JP2963496B2 - Benzopyranopyridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a compound represented by the general formula (I): (Wherein, R ¹ represents a cycloalkyl group, a cycloalkenyl group or an aryl group, and the cycloalkyl group, the cycloalkenyl group and the aryl group are one substituent selected from an alkyl group, a halogen atom and a halogenoalkyl group. X represents a single bond, an alkylene group or an alkenylene group, and R ² represents an amino group or a hydroxyl group.) And a salt thereof.

The compound of the general formula (I) has excellent anti-ulcer action and anti-allergic action and is useful as a medicine.

<Prior art> As a compound having a benzopyranopyridine skeleton having an antiallergic effect, 2-amino-7-isopropyl-5-
Oxo-5H-1-benzopyrano [2,3-b] pyridine-
3-carboxylic acid (amlexanox), lower alkyl group-substituted 2-amino or 2-hydroxy-5-oxo-
5H-1-benzopyrano [2,3-b] pyridine-3-carboxylic acid (see JP-A-61-10587) is known. Among them, amlexanox is clinically used as a therapeutic agent for asthma.

However, only the antiallergic effect is known for the biological activity of these compounds, and the antiulcer effect is not known.

<Problems to be Solved by the Invention> The present inventors have intensively studied to find a compound having excellent anti-ulcer action and anti-allergic action, and as a result, completed the present invention.

<Constitution of the Invention> The present invention relates to a compound of the formula (I) and a salt thereof.

In the formula (I), examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl and the like.

Examples of the halogen atom include fluorine, chlorine, bromine, and iodine.

A halogenoalkyl group means one or more of the above halogen atoms substituted with an alkyl group, and examples thereof include halogenomethyl, halogenoethyl, halogenobutyl, dihalogenomethyl, dihalogenobutyl, and trihalogenomethyl. I can do it.

Examples of the cycloalkyl group include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like.

Examples of the aryl group include phenyl, naphthyl, biphenyl and the like.

Examples of the cycloalkenyl group include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclodecenyl and the like.

The alkylene group means methylene or polymethylene which may be substituted by the alkyl group, and examples thereof include methylene, ethylene, propylene, and butylene.

Examples of alkenylene include vinylene, propenylene, butenylene, 1-pentenylene, 2-methyl-1-butenylene, 2-methyl-2-butenylene and the like.

Salts of the compounds of formula (I) include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and amines such as ammonia, tris (hydroxymethyl) aminomethane, N-methylglucamine and carboxyl groups. Salts and the like can be exemplified.

The compound of formula (I) may have various isomers derived from the partial structures R ¹ and X, and these various isomers and mixtures thereof are also included in the present invention.

The compound represented by the formula (I) can be produced according to the following reaction formula.

(Wherein R ¹ , R ² and X are the same as above, and R ³ represents an alkyl group.) That is, the compound of the formula (II) is reacted with an acid in the presence or absence of a solvent of about 70 to about The compound of formula (I) can be produced by heating and reacting at 180 ° C. for about 30 minutes to 20 hours.
Examples of usable solvents include water and organic solvents such as acetic acid and propionic acid. Examples of the acid include inorganic acids such as sulfuric acid and organic acids such as trifluoroacetic acid.

In the formula (I), the compound wherein R ² is an amino group is represented by the formula (III) (Wherein R ¹ and X are the same as described above) by heating and reacting with pyridine and cyanoacetic acid at about 70 to 150 ° C. for about 1 to 10 hours in the presence or absence of a solvent. I can do it. Pyridine as a solvent,
Examples include basic solvents such as picoline and the like, and organic solvents such as ethanol, isopropanol and butanol.

The starting compounds (II) and (III) used in the above-mentioned production method are novel compounds and can be produced by the following method.

(In the formula, R ¹ , R ² , R ³ and X are the same as described above.) The above reaction step will be briefly described.

Solvents of the formula (IV) which do not participate in the reaction, for example
Reaction with a base such as pyridine and acetic anhydride in the presence or absence of benzene, toluene, etc. to form an acetyl form,
The compound of formula (V) can be prepared by heating to 100 to 150 ° C. with anhydrous aluminum chloride.

The compound of formula (VI) can be prepared by reacting the compound of formula (V) with dimethylformamide and phosphorus oxychloride. The reaction is usually performed at -30 to 50 ° C for 30 minutes to
Performed for 5 hours.

The compound of formula (VI) is reacted with hydroxyamine hydrochloride at 20 to 100 ° C. in the presence or absence of a solvent which does not participate in the reaction, for example, tetrahydrofuran, methanol, ethanol and the like.
The compound of formula (VII) can be produced by reacting for 0 minute to 5 hours.

Compound of formula (VII) in alkaline aqueous solution at 50-100 ° C
The compound of formula (III) can be produced by heating for 30 minutes to 2 hours. 0.
A 5N to 2N aqueous potassium hydroxide solution, an aqueous sodium hydroxide solution and the like can be exemplified.

Dialkyl malonate in the presence of an organic base such as pyridine, 1,5-diazabicyclo [4,3,0] -5-nonene or in the presence or absence of an organic solvent such as methanol or ethanol Alternatively, the compound of formula (II) can be produced by reacting with a cyanoacetic acid alkyl ester. The reaction is usually performed at 50-100 ° C for 5-30 hours.

The starting compound of the formula (IV) in the above production method can be produced by appropriately combining known methods. Representative examples are shown below.

(Wherein, R ¹ and X are the same as above, and Y represents an alkylene group or an alkenylene group.) That is, a compound of the formula (VIII) is combined with a compound of the formula (IX) in the presence of aluminum chloride and Friedel. The compound of formula (X) can be produced by reacting under the conditions of the Kraft reaction.

The compound of the formula (XI) can be produced by reducing the compound of the formula (X) using a reaction such as Clementen reduction or Wolfkinschner reduction.

The compound of the formula (IV) can be produced by reacting the compound of the formula (XI) with a reagent such as aluminum chloride in a suitable organic solvent such as dimethyl sulfide at a temperature around room temperature.

The compounds according to the invention are usually administered orally or parenterally. In the case of oral administration, the dose is usually 10 to 200 mg per adult per day, which may be administered in 2 or 3 divided doses a day. Is also good.

The compound represented by the formula (I) or a salt thereof according to the present invention can be used together with additives such as an excipient, a binder, a disintegrant, and a dissolving agent, in the form of tablets, capsules, powders, granules, and syrups by known preparation techniques. Agents, solutions, injections, etc.

<Effect of the Invention> The compound of the present invention has an anti-ulcer effect, and has esophagitis,
It is an excellent preventive and therapeutic agent for fire extinguisher diseases such as esophageal ulcer, gastritis, gastric ulcer, duodenal ulcer, small intestine, colitis, and gastrointestinal bleeding. Further, the compound of the present invention has a leukotriene D ₄ (hereinafter referred to as “LTD _4” ) antagonism, and has bronchial asthma, allergic gastrointestinal disease, allergic conjunctivitis,
Allergic diseases such as allergic rhinitis, hay fever, urticaria, hematitis, keratitis, dermatitis, acute and chronic rhinitis,
It is also excellent as a prophylactic or therapeutic agent for inflammatory diseases such as acute and chronic bronchitis and upper respiratory inflammation.

Hereinafter, the present invention will be described with reference examples, examples, and test examples, but the present invention is not limited thereto.

Reference Example 1 2-amino-4-oxo-6- (2-phenylethyl)
4H-1-benzopyran-3-carbaldehyde 1) 2-hydroxy-5- (2-phenylethyl) acetophenone 19.82 g of 4- (2-phenylethyl) phenol, 30 ml of pyridine and 90 ml of benzene are mixed, and acetic anhydride is added at room temperature. 12.5m
A solution of 15 ml of l-benzene was added dropwise. After heating and refluxing for 1.5 hours, the mixture was placed in ice water containing 400 ml of 1N hydrochloric acid and extracted with benzene. After washing with water and saturated saline and drying, the solvent is distilled off and the oily residue is heated to a bath temperature of 120 to 140 ° C. to dry anhydrous aluminum chloride 1
7.5 g was added in several portions. After heating at the same temperature for 30 minutes, the mixture was cooled, ice was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluted with chloroform) to obtain 12.2 g of 2-hydroxy-5- (2-phenylethyl) acetophenone.

Oil IRν (neat) cm ^-1 : 3030,2920,1640,1480,1365,1295 NMR (CDCl ₃ ) δ: 2.52 (3H, s) 2.88 (4H, s) 6.89 (1H, d, J = 9Hz) 7.1-7.4 (7H, m) 12.09 (1H, s) 2) 4-oxo-6- (2-phenylethyl) -4H-
1-Benzopyran-3-carbaldehyde 2-hydroxy-5- (2-phenylethyl) acetophenone (47.5 g) and dimethylformamide (200 ml) were mixed, cooled to an internal temperature of -30 to -20 DEG C., and phosphorus oxychloride (72 ml) was added over 1 hour. It was dropped. After the dropwise addition, the mixture was stirred at the internal temperature of 40 to 50 ° C. for 2 hours, poured into ice water and extracted with ethyl acetate. After washing with water and saturated saline, drying, the solvent was distilled off, and the crystalline residue was recrystallized from ethyl acetate-petroleum ether to give brown powder 4-oxo-6- (2-phenylethyl) having a melting point of 96 to 98 ° C. -4H-1-
22.6 g of benzopyran-3-carbaldehyde were obtained.

Elemental analysis value (%). Theoretical value (C ₁₈ H ₁₄ O ₃ ): C, 77.68; H, 5.07 Observed value: C, 77.50; H, 5.28 IRν (KBr) cm ⁻¹ : 2840, 1690, 1665, 1595, 1470, 1300. NMR ( CDCl ₃ ) δ: 2.9-3.1 (4H, m) 7.1-7.6 (7H, m) 8.10 (1H, brs) 8.52 (1H, s) 10.39 (1H, s) 3) 4-oxo-6- (2- Phenylethyl) -4H-
1-benzopyran-3-carbaldehyde oxime 4-oxo-6- (2-phenylethyl) -4H-1-
Benzopyran-3-carbaldehyde 16.7 g in ethanol 1
The mixture was dissolved in 00 ml and 200 ml of tetrahydrofuran, an aqueous solution (40 ml) of 4.59 g of hydroxylamine hydrochloride was added, and the mixture was heated under reflux at room temperature for 1 hour and further for 1 hour. After cooling, the mixture was concentrated under reduced pressure to about 100 ml, and the precipitate was collected by filtration. After washing with water and ethanol and drying, brown crystals of 4-oxo-6- (2
-Phenylethyl) -4H-1-benzopyran-3-carbaldehyde oxime (15.1 g) was obtained.

Elemental analysis value (%). Theoretical value (C ₁₈ H ₁₅ NO ₃ ): C, 73.70; H, 5.15; N, 4.78 Found: C, 73.43; H, 5.17; N, 4.68 IRν (KBr) cm ⁻¹ : 3280, 3060, 1630, 1610,1600,1480. NMR (DMSO-d ₆ ) δ: 2.9-3.1 (4H, m) 7.23 (5H, s) 7.6-7.8 (2H, m) 7.91 (1H, brs) 8.08 (1H, s) 8.62 (1H, s) 11.34 (1H, s) 4) 2-amino-4-oxo-6- (2-phenylethyl) -4H-1-benzopyran-3-carbaldehyde 4-oxo-6- (2-phenyl Ethyl) -4H-1-
Benzopyran-3-carbaldehyde oxime 8.80 g, 0.5 N
15 ml of sodium hydroxide was mixed and heated at a bath temperature of 70 to 90 ° C. for 1 hour. After cooling, water was added and the precipitate was collected by filtration. After washing with water, drying and recrystallization from chloroform-ethanol, melting point 24
6.96 g of 2-amino-4-oxo-6- (2-phenylethyl) -4H-1-benzopyran-3-carbaldehyde at 0 to 245 ° C. was obtained as brown prism crystals.

Elemental analysis value (%). Theoretical value (C ₁₈ H ₁₅ NO ₃ ): C, 73.70; H, 5.15; N, 4.78 Found: C, 73.43; H, 5.14; N, 4.71 IRν (KBr) cm ⁻¹ : 3300, 3150, 1675, _{. 1615,1580,1475 NMR (DMSO-d 6} ) δ: 2.95 (4H, brs) 7.22 (5H, s) 7.28 (1H, d, J = 8.5Hz) 7.53 (1H, dd, J = 8.5Hz) 7.86 (1H, d, J = 2 Hz) 9.60 (2H, br) 10.08 (1H, s) Reference Example 2 2-amino-6- [2- (3-chlorophenyl) ethyl] -4-oxo-4H-1-benzopyran -3-Carbaldehyde The following compound was obtained in the same manner as in Reference Example 1.

1) 5- [2- (3-chlorophenyl) ethyl] -2
-Hydroxyacetophenone oil IRν (neat) cm ^-1 : 3020,2930,1640,1480. NMR (CDCl ₃ ) δ: 2.55 (3H, s) 2.87 (4H, s) 6.90 (1H, d, J = 9 Hz) 7.0-7.5 (m, 6H)) 12.11 (1H, s) 2) 6- [2- (3-chlorophenyl) ethyl) -4
-Oxo-4H-1-benzopyran-3-carbaldehyde Melting point 121-124 ° C Elemental analysis (%). Theoretical value _{(C 18 H 13 ClO 3)} :. C, 69.13; H, 4.19 Found:. C, 69.13; H, 4.31 IRν (KBr) cm -1: 3070,2930,2870,1690,1660,1605, 1565,1480,1315. NMR (CDCl ₃ ) δ: 2.9-3.1 (m, 4H) 7.0-7.6 (m, 6H) 8.10 (brs, 1H) 8.53 (s, 1H) 10.39 (s, 1H,) 3) 6- [2- (3-chlorophenyl) ethyl] -4
-Oxo-4H-1-benzopyran-3-carbaldehyde oxime Melting point 154-158 ° C Elemental analysis (%). Theoretical value _{(C 18 H 14 ClNO 3)} :. C, 65.96; H, 4.31; N, 4.27 Found:. C, 66.57; H, 4.54; N, 4.15 IRν (KBr) cm -1: 3250,1635, 1615,1600,1480. NMR (CDCl ₃ ) δ: 2.9-3.1 (4H, m) 7.0-7.6 (7H, m) 7.93 (1 / 2H, s) 8.09 (1H, brs,) 8.33 (1H, s) 9.50 (1 / 2H, s). 4) 2-amino-6- [2- (3-chlorophenyl)
Ethyl] -4-oxo-4H-1-benzopyran-3-carbaldehyde Melting point 255-260 ° C Elemental analysis (%). Theoretical value _{(C 18 H 14 ClNO 3)} :. C, 65.96; H, 4.31; N, 4.27 Found:. C, 66.38; H, 4.48; N, 4.29 IRν (KBr) cm -1: 3300,3160, 1660,1610,1575,1470. NMR (DMSO-d ₆ ) δ: 2.96 (4H, s) 7.2-7.5 (5H, m) 7.56 (1H, dd, J = 2Hz, J = 8.5Hz) 7.88 (1H, d, J = 2 Hz) 9.60 (2H, br) 10.08 (1 H, s) Reference Example 3 2-hydroxy-5-oxo-7- (2-phenylethyl) -5H-1-benzopyrano [2,3-b] Pyridine-3
-Carboxylic acid methyl ester 2-amino-4-oxo-6- (2-phenylethyl) -4H-1-benzopyran-3-carbaldehyde 1.47
g, malonic acid dimethyl ester 2.20 g, pyridine 5.0 ml, 1,5
-Diazabicyclo [4.3.0] -5-nonene (0.35 ml) and methanol (20 ml) were mixed and heated under reflux for 17 hours. After cooling, the mixture was concentrated, and water and concentrated hydrochloric acid were added thereto under ice cooling to make the mixture acidic, and the precipitate was collected by filtration. After washing with water, drying and recrystallization from chloroform-methanol, 2-hydroxy-5-oxo-7- (2-phenylethyl) -5H-1-benzopyrano [2,3-b] pyridine-3-carboxylic acid methyl ester 1.21 g was obtained as a brown powder.

233-236 ° C Elemental analysis (%). Theoretical value (C ₂₁ H ₁₇ NO ₅ ): C, 70.39; H, 4.57; N, 3.73. Observed value: C, 70.91; H, 4.65; N, 3.99. IRν (KBr) cm ⁻¹ : 3200 to 2700, 1700,1680,1640,1610. NMR (CDCl ₃ ) δ: 2.9-3.1 (4H, m) 4.06 (3H, s) 7.1-7.4 (5H, m) 7.5 (2Hm) 8.10 (1H, brs) 9.22 (1H , s) Reference Example 4 7- [2- (3-chlorophenyl) ethyl] -2-hydroxy-5-oxo-5H-1-benzopyrano [2,3-
b] Methyl pyridine-3-carboxylate 2-amino-6- [2- (3-
Chlorophenyl) ethyl] -4-oxo-4H-1-benzopyran-3-carbaldehyde from 7- [2- (3-chlorophenyl) ethyl] -2-hydroxy-5-oxo-5H-1-benzopyrano [2,3 -B] Pyridine-3-carboxylic acid methyl ester was obtained.

236-239 ° C Elemental analysis (%). Theoretical value (C ₂₁ H ₁₆ ClNO ₅ ): C, 64.47; H, 3.94; N, 3.42. Actual value: C, 64.97; H, 4.09; N, 3.69. IRν (KBr) cm ⁻¹ : 3200 to 2700, 1745,1670,1605. NMR (CDCl ₃ ) δ: 3.0 (4H, brs) 4.07 (3H, s) 7.0-7.3 (4H, m) 7.49 (2H, s) 8.09 (1H, brs) 9.22 (1H, s) Reference Example 5 1) 4-cyclohexylacetylanisole (97.9 g), diethylene glycol (390 ml), 40% aqueous sodium hydroxide solution (100.6 ml), 100% hydrazine monohydrate (100.6 ml)
Was added and the mixture was heated under reflux for 11 days. After cooling, the reaction mixture was poured into water and extracted with n-hexane. Wash with water, dilute aqueous hydrochloric acid, aqueous sodium bicarbonate, water and dry. Concentrate this,
44 g of a yellow oil were obtained. This oily substance is silica gel 200 g / n
-Purified with hexane. The fraction was concentrated to obtain 30.2 g of 4- (2-cyclohexylethyl) -anisole as a colorless oil.

_{NMR (CDCl 3): ppm 7.10} (2H, d, J = 8.8Hz), 6.81 (2H, d, J = 8.8Hz), 3.78 (3H, s), 2.56 (. 2H, t, J = 9.0Hz) , 1.92-0.76 (13H, m) 2) Suspension of 6.7 g of aluminum chloride in 25 ml of carbon tetrachloride,
After dropping 5.3 g of acetyl chloride, the mixture was heated and stirred at 35 to 40 ° C. for 1 hour. 7.3 g of 4- (2-cyclohexylel) anisole
Was dissolved in 10 ml of carbon tetrachloride, and added to the above suspension while maintaining the internal temperature at 5 ° C. or lower, and the mixture was stirred as it was for 6 hours (−5 overnight).
℃). The reaction mixture was poured into a mixture of ice and dilute aqueous hydrochloric acid, chloroform was added, and the mixture was stirred. The organic layer was separated, washed with water, dried and the solvent was removed to obtain 8.7 g of a colorless oil. This oily substance was subjected to silica gel chromatography (silica gel 190
g, n-hexane to n-hexane-acetic acid ethyl ester = 200: 1) and purified as a colorless oil.
Cyclohexylethyl) -2-methoxyacetophenone
6.7 g were obtained.

NMR (CDCl ₃ ): ppm 7.53 (1H, d, J = 2.4 Hz), 7.27 (1H, dd, J = 2.4,8.5 Hz), 6.86 (1H, d, J = 8.5 Hz), 3.88 (3H, s ), 2.60 (3H, s), 2.58 (2H, t, J = 9.0Hz), 1.97-0.80 (13H, m) 3) 8.3 g of aluminum chloride on ice water bath and 60 ml of methylene chloride
And 7.7 g of dimethyl sulfide was added to make a solution. 7.5 g of 5- (2-cyclohexylethyl) -2-methoxyacetophenone was dissolved in 30 ml of methylene chloride and added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 20 hours, poured into a mixture of ice and a dilute hydrochloric acid aqueous solution, and extracted with chloroform. After washing with brine and drying, the solvent was removed and 5- (2) was obtained as a colorless oil.
6.5 g of -cyclohexylethyl) -2-hydroxyacetophenone were obtained.

NMR (CDCl ₃ ): ppm 7.49 (1H, d, J = 2.0 Hz), 7.28 (1H, dd, J = 2.0,8.5 Hz), 6.89 (1H, d, J = 8.5 Hz), 2.62 (3H, s ), 2.59 (2H, t, J = 9.0 Hz), 2.00 to 0.80 (13H, m) The following compounds were obtained in the same manner as Reference Example 1.

4) 4-oxo-6- (2-cyclohexylethyl)
-4H-1-benzopyran-3-carbaldehyde _{NMR (CDCl 3): ppm 2.00-0.80} (13H, m), 2.76 (2H, t, J = 8.5Hz), 7.43 (1H, d, J = 8.5Hz) , 7.59 (1H, dd, J = 2.0,8.5 Hz), 8.09 (1H, d, J = 2.0 Hz), 8.53 (1H, s), 10.40 (1H, s) 5) 4-oxo-6- (2 -Cyclohexylethyl)
-4H-1-benzopyran-3-carbaldehyde oxime Melting point 120-150 ° C Elemental analysis C ₁₈ H ₂₁ NO ₃ Theory C 72.22 H 7.07 N 4.68 Observed C 72.38 H 7.07 N 4.72 IRν (KBr) cm ^-1 : 3220,2920,2840,1650,1620,1480 NMR (CDCl ₃ ) δ: 0.78-1.92 (13H, m), 2.74 (2H, t, J = 8.8Hz), 7.38 (1H, d, J = 8.8Hz) 7.57 (1H, dd, J = 2.2,8.8 Hz) 7.91 (1 / 2H, s), 8.05 (1H, brs), 8.32 (1H, s) 9.48 (1 / 2H, s).

6) 2-amino-6- (2-cyclohexylethyl)
-4-oxo-4H-1-benzopyran-3-carbaldehyde Melting point 274-277 ° C Elemental analysis C ₁₈ H ₂₁ NO ₃ Theoretical C 72.22 H 7.07 N 4.68 Observed C 71.95 H 7.07 N 4.91 IRν (KBr) cm ^{-1: 3300,3150,2920,1675,1615,1585,1475 NMR (DMSO-d} 6) δ: 0.80-2.00 (13H, m), 2.69 (2H, t, J = 8.3Hz), 7.30 (1H, d, J = 8.3 Hz), 7.56 (1H, dd, J = 2.2, 8.3 Hz) 7.81 (1H, d, J = 2.2 Hz), 9.55 (2H, br), 10.08 (1H, s).

Example 1 2-amino-5-oxo-7- (2-phenylethyl)
-5H-1-benzopyrano [2,3-b] pyridine-3-carboxylic acid 2-amino-4-oxo-6- (2-phenylethyl) -4H-1-benzopyran-3-carbaldehyde 1.64
g Cyanoacetic acid (1.15 g) and pyridine (6 ml) were mixed.
The mixture was heated and stirred at 130130 ° C. for 5 hours (additionally 1.75 g of cyanoacetic acid was added). After cooling, the precipitate was collected by filtration, washed with ethanol and ether, and washed with 2-amino-5-oxo-7- (2
-Phenylethyl) -5H-1-benzopyrano [2,3-
b] 1.63 g of pyridine-3-carboxylic acid were obtained. Recrystallization from dimethylformamide gave a yellow powder.

Melting point 300 ° C or higher Elemental analysis value (%). Theoretical value (C ₂₁ H ₁₆ N ₂ O ₄ ): C, 69.99; H, 4.48; N, 7.78. Observed value: C, 69.97; H, 4.70; N, 7.80. IRν (KBr) cm ⁻¹ : 3400, 3350-2600,1705,1600,1580,1445 NMR (DMSO-d ₆ ) δ: 2.98 (4H, s) 7.23 (5H, s) 7.45 (1H, d, J = 8 Hz) 7.65 (1H, dd, J = 7.95 (1H, d, J = 2Hz) 8.24 (2H, br) 8.83 (1H, s) Example 2 2-Amino-7- [2- (3-chlorophenyl) ethyl] -5 Oxo-5H-1-benzopyrano [2,3-b]
Pyridine-3-carboxylic acid 2-Amino-6- [2- (3-
Chlorophenyl) ethyl] -4-oxo-4H-1-benzopyran-3-carbaldehyde from 2-amino-7-
[2- (3-chlorophenyl) ethyl] -5-oxo-
5H-1-benzopyrano [2,3-b] pyridine-3-carboxylic acid was obtained.

289-294 ° C Elemental analysis (%). Theoretical value (C ₂₁ H ₁₅ N ₂ O ₄ ): C, 63.88; H, 3.83; N, 7.10. Observed value: C, 64.07; H, 3.95; N, 7.12. IRν (KBr) cm ⁻¹ : 3400, _{3300~2700,1695,1600,1575,1460 NMR (DMSO-d 6)} δ: 2.98 (4H, brs) 7.1-7.3 (4H, m) 7.46 (1H, d, J = 8.5Hz) 7.67 (1H, dd , J = 2 Hz, J = 8.5 Hz) 7.96 (1H, d, J = 2 Hz) 8.22 (2H, br) 8.83 (1H, s) 13.3 (1H, br). Example 3 2-hydroxy-5-oxo-7- (2-phenylethyl) -5H-1-benzopyrano [2,3-b] pyridine-3
-Carboxylic acid 2-hydroxy-5-iso-7- (2-phenylethyl) -5H-1-benzopyrano [2,3-b] pyridine-
3-Carboxylic acid methyl ester 1.00 g, concentrated sulfuric acid 6 ml, water 6 ml
And acetic acid (13 ml) were mixed, heated at a bath temperature of 130 to 150 ° C. for 10 hours, and then poured into ice water (100 ml). The precipitate is collected by filtration, washed with water and dried, and dried with 2-hydroxy-5-oxo-7- (2-phenylethyl) -5H-1-benzopyrano [2,3-b] pyridine-3.
0.94 g of carboxylic acid was obtained.

 Recrystallized from dimethylformamide-ethanol.

Melting point 300 ° C or higher Elemental analysis value (%). Theoretical value (C ₂₁ H ₁₅ NO ₅ ): C, 69.80; H, 4.18; N, 3.88. Found: C, 69.56; H, 4.26; N, 3.96. IRν (KBr) cm ⁻¹ : 3200 to 2600, _{. 1745,1660,1615 NMR (DMSO-d 6} ) δ: 3.0 (4H, br) 7.24 (5H, s) 7.54 (1H, d, J = 8.5Hz) 7.73 (1H, dd, J = 2Hz, J = 8.5 Hz) 7.97 (1H, d, J = 2 Hz) 8.80 (1 H, s) 8.5-9.5 (2H, br) Example 4 7- [2- (3-chlorophenyl) ethyl] -2-hydroxy-5-oxo -5H-1-benzopyrano [2,3-
b] Pyridine-3-carboxylic acid 7- [2- (3-chlorophenyl) ethyl] -2-hydroxy-5-oxo-5H-1-in the same manner as in Example 3.
Benzopyrano [2,3-b] pyridine-3-carboxylate methyl ester to 7- [2- (3-chlorophenyl) ethyl] -2-hydroxy-5-oxo-5H-1-benzopyrano [2,3-b] Pyridine-3-carboxylic acid was obtained.

296-300 ° C (decomposition) Elemental analysis (%). Theoretical value (C ₂₁ H ₁₄ ClNO ₅ ): C, 63.72; H, 3.57; N, 3.54. Found: C, 63.95; H, 3.80; N, 3.44. IRν (KBr) cm ⁻¹ : 3200 to 2500, 1745,1660,1615,1475,1390. NMR (DMSO-d ₆ ) δ: 2.99 (4H, brs) 7.2-7.4 (4H, m) 7.53 (1H, d, J = 8.5 Hz) 7.70 (1H, dd, J = 2 Hz, J = 8.5 Hz) 7.98 (1 H, d, J = 2 Hz) 8.79 (1 H, s) 9.0-10.0 (2 H, br) Example 5 As in Example 1, 2-amino-7- ( 2-cyclohexylethyl) -5-oxo-5H-1-benzopyrano [2,3-b] pyridine-3-carboxylic acid was obtained.

Melting point 295 ° C or higher (decomposition) Elemental analysis value C ₂₁ H ₂₂ N ₂ O ₄ Theoretical value C 68.84 H 6.05 N 7.65 Actual value C 68.71 H 6.14 N 7.70 IRν (KBr) cm ^-1 : 3400,3350-2700,1710, 1615,1585,1450 NMR (DMSO-d ₆ ) δ: 0.60-1.89 (13H, m), 2.72 (2H, d, J = 8.5 Hz), 7.49 (1H, d, J = 8.5 Hz), 7.67 (1H , dd, J = 2.0, 8.5 Hz) 7.87 (1H, d, J = 2.0 Hz), 8.24 (2H, brs), 8.79 (1H, s).

Example 6 Formulation Example 1 Compound of Example 1 50 mg Lactose 35 mg Starch 24.5 mg Magnesium stearate 0.5 mg One tablet is manufactured from the above.

Formulation Example 2 Compound of Example 1 1,000 mg Polysorbate 80 1,000 mg Syrup A suitable amount A 100 ml syrup is produced from the above amount.

Test Example 1 Effect of alcohol hydrochloride on gastric mucosal necrosis formation Sprague-Dawley rats (6 weeks old, male) were fasted for 24 hours and then subjected to experiments. Gastric mucosal necrosis is caused by hydrochloric acid alcohol (60
% Ethanol-150 mM hydrochloric acid solution) was orally administered [K. Takeuchi et al., Japan. J. Pharmaco.
l., Vol.44, Page 269 (1987)].

The test compound is suspended in a 0.5% carboxymethylcellulose aqueous solution (hereinafter, 0.5% CMC) and 0.3, 1, 3, or 10 mg / kg
Was orally administered 30 minutes before the induction of gastric mucosal injury. The dose was constant at 5 ml / kg, and the same amount of 0.5% CMC was used for the disease control group.
Only was administered orally.

One hour after the administration of the hydrochloric acid alcohol, the animals were killed by cervical dislocation and the stomach was removed. Immediately 10 ml of 3% formalin solution
Was injected into the stomach and immersed in the same formalin solution for about 30 minutes to fix it lightly. After the fixation was completed, an incision was made along the greater curvature, and the length (mm) of the necrotic lesion formed on the gastric mucosa was measured with a vernier caliper, and the total per animal was used as the lesion index.

The inhibition rate was calculated by the following formula, and a 50% inhibition dose (ED ₅₀ value) was calculated from the inhibition rate.

As a result, the ED ₅₀ value of the compound of Example 1 was 4.5 mg / kg.

The LTD ₄ antagonism of Test Example 2 LTD ₄ antagonism test compound of the present invention was confirmed by inhibitory effect on the contraction of isolated guinea pig ileum by LTD _4.

That is, a male guinea pig weighing 300 to 600 g was exsanguinated and killed, and the ileum was removed to prepare a specimen about 2 cm in length. This ileum specimen was aerated with a gas mixture of 95% O ₂ -5% CO ₂ by Tyr.
The suspension was suspended in a Magnus bath filled with 5 ml of ode solution (30 ± 1 ° C.). Ileum contraction was recorded on a recorder with an isotonic transducer under a load of 0.6 g. After confirming that a stable contraction reaction occurs, it was induced LTD ₄ (3.0ng / ml) was added contractile responses. The pretreatment time of the drug was 1 minute, and the degree of contraction generated at that time was compared with the contraction without the test drug added, and the 50% inhibitory dose (IC ₅₀ value) was calculated from the inhibition rate. The results are shown in Table 1.

Test Example 3 The compounds of Examples 1, 2, 3, and 4 were orally administered to mice, and acute toxicity was examined. As a result, the LD ₅₀ of each compound was 1,000 mg / kg or more.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ identification code FI A61K 31/00 637 A61K 31/00 637E 643 643D 31/435 603 31/435 603 (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 491/052 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula (Wherein, R ¹ represents a cycloalkyl group, a cycloalkenyl group or an aryl group, and the cycloalkyl group, the cycloalkenyl group and the aryl group are one substituent selected from an alkyl group, a halogen atom and a halogenoalkyl group. X represents a single bond, an alkylene group or an alkenylene group, and R ² represents an amino group or a hydroxyl group) and salts thereof.