) 14.9 g of 7-chloro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone obtained in Example 8 in 250 ml. It was dissolved in ethanol, to which 7 g of hydroxylamine hydrochloride and 8.5 g of pyridine were added, and the mixture was reacted under reflux for 1.5 hours. 1 reactant
It was poured into 1 l of water, filtered, washed with water, dried and recrystallized with ethanol to give white crystals 7-chloro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone-4. -13.6 g of oxime are obtained. Melting point: 166.0-168.4 ° C. IR (KBr, cm -1): 33301635, 1400 NMR (DMSO-d6, ppm): 2.20 (3H,
s), 2.81 (2H, t), 3.77 (2H, t),
7.05-7.98 (7H, m)

Step 2) 250 ml of 13.6 g of the above compound
Was dissolved in dichloromethane, and 7 g of sulfur trioxide pyridine complex salt was added thereto, and the mixture was reacted at room temperature for 24 hours, and then the solvent dichloromethane was distilled off under reduced pressure of about 150 ml. 200 ml of methanol was added to the residual liquid, and an aqueous solution prepared by dissolving 6 g of potassium carbonate in 10 ml of water was added thereto all at once. The mixture was treated in the same manner as in Example 9 to give white crystals of 7-chloro-
2,3-dihydro-1- (2-methylbenzoyl) -4
13 g of potassium (1H) -quinolinone-4-oxime-O-sulfonate was obtained. The obtained product is IR, NM
The R spectrum and melting point were completely in agreement with those of the product obtained in Example 9.

Example 11 7-Chloro-6-fluoro-2,3-dihydro-1-
(2-Methylbenzoyl) -4 (1H) -quinolinone-
Potassium 4-oxime-O-sulfonate (Compound 18)
Step 1) Using 3-chloro-4-fluoroaniline and acrylic acid or methyl acrylate as raw materials, W. S. Johnson et al. (Journal of the American Chemical Society, 71, 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 kept at 110 ° C to 70
Stir for minutes. Pour the reaction into 1.5 liters of ice water,
1.5 l of dichloromethane was added for liquid separation. The organic layer was washed twice with 300 ml of saturated saline, washed 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 7-chloro-6-fluoro-2,3-dihydro-4. 20 g of (1H) -quinolinone was obtained. Melting point: 192.0-194.0 ° C IR (KBr, cm-1): 3350, 1645, 125
0.1160 NMR (DMSO-d6 + CDCl3ppm): 2.61
(2H, t), 3.52 (2H, t), 6.83 (1
H, d), 7.43 (1H, d)

Step 2) 15 g of the compound obtained in Step 1,
2-methylbenzoyl chloride 17g, pyridine 12g
And 200 ml of dichloromethane were reacted in the same manner as in Example 8 to give 7-chloro-6-fluoro-2,3.
-Dihydro-1- (2-methylbenzoyl) -4 (1
21 g of H) -quinolinone was obtained. Melting point: 84.9-88.7 ° CIR (KBr, cm -1):
1700, 1665, 1480, 1370 NMR (CDCl3, 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,
The reaction was performed in the same manner as in Example 9 using 3.6 g of hydroxylamine-O-sulfonic acid, 4.4 g of potassium carbonate and 100 ml of methanol, and 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 ° C (decomposition) IR (KBr, cm-1): 1650, 1375, 121
0 NMR (DMSO-d6, ppm): 2.23 (3H,
s), 2.82 (2H, t), 3.75 (2H, t),
7.16-7.79 (6H, m)

The melting point or IR and N of the intermediate compound of the present invention and the compound produced through the intermediate compound are
It is summarized in Tables 8 to 18 together with MR data (data marked with * was measured at 60 MHz and other data was measured at 90 MHz) (Example numbers 1 to 14 are missing numbers). Synthetic methods of these compounds are classified into five types shown in Table 7.

[0057]

[Table 10]

[0058]

[Table 11]

[0059]

[Table 12]

[0060]

[Table 13]

[0061]

[Table 14]

[0062]

[Table 15]

[0063]

[Table 16]

[0064]

[Table 17]

[0065]

[Table 18]

[0066]

[Table 19]

[0067]

[Table 20]

[0068]

[Table 21]

[0069]

[Table 22]

[0070]

[Table 23]

[0071]

[Table 24]

[0072]

[Table 25]

[0073]

[Table 26]

[0074]

[Table 27]

[0075]

[Table 28]

[0076]

[Table 29]

[0077]

[Table 30]

[0078]

[Table 31]

[0079]

[Table 32]

[0080]

[Table 33]

[0081]

[Table 34]

[0082]

[Table 35]

[0083]

[Table 36]

[0084]

[Table 37]

[0085]

[Table 38]

[0086]

[Table 39]

[0087]

[Table 40]

[0088]

[Table 41]

[0089]

[Table 42]

[0090]

[Table 43]

[0091]

[Table 44]

[0092]

[Table 45]

Next, formulation examples containing the final compound produced from the intermediate compound of the present invention will be shown. Formulation Example A Capsule Compound 6 40 g Lactose 645 g Magnesium stearate 15 g The above ingredients are weighed and mixed uniformly. The mixed powder was Each of the hard capsules of No. 1 is filled with 350 mg each to obtain a capsule.

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

Formulation Example C Powder 7 Compound 100 g Lactose 890 g Magnesium stearate 10 g The above ingredients were weighed and mixed uniformly to obtain 10
% Powder.

Formulation Example D Suppository Compound 4 100 g Polyethylene glycol 1500 180 g Polyethylene glycol 4000 720 g Compound 4 was well ground in a mortar to give a fine powder,
A rectal suppository is prepared by the fusion method.

Formulation Example E Injectable Compound 7 1 g Sterile distilled water for injection 200 ml Compound 7 was weighed and then dissolved in sterile distilled water for injection,
After sterilization by filtration, dispense 2 ml each into a 5 ml ampoule and seal it to prepare an injection.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location (C07D 401/06 213: 00 215: 00) (C07D 409/06 215: 00 333: 00) ( 72) Inventor Akinori Haga 739 Shinmaruko, Nakahara-ku, Kawasaki, Kanagawa

Claims (17)

[Claims] 1. A compound represented by the general formula (IV): (In the formula, R ¹ is a linear or branched alkyl group having 3 to 8 carbon atoms, a linear or branched halogenated alkyl group having 2 to 4 carbon atoms, or 3 to 6 carbon atoms.
Cycloalkyl groups, main Tokishimechiru group, a methoxycarbonylethyl group, a benzyl group, a styryl group, a naphthyl group, a pyridyl group, a thienyl group, a pyrazinyl group, a phenyl group or a linear or branched C1 -C4, Alkyl group, hydroxyl group, nitro group, lower alkoxy group,
A phenyl group substituted with 1 to 5 substituents of the same or different type selected from the group consisting of a trifluoromethyl group and a halogen atom at any position, R ² and R ³ being the same or different, each being hydrogen; Represents an atom or a methyl group, and R ⁵ represents 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, an acetyl group, a methyl group, a trifluoromethyl group. represents a methoxycarbonyl group or a methoxy group, R ⁶ is a halogen atom, a hydroxyl group, a methylthio group, methylsulfinyl group, a methanesulfonyl group, N, N-dimethylamino group, a nitro group, an acetyl group, a methyl group, a trifluoromethyl group Represents a methoxycarbonyl group or a methoxy group. ) Express in 1 - acyl-2,3-dihydro -4 (IH) - quinolinone derivative. 2. The compound according to claim 1, wherein R ⁶ is a halogen atom. 3. The compound according to claim 2, wherein R ¹ is a phenyl group. 4. The compound according to claim 2, wherein R ¹ is a 2-halophenyl group. 5. The compound according to claim 2, wherein R ¹ is a 2-methylphenyl group. 6. The compound according to claim 2, wherein R ¹ is a 2-ethylphenyl group. 7. The compound according to claim 2, wherein R ¹ is a 2-trifluoromethylphenyl group. 8. The compound according to claim 2, wherein R ¹ is a 2-methoxyphenyl group. 9. The compound according to claim 2, wherein R ¹ is a 2-nitrophenyl group. 10. The compound according to claim 2, wherein R ¹ is a 4-chlorophenyl group. 11. The compound according to claim 2, wherein R ¹ is a 2,4-dichlorophenyl group. 12. The compound according to claim 2, wherein R ¹ is a 2,4-dimethylphenyl group. 13. The compound according to claim 2, wherein R ¹ is a 2,6-difluorophenyl group. 14. The compound according to claim 2, wherein R ¹ is a 2,3-dimethoxyphenyl group. 15. The compound according to claim 2, wherein R ¹ is a 4-chloro-2-methylphenyl group. 16. The compound according to claim 2, wherein R ¹ is a 1,1-dimethylethyl group. 17. The compound according to claim 2, wherein R ¹ is a 2-chloro-1,1-dimethylethyl group.