KR950006712B1 - Process for preparing of 1-acyl-2,3-dihydro-4(1h)-quinolone-4-oxime derivatives - Google Patents

Abstract

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Description

[Name of invention]

1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivative

Detailed description of the invention

[Background of invention]

The present invention relates to novel 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivatives. More specifically, 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivative and preparation method thereof, and new intermediate compound 1-acyl-2,3-dihydro- A 4 (1H) -quinolinone derivative and a method for preparing the same, and a composition formulation of the derivative having excellent diuretic effect of preventing and / or treating high blood pressure and edema and relieving ascites.

Benzothiazide derivatives, or so-called loop diuretics, have been widely used as antihypertensive agents to treat hypertension. These agents act primarily on the distal part of the renal tubule or the Henles's loop, increasing the excretion of electrolytes and water. However, most of these diuretics are associated with various side effects such as hypocalcemia, hyperglycemia, hypoglycemic sugar tolerance and lipid metabolism abnormalities.

Diuretics are used to treat edema caused by retention of water and electrolytes due to heart or kidney dysfunction or metabolic disorders. However, in the conventional diuretics, ascites is observed in patients with abdominal tumors or cirrhosis. It has very little effect on water retention.

These benzothiazide diuretics and loop diuretics are known to each have a part of the same chemical structure.

In the above situation, it was desired to develop a new diuretic having a therapeutic effect during hypertension, edema, and ascites while synthesizing a compound having a new chemical structure different from the known diuretic, without accompanying the side effects.

[Summary of invention]

One object of the present invention is to provide novel 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivatives and salts thereof, and the derivatives and solvates of the salts thereof.

Another object of the present invention is to provide a method for preparing a novel 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivative.

It is another object of the present invention to contain a novel 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivative as an active ingredient, and to provide therapeutic effects against hypertension, edema and ascites. In providing a pharmaceutical composition.

Another object of the present invention is a novel 1-acyl-2,3, which is an intermediate compound used in the synthesis of the 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivative. The present invention provides a dihydro-4 (1H) -quinolinone derivative and a method of preparing the same.

The invention relates to 1-acyl-2,3-dihydro-4 (1H) -quinolinone derivatives, ie O-sulfates, O-mesylate, O-methylphosphates and O-carboxymethyl ethers, in particular 4-oxime Is based on the selection of O-sulfate.

Compounds of the present invention containing these substituents possess excellent effects on hypertension, edema and diuresis, along with therapeutic effects on ascites, and exhibit excellent therapeutic effects on the aforementioned diseases and heart and kidney failure.

The present inventors have continued to develop new dihydroquinolinone oxime derivatives exhibiting satisfactory diuretic activity, and as a result, it is possible to prevent and / or treat high blood pressure and edema, as well as to provide excellent diuretic effect in removing ascites. Retained 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivatives, in particular 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4- The development of oxime-O-sulfate has led to the completion of the present invention which can meet conventional needs.

The present invention relates to 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivatives of the general formula (I), salts thereof and solvates of the derivatives and salts thereof.

In the general formula above, R ¹ is alkyl having a straight or branched chain having 1 to 8 carbon atoms, halogenated alkyl having a straight or branched chain having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, and lower alkyloxy. , Methoxymethyl, methoxycarbonylethyl, benzyl, styryl, naphthyl, pyridyl, thienyl, pyrazinyl, phenyl or substituted (substituted with alkyl or hydroxyl having straight or branched chain of 1 to 4 carbon atoms) , Same or different 1 to 5 substituents selected from the group consisting of nitro, lower alkyloxy, trifluoromethyl and halogen atoms), R ² and R ³ are the same or different, hydrogen atom or methyl, R ⁴ is carboxymethyl, sulfo, methanesulfonyl or methoxyphosphoryl, R ⁵ and R ⁶ are the same or different, hydrogen atom, halogen atom, hydroxyl, methylthio, methylsulfinyl, methanesulfonyl, N , N-dimethyl Unexposed, and nitro, acetyl, methyl, trifluoromethyl, methoxycarbonyl or methoxy, wave shaping illustrates the binding of anti-type (anti) or new type (syn).

On the other hand, the present invention relates to a 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivative. The present invention also relates to a pharmaceutical composition containing 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivative as an active ingredient as a therapeutic agent in hypertension, edema and ascites.

In addition, the present invention relates to a novel 1-acyl-2,3-dihydro-4 of an intermediate compound in the synthesis of 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivative (1H) -quinolinone derivatives and a method for producing the same.

The compounds of the present invention of general formula (I) are chemically novel compounds and can generally be prepared according to the preparation methods described below.

That is, 5-chloro-2,3-dihydro-4 (1H) -quinolinone and 7-chloro-2,3-dihydro-4 (1H) -quinolinone [see; French Patent No. 1,514,280], 6-chloro-2,3-dihydro-4 (1H) -quinolinone [see; The Journal of American Chemical Society, Vol. 71, p. 1901-1904 (1949) and US Pat. No. 2,558,211] and 8-chloro-2,3-dihydro-4 (1H) -quinolinone [see; French Patent No. 1,514,280] and the like, 2,3-dihydro-4 (1H) -quinolinone or a derivative thereof, or a mono- or di-substituted aniline is usually substituted with γ-butyrolactone or acrylic acid. Reacted and prepared by cyclocondensation of the resulting N-carboxyethylated aniline in a 1 or 2 substitution reaction by a Friedel-Crafts reaction (see Step 1 of Example 8, product Are shown in Table 8), novel mono- or di-substituted 2,3-dihydro-4 (1H) -quinolinones of the invention, for example 6-chloro-7-fluoro-2,3- Dihydro-4 (1H) -quinolinone, 7-chloro-6-fluoro-2,3-dihydro-4 (1H) -quinolinone, or 6,7-difluoro-2,3- Dihydro-4 (1H) -quinolinone is reacted with a reactive derivative of carboxylic acid (e.g. acid halide) in an organic solvent, optionally in the presence of an antacid, to introduce an acyl moiety, 1-acyl-2, 3-Dihydro-4 (1H) -quinolinone derivative is obtained as an intermediate compound.

As the organic solvent, chloroform, dichloromethane, ether, tetrahydrofuran, dioxane, benzene or ethyl acetate may be used, and as an antacid, an organic base (for example, pyridine, triethylamine or N, N-dimethylaniline) or inorganic Bases such as potassium carbonate, sodium carbonate or sodium hydrogen carbonate may be used.

Acid halides include acid halides corresponding to R ¹ of formula (I), for example 2-methylbenzoyl chloride 2,4-dichlorobenzoyl chloride, 2-bromobenzoyl chloride, 4-chlorobenzoyl chloride, 2,2-dimethyl Propionyl chloride or propionyl bromide can be used.

The intermediate compound 1-acyl-2,3-dihydro-4 (1H) -quinolinone derivative thus obtained is reacted with hydroxylamine in an organic solvent such as methanol, ethanol, tetrahydrofuran or dimethylformamide. To give the corresponding 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime, which is then sulfonated (e.g. sulfur trioxide-pyridine complex or sulfur trioxide-dimethylform Amide complexes) or halogenated phosphate esters (e.g. methyl dichlorophosphate) and bases (e.g. n-butyllithium, sodium hydride or phenyllinium), or halogenated acetic acid or esters thereof (e.g. bromoacetic acid or methyl bromine) Parent acetate) and base (e.g. potassium or sodium hydroxide) or methanesulfonyl halide (e.g. methanesulfonyl chloride) and base (e.g. triethylamine or diethylaniline) And then hydrolyzed in a conventional manner as needed to yield the corresponding product, i.e. 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonic acid derivative, 1-acyl Monomethyl ester derivative of -2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-phosphate, 1-acyl-2,3-dihydro-4 (1H) -quinolinone- 4-oxime-O-acetic acid derivatives and 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-methane sulfonyl derivatives are obtained, respectively.

The intermediate compound 1-acyl-2,3-dihydro-4 (1H) -quinolinone derivative is substituted with hydroxylamine-O-sulfonic acid and an organic solvent (eg, methanol, ethanol, tetrahydrofuran or dimethylformamide). 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonic acid derivatives by reaction in the presence of pyridine, N, N-dimethylaniline, potassium acetate, sodium carbonate or potassium carbonate May be obtained.

In order to examine the effects on the representative compounds of the present invention, data on the diuretic effect, blood pressure lowering, anti-edema effect, and ascites clearance effect are shown below.

TABLE 1

For R ⁴ , the free acid form is shown in the table above, but these compounds may also be isolated as salts of the corresponding acids.

Experimental Example 1

[Diuretic effect of dog]

Mongrel dogs weighing 7 to 15 kg are starved overnight, then pentobarbital anesthetized (30 mg / kg body weight), laid on their side, and fixed with saline to the femoral vein through a catheter at a rate of 0.15 ml / kg / min. Injection continued.

The dog's abdomen was then incised and a cannula was inserted into the left urinary tract and urine was collected at 10 minute intervals. After the test compound was injected intravenously, the change in urine volume was examined, and the rate of increase in urine volume was calculated according to the following equation.

Increased urination volume = (volume of urine 90 minutes after compound administration)

[(30 minutes of urination before compound administration) × 3]

Increase rate of urination amount = (increased amount of urination by compound before test) ÷ (furosemide

Increased urination volume) × 100

The results are shown in Table 2 below.

TABLE 2

It can be seen that all test compounds show excellent diuretic action.

Experimental Example 2

[Inhibitory Effect on Carrageenan-Infected Leg Edema in Rats]

Test compounds or phenylbutazone were administered orally to the tester rats (weight of about 120 g) in each test group (3 to 5 mice in each group). One hour after oral administration, 1% carrageenan-containing saline was subcutaneously injected in the left hind paw. The volume of each leg was measured before and after carrageenan injection, and the edema index was calculated by dividing the volume change by the volume before injection. The dose at which edema was inhibited 30% (ED ₃₀ ) was calculated for each compound.

The results are shown in Table 3.

TABLE 3

All test compounds show excellent edema suppression effect.

Experimental Example 3

[Blood pressure lowering effect on spontaneous hypertensive rats]

Test compounds were orally administered once a day for 7 days to spontaneous hypertensive rats (SHRs: 250 to 300 g body weight) of each test group (3 to 5 rats in each group). The average blood pressure of the test rats was 170-190 mmHg. Blood pressure before and after administration was measured by a plethysmograph.

The results are shown in Table 4 below.

TABLE 4

All test compounds show excellent blood pressure lowering.

Experimental Example 4

[Therapeutic Effect of Peripheral Tumor Oncism]

10 ⁶ P388 rat leukemia cells were transplanted into the peritoneum of 6-7 week-growing BDF ₁ mice, and two days later the test compound was injected intravenously into tumor development mice of each test group (6 groups). Multiple doses were measured 5 hours after administration.

The ascites treatment effect for each compound was calculated according to the plural relative comparative amounts. The results are shown in Table 5.

TABLE 5

All test compounds showed better effects than furosemide in ascites treatment of tumorigenic mice.

Experimental Example 5

[Acute Toxicity]

The test compound was intraperitoneally administered to each test group (5 groups in 1 group) of ICR mice (weight, about 20 g) and mortality was examined 7 days after administration. The results are shown in Table 6 below.

TABLE 6

The dosage is significantly greater than the amount required for their pharmacology. Therefore, it can be seen that the stability of these compounds is a large margin.

As examined in the above experimental example, the compound of the present invention has a strong diuretic effect, not only can prevent or treat hypertension, edema and ascites, but also has very high stability in its pharmacological action. Thus, the compounds of the present invention can effectively treat edema, hypertension and chronic ascites symptoms due to heart, kidney or liver failure.

The 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivative of the present invention represented by general formula (I) is reacted with a organic salt base or an organic base to be a pharmaceutically acceptable salt. Can be converted to Representative salts of the compounds of general formula (I) include alkali metal salts (e.g. sodium salts, potassium salts), alkaline earth metal salts (e.g. calcium salts), salts of organic bases (e.g. ammonium salts, benzylamine salts, di Ethylamine salts), and salts of amino acids (eg, arginine salts, lysine salts).

The 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivative of the present invention is a pharmaceutical composition, i.e., 1-acyl-2,3-dihydro- as an active ingredient with a suitable carrier. It can be prepared with a pharmaceutical composition containing 4 (1H) -quinolinone-4-oxime derivative. Pharmaceutical compositions are employed in solid form, i.e. tablets, granules, powders and capsules, or liquid suspensions, for example, injectable suspensions prepared in injection or suspension aids (e.g. gum arabic or Tween 80). Pharmaceutical compositions can be administered orally or intravenously, while also subcutaneous, intradermal or intramuscular injection. The pharmaceutical composition may also be prepared by inhalation administration (eg, aerosol), topical administration as an ointment or suppositories. The dosage is adjusted according to the condition of the patient, the type and condition of the disease, and about 1 to about 5000 mg, preferably about 10 to about 1000 mg may be used in the adult daily dose.

Next, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited thereto.

Example 1

[Preparation of 7-chloro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone]

To a mixture of 20.0 g of 7-chloro-2,3-dihydro-4 (1H) -quinolinone, 26 g of pyridine and 200 ml of dichloromethane, 26 gdml 2-methylbenzoyl chloride was added dropwise while stirring at room temperature. This mixture was then stirred at reflux for 4 hours. The reaction mixture was poured into 500 ml of water and shaken by addition of 1000 ml of dichloromethane. The organic layer was washed once with 100 ml of 1N HCl, twice with 200 ml of water each time, and once with saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized to give white crystals 7-chloro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone.

Yield: 28 g

Melting Point: 106.5-108.1 ° C

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, aromatic)

Example 2

[Preparation of 6-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone]

In a mixture of 20 g 6-chloro-2,3-dihydro-4 (1H) -quinolinone, 26 g pyridine and 200 ml dioxane, 30 g of 2,4-dichlorobenzoyl chloride was cooled at 0 ° C to 5 ° C. The mixture was added dropwise while stirring, and then the mixture was reacted at room temperature for 3 hours. The reaction mixture was poured into 500 ml of water and shaken by addition of 1000 ml of dichloromethane. The organic layer was washed once with 100 ml of 1N HCl, twice with 200 ml of water each time, and once with saturated aqueous NaCl solution, and then dried over anhydrous sodium sulfate. Dichloromethane was evaporated under reduced pressure and the residue was recrystallized from dichloromethane and N-hexane to give 6-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quine as white crystals. Nolinone was obtained.

Yield: 35 g

Melting Point: 176.8-177.8 ° C

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 3

[Preparation of 8-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone]

To a mixture of 30 g of 8-chloro-2,3-dihydro-4 (1H) -quinolinone, 52 g of pyridine and 400 ml of dioxane was added dropwise with stirring 100 g of 2,4-dichlorobenzoyl chloride at room temperature, The mixture was heated at reflux for 5 hours. After cooling, the reaction mixture was treated according to the method of Example 2, by which 61 g of 8-chloro-1- (2,4-dichlorobenzoyl) -4-[(2,4-dichlorobenzoyl) oxy] -1,2- Dihydroquinolinone was obtained. All of the product was dissolved in 400 ml of ethanol, 4.5 g of NaOH was added slowly to the resulting solution over 30 minutes while maintaining the temperature at 0 ° C to 5 ° C, the mixture was stirred at room temperature for 1 hour, and then the reaction mixture was dissolved in 1000 ml of Pour into water and shake with adding 2000 ml of dichloromethane. The organic layer was washed twice with 300 ml each of water and once with 300 ml of saturated NaCl aqueous solution, and then dried over anhydrous sodium sulfate. Dichloromethanol was evaporated under reduced pressure and the residue was recrystallized from dichloromethane and n-hexane to give white crystals 8-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinoli Rice fields were obtained.

Yield: 32 g

Melting point: 157.0 ~ 159.4 ° C

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 4

[Preparation of 6-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-3-methyl-4 (1H) -quinolinone]

After cooling a solution of 4.7 g of diisopropylamine and 100 ml of anhydrous tetrahydrofuran to -20 ° C to -15 ° C, 29 ml of an n-hexane solution of 1.6N butyllithium was added dropwise over 30 minutes in a nitrogen atmosphere. The mixed solution was brought to 0 ° C. and stirred for 30 minutes. The solution was cooled to −75 ° C. with acetone-dry ice and 15 g of 6-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone and 150 ml anhydrous tetra A solution of hydrofuran was added dropwise over 1 hour. The reaction mixture was stirred again at -75 ° C for 1 hour, and 18 g of methyl iodide was added dropwise over 30 minutes under stirring.

The reaction mixture was slowly warmed to 0 ° C. over 2 h and acidified with 2N HCl under cooling to become slightly acidic. The reaction mixture was poured into 300 ml of water and shaken by addition of 500 ml of ethyl acetate. The organic layer was washed once with 200 ml of saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure and the residue was treated with silica gel column chromatography (eluent: a mixture of hexane-ethyl acetate (4: 1)) to give 6-chloro-1- (2,4-dichlorobenzoyl) as white crystals. ) -2,3-dihydro-3-methyl-4 (1H) -quinolinone was obtained.

Yield: 7.8 g

Melting point: 156.7 to 159.4 ° C

IR (KBr, cm ^-1 ): 1690, 1650, 1470, 1385

NMR (CDCl ₃ , ppm): 1.35 (3H, d), 3.61 (1H, m), 4.38 (2H, d), 6.89-7.95 (6H, m)

Example 5

[Preparation of 7-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone]

To a mixture of 25 g of 7-chloro-2,3-dihydro-4 (1H) -quinolinone, 32 g of pyridine and 200 ml of dioxane, 37 g of 2,4-dichlorobenzoyl chlorolide was added from 0 ° C to 5 ° C. After cooling and dropping while stirring at temperature, the mixture was reacted at room temperature for 3 hours. The reaction mixture was treated according to the method of Example 2 to yield white crystals 7-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone.

Yield: 43 g

Melting point: 159.0 ~ 162.9 ° C

IR (KBr, cm ^-1 ): 1695, 1660, 1395, 1195

NMR (CDCl ₃ , ppm): 2.78 (2H, t), 4.08 (2H, t), 7.03-7.95 (6H, m, aromatic)

Example 6

[Preparation of 7-chloro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone-4-oxime-O-sulfonic acid potassium salt (Compound 6)]

Of 10.0 g of 7-chloro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone (obtained in Example 1), 150 ml of methanol and 100 ml of dichloromethane 11 g of hydroxylamine-O-sulfonic acid was added to the mixture under stirring at room temperature, and then the mixture was stirred at room temperature for 30 minutes, and aqueous potassium carbonate solution (14 g dissolved in 20 ml of water) was added all at once. The reaction mixture was stirred at rt for 2 h, then the solvent was evaporated under reduced pressure. The residue was treated with silica gel column chromatography (eluent: a mixture of dichloromethane-methanol (5: 1)), recrystallized with a methanol-4 carbon chloride mixed solvent, and white crystals of 7-chloro-2,3-di. Hydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone-4-oxime-O-sulfonic acid potassium salt was obtained.

Yield: 12.0 g

Melting Point: 189.0 ° C (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, aromatic)

Example 7

[Preparation of 7-chloro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone-4-oxime-O-sulfonic acid potassium salt (Compound 6)]

[Course 1]

Into a mixture of 14.9 g of 7-chloro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone (obtained in Example 1) and 250 ml of ethanol 7 g of hydroxide Oxylamine hydrochloride and 8.5 g of pyridine were added and the mixture was heated at reflux for 1.5 hours. After cooling, the reaction mixture was poured into 1000 ml of water, and the precipitated precipitate was separated by filtration, the product was washed and dried, and then recrystallized with ethanol to give 7-chloro-2,3-dihydro-1- ( 2-Methylbenzoyl) -4 (1H) -quinolinone-4-oxime was obtained.

Yield: 13.6 g

Melting point: 166.0 to 168.4 ° C

IR (KBr, cm ^-1 ): 3330, 1635, 1400

NMR (DMSO-d ₆ , ppM): 2.20 (3H, s), 2.81 (2H, t), 3.77 (2H, t), 7.05-7.98 (7H, m, aromatic)

[Course 2]

13.6 g of the product of Procedure 1 were dissolved in 250 ml of dichloromethane, 7 g of sulfur trioxide-pyridine complex was added, then the reaction mixture was stirred for 24 hours at room temperature, and about 150 ml of the solvent was evaporated under reduced pressure. 200 ml of methane was added to the residue, and then potassium carbonate solution (6 g dissolved in 10 ml of water) was added all at once, followed by treatment according to the method of Example 6 to obtain 7-chloro-2,3-di of white crystals. 13 g of hydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone-4-oxime-O-sulfonic acid potassium salt were obtained.

Melting point, IR and NMR spectrum were in full agreement with those of the product of Example 6.

Example 8

Preparation of [7-Chloro-6-fluoro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone-4-oxime-O-sulfonic acid potassium salt (Compound 18) ]

[Course 1]

[Preparation of 7-chloro-6-fluoro-2,3-dihydro-4 (1H) -quinolinone]

Synthesis from 600 g polyphosphoric acid and 38 g 3- (3-chloro-4-fluorophenylamino) propionic acid [3-chloro-4-fluoroaniline and acrylic acid or methyl acrylate. Reference: The Journal of American Chemical Society, Vol. 71, p. 1901 (1949)] was stirred at 110 ° C. for 70 minutes. The reaction mixture was poured into 1500 ml of water, shaken by adding 1500 ml of dichloromethane, and then the organic layer was washed twice with 200 ml each of saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. Dichloromethane was evaporated under reduced pressure and the residue was treated with silica gel column chromatography (eluent: n-hexane-ether (4: 1) mixture) to give light yellow crystals of 7-chloro-6-fluoro-2, 3-dihydro-4 (1H) -quinolinone was obtained.

Yield: 20 g

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)

[Course 2]

[Preparation of 7-chloro-6-fluoro-1- (2-methylbenzoyl) -2,3-dihydro-4 (1H) -quinolinone]

15 g of the product of Procedure 1, 17 g of 2-methylbenzoyl chloride, 12 g of pyridine and 200 ml of dichloromethane were reacted and purified according to the method of Example 1 to obtain 7-chloro-6-fluoro-2,3-dihydro-1. -(2-methylbenzoyl) -4 (1H) -quinolinone was obtained.

Yield: 21 g

Melting Point: 84.9 to 88.7 ° C

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)

[Course 3]

[Preparation of 1- (2-methylbenzoyl) -7-chloro-6-fluoro-2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonic acid potassium salt]

10 g of the product of step 2, 3.6 g of hydroxylamine-O-sulfonic acid, 4.4 g of potassium carbonate and 100 ml of methanol were reacted and purified according to the method of Example 6 to obtain white crystals 1- (2-methylbenzoyl) -7 -Chloro-6-fluoro-2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonic acid potassium salt was obtained.

Yield: 4 g

Melting Point: 204.1 ° C (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, aromatic)

Example 9

[Preparation of 7-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonic acid potassium salt (Compound 11)]

14.5 g of 7-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone (obtained in Example 5), 200 ml of methanol and 200 ml of dichloro 4.6 g of hydroxylamine-O-sulfonic acid was added to the mixture of methane with stirring. After stirring for 30 minutes at room temperature, an aqueous potassium carbonate solution (5.6 g dissolved in 10 ml of water) was added all at once, stirred for 2 hours, and then the precipitated precipitate was separated by filtration and the solvent was evaporated under reduced pressure.

The residue was treated with silica gel column chromatography (eluent: a mixture of dichloromethane-methanol (10: 1)), recrystallized with methanol and carbon tetrachloride, to give 7-chloro-1- (2,4 as white crystals. -Dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonic acid potassium salt was obtained.

Yield: 10.0 g

Melting Point: 217.5 ° C (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 10

[Preparation of 7-chloro-1- (2,4-dichlorobenzoyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonic acid sodium salt (Compound 11)]

14.5 g of 7-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -kinolinone (obtained in Example 5), 200 ml of methanol and 200 ml of dichloro 4.6 g of hydroxylamine-O-sulfonic acid was added to the mixture of methane with stirring. After stirring for 30 minutes at room temperature, an aqueous sodium carbonate solution (4.3 g dissolved in 10 ml of water) was added all at once, stirred for 2 hours, and then the precipitated precipitate was separated by filtration and the solvent was evaporated under reduced pressure. The residue was treated with silica gel column chromatography (eluate: a mixture of dichloromethane-methanol (10: 1)), recrystallized from methanol and carbon tetrachloride, to give 7-chloro-1- (2,4- as white crystals. Dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonic acid sodium salt was obtained.

Yield: 8.0 g

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), 7.25-8.15 (6H, m, aromatic)

Example 11

[Preparation of 7-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonic acid potassium salt (Compound 11)]

[Course 1]

17.5 g of 7-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone (obtained in Example 5), 7 g in a mixture of 250 ml ethanol Hydroxylamine hydrochloride and 8.5 g pyridine were added and the mixture was heated at reflux for 1.5 h. After cooling, the reaction mixture was poured into 1000 ml of water and the precipitate precipitated was isolated by filtration, the product was washed, dried and recrystallized with ethanol to give 7-chloro-1- (2,4-dichlorobenzoyl) as white crystals. -2,3-dihydro-4 (1H) -quinolinone-4-oxime was obtained.

Yield: 16 g

Melting Point: 230.7 to 232.3 ° C

IR (KBr, cm ^-1 ): 3250, 1635, 1420, 945

NMR (DMSO-d ₆ , ppm): 2.72 (2H, t), 3.57 (2H, t), 7.05-7.94 (6H, m, aromatic)

[Course 2]

16 g of the product of Procedure 1 were dissolved in 250 ml of dichloromethane and 7 g of sulfur trioxide-pyridine complex was added, then the reaction mixture was stirred at room temperature for 24 hours and the solvent was evaporated under reduced pressure. 200 ml of methanol was added to the residue, and then aqueous potassium carbonate solution (6 g dissolved in 10 ml of water) was added all at once, and then the mixture was treated according to the method of Example 9 to obtain 7-chloro-1- of white crystals. 13 g of (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone-4-oxime-O-sulfonic acid potassium salt was obtained.

Melting point, IR and NMR spectra were in full agreement with those of the product of Example 9.

Example 12

[Preparation of 6-chloro-2,3-dihydro-1- (1-oxopropyl) -4 (1H) -quinolinone-4-oxime-O-acetic acid (compound 14)]

12.7 g of 6-chloro-2,3-dihydro-1- (1-oxopropyl) -4 (1H) -quinolinone- in a mixture of 7.7 g bromoacetic acid, 6.5 g potassium hydroxide and 60 ml water 4-oxime was slowly added under ice cold cooling. The mixture was stirred at rt for 24 h and adjusted to pH 3.0 with 2N HCl in ice cold water. The acidified mixture was poured into 150 ml of water, shaken with 500 ml of ethyl acetate, and the organic layer was washed once with 500 ml of saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was treated with silica gel column chromatography (eluent: a mixture of dichloromethane-methanol (9: 1)) to give 6-chloro-2,3-dihydro-1- (1) as white crystals. -Oxopropyl) -4 (1H) -quinolinone-4-oxime-O-acetic acid was obtained.

Yield: 10.5 g

Melting Point: 142.8 ~ 144.0 ℃

IR (KBr, cm ^-1 ): 330, -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 13

[Preparation of 6-chloro-2,3-dihydro-1- (1-oxopropyl) -4 (1H) -quinolinone-4-oxime-O-phosphate monomethyl ester (Compound 15)]

Cool a solution of 7.5 g of 6-chloro-2,3-dihydro-1- (1-oxopropyl) -4 (1H) -quinolinone-4-oxime and 150 ml of anhydrous tetrahydrofuran (-75 ° C.) To this, 21 ml of an n-hexane solution of 1.6 N butyllithium was added over 30 minutes under a nitrogen site, followed by stirring at -75 ° C for 30 minutes. 4.9 g of methyl dichlorophosphate was added dropwise to the mixture over 30 minutes at -75 ° C, and stirred again at -70 ° C to -60 ° C for 30 minutes. The reaction mixture was slowly warmed to about 0 ° C. and acidified to pH 2.0 with 1N HCl. The acidified mixture was stirred at room temperature for 5 hours, poured into 200 ml of water, 500 ml of ethyl acetate was added and shaken, then the organic layer was washed once with 200 ml of saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure, and the residue was treated with silica gel column chromatography (eluent: a mixture of dichloromethane-methanol (19: 1)) to give 6-chloro-2,3-dihydro-1 as white crystals. -(1-oxopropyl) -4 (1H) -quinolinone-4-oxime-O-phosphate monomethyl ester was obtained.

Yield: 7.2 g

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), 2.88 (2H, t), 3.62 (3H, d), 3.78 (2H, t), 7.22-7.85 (3H , m, aromatic)

Example 14

[Preparation of 6-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone-4-oximemesylate]

10.0 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 3.5 g of methanesulfonyl chloride was added to the mixture at −20 ° C. under stirring. The mixture was stirred at -20 [deg.] C. for 30 minutes and 300 ml of dichloromethane were added. The reaction mixture was washed sequentially with 1N HCl, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous NaCl solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized from ether and n-hexane to give white crystals 6-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinoli Non-4-oxime mesylate was obtained.

Yield: 11 g

Melting Point: 197.4 to 198.1 ° C

IR (KBr, cm ^-1 ): 1660, 1365, 1180

NMR (DMSO-d ₆ , ppm): 3.03 (2H, t), 3.38 (3H, s), 3.72 (2H, t), 7.12-7.92 (6H, m, aromatic)

The compounds of Examples 15-266 are then listed in Tables 8-18, and the corresponding data (IR and NMR data) and melting point or decomposition temperature are shown. NMR data are generally measured at 90 MHz, except for a few data, and some are measured at 60 MHz, with an asterisk (*).

Methods for preparing these compounds can be divided into three groups, which are shown in Table 7 below.

TABLE 7

TABLE 8

TABLE 9

TABLE 10

TABLE 11

TABLE 12

Table 13a

Table 13b

TABLE 14

TABLE 15

TABLE 16

TABLE 17

NMR spectra shown at 60 MHz are asterisk (*).

TABLE 18

Representative preparation examples of the compounds of the present invention are described below, but are not limited thereto.

[Formulation A (capsules)]

40 g of compound 6645 g lactose and 9 g magnesium stearate were mixed well to achieve a homogeneity. 350 mg of the mixture was filled into No. 1 hard gelatin capsules to obtain a capsule.

[Formulation B (tablet)]

50 g of compound 6,800 g of lactose, 120 g of potato starch, 15 g of polyvinyl alcohol and 15 g of magnesium stearate were weighed, respectively, and then a predetermined amount of compound 6, lactose and potato starch were mixed homogeneously and sufficiently. Polyvinyl alcohol solution was added to the mixture to granulate by wet process, and then the granules were dried and mixed with stearate to tablet each 200 mg of tablets.

[Preparation C (powder)]

100 g of compound, 11,890 g of lactose and 10 g of magnesium stearate were weighed on a balance and thoroughly mixed to make a homogeneous 10% powder.

[Formulation D (work suppository)]

100 g of compound 4, 180 g of polyethylene glycol 1500 and 720 g of polyethylene glycol 4000 were caused to mix well, melted, and then molded in a mold to prepare suppositories.

[Formulation E (injective)]

1 g of compound 11 is weighed out and dissolved in 200 ml of distilled water, which is then filtered and sterilized. 2 ml of sterile solution was injected into each 5 ml ampoule and an injection was prepared by sealing.

Claims (10)

The 1-acyl-2,3-dihydro-4 (1H) -quinolinone derivative of formula (II) is reacted with hydroxyl amine to give the corresponding 1-acyl-2,3-dihydro-4 (1H Formula) characterized in that a) -quinolinone-4-oxime derivative is obtained and then reacted with a complex of sulfur trioxide, a halogenated phosphate ester, a halogenated acetic acid, a halogenated acetic acid ester or a methanesulfonyl halide 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivatives thereof, salts thereof, and methods for preparing these derivatives and solvates thereof

In formulas (I) and (II) above, R ¹ is alkyl having a straight or branched chain having 1 to 8 carbon atoms, halogenated alkyl having a straight or branched chain having 1 to 4 carbon atoms, and having 3 to 6 carbon atoms. Cycloalkyl, lower alkyloxy, methoxymethyl, methoxycarbonylethyl, benzene, styryl, naphthyl, pyridyl, thienyl, pyrazinyl, phenyl or substituted (substituents are straight chain of 1 to 4 carbon atoms) Or the same or different 1 to 5 substituents selected from the group consisting of alkyl, hydroxyl, nitro, lower alkyloxy, trifluoromethyl and halogen atoms having a side chain) and R ² and R ³ are the same or different Is hydrogen atom or methyl, R ⁴ is carboxymethyl, sulfo, methanesulfonyl or methoxyphospho, R ⁵ and R ⁶ are the same or different, hydrogen atom, halogen atom, hydroxyl, methylthio, methyl Sulfinyl, methanesulfonyl, N, N- Methyl amino, nitro, acetyl, methyl, trifluoromethyl, methoxycarbonyl or methoxy, the wave line represents a bond of anti-form (anti) or new type (syn). The 1-acyl-2,3-dihydro-4 (1H) -quinolinone derivative of the general formula (II) is substituted with an organic base such as pyridine, N, N-dimethylaniline or potassium acetate or potassium carbonate or sodium carbonate. 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime of formula (III) characterized by reacting with hydroxylamine-O-sulfoic acid in the presence of an inorganic base such as -O-sulfoic acid derivatives, salts thereof, and methods for preparing solvates thereof

In general formulas (II) and (III), R ¹ is alkyl having a straight or branched chain having 1 to 8 carbon atoms, halogenated alkyl having a straight or branched chain having 1 to 4 carbon atoms, and having 3 to 6 carbon atoms. Cycloalkyl, lower alkyloxy, methoxymethyl, methoxycarbonylethyl, benzene, styryl, naphthyl, pyridyl, thienyl, pyrazinyl, phenyl or substituted (substituents are straight chain of 1 to 4 carbon atoms) Or the same or different 1 to 5 substituents selected from the group consisting of alkyl, hydroxyl, nitro, lower alkyloxy, trifluoromethyl and halogen atoms having a side chain) and R ² and R ³ are the same or different And hydrogen or methyl, R ⁵ and R ⁶ are the same or different, hydrogen atom, halogen atom, hydroxyl, methylthio, methylsulfinyl, methanesulfonyl, N, N-dimethylamino, nitro, acetyl, Methyl, trifluoromethyl, methoxy Carboxylic and carbonyl or methoxy, wave line represents a bond of anti-form (anti) or new type (syn). 2,3-dihydro-4 (1H) -quinolinone derivatives of the general formula (IV) and acyl chloride are organic bases such as pyridine, N, N-dimethylaniline, or potassium acetate or inorganic such as potassium carbonate or sodium carbonate 1-acyl-2 of general formula (II), which is an intermediate in the synthesis of 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivative characterized by reacting in the presence of a base, 3-Dihydro-4 (1H) -quinolinone derivatives, salts thereof, and methods for producing solvates of these derivatives and salts thereof.

In formulas (II) and (IV) above, R ¹ is alkyl having a straight or branched chain having 1 to 8 carbon atoms, halogenated alkyl having a straight or branched chain having 1 to 4 carbon atoms, and having 3 to 6 carbon atoms. Cycloalkyl, lower alkyloxy, methoxymethyl, methoxycarbonylethyl, benzene, styryl, naphthyl, pyridyl, thienyl, pyrazinyl, phenyl or substituted (substituents are straight chain of 1 to 4 carbon atoms) Or the same or different 1 to 5 substituents selected from the group consisting of alkyl, hydroxyl, nitro, lower alkyloxy, trifluoromethyl and halogen atoms having a side chain) and R ² and R ³ are the same or different And hydrogen or methyl, R ⁵ and R ⁶ are the same or different, hydrogen atom, halogen atom, hydroxyl, methylthio, methylsulfinyl, methanesulfonyl, N, N-dimethylamino, nitro, acetyl, Methyl, trifluoromethyl, methoxy Carbonyl or methoxy. The process according to claim 3, wherein at least one of R ⁵ and R ⁶ in the prepared compound is a halogen atom at the 7-position. The process according to claim 1, wherein R ⁴ is sulfo in the prepared compound. The process according to claim 2, wherein at least one of R ⁵ and R ⁶ in the prepared compound is a halogen atom at the 7-position. 7. A process according to claim 6 wherein R ¹ is 2-methylphenyl in the prepared compound. The method according to claim 1, wherein the bond represented by the wavy line in the prepared compound is a syn-type bond. The method according to claim 2, wherein the bond represented by the wavy line in the prepared compound is a syn-type bond. The process according to claim 5, wherein at least one of R ⁵ and R ⁶ in the prepared compound is a halogen atom at the 7-position.