JPH0386884A - Benzopyranopyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is cycloalkyl, cycloalkenyl or aryl; X is single bond, alkylene or alkenylene; R<2> is amino or OH). EXAMPLE:2-amino-5-oxo-7-(2-phenylethyl)-5H-1-benzopyrano[2,3-b]pyridin e-3- carboxylic acid. USE:Anti-ulcer agent or anti-allergic agent. PREPARATION:A compound expressed by formula II (R<3> is alkyl) is reacted with pyridine and cyanoacetic acid occasionally in the presence of a solvent such as pyridine or ethanol at 70-150 deg.C for 1-10hr.

Description

Detailed Description of the Invention <Industrial Field of Application> The present invention is directed to a compound of the general formula (I) (wherein Hl means a cycloalkyl group, a cycloalkenyl group, or an aryl group, and the cycloalkyl group, cycloalkenyl group The aryl group may have one or more substituents selected from an alkyl group, a halogen atom, and a halogenoalkyl group.

X means a single bond, an alkylene group or an alkenylene group, and R2 means an amino group or a hydroxyl group. ) and its salts.

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

<Prior art> As a compound with a benzopyranopyridine skeleton having an antiallergic effect, 2-acuno-7-itubroby-5-
Oxo-5) 1-1-benzopyrano[2,3-b] pyridine-3-carboxylic acid (amlexanox), lower alkyl substituted 2-amino or 2-hydroxy-5-
Oxo-58-1-benzopyrano[2,3-b]pyridine-3-carvone M (see JP-A-61-10587) is known. Among them, amlexanox is clinically used as an asthma treatment drug.

However, regarding the biological activities of these compounds, only their anti-allergic effects are known, but their anti-ulcer effects are not known.

<Problems to be Solved by the Invention> The present inventors have completed the present invention as a result of intensive studies to find a compound having excellent anti-ulcer and anti-allergic effects.

<Structure of the invention> - The present invention relates to compounds of formula (I) and salts thereof.

In formula (1), the alkyl group is methyl, ethyl, propyl, isopropyl, butyl.

Examples include tertiary butyl.

Examples of halogen atoms include fluorine, chlorine, and bromine.

I can mention iodine.

The term "halogenoalkyl group" means one in which one or more of the halogen atoms mentioned above is substituted with an alkyl group, examples of which include halogenomethyl and halogenoethyl.

Examples include halogenobutyl, dihalogenomethyl, dihalogenobutyl, trihalogenomethyl, and the like.

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

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

Cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,
Examples include cyclodecenyl.

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

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

Salts of the compound of formula (1) include alkali metals such as sodium and potassium, alkaline earth metals such as calcium, or ammonia such as ammonia, tris(hydroxymethyl)aminomethane, and N-methylglucamine, and carboxyl groups. Examples include salts such as

Regarding the compound of formula (I), various isomers derived from its partial structures R1 and X may exist, and these various isomers and mixtures thereof are also included in the present invention.

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

(II) (In the formula, nl, R2 and X are the same as above, and R2
means an alkyl group. ) That is, the compound of formula (I) can be produced by reacting the compound of formula (II) with an acid at about 70 to 180° C. for about 30 minutes to 20 hours in the presence or absence of a solvent. Examples of solvents that can be used include water or organic solvents such as acetic acid and propionic acid, and examples of acids that can be used include inorganic acids such as sulfuric acid and organic acids such as triple oroacetic acid.

In addition, a compound in which R2 is an ayono group in formula (I) is:

Alternatively, a compound represented by formula (III) (wherein 11 and It can be manufactured. Examples of the solvent include basic solvents such as pyridine and picoline, and organic solvents such as ethanol, isopropanol and butanol.

Raw material compound (II) used in the above production method and (
111) is a new compound and can be produced by the method described below.

(ff) (v) (i) (In the formula, R', R2, R'o, and l) The above reaction step will be briefly explained.

A compound of formula (l) is reacted with a base such as pyridine and acetic anhydride in the presence or absence of a solvent 1 that does not participate in the reaction, such as benzene, toluene, etc., to form an acetyl compound, and the compound is reacted with anhydrous aluminum chloride at 100 to 150°C. The compound of formula (V) can be produced by heating to .

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

The compound of formula (Vl) and hydroxyl hydrochloride are mixed in the presence or absence of a solvent that does not participate in the reaction, such as tetrahydrofuran, methanol, ethanol, etc.
The compound of formula (■) can be produced by reacting at ℃ for 30 minutes to 5 hours.

The compound of formula (■) was heated in an alkaline aqueous solution at 50 to 100°C.
By heating for 230 minutes to 2 hours, the heptacompound of formula (II) can be produced. Examples of the alkaline aqueous solution include 0.5N to 2N potassium hydroxide aqueous solution, sodium hydroxide aqueous solution, etc. I can do it.

The compound of formula (III) is converted into dialkyl malonic acid ester in the presence of an organic base such as pyridine or 1,5-diazabicyclo[4,3,0]-5-nonene in the presence or absence of an organic solvent such as methanol or ethanol. or by reacting with a cyanoacetic acid alkyl ester, formula (II)
Compounds of can be produced.

The reaction is usually carried out at 50 to IQO°C for 5 to 30 hours.

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

(■) ([) (X) (In the formula, R1 and X are the same as above, and Y means an alkylene group or an alkenylene group.) That is, the formula (VIII
The compound of formula (X) can be produced by reacting the compound of formula (X) with the compound of formula (IX) in the presence of almonium chloride under Friedelta raft reaction conditions.

A compound of formula (XI) can be produced by reducing a compound of formula (X) using a reaction such as Clemensen reduction or Orfkischner reduction.

A compound of formula (IV) can be prepared by reacting a compound of formula (XI) with a reagent such as almonium chloride in a suitable organic solvent such as dimethyl sulfite at a temperature around room temperature.

The compounds according to the invention are usually administered orally or parenterally. Dosage is for oral administration.

The dose is usually 10 to 200 mg per adult per day, which may be administered in divided doses 2 to 3 times a day, and may be increased or decreased as appropriate depending on the patient's symptoms.

The compound represented by formula (I) of the present invention or a salt thereof is:
With additives such as excipients, binders, disintegrants, and solubilizers, tablets, capsules, powders, granules,
It can be in the form of syrup, liquid, injection, etc.

<Effects of the Invention> The compound of the present invention has an anti-ulcer effect on 1 esophagitis, 1 esophageal ulcer, gastritis, gastric ulcer, and duodenal ulcer.

It is excellent as a preventive and therapeutic agent for gastrointestinal diseases such as small enteritis, major heat infection, and gastrointestinal bleeding. A further compound of the present invention is leukotriene 04 (hereinafter referred to as leukotriene 04).

LTD4) It has an antagonistic effect and is effective against allergic diseases such as bronchial asthma, allergic gastrointestinal diseases, allergic conjunctivitis, allergic rhinitis, hay fever, and measles, hematitis,
It is also an excellent preventive or therapeutic agent for inflammatory diseases such as keratitis, dermatitis, acute and chronic rhinitis, acute and chronic bronchitis, and upper respiratory tract inflammation.

The present invention will be explained below using reference examples, working examples, and test examples, but the present invention is not limited by these.

Reference example 1 2-a≧no 4-oxo-6-(2-phenylethyl)
-4H~1-benzopyran-3-carbaldehyde l〉2
-Hydroxy-cy(2-phenylethyl)acetophenone 4-(2-phenylethyl)phenol 19.82g,
Pyridine 30ml 1. 90 ml of benzene was mixed, and a solution of 12.5 ml of acetic anhydride and 15 ml of benzene was added dropwise at room temperature.

After heating under reflux 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, remove the oily residue after distilling off the solvent at a bath temperature of 120 to 140°C.
17.5 g of anhydrous aluminum chloride was added in several portions. Heat at the same temperature for 30 minutes and then cool.

Ice was added and the mixture was extracted with ethyl acetate. The mixture was washed with water and saturated brine, 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 IRV (neat) cm-': 3030, 2920.1640.1480.1365.
1295NMR (CDCb) δ: 2.52 (3H, S) 2.88 (41 (, S) 6.89 (IH, d, J = 98x) 7.1-7.4 (78, In) 12.09 (IH, 5) 2) 4-oxo-6-(2-phenylethyl) -4)
1-1-Benzopyran-3-carbaldehyde 47.5 g of 2-hydroxy-5-(2-phenylethyl)acetophenone and 200 ml of dimethylformamide were mixed and cooled to an internal temperature of -30 to -20°C to give 72% of phosphorus oxychloride.
ml was added dropwise over 1 hour.After adding 0 drops, the internal temperature was 40-50.
The mixture was stirred at ℃ for 2 hours, and the reaction mixture was poured into ice water and extracted with ethyl acetate. After washing with water and saturated saline and drying, the solvent was distilled off and the crystalline residue was recrystallized from ethyl acetate-petroleum ether to yield 4-oxo-6-(2-phenylethyl) as a brown powder with a melting point of 96-98°C. 22.8 g of -48-1-benzopyran-3-carbaldehyde was obtained.

elemental analysis chain).

Theoretical value (Csa) It40s): C, 77, 68H
H, 5,07 actual value: C, 77,50;
H,5,28IRν(KBr)am-': 2840, 1690.1865.1595.1470,
1300°NMR (f; DCIs) δ: 2.9-3.1 (4)1. m) 7.1-7.6 (7H, m) 8.10 (IH, brs) 8.52 (18,5) 10.39 (1)1,5) 3) 4-oxo-6-(2 -phenylethyl) -4)
1-1-benzopyran-3-carbaldehyde oxime 4
-oxo-6-(2-phenylethyl) -4H-1-
16.7 g of benzopyran-3-carbaldehyde was added to 100 ml of ethanol. Dissolved in 200 ml of tetrahydrofuran, an aqueous solution of 4.59 g of hydroxyl hydrochloride (40
ml) was added thereto, and the mixture was heated under reflux for 1 vf at room temperature for an additional 1 hour. After cooling, the mixture was concentrated under reduced pressure to approximately 100 ml, and the precipitate was collected by filtration.

After washing with water and ethanol, drying, melting point 180-183℃
Brown crystals of 4-oxo-6-(2-phenylethyl)
15.1 g of -48-1-benzopyran-3-carbaldehyde oxime was obtained.

Elemental analysis value (!¥).

Theoretical value (C+aH+5NO3): C, 73,70; H, 5,15; N, 4.78 Actual value: C, 73,43,) 1,5.27; N, 4.6
8IRu (KBr) cm-': 3280, 3060.1830. 1610, 1600
, 1480°NMR (DMSO-do) δ: 2.9-3.1 (4)1. ff1) 7.23 (5H, s) 7.6-7.8 (2H, m) 7.91 (IH, brs) 8.08 (IH, S) 8.62 (IH, 5) 11.34 ( IH, 5) 4) 2-Amino-4-oxo-6-(2-phenylethyl)-4) 1-1-benzopyran-3-carbaldehydethi 4-oxo-6-(2-phenylethyl)-48-1 −
Benzopyran-3-carbaldehyde oxime 8.80g
, 15ml of 0.5N sodium hydroxide was mixed and the bath temperature was 70°C.
Heated at ~90°C for 1 hour. After cooling, water was added and the precipitate was collected by filtration. After washing with water, drying and recrystallizing from chloroform-ethanol, 2-amino-4-
6.96 g of oxo-6-(2-phenylethyl)-4H-1-benzopyran-3-carbaldehyde was obtained as brown prism crystals.

elemental analysis chain).

Theoretical value (C+aH+5NOs): C, 73,70; Ls, 15: N, 4.78 Actual value: C, 73,43,) 1,5.14. N, 4.71
1Rυ(KBr) cm-': 3300, 3150.1675.1615.1580,
1475°NMR (DMSO-do) δ: 2.95 (4H, brs) 7.22 (5) 1. s) 7.28 (IH, d, J-11, 51 (Z) 7.53
(LH, dd, J-8, 5Hz) 7.136 (IH
, d, J-2H2) 9.60 (2H, br) 10.08 (l) I, S) Reference example 2 2-amino-6-[2-(3-chlorophenyl)ethyl]-4-oxo 4H- 1-Benzobyran-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 IRu (neat) cm-': 3020, 2930.1640.1480°NMR (C
D (:1.) δ: 2.55 (3H, s) 2.87 (4H, s) 6.90 (IH, d, J = 91 (z) 7.0-7.5 (m, 6) 1)) 12.11 (IH, 5) 2) 8-[2-(3-chlorophenyl)ethyl]-
4-Oxo 4H-1-benzopyran-3-carbaldehyde Melting point 121-124°C Elemental analysis value).

Theoretical value (C+aH+5CIO3): C, 69, 13: ) 1,4.19° Actual value: C, 69, 13, H, 4, 31° IRZ/
(KBr) cm-': 3070, 2930.28?0.1690.1660.
1605.1565° 1480, 1315° NMR (CDC13) δ: 2.9-3.1 (m, 4) 1) 7.0-7.6 (m, 8H) 8.10 (brs, IH) 8. 53(s, IH) 10.39(s, IH,) 3) 8-[2-(3-chlorophenyl)ethyl]-
4-Oxo 4H-1-Benzobyran-3-carbaldehyde oxime Melting point 154-158°C Elemental analysis value).

Theoretical value (CI8H14CINO3): C, 65, 9
6; H, 4, 31; N, 4.27° Actual measurement: C,
66,57: )! , 4.54. N, 4.15°IR
ν(KBr)c1': 3250, 1635.1B15.1600.1480°NMR (CDCIs) δ: 2.9-3.1 (48, m) 7.0-7.6 (7H, m) 7.93 (1/2H, S) 8.09 (IH, brs,) 8.33 (IH, 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 value (t).

Theoretical value (C1ll) 114CINO3): c, as
, 9a; H, 4, 31: N, 4.27° Actual value:
C, 68,3U H, 4,48; N, 4.29°IR
V (KBr) cm-': 3300, 3160.1660.1610.1575.
1470° NMR (DMSO-da) δ: 2.96 (4H, S) 7.2-7.5 (5H, m) 7.56 (IH, dd, J=2Hz, J-8,5Hz
) 7.88 (IH, d, J=2Hz) 9.60 (2H, br) 10.08 (IH, s) Reference Example 3 2-Hydroxy-5-oxo-7-(2-phenylethyl)-5 ) 1-1-benzopyrano[2,3-bl pyridine-3-carboxylic acid methyl ester 2-amino-4-oxo-6-(2-phenylethyl)
-48-1-benzopyran-3-carbaldehyde 1.4
7g, malonic acid dimethyl ester 2.20g, pyridine 5.0ml, 1.5-diazabicyclo[4,3,0]-
0.35 ml of 5-nonene and 20 ml of methanol were mixed and heated under reflux for 17 hours. After cooling, the mixture was concentrated and acidified with water and concentrated hydrochloric acid under water cooling, and the precipitate was collected by filtration. After washing with water and drying, it was recrystallized from chloroform-methanol and 2-hydroxy-5-oxo-7-(2-phenylethyl)-58
1.21 g of -1-benzopyrano[2,3-bl pyridine-3-carboxylic acid methyl ester was obtained as a brown powder.

Melting point 233-236℃ elemental analysis chain).

Theoretical value (C2+)l+yNOs): C, 70, 39
; H, 4,57; N, 3.73° Actual measurement: C, 7
0,91; H, 4,65; N, 3.99°IRV
(KBr)am-': 3200-2700. 1700. 1680. 16
40. 1610°NMR (CDC13) δ: 2.9-3.1 (4H, m) 4.06 (3H, s) 7.1-7.4 (5H, m) 7.5 (2Hm) 8.10 ( IH, brs) 9.22 (IH, S) Reference Example 4 7-(2-(3-chlorophenyl)ethyl]-2-hydroxy-5-oxo-5H-1-benzopyrano[2,3
-bl Pyridine-3-carboxylic acid methyl ester In the same manner as in Reference Example 3, 7- [2-(3-chlorophenyl)ethyl]-2-hydroxy-5-oxo-5H-1-benzopyrano[2,3-bl pyridine-
3-carboxylic acid methyl ester was obtained.

Melting point 236-239℃ Elemental analysis value (96).

Theoretical value (C2t)I+aCINOs): C, 64,
47,) 1.3.94. N, 3.42° Actual value: C,
64,97,H,4,09: N, 3.69°IRV
(KBr) cm-': 3200-2700. 1745. 1670. 16
05°NMR (CDCIs) δ: 3.0 (4H, brs) 4.07 (3H, s) 7.0-7.3 (4H, m) 7.49 (2H, s) 8.09 (ILbrs) 9.22 (IH, s) Reference Example 5 1) 97.9 g of 4-cyclohexylacetylanisole
390 ml of diethylene glycol, 100.6 ml of 40% aqueous sodium hydroxide solution, and 100.6 ml of 100% hydrazine monohydrate were added to the mixture, and the mixture was heated under reflux for 11 days. After cooling, the reaction mixture was poured into water, extracted with n-hexane, washed with water, diluted aqueous hydrochloric acid solution, aqueous sodium bicarbonate solution, and water, and dried. this? R condensation, yellow oily substance 4
4g was obtained. This oil was purified using 200 g of silica gel/n-hexane. The fractions were concentrated to obtain 30.2 g of 4-(2-cyclohexylethyl)-anisole as a colorless oil.

NMR (CDCIs): ppff17.10 (2)
! , d, J-8,8Hz), 8.131(2H, d,
J-8,814x).

3.78 (3H, S), 2.56 (2) 1. t, J
-9,0)IZ).

1.92-0.78 (13H, m) 2) Suspend 6.7 g of aluminum chloride in 25 ml of carbon tetrachloride, dropwise add 5.3 g of acetyl chloride, and then heat to 35-40°C.
The mixture was heated and stirred for 1 hour. Dissolve 7.3 g of 4-(2-cyclohexyl)anisole in 10 ml of carbon tetrachloride,
The reaction mixture was poured into a mixture of ice and dilute hydrochloric acid solution, and chloroform was added and 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 oil was chromatographed on silica gel (
Purify fraction 11 with silica gel (190g% n-hexane to n-hexane-acetic acid ethyl ester = 200:1) to obtain 5-(2-cyclohexylethyl)-2 as a colorless oil.
- 6.7 g of methoxyacetophenone were obtained.

NMR (CDCIs): 1) Pff17.53 (
1)! , d, J-2,4Hz).

7.27 (11(, dd, J-2,4,8,51(
Z).

6.86 (IH, d, J-8, 5H2), 3.88
(3M, s).

2.60 (3H, s), 2.58 (2H, t, J-
9,0Hx).

1.97-0.80 (13)1. m) 3) On an ice water bath, 8.3 g of aluminum chloride was suspended in 60 ml of methylene chloride, and 7.7 g of dimethyl sulfide was added to form a solution.

Dissolve 7.5 g of 5-(2-cyclohexylethyl)-2-methoxyacetophenone in 30 ml of methylene chloride,
dripped. After the dropwise addition, the mixture was stirred at room temperature for 20 hours, poured over a mixture of ice and dilute aqueous hydrochloric acid solution, washed with brine extracted with chloroform, dried, and the solvent removed to give 5-(2-cyclohexylethyl) as a colorless oil. )-2-Hydroxyacetophenone (6.5 g) was obtained.

NMR (CDCIs): l+l)f! 17.49
(1)! , d, J-2, 0H2).

7.28 (IH, d, d, J-2, 0, 8, 5Hz)
.

6.89 (IH, d, J-8, 5) 12), 2.8
2 (3)1. s).

2.59(2)1. t, J-9,0)12), 2.0
0-0.80(13)1. m) The following compound was obtained in the same manner as Reference Example 1.

4) 4-oxo-6-(2-cyclohexylethyl)
-4H-1-benzopyran-3-carbaldehyde NMR (CDCIs): l) I) m2.00-0.
80 (13H, m), 2.76 (2H, t, J=8
．． 5Hz).

7.43 (IH, d, J-8, 58Z).

7.59 (IH, d, d, J=2.0, 8.5Hx).

8.09 (18,d, J-2,0Hz), 8.53
(IH,s).

10.40 (18,5) 5) 4-oxo-6-(2-cyclohexylethyl)
-4H-1-benzopyran-3-carbaldehyde oxime Melting point 120-150℃ Elemental analysis value C+aH2+NOs Theoretical value C72,22H7,07N 4.68 Actual value
C72,38H7,07N 4.72I Rv (KB
r) cm-I: 3220, 2720.2840.1 [i50.1620
．． 148ONMR, (CDCl2)δ: 0.78-1.92(13)1. m), 2.74 (2
H, t, J-8, 8Hz), 7.38 (IH, d, J
-8,8Hz), 7.57 (IH, d, d, J-2,2
,8,88x)7.91(1/2H,s),8.05
(18, brs), 8.32 (IH, s) 9.48 (1
/2)1. s).

6) 2-amino-6-(2-cyclohexylethyl)-
4-Oxo-48-1-benzopyran-3-carbaldehyde Melting point 274-277°C Elemental analysis value C+aHz+NOs Theoretical value C72,22H7,07N 4. [ta actual measurement value C71,9587,07N 4.911Rν(KBr
) cll: 3300, 3150.2920.1675.1615.
1585.1475NMR (DMSO-d6) δ
: 0.80-2.00 (13H, m), 2.69 (2
B, t, J-8, 3Hz), 7.30 (IH, d, J=
8.3Hx), 7.56(1)1. d, d, J-2, 2
, 8, 3H2) 7.81 (IH, d, J-2, 2Hz)
, 9.55 (2H, br), 10.08 (1)1. s
).

Example 1 2-amino-5-oxo-7-(2-phenylethyl-
1-benzopyrano[2.3-bl pyridine-3-carboxylic acid 2-amino-4-oxo-6-(2-phenylethyl)
-4H-1-benzobilane-3-carbaldehyde 1.6
1.15 g of 4g cyanoacetic acid and 6 ml of pyridine were mixed, and the mixture was heated and stirred at a bath temperature of 110 to 130°C for 5 hours (1.75 g of cyanoacetic acid was added during the process). After cooling, the precipitate was collected by filtration and washed with ethanol and ether to give 2-amino-5-oxo-7-(2-phenylethyl)-5)1-
1.63 g of 1-benzopyrano[2.3-bl pyridine-3-carboxylic acid was obtained. Recrystallization from dimethylformamide gave a yellow powder.

Melting point 300℃ or higher elemental analysis value body).

Theoretical value (C2tH+sN204): C, 69.99; H, 4.48. N, 7.78.

Actual value: C, 69.97. H, 4.70. N,7
．． 80.

IRv(KBr)cl': 3400, 3350-2600. 1705, 1
600. 1580.1445NMR (flMSO-
C16n δ: 2, 98 (4H, S) 7, 23 (51 (, s) 7, 45 (1) 1, d, J-8Hz) 7, 65 (IH, dd, J = 2Hz, J-8 )1z)7
, 95 (IH, d, J-2Hz) 8, 24 (2) 1, br) a. 83 (18,s) Example 2 2-amino-7-(2-(3-chlorophenyl)ethyl]-5-oxo 5H-1-benzopyrano[2.3
-bl Pyridine-3-carboxylic acid 2-amino-6-[2-(3-chlorophenyl)ethyl]-4-oxo-4H-1-benzopyran-3-carbaldehyde was added to Kuno 7-
[2-(3-chlorophenyl)ethyl no 5-oxo-50-! -benzopyrano[2.3-bl pyridine-
3-carboxylic acid was obtained.

Melting point 289-294℃ Elemental analysis value (*).

Theoretical value ((:21H15N204) :C, 63.88
．． H, 3.83: N, 7.10.

Actual value: C, 64.07, )1, 3.95, N,
7.12.

IRv (KBr) cm-': 3400, 3300 ~ 2700, 1695, 1
600, 1575.146ONMR (0M50-d
a) δ: 2, 98 (4H, brs) 7, 1-7.3 (4H.n+) 7, 46 (IH, d.J-8.5) 1z) 7, 67
(IH, dd, J-2Hz, J-8.51(z)7, 9
8 (IH, d, J-2Hz) 8, 22 (2H, br) 8, 83 (IH, S) 13, 3 (IH, br).

Example 3 2-Hydroxy-5-oxo-7-(2-phenylethyl)-SH-t-benzopyrano[2.3-bl Pyridine-3-carboxylic acid 2-hydroxy-5-oxo-7-(2- Phenylethyl)-58-1-benzopyrano[2.3-bl 1.00 g of pyridine-3-carboxylic acid methyl ester, 6 ml of concentrated sulfuric acid, 6 ml of water, and 13 ml of acetic acid were mixed. After heating for 10 hours at a bath temperature of 13°C to 150°C, the mixture was poured into 100ml of ice water. Filter the precipitate.

After washing with water and drying, 2-hydroxy-5-oxo-7-(2
-phenylethyl)-58-1-benzopyrano[2.3
-bl 0.94 g of pyridine-3-carboxylic acid was obtained.

Recrystallized from dimethylformarodethanol.

Melting point 300℃ or higher Elemental analysis value (*).

Theoretical value (C21HI5NOB): c, a9. ao; H, 4.18; N, 3.88.

Actual value: C, 69.56. H, 4.26; N, 3
．． 96.

IRy (KBr) cm-': 3200-2800, 1745.1860.1615°NMR (DMSO-da) δ: 3.0 (4H, br) 7.24 (5H, s) 7.54 (IH, d, J-8,5Hz) 7.73 (
IH, dd, J-2Hz, J-8,5Hz) 7.97
(IH, d, J-2Hz) 8.80 (IH, s) 8.5-9.5 (2H, br) Example 4 7-[2-(3-chlorophenyl)ethyl go 2-hydroxy-5-oxo -5H-1-benzopyrano[2,3
-b] Pyridine-3-carboxylic acid 7-(2-(3-chlorophenyl)ethylgo 2-hydroxy-5-oxo-5H-1-
Benzopyrano[2,3-b]pyridine-3-carboxylic acid methyl ester to 7-(2-(3-chlorophenyl)ethylgo 2-hydroxy-5-oxo-5H-1
-benzopyrano[2,3-bl pyridine-3-carboxylic acid was obtained.

Melting point 296-300℃ (decomposition) Elemental analysis value (*).

Theoretical value (021H14CINOB): C, 63, 7
2; H, 3,57, N, 3.54° Actual value: C, 6
3,95,H,3,80,N, 3.44゜IRy(NiB
r) cm-': 3200-2500.1745.1B60.1615.
1475.1390°NMR (DMSQ-ds) δ: 2.99 (4H, brs) 7.2-7.4 (4H, l11) 7.53 (IH, d, J-11, 5Hz) 7.70 (
IH, dd, J-2Hz, J-8,5Hz) 7.98 (
lH, d, J-2H23 8,79 (IH, s) 9.0-10.0 (2) 1. br) Example 5 2-amino-7-(2-cyclohexylethyl)-5-oxo-5H-1-penzovirano[2,3-b]pyridine-3-carboxylic acid was obtained in the same manner as in Example 1. .

Melting point 295℃ or higher (decomposition) Elemental analysis value C21H22NxOa Theory M c ea, a4Ha, as N y, 6s
Actual measurement value C88, 71H6, 14N 7.70IRv (
Br) cm-': 3400, 3350~27G0.1710.1615.
1585.145ONMR (DMSO-da) δ: 0.60-1.89 (138, m), 2.72 (2) 1
．． d, J-8,5Hz).

7.49 (1o, a, , +-a, 5nz), 7.8
7 (1)1. dd, J-2,0,8,5H2)7.8
7 (IH, d, J-2, 0H2), 8.24 (2H,
brs), 8.79CIH,S).

Example 6 Shikamariyu Compound of Example 1 50mg Lactose 35mg Starch 24.5+ng Magnesium stearate Tablet 1 from 0.5mg or more
Manufacture tablets.

Compound of Example 1 1,000mg Polysorbate 80 1,000mg Syrup Produce 100ml of syrup from an appropriate amount or more.

Test Example 1 Effect of hydrochloric acid alcohol on gastric mucosal necrosis formation Sprague-Dawley rats (6 weeks old, male)
were subjected to experiments after fasting for 24 hours. For gastric mucosal necrosis, use hydrochloric acid alcohol (60 ztanol - 150mM hydrochloric acid solution) 1
[K, Dake] was induced by oral administration of ml.
uchj at al.

Japan, J. Pharmacol,, Vol.
44. See Page 269 (1987)].

The test compound was suspended in a 0.596 carboxymethyl cellulose aqueous solution (hereinafter referred to as 0.5k (:MC)), and
,1,3. Alternatively, it was orally administered at a dose of IOB/kH 30 minutes before induction of gastric mucosal damage. The amount of administered liquid was kept constant at sml/kg, and the disease control group C was orally administered only the same amount of 0.5 zero CMC.

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

The inhibition rate was calculated using the following formula, and the 50 zero inhibition dose (ED, value) was further calculated from the inhibition rate.

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

Test Example 2 LTD4 Antagonism Test The LTD4 antagonism of the compound of the present invention and the inhibitory effect on the contraction of isolated guinea pig ileum caused by LTD4 were further confirmed.

Specifically, male guinea pigs weighing 300 to 600 g were killed by exsanguination, and the ileum was removed to prepare a specimen approximately 2 cm in length. This time lli! yA tree 95k (h-5! IFCO
5 ml of Tyrode's solution (30
The cells were suspended in a Magnus chamber filled with temperature (±1°C). Ileal contractions were recorded on a recorder with an isotonic transducer under a load of 0.6 g. After confirming that a stable contraction reaction occurred, LTD4 (3,0 ng/m
l) was added to induce a contraction reaction. The pretreatment time for the drug was 1 minute, and the degree of contraction that occurred at that time was compared with the contraction when no test drug was added, and the 5-jo inhibitory dose (ICs) was determined from the inhibition rate.
. value) was calculated. The results are shown in Table 1.

Table 1 Test Example 3 The compounds of Examples 1, 2.3, and 4 were orally administered to mice, and the acute toxicity was examined. As a result, the LD of these compounds.

were all 1,000 mg/kg or more.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 means a cycloalkyl group, a cycloalkenyl group, or an aryl group, and The group may have one or more substituents selected from an alkyl group, a halogen atom, and a halogenoalkyl group, X means a single bond, an alkylene group or an alkenylene group, and R^2 means an amino group or a hydroxyl group. ) and its salts.