JPH05310724A - Coumarone derivative or dihydrobenzofuran derivative - Google Patents

Abstract

PURPOSE:To provide a coumarone derivative or a dihydrobenzofuran derivative having a combination of leukotriene production-inhibitory activity and thromboxane synthesis-inhibitory activity, thus useful for preventing or curing asthema or hepatopathy. CONSTITUTION:The compound of formula I {R<1> to R<3> are each H, OH or of formula IV [A is H or heteroarylalkyl; B is H, carboxyl or protected carboxyl; Y is of formula VII, VIII or IX (p and q are each 0-6)]; X is OH or protected OH; n is 2 or 3} or a salt thereof, e.g. 3,4-dihydro-7- hydroxy-6-(methoxymethoxy)-5-(3-pyridylmethyl-2H-1-benzopyrane. The compound of the formula I [where, R<1> is of formula X (R<1a>) and R<2> is of formula XI (R<2a>)] (a compound of formula V) can be obtained by the following process: a compound of formula II is put to addition reaction, acetylation, catalytic reduction, etc., to produce a compound of formula III, which is then put to de-t-butyldimethylsilylation and oxidation with MnO2 into a compound of formula IV, which is, in turn, subjected to Wittig-Honer reaction.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a chroman derivative or a dihydrobenzofuran derivative having an excellent action as a medicine.

[0002]

Background of the Invention and Prior Art In recent years, bronchial asthma has shown a marked increase tendency, and an approach as an anti-asthma drug is also a bronchodilator such as a xanthine preparation or a β-stimulant, and release or production of a mediator represented by histamine. Multifaceted trials such as inhibitors have been made. Particularly in recent years, the role of mediators in asthma has been rapidly elucidated, and in addition to histamine, leukotrienes (hereinafter abbreviated as LTs), P
AF, thromboxane (hereinafter abbreviated as TXs), etc. have come to be known, and in particular, arachidonic acid cascade metabolites LTs and TXs have been studied from all directions. It is also known that these mediators interact in a complex manner, and when considering various pathological conditions of asthma, it is easy to conclude that there is a limit to the improvement of the efficacy rate and improvement rate with only a single mediator inhibitor. Be done.

Also, as LTs and TXs have been studied, it has been found that they are involved in the onset and progression of liver diseases. That is, blood L in patients with alcoholic hepatitis and chronic hepatitis
Ts and TXs concentrations are significantly higher than those of healthy people,
It has been reported that LTs cause hepatic disorder in hypoxia in cultured cell lines. Thus, although LTs and TXs act not only by themselves, but they often interact with each other and are involved in the onset / progression of diseases, and a drug that suppresses the production of both mediators has been craved, but it is still in the market. The reality is that it doesn't appear.

In view of the above situation, the present inventors have
We have started research on a drug that has both the leukotriene production inhibitory action and the thromboxane synthesis inhibitory action. As a result, the following chroman derivatives or dihydrobenzofuran derivatives have these two actions at the same time in a well-balanced manner, and are known to have a mucosal protective action, such as prostaglandin E _{2 and the} like. They have found that they do not suppress the production of cascade metabolites and completed the present invention.

[0005]

The compound of the present invention is a chroman derivative or dihydrobenzofuran derivative represented by the following general formula (I) and a pharmacologically acceptable salt thereof.

[0006]

[Chemical 6]

[Wherein R ¹ , R ² and R ³ are the same or different hydrogen atoms, hydroxyl groups or formulas

[0008]

[Chemical 7]

[In the formula, A means a hydrogen atom or a heteroarylalkyl group. B means a hydrogen atom, a carboxyl group or a protected carboxyl group. Y is an expression

[0010]

[Chemical 8]

(Wherein p represents 0 or an integer of 1 to 6), a group represented by the formula:

[0012]

[Chemical 9]

(Wherein q represents 0 or an integer of 1 to 6), or a group represented by the formula:

[0014]

[Chemical 10]

Means a group represented by: ] It means the group shown by. X means a hydroxyl group or a protected hydroxyl group. n means an integer of 2 or 3. } In the general formula (I), examples of the protected hydroxyl group represented by X include a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group. , Butyl group, isobutyl group, sec-
Butyl group, tert-butyl group, pentyl group (amyl group),
Isopentyl group, neopentyl group, 1-methylbutyl group, 1,2-dimethylpropyl group, isohexyl group, 2
-A group protected with a methylpentyl group, a 1,2,2-trimethylpropyl group, a 1-ethyl-2-methylpropyl group or the like, that is, when it is an alkoxy group, an acetyl group, a propionyl group, a butyroyl group, a pivaloyl group, Examples thereof include a group protected by an acyl group such as a nicotinoyl group, that is, a case where an ester is formed. In short, any group that can be decomposed into a hydroxyl group by some means in the living body may be used.

The term "heteroaryl" in the heteroarylalkyl group in the definition of A means a 5- or 6-membered ring containing 1 to 2 nitrogen atoms, sulfur atoms or oxygen atoms, and examples thereof include pyridyl, imidazolyl, Ruffles, thienyl,
Examples thereof include pyrazyl. In this case, the alkyl group, that is, the alkylene chain has 1 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 4 to 6 carbon atoms.

In the "protected carboxyl group" in the definition of B, the protecting group means a lower alkyl group such as methyl, ethyl, t-butyl; p-methoxybenzyl, p.
-Lower alkyl group substituted with a phenyl group which may have a substituent such as nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl; 2,2,2-trichloroethyl, 2-iodoethyl Halogenated lower alkyl groups such as; pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl,
Lower alkanoyloxy lower alkyl groups such as butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl, 2-pivaloyloxyethyl; palmitoyloxyethyl, heptadeca Higher alkanoyloxy lower alkyl groups such as noyloxymethyl, 1-palmitoyloxyethyl; methoxycarbonyloxymethyl, 1-
Lower alkoxycarbonyloxy lower alkyl groups such as butoxycarbonyloxyethyl and 1- (isopropoxycarbonyloxy) ethyl; carboxy lower alkyl groups such as carboxymethyl and 2-carboxyethyl; heterocyclic groups such as 3-phthalidyl; 4- Benzoyloxy lower alkyl group optionally having substituents such as glycyloxybenzoyloxymethyl, 4- [N- (t-butoxycarbonyl) glycyloxy] benzoyloxymethyl; (5
A (substituted dioxolene) lower alkyl group such as -methyl-2-oxo-1,3-dioxolen-4-yl) methyl;
Cycloalkyl-substituted lower alkanoyloxy lower alkyl groups such as 1-cyclohexylacetyloxyethyl, 1
And cycloalkyloxycarbonyloxy lower alkyl groups such as cyclohexyloxycarbonyloxyethyl and the like. Further, various acid amides may be used. In short, it is decomposed by some means in vivo,
Any protective group may be used as long as it can be a carboxylic acid.

P means 0 or an integer of 1 to 6. q means 0 or an integer of 1 to 6. n means an integer of 2 or 3.

The pharmacologically acceptable salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate, such as acetate, maleate, tartrate and methanesulfonate.
Examples thereof include organic acid salts such as benzene sulfonate and toluene sulfonate, and salts with amino acids such as arginine, aspartic acid and glutamic acid.

Further, depending on the compound, Na, K, Ca,
It may take a metal salt such as Mg and is included in the pharmacologically acceptable salt of the present invention. Further, the compound of the present invention is
For example, as is clear from its chemical structure, geometric isomers (cis isomer, trans isomer) may exist, but it goes without saying that any isomer is included in the scope of the present invention.

Typical methods for producing the compound of the present invention are listed below. Production Method 1 In the general formula (I), R ¹ is a formula

[0022]

[Chemical 11]

(Wherein A, B and p have the above-mentioned meanings), R ² is a group represented by the formula

[0024]

[Chemical formula 12]

When the group is represented by (wherein A and B have the above meanings), they can be produced by the following method.

[0026]

[Chemical 13]

[Wherein R ³ , X, and n have the above-mentioned meanings. R ^1a is the formula

[0028]

[Chemical 14]

(Wherein A, B and p have the above-mentioned meanings). R ^2a is the formula

[0030]

[Chemical 15]

(In the formula, A and B have the above-mentioned meanings). That is, in the first step, the compound (II) is subjected to an addition reaction, acetylation, catalytic reduction, etc. by a conventional method to obtain a compound (III), and the obtained compound (III) is detert-butylated in the second step. In this method, the compound (IV) is obtained by dimethylsilylation and then MnO ₂ oxidation, and the Wittig-Horner reaction is further carried out to obtain the target compound represented by the general formula (V). In the above series of equations, R ¹
Is the expression

[0032]

[Chemical 16]

(Wherein A, B and p have the above-mentioned meanings), R ² is a group represented by the formula

[0034]

[Chemical 17]

Although the case where the group represented by the formula (A and B have the above-mentioned meanings) is shown, the case where the above-mentioned substituents are actually bonded to other positions is also the same as the above-mentioned method. Can be manufactured.

Production Method 2 In the general formula (I), R ¹ is a formula

[0037]

[Chemical 18]

(Wherein A, B and q have the above-mentioned meanings), R ² is a group represented by the formula

[0039]

[Chemical 19]

When the group is represented by (wherein A and B have the above meanings), they can be produced by the following method.

[0041]

[Chemical 20]

[0042]

[Chemical 21]

[In the series of formulas, R ³ , X, and n have the above-mentioned meanings. R ^1b is the formula

[0044]

[Chemical formula 22]

(Wherein A, B and q have the above-mentioned meanings), R ^2b is a group represented by the formula:

[0046]

[Chemical formula 23]

(Wherein A and B have the above-mentioned meanings). That is, the compound (II) is formylated by a usual method in the first step, and the obtained compound (VI) is subjected to the Bayer-Villiger reaction, the formate hydrolysis and the alkylation reaction in the second step. Compound (VIII) is obtained by detert-butyldimethylsilylation and oxidation in the third step, and then the Wittig-Horner reaction or Wittig reaction is performed in the fourth step to obtain the target compound (IX). Is a way to get. still,
In the above series of equations, R ¹ is

[0048]

[Chemical formula 24]

(Wherein A, B and q have the above-mentioned meanings), R ² is a group represented by the formula

[0050]

[Chemical 25]

The production method when the group is represented by the formula (A and B have the above meanings) is shown. However, when the above substituents are bonded to other positions, the above method is also applicable. It can be manufactured in a similar manner.

Production Method 3 In the general formula (I), those in which X is a hydroxyl group can be obtained by deprotection by the following method.

[0053]

[Chemical formula 26]

(In the series of formulas, R ¹ , R ² , R ³ and n have the above-mentioned meanings. X'means a hydroxyl-protecting group.) That is, the compound (X) can be prepared by a commonly used method. This is a method of obtaining the target compound (XI) by removing the protecting group.

Production Method 4 In the general formula (I), R ² is of the formula

[0056]

[Chemical 27]

When the group is represented by the formula (A and B have the above-mentioned meanings), they can also be produced by the following method.

[0058]

[Chemical 28]

(In the series of formulas, R ¹ , R ³ , A, B, n and X have the above-mentioned meanings.) That is, the compound (XII) is subjected to catalytic hydrogenation in the usual manner to obtain the target compound ( XIII) is obtained.

[0060] shown below a representative method for producing a starting material for the production method described above manufacturing method of the starting materials. The general formula (II) used as the starting material in the production methods 1 and 2
The compound represented by can be produced by the following method.

[0061]

[Chemical 29]

(In the series of formulas, R ³ , X, X ', n has the above-mentioned meanings.) That is, in the first step, the compound (XIV) is brominated by a conventional method to obtain the compound (XV). In the second step, the hydroxyl group of the compound (XV) is protected by a conventional method to obtain a compound (XVI), and in the third step, the compound (XVI) is reduced by a conventional method.
In this method, compound (II) is obtained by carrying out tert-butyldimethylsilylation.

In tert-butyldimethylsilylation,
Examples of preferable reaction solvent include N, N-dimethylformamide. The preferred reaction temperature is about 0.
℃ to 25 ℃. The reaction of attaching a protective group to a hydroxyl group is
Although any commonly used method can be performed, a method such as reaction with chloromethyl methyl ether in the presence of sodium hydride is preferable. In this case, the reaction solvent is preferably N, N-dimethylformamide or the like. The reaction temperature is preferably about 0 ° C to 10 ° C.

The reduction in the third step can be carried out by any conventional method, but sodium borohydride reduction is preferred. In this case, the reaction solvent is preferably ethanol or the like. Further, the reaction can proceed sufficiently at room temperature. In addition, the compound obtained by reduction is treated with N, N-
The target raw material compound (II) can be obtained by dissolving it in dimethylformamide or the like and reacting it with tert-butyldimethylsilyl chloride. A compound having a bromine group or a t-butyldimethylsilyloxymethyl group different from the above position can also be produced according to the above method.

[0065]

[Embodiment of the Invention] Next, experimental examples will be given in order to describe the effect of the compound of the present invention in detail. Experimental example Leukotriene B ₄ (LTB from rat peritoneal infiltrating cells
₄ ), thromboxane B ₂ (TxB ₂ ) production inhibitory action <Experimental method> 6% w / v glycogen (Type II from Oy) was intraperitoneally administered to Fischer male rats weighing 150 to 200 g.
(ster, Sigma) 10 ml of physiological saline solution is injected. After 20 to 24 hours, peritoneal exudate cells are collected from the rat, washed, and then suspended in Hank's balanced salt solution (HBSS) at a concentration of 5 × 10 ⁶ / ml. 96-well culture plate (Costar) in which the test drug diluted to the specified concentration was dispensed at 10 μl / well
(Registered trademark)), 100 μl / well of this cell suspension is dispensed. After incubating the plate for 5 minutes at 37 ° C, A-23187 (calcium ionophore, CAL
BIOCHEM®) is added to a final 2 μg / ml. After reacting for another 10 minutes at 37 ° C., the plate is transferred to ice and BW755C solution is added to a final concentration of 100 μM. After centrifuging this plate at 15000 rpm for 10 minutes, the supernatant was recovered and LTB ₄ , Tx in the supernatant was collected.
B ₂ was measured by an oxygen immunoassay using an EIA kit manufactured by Cayman.

<Results> The inhibitory action on leukotriene B ₄ and thromboxane B ₂ production of each compound (shown in Example No. in Examples described later) is shown in the following Table 1 by IC ₅₀ .

[0067]

[Table 1]

From the above-mentioned pharmacological experimental examples, it is clear that the compound of the present invention has both the leukotriene (LTs) production inhibitory action and the thromboxane (TXs) synthesis inhibitory action. Therefore, the compound of the present invention is
It is effective as a prophylactic / therapeutic agent for diseases for which production suppression or TXs synthesis inhibition is effective.

Examples of diseases for which these effects are effective include asthma, various liver diseases (chronic hepatitis, acute hepatitis, drug-toxic liver injury, viral hepatitis, alcoholic hepatitis, jaundice,
Cirrhosis), ischemic heart disease (myocardial infarction, angina, etc.), ischemic brain disease (cerebral embolism, cerebral thrombosis, etc.), and various renal diseases (renal failure, nephrosis, nephritis, etc.). Furthermore, the compound of the present invention is highly safe, and in this sense, the value of the present invention is high.

When the compound of the present invention is administered as a therapeutic / preventive agent for these diseases, it is administered as tablets, powders, granules, capsules, syrups and inhalants. The dose varies significantly depending on the degree of symptoms, age, type of disease, etc.
Usually about 0.1 mg to 1,000 mg per day for adults,
Preferably, about 1 mg to 500 mg is administered once or several times a day. In the case of injection, it is usually 1 μg / kg to 3,000 μg / kg, preferably about 3 μg / kg to 1,000 μg / kg.

In formulating, a usual pharmaceutical carrier is used, and it is manufactured by a conventional method. That is, when preparing a solid preparation for oral use, the main ingredient is an excipient, and if necessary, a binder, a disintegrant,
After adding a lubricant, a coloring agent, a flavoring agent and the like, tablets, coated tablets, granules, powders, capsules and the like are prepared by a conventional method.

As the excipient, for example, lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose,
Silicon dioxide or the like, as the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose,
Hydroxypropyl methylcellulose, calcium citrate, dextrin, pectin, etc. are lubricants.
For example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc. are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents, cocoa powder, peppermint, aromatic acid, peppermint Oil, Borneolum, cinnamon powder, etc. are used. Needless to say, these tablets and granules may be sugar-coated, gelatin-coated or any other suitable coating. When preparing an injection, a pH adjusting agent, a buffer, a stabilizer, a solubilizing agent, etc. are added to the main drug as necessary, and subcutaneous, intramuscular,
It will be an intravenous injection.

[0073]

EXAMPLES Examples of the present invention will be given below, but it goes without saying that the present invention is not limited thereto. In addition, Production Examples of raw material compounds used in producing the target substance of the present invention are also shown below. In the examples, Me represents a methyl group and Et represents an ethyl group.

Production Example 1 3,4-dihydro-6- (methoxymethoxy) -2H-
1-benzopyran-7-carbaldehyde

[0075]

[Chemical 30]

3,4-dihydro-6-hydroxy-2H
-1-benzopyran-7-carbaldehyde 12.7 g was added to N,
It was dissolved in 100 ml of N-dimethylformamide and cooled to 0 ° C. 4.0 g of 60% sodium hydride was added below 10 ° C. Continuously add 6.9 g of chloromethyl methyl ether to 30
Stir for minutes. The reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / hexane) to give the title compound (1.9 g) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
2.00 (tt, J = 6.0,6.0Hz, 2H), 2.83 (t, J = 6.0Hz, 2H), 3.52
(s, 3H), 4.16 (t, J = 6.0Hz, 2H), 5.21 (s, 2H), 6.91 (s, 1H),
7.24 (s, 1H), 10.38 (s, 1H) Production Example 2 7-Bromo-3,4-dihydro-5-methoxy-6-
(Methoxymethoxy) -2H-1-benzopyran

[0078]

[Chemical 31]

(1) 7-Bromo-3,4-dihydro-6-
(Methoxymethoxy) -2H-1-benzopyran-5-
Dissolve 1.37 g carbaldehyde in 50 ml dichloromethane,
1.28 g of 80% m-chloroperbenzoic acid was added in small portions. The reaction solution was gently heated to reflux. It was heated as it was and refluxed for 30 minutes. The reaction mixture was ice-cooled, and 30 ml of saturated aqueous sodium thiosulfate solution was added. The precipitated insoluble material was filtered off and washed with dichloromethane. The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. (2) Dissolve 1.3 g of the obtained residue in 30 ml of ethanol,
An aqueous solution of sodium hydroxide N was added, and the mixture was refluxed for 30 minutes. The reaction solution was cooled, adjusted to pH 5 with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. (3) 1.2 g of the obtained residue was dissolved in 20 ml of N, N-dimethylformamide and cooled to 0 ° C. 360 mg of 60% sodium hydride was added below 10 ° C. After stirring at room temperature for 30 minutes, 1.29 g of methyl iodide was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give 1.1 g of the title compound as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.94 (tt, J = 7.0,7.0Hz, 2H), 2.68 (t, J = 7.0Hz, 2H), 3.65
(s, 3H), 3.81 (s, 3H), 4.09 (t, J = 7.0Hz, 2H), 5.06 (s, 2H),
6.80 (s, 1H) Example 1 3,4-dihydro-7-hydroxy-6- (methoxymeth)
Toxy) -5- (3-pyridylmethyl) -2H-1-be
Nzopyran

[0081]

[Chemical 32]

(1) 5-Bromo-3,4-dihydro-6-
(Methoxymethoxy) -7- (phenylmethoxy) -2
1.3 g of H-1-benzopyran was added to anhydrous tetrahydrofuran
It was dissolved in 30 ml and cooled to -70 ° C under a nitrogen stream. to this
2.7M of 1.6M n-butyllithium hexane solution is -65
The mixture was added below ℃ and stirred at that temperature for 30 minutes. In this
470 mg of 3-pyridinecarboxaldehyde was added all at once. The temperature was slowly returned to room temperature, 50 ml of water was added, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. (2) 2.0 g of the residue obtained in (1) was dissolved in 5 ml of pyridine, 5 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure. (3) Dissolve 2 g of the residue obtained in (2) in 200 ml of ethanol, add 1.3 g of 10% palladium-carbon (50% hydrous product),
Hydrogenation was carried out at room temperature and atmospheric pressure for 6 hours. The palladium carbon was filtered off using Celite, and the solvent was evaporated under reduced pressure.
The precipitated crystals were washed with isopropyl ether-ethanol (5
%) When washed with a mixed solution, 800 mg of the title compound was obtained as white crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.94 (tt, J = 7.0,7.0Hz, 2H), 2.51 (t, J = 7.0Hz, 2H), 3.58
(s, 3H), 3.95 (s, 2H), 4.07 (t, J = 7.0Hz, 2H), 4.75 (s, 2H),
6.43 (s, 1H), 7.18 (dd, J = 5.0,8.0Hz, 1H), 7.34 (dt, J = 1.
5,8.0Hz, 1H), 8.41 (dd, J = 1.5,5.0Hz, 1H), 8.44 (d, J = 1.5H
z, 1H) Example 2 2,3-dihydro-6-hydroxy-5- (methoxymeth)
Toxy) -4- (3-pyridylmethyl) benzofuran

[0084]

[Chemical 33]

The title compound was obtained as white crystals from 4-bromo-2,3-dihydro-5- (methoxymethoxy) -6- (phenylmethoxy) benzofuran in the same manner as in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
2.98 (t, J = 8.5Hz, 2H), 3.58 (s, 3H), 3.90 (s, 2H), 4.53
(t, J = 8.5Hz, 2H), 4.71 (s, 2H), 6.40 (s, 1H), 7.19 (dd, J =
5.0,8.0Hz, 1H), 7.41 (dt, J = 1.5,8.0Hz, 1H), 8.44 (dd, J =
1.5,5.0Hz, 1H), 8.48 (d, J = 1.5Hz, 1H) Example 3 4-{[3,4-dihydro-6- (methoxymethoxy)
-5- (3-pyridylmethyl) -2H-1-benzopyra
Nethyl-7-yl] oxy} butyrate ethyl

[0087]

[Chemical 34]

Example 1 was carried out in the same manner as in (3) of Production Example 2.
3,4-dihydro-7-hydroxy-6-obtained in
(Methoxymethoxy) -5- (3-pyridylmethyl)-
The title compound was obtained by reacting 2H-1-benzopyran with ethyl 4-bromobutyrate.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.25 (t, J = 7.0Hz, 2H), 1.89 (tt, J = 7.0,7.0Hz, 2H), 2.13 (t
t, J = 7.5,7.5Hz, 2H), 2.44 (t, J = 7.5Hz, 2H), 2.50 (t, J = 7.
0Hz, 2H), 3.97 (t, J = 7.5Hz, 2H), 4.03 (t, J = 7.0Hz, 2H), 4.
13 (q, J = 7.0Hz, 2H), 5.00 (s, 2H), 6.48 (s, 1H), 7.15 (dd, J
= 5.0,8.0Hz, 1H), 7.41 (dt, J = 1.5,8.0Hz, 1H), 8.39 (dd, J =
1.5,5.0Hz, 1H), 8.46 (d, J = 1.5Hz, 1H) Example 4 (E) -3- [3,4-dihydro-6- (methoxymeth)
Xy) -2H-1-benzopyran-7-yl] -2-
[5- (3-pyridyl) pentyl] ethyl acrylate

[0090]

[Chemical 35]

While 340 mg of 60% sodium hydride was suspended in 20 ml of N, N-dimethylformamide, 3.4 g of ethyl 2-diethylphosphono-7- (3-pyridyl) heptanoate (Wittig-Horner reagent) was added. Drop at room temperature,
Stir for 20 minutes. 3,4-dihydro-6- (methoxymethoxy) -2H obtained in Production Example 1 was added to the obtained transparent solution.
-1-benzopyran-7-carbaldehyde 1.9 g N,
After a 5 ml solution of N-dimethylformamide was added dropwise, the mixture was stirred at room temperature for 2 hours. The reaction solution was added to 300 ml of ice water, extracted twice with ethyl acetate, and the organic layer was dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give the title compound (900 mg) as a brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.33 (t, J = 7.0Hz, 3H), 1.39 (tt, J = 7.5,7.5Hz, 2H), 1.51
~ 1.61 (m, 4H), 1.98 (tt, J = 6.0,6.0Hz, 2H), 2.46 (t, J = 7.5
Hz, 2H), 2.58 (t, J = 7.5Hz, 2H), 2.76 (t, J = 6.0Hz, 2H), 3.4
6 (s, 3H), 4.13 (t, J = 6.0Hz, 2H), 4.26 (q, J = 7.0Hz, 2H), 5.
10 (s, 2H), 6.72 (s, 1H), 6.82 (s, 1H), 7.19 (dd, J = 5.5,8.0
Hz, 1H), 7.47 (dt, J = 1.5,8.0Hz, 1H), 7.73 (s, 1H), 8.41
(d, J = 1.5Hz, 1H), 8.44 (dd, J = 1.5,5.5Hz, 1H) Example 5 (E) -3- [2,3-dihydro-5- (methoxymeth)
Xy) -6-benzofuranyl] -2- [5- (3-pyri
Dill) pentyl] ethyl acrylate

[0093]

[Chemical 36]

The title compound was obtained in the same manner as in Example 4 from 2,3-dihydro-5- (methoxymethoxy) -benzofuran-6-carbaldehyde.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.33 (t, J = 7.0Hz, 3H), 1.35 ~ 1.43 (m, 2H), 1.50 ~ 1.63
(m, 4H), 1.70 to 1.80 (m, 2H), 2.46 (t, J = 7.5Hz, 2H), 2.56
(t, J = 7.5Hz, 2H), 3.21 (t, J = 8.5Hz, 2H), 3.48 (s, 3H), 4.2
5 (q, J = 7.0Hz, 2H), 4.54 (t, J = 8.5Hz, 2H), 5.08 (s, 2H), 6.
68 (s, 1H), 7.03 (s, 1H), 7.18 (dd, J = 5.0,8.0Hz, 1H), 7.46
(dt, J = 1.5,8.0Hz, 1H), 7.73 (s, 1H), 8.34 (d, J = 1.5Hz, 1
H), 8.41 (dd, J = 1.5,5.0Hz, 1H) Example 6 (E) -3- [3,4-dihydro-5-methoxy-6-
(Methoxymethoxy) -2H-1-benzopyran-7-
Il] -2- [5- (3-pyridyl) pentyl] acryl
Ethyl acetate

[0096]

[Chemical 37]

By a method similar to that in Example 4, the title compound was obtained.・¹ H-NMR (400MHz, CDCl ₃ ) δ ppm; 1.31 (t, J = 7.0H
z, 3H), 1.40 (tt, J = 7.5,7.5Hz, 2H), 1.53 to 1.65 (m, 4H),
1.96 (tt, J = 7.0,7.0Hz, 2H), 2.46 (t, J = 7.5Hz, 2H), 2.58
(t, J = 7.5Hz, 2H), 2.73 (t, J = 7.0Hz, 2H), 3.55 (s, 3H), 3.8
0 (s, 3H), 4.10 (t, J = 7.0Hz, 2H), 4.24 (q, J = 7.0Hz, 2H), 4.
98 (s, 2H), 6.53 (s, 1H), 7.18 (dd, J = 5.0,8.0Hz, 1H), 7.46
(dt, J = 1.5,8.0Hz, 1H), 8.40-8.43 (m, 2H) Example 7 (E) -3- [2,3-dihydro-4-methoxy-5-
(Methoxymethoxy) -6-benzofuranyl)]-2-
[5- (3-pyridyl) pentyl] ethyl acrylate

[0098]

[Chemical 38]

By a method similar to that in Example 4, the title compound was obtained.・¹ H-NMR (400MHz, CDCl ₃ ) δ ppm; 1.33 (t, J = 7.0H
z, 3H), 1.36 ~ 1.41 (m, 2H), 2.26 ~ 1.62 (m, 4H), 2.45 (t, J
= 7.5Hz, 2H), 2.56 (t, J = 7.5Hz, 2H), 3.29 (t, J = 8.5Hz, 2
H), 3.54 (s, 3H), 3.89 (s, 3H), 4.24 (q, J = 7.0Hz, 2H), 4.5
6 (t, J = 8.5Hz, 2H), 4.96 (s, 2H), 6.43 (s, 1H), 7.20 (dd, J =
5.0,8.0Hz, 1H), 7.46 (dt, J = 1.5,8.0Hz, 1H), 7.77 (s, 1H),
8.41 (d, J = 1.5Hz, 1H), 8.44 (dd, J = 1.5,5.0Hz, 1H) Example 8 (E) -3- [2,3-dihydro-5- (methoxymeth)
Xy) -4-methyl-6-benzofuranyl] -2- [5
-(3-Pyridyl) pentyl] ethyl acrylate

[0100]

[Chemical Formula 39]

By a method similar to that in Example 4, the title compound was obtained.・¹ H-NMR (400MHz, CDCl ₃ ) δ ppm; 1.32 (t, J = 7.0H
z, 3H), 1.33 to 1.60 (m, 6H), 2.21 (s, 3H), 2.46 (t, J = 7.0H
z, 2H), 2.57 (t, J = 7.0Hz, 2H), 3.13 (t, J = 8.5Hz, 2H), 3.59
(s, 3H), 4.25 (q, J = 7.0Hz, 2H), 4.59 (t, J = 8.5Hz, 2H), 4.
84 (s, 2H), 6.54 (s, 1H), 7.19 (dd, J = 5.0,8.0Hz, 1H), 7.46
(dt, J = 1.5,8.0Hz, 1H), 7.75 (s, 1H), 8.40 (d, J = 1.5Hz, 1
H), 8.41 (dd, J = 1.5,5.0Hz, 1H) Example 9 (E) -3- [2,3-dihydro-4-methoxy-5-
(Methoxymethoxy) -7-methyl-6-benzofurani
L] -2- [5- (3-pyridyl) -pentyl] acryl
Ethyl acetate

[0102]

[Chemical 40]

By a method similar to that in Example 4, the title compound was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm; 1.24 (tt, J = 7.
5,7.5Hz, 2H), 1.32 (t, J = 7.0Hz, 3H), 1.41 (tt, J = 7.5,7.5H
z, 2H), 1.47 (tt, J = 7.5,7.5Hz, 2H), 1.98 (s, 3H), 2.18 (t,
J = 7.5Hz, 2H), 2.48 (t, J = 7.5Hz, 2H), 3.27 (t, J = 8.5Hz, 2
H), 3.48 (s, 1H), 3.82 (s, 3H), 4.25 (q, J = 7.5Hz, 2H), 4.5
5 (t, J = 8.5Hz, 2H), 4.88 (s, 2H), 7.16 (dd, J = 5.0,8.0Hz, 1
H), 7.40 (dt, J = 1.5,8.0Hz, 1H), 7.45 (s, 1H), 8.35 (d, J =
1.5Hz, 1H), 8.41 (dd, J = 1.5, 5.0Hz, 1H) Example 10 (E) -3- [2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -7-benzofuranyl] -2-
[5- (3-pyridyl) pentyl] ethyl acrylate

[0104]

[Chemical 41]

By a method similar to that in Example 4, the title compound was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm; 1.25 to 1.37 (m,
5H), 1.48 (tt, J = 7.5,7.5Hz, 2H), 1.53 (tt, J = 7.5,7.5Hz, 2
H), 2.31 (t, J = 7.5Hz, 2H), 2.53 (t, J = 7.5Hz, 2H), 3.15 (t,
J = 8.5Hz, 2H), 3.53 (s, 3H), 3.74 (s, 3H), 4.25 (q, J = 7Hz,
2H), 4.51 (t, J = 8.5Hz, 2H), 5.11 (s, 2H), 7.00 (s, 1H), 7.1
8 (dd, J = 5.0,8.0Hz, 1H), 7.41 (dt, J = 1.5,8.0Hz, 1H), 7.4
4 (s, 1H), 8.38 (d, J = 1.5Hz, 1H), 8.41 (dd, J = 1.5,5.0Hz, 1
H) Example 11 (Z) -3- [2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -7-benzofuranyl] -2-
[5- (3-pyridyl) pentyl] ethyl acrylate

[0106]

[Chemical 42]

By a method similar to that in Example 4, the title compound was obtained.・¹ H-NMR (400MHz, CDCl ₃ ) δ ppm; 1.09 (t, J = 7.0H
z, 3H), 1.42 (tt, J = 7.0,7.0Hz, 2H), 1.57 (tt, J = 7.0,7.0H
z, 2H), 1.66 (tt, J = 7.0,7.0Hz, 2H), 2.46 (t, J = 7.0Hz, 2H),
2.61 (t, J = 7.0Hz, 2H), 3.13 (t, J = 8.5Hz, 2H), 3.53 (s, 3
H), 3.71 (s, 3H), 4.13 (q, J = 7.0Hz, 2H), 4.51 (t, J = 8.5H
z, 2H), 5.10 (s, 2H), 6.56 (s, 1H), 6.93 (s, 1H), 7.19 (dd,
J = 5.0,8.0Hz, 1H), 7.49 (dt, J = 1.5,8.0Hz, 1H), 8.43 (dd, J
= 1.5,5.0Hz, 1H), 8.44 (d, J = 1.5Hz, 1H) Example 12 (E) -3- [6-ethoxy-2,3-dihydro-5-
(Methoxymethoxy) -7-benzofuranyl] -2-
[5- (3-pyridyl) pentyl] ethyl acrylate

[0108]

[Chemical 43]

By a method similar to that in Example 4, the title compound was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm; 1.24 to 1.38 (m,
8H), 1.40 to 1.58 (m, 4H), 2.31 (t, J = 7.5Hz, 2H), 2.53 (t, J
= 7.5Hz, 2H), 3.15 (t, J = 8.5Hz, 2H), 3.53 (s, 3H), 3.94 (q,
J = 7.0Hz, 2H), 4.24 (q, J = 7.0Hz, 2H), 4.50 (t, J = 8.5Hz, 2
H), 5.09 (s, 2H), 7.00 (s, 1H), 7.18 (dd, J = 5.0,8.0Hz, 1
H), 7.43 (dt, J = 1.5,8.0Hz, 1H), 7.46 (s, 1H), 8.38 ~ 8.45
(m, 2H) Example 13 (E) -3- [2,3-dihydro-5- (methoxymeth)
Xy) -6-Propoxy-7-benzofuranyl] -2-
[5- (3-pyridyl) pentyl] ethyl acrylate

[0110]

[Chemical 44]

By a method similar to that in Example 4, the title compound was obtained.・¹ H-NMR (400MHz, CDCl ₃ ) δ ppm; 1.98 (t, J = 7.0H
z, 3H), 1.24 to 1.34 (m, 5H), 1.43 to 1.58 (m, 4H), 1.70 (tt,
J = 7.5,7.5Hz, 2H), 2.31 (t, J = 7.0Hz, 2H), 2.53 (t, J = 7.0H
z, 2H), 3.15 (t, J = 8.5Hz, 2H), 3.52 (s, 3H), 3.83 (t, J = 7.5
Hz, 2H), 4.25 (q, J = 7.0Hz, 2H), 4.50 (t, J = 8.5Hz, 2H), 5.0
9 (s, 2H), 6.99 (s, 1H), 7.18 (dd, J = 5.0,8.0Hz, 1H), 7.43
(dt, J = 1.5,8.0Hz, 1H), 7.48 (s, 1H), 8.38 (d, J = 1.5Hz, 1
H), 8.41 (dd, J = 1.5,5.0Hz, 1H) Example 14 (E) -3- [6-heptyloxy-2,3-dihydro
-5- (Methoxymethoxy) -7-benzofuranyl]-
2- [5- (3-pyridyl) pentyl] ethyiacrylic acid
Le

[0112]

[Chemical 45]

By a method similar to that in Example 4, the title compound was obtained.・¹ H-NMR (400MHz, CDCl ₃ ) δ ppm; 0.86 (t, J = 7.0H
z, 3H), 1.25 to 1.58 (m, 17H), 1.60 to 1.70 (m, 2H), 2.30 (t,
J = 7.5Hz, 2H), 2.50 (t, J = 7.5Hz, 2H), 3.14 (t, J = 8.5Hz, 2
H), 3.52 (s, 3H), 3.85 (t, J = 7.0Hz, 2H), 4.24 (q, J = 7.0Hz,
2H), 4.51 (t, J = 8.5Hz, 2H), 5.09 (s, 2H), 6.99 (s, 1H), 7.1
8 (dd, J = 5.0,8.0Hz, 1H), 7.42 (dt, J = 1.5,8.0Hz, 1H), 7.4
7 (s, 1H), 8.38 (d, J = 1.5Hz, 1H), 8.41 (dd, J = 1.5,5.0Hz, 1
H) Example 15 (E) -3- [2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -4-methyl-7-benzofurani
] -2- [5- (3-pyridyl) pentyl] acrylic
Ethyl acid

[0114]

[Chemical 46]

The title compound was obtained in the same manner as in Example 4. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm; 1.19 to 1.27 (m,
2H), 1.31 (t, J = 8Hz, 3H), 1.42 ~ 1.60 (m, 4H), 2.21 (s, 3
H), 2.30 (t, J = 7.5Hz, 2H), 2.54 (t, J = 7.5Hz, 2H), 3.08
(t, J = 8.5Hz, 2H), 3.58 (s, 3H), 3.70 (s, 3H), 4.24 (q, J = 7.
5Hz, 2H), 4.51 (t, J = 8.5Hz, 2H), 5.00 (s, 2H), 7.17 (dd, J =
5.0,8.0Hz, 1H), 7.43 (dt, J = 1.5,8.0Hz, 1H), 7.44 (s, 1H),
8.39 (dd, J = 1.5,5.0Hz, 1H), 8.41 (d, J = 1.5Hz, 1H) Example 16 (E) -3- [2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -4-methyl-7-benzofurani
] -2- [6- (3-pyridyl) hexyl] acryl
Ethyl acid

[0116]

[Chemical 47]

2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -4-methyl-benzofuran-7
-Carbaldehyde and 2-diethylphosphono-8- (3-
The title compound was obtained by reacting with pyridyl) ethyl octylate according to the method of Example 4.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.23 to 1.29 (m, 4H), 1.33 (t, J = 7.0Hz, 3H), 1.37 to 1.48
(m, 2H), 1.49 to 1.58 (m, 2H), 2.23 (s, 3H), 2.29 (t, J = 7.0H
z, 2H), 2.55 (t, J = 7.0Hz, 2H), 3.09 (t, J = 8.5Hz, 2H), 3.60
(s, 3H), 3.71 (s, 3H), 4.24 (q, J = 7.0Hz, 2H), 4.54 (t, J = 8.
5Hz, 2H), 5.02 (s, 2H), 7.18 (dd, J = 5.0,8.0Hz, 1H), 7.43
(s, 1H), 7.45 (dt, J = 1.5,8.0Hz, 1H), 8.39 to 8.44 (m, 2H) Example 17 4-{[3,4-dihydro-6- (methoxymethoxy)
-7-[(E) -2- (3-pyridyl) -1-vinyl]
-2H-1-benzopyran-5-yl] oxy} butyric acid

[0119]

[Chemical 48]

970 mg of 3-pyridylmethyltriphenylphosphonium chloride hydrochloride was suspended in 20 ml of N, N-dimethylformamide, and 60% sodium hydride under ice cooling.
180 mg was added. 4-{[7-formyl-3,4-
Ethyl dihydro-6- (methoxymethoxy) -2H-1-benzopyran-5-yl] oxy} butyrate 400 mg
Was added at room temperature and stirred for 1 hour and a half. Ice water was added to the reaction mixture, the pH was adjusted to 6 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (560 mg) as a brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.93 (tt, J = 7.0,7.0Hz, 2H), 2.05 (t, J = 7.5Hz, 2H), 2.51
(t, J = 7.5Hz, 2H), 2.71 (t, J = 7.0Hz, 2H), 3.48 (s, 3H), 4.0
0 (t, J = 7.5Hz, 2H), 4.05 (t, J = 7.0Hz, 2H), 4.96 (s, 2H), 6.
35 (s, 1H), 6.55 (d, J = 13.0Hz, 1H), 6.76 (d, J = 13.0Hz, 1H),
7.20 (dd, J = 5.0,8.0Hz, 1H), 7.59 (dt, J = 1.5,8.0Hz, 1H),
8.38 (dd, J = 1.5,5.0Hz, 1H), 8.44 (d, J = 1.5Hz, 1H) Example 18 (E) -3- (3,4-dihydro-6-hydroxy-2)
H-1-benzopyran-7-yl) -2- [5- (3-
Pyridyl) pentyl] acrylic acid

[0122]

[Chemical 49]

(1) (E) -3- (3,4-dihydro-6)
-(Methoxymethoxy) -2H-1-benzopyran-7
Ethyl (2-yl) -2- [5- (3-pyridyl) pentyl] acrylate (900 mg) was dissolved in ethanol (50 ml), 5 M aqueous sodium hydroxide solution (2 ml) was added, and the mixture was heated under reflux for 1 hr. The reaction mixture was adjusted to pH 6 with 2M hydrochloric acid under ice cooling and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

(2) The residue obtained in (1) was dissolved in 30 ml of acetone, 1.5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 3 hours.
Add 10 ml of water, add saturated aqueous sodium hydrogen carbonate solution,
The pH was set to 6. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Chloroform-isopropyl ether was added to the residue for crystallization to give 360 mg of the title compound.
Was obtained as pale yellow crystals.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.39 (tt, J = 7.5,7.5Hz, 2H), 1.59 (tt, J = 7.5,7.5Hz, 2H),
1.61 (tt, J = 7.5,7.5Hz, 2H), 1.95 (tt, J = 6.0,6.0Hz, 2H),
2.48 (t, J = 7.5Hz, 2H), 2.59 (t, J = 7.5Hz, 2H), 2.72 (t, J =
6.0Hz, 2H), 4.10 (t, J = 6.0Hz, 2H), 6.59 (s, 1H), 6.68 (s, 1
H), 7.21 (dd, J = 5.5,8.0Hz, 1H), 7.50 (dt, J = 1.5,8.0Hz, 1
H), 7.91 (s, 1H), 8.41 (bs, 2H) Example 19 4-{[2,3-dihydro-5-hydroxy-4- (3
-Pyridylmethyl) -benzofuran-6-yl] oxy
Si} butyric acid

[0126]

[Chemical 50]

2,3-dihydro-prepared in Example 2
6-hydroxy-5- (methoxymethoxy) -4- (3
-Pyridylmethyl) benzofuran from 600 mg of the title compound 28 in the same manner as in Example 3 and then in Example 18 (1) (2).
0 mg was obtained as white crystals.

Melting point: 134 to 136 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm; 1.90 (tt, J =
7.0,7.0Hz, 2H), 2.42 (t, J = 7.0Hz, 2H), 2.97 (t, J = 8.5Hz,
2H), 3.85 (s, 2H), 3.90 (t, J = 7.0Hz, 2H), 4.40 (t, J = 8.5H
z, 2H), 6.35 (s, 1H), 7.25 (dd, J = 5.0,8.0Hz, 1H), 7.54 (d
t, J = 1.5,8.0Hz, 1H), 8.35 (dd, J = 1.5,5.0Hz, 1H), 8.44 (d,
J = 1.5 Hz, 1H) Example 20 (E) -3- [3,4-dihydro-6- (methoxymeth)
Xy) -5- (3-pyridylmethyl) -2H-1-ben
Zopyran-7-yl] ethyl acrylate

[0129]

[Chemical 51]

As in Example 4, using 3,4-dihydro-6- (methoxymethoxy) -5- (3-pyridylmethyl) -2H-1-benzopyran-7-carbaldehyde and ethyl diethylphosphonoate. The title compound was obtained by performing a Wittig-Horner reaction.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.32 (t, J = 7.0Hz, 3H), 1.91 (tt, J = 7.0,7.0Hz, 2H), 2.52
(t, J = 7.0Hz, 2H), 3.50 (s, 3H), 4.04 (s, 2H), 4.06 (t, J = 7.
0Hz, 2H), 4.23 (q, J = 7.0Hz, 2H), 4.85 (s, 2H), 6.36 (d, J = 1
5.0Hz, 1H), 6.97 (s, 1H), 7.15 (dd, J = 5.0,8.0Hz, 1H), 7.3
5 (dt, J = 1.5,8.0Hz, 1H), 7.92 (d, J = 15.0Hz, 1H), 8.39 (dd,
J = 1.5,5.0Hz, 1H), 8.43 (d, J = 1.5Hz, 1H) Example 21 (E) -3- [3,4-dihydro-6-hydroxy-8]
-Methyl-5- (3-pyridylmethyl) -2H-1-be
Nzopyran-7-yl] acrylic acid

[0132]

[Chemical 52]

3,4-Dihydro-6- (methoxymethoxy) -8-methyl-5- (3-pyridylmethyl) -2H
1.0 g of the title compound was obtained as yellow crystals in the same manner as in Example 20 and Example 18 using 900 mg of -1-benzopyran-7-carbaldehyde.

Melting point: 198 to 200 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm; 1.80 (tt, J =
7.0,7.0Hz, 2H), 2.11 (s, 3H), 2.52 (t, J = 7.0Hz, 2H), 3.96
(s, 2H), 3.98 (t, J = 7.0Hz, 2H), 6.34 (d, J = 15.0Hz, 1H), 7.
23 (dd, J = 5.0,8.0Hz, 1H), 7.41 (dt, J = 1.5,8.0Hz, 1H), 7.7
4 (d, J = 15.0Hz, 1H), 8.31 (dd, J = 1.5,5.0Hz, 1H), 8.36 (d, J
= 1.5 Hz, 1H) Example 22 3- [3,4-dihydro-6-hydroxy-8-methyl
-5- (3-pyridylmethyl) -2H-1-benzopyra
N-7-yl] propionic acid

[0135]

[Chemical 53]

500 mg of the compound obtained in Example 21 was dissolved in 200 ml of ethanol, 150 mg of 10% palladium carbon (50% water-containing product) was added, and hydrogenation was carried out at room temperature and atmospheric pressure for 2 hours.
The palladium carbon was filtered off using Celite, and the solvent was evaporated under reduced pressure. The precipitated crystals were washed with ethanol to give the title compound (200 mg) as white crystals.

Melting point: 190 to 191 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm; 1.78 (tt, J =
7.0,7.0Hz, 2H), 2.02 (s, 3H), 2.35 (t, J = 7.5Hz, 2H), 2.47
(t, J = 7.5Hz, 2H), 2.82 (t, J = 7.5Hz, 2H), 3.92 (s, 2H), 3.9
6 (t, J = 7.0Hz, 2H), 7.22 (dd, J = 5.0,8.0Hz, 1H), 7.41 (dt, J
= 1.5,8.0Hz, 1H), 8.32 (dd, J = 1.5,5.0Hz, 1H), 8.35 (d, J =
1.5 Hz, 1H) Example 23 (E) -3- [3,4-dihydro-6- (methoxymeth)
Xy) -7-methyl-5- (3-pyridylmethyl) -2
H-1-benzopyran-8-yl] ethyl acrylate

[0138]

[Chemical 54]

By a method similar to that in Example 20, the title compound was obtained.・¹ H-NMR (400MHz, CDCl ₃ ) δ ppm; 1.32 (t, J = 7.0H
z, 3H), 1.91 (tt, J = 7.0,7.0Hz, 2H), 2.38 (s, 3H), 2.53 (t,
J = 7.0Hz, 2H), 3.48 (s, 3H), 4.06 (s, 2H), 4.24 (q, J = 7.0H
z, 2H), 4.85 (s, 2H), 6.59 (d, J = 15.0Hz, 1H), 7.16 (dd, J =
5.0,8.0Hz, 1H), 7.36 (dt, J = 1.5,8.0Hz, 1H), 7.87 (d, J = 1
5.0Hz, 1H), 8.41 (dd, J = 1.5,5.0Hz, 1H), 8.45 (d, J = 1.5Hz,
1H) Example 24 3- [3,4-dihydro-6-hydroxy-5- (3-
Pyridylmethoxy) -2H-1-benzopyran-7-i
] Acrylic acid

[0140]

[Chemical 55]

By a method similar to that in Example 18 and Example 20, from 150 mg of 3,4-dihydro-6- (methoxymethoxy) -5- (3-pyridylmethoxy) -2H-1-benzopyran-7-carbaldehyde. 130 mg of the compound was obtained as pale yellow crystals.

Melting point: 228 to 230 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm; 1.80 (tt, J =
7.0,7.0Hz, 2H), 2.61 (t, J = 7.0Hz, 2H), 4.00 (t, J = 7.0Hz,
2H), 4.91 (s, 2H), 6.41 (d, J = 15.0Hz, 1H), 6.80 (s, 1H), 7.
41 (dd, J = 5.0,8.0Hz, 1H), 7.79 (d, J = 15.0Hz, 1H), 7.90 (d
t, J = 1.5,8.0Hz, 1H), 8.53 (dd, J = 1.5,5.0Hz, 1H), 8.66 (d,
J = 1.5 Hz, 1H), 8.96 (bs, 1H) Example 25 (E) -3- (2,3-dihydro-5-hydroxy-6)
-Benzofuranyl) -2- [5- (3-pyridyl) pen
Chill] acrylic acid

[0143]

[Chemical 56]

(E) -3- [2,3-dihydro-5-
(Methoxymethoxy) -6-benzofuranyl] -2-
[5- (3-pyridyl) pentyl] ethyl acrylate
From 1.0 g of the title compound by the same method as in Example 18.
270 mg were obtained as yellow crystals.

Melting point: 205 to 206 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm; 1.22 to 1.32
(m, 2H), 1.42 to 1.58 (m, 4H), 2.34 (t, J = 7.5Hz, 2H), 2.53
(t, J = 7.5Hz, 2H), 3.09 (t, J = 8.5Hz, 2H), 4.41 (t, J = 8.5H
z, 2H), 6.56 (s, 1H), 6.78 (s, 1H), 7.26 (dd, J = 5.0,8.0Hz,
1H), 7.56 (dt, J = 1.5,8.0Hz, 1H), 7.64 (s, 1H), 8.35 (dd, J
= 1.5,5.0Hz, 1H), 8.36 (d, J = 1.5Hz, 1H), 9.29 (bs, 1H) Example 26 (E) -3- (3,4-dihydro-6-hydroxy-5)
-Methoxy-2H-1-benzopyran-7-yl) -2
-[5- (3-Pyridyl) pentyl] acrylic acid

[0146]

[Chemical 57]

(E) -3- [3,4-dihydro-6-
140 mg of the title compound was obtained from 420 mg of ethyl (methoxymethoxy) -5-methoxy-2H-1-benzopyran-7-yl] -2- [5- (3-pyridyl) pentyl] acrylate by the same method as in Example 18. Obtained as yellow crystals.

Melting point: 168 to 170 ° C. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) δ ppm; 1.40
(tt, J = 7.5,7.5Hz, 2H), 1.54 to 1.65 (m, 4H), 1.96 (tt, J = 7.
0,7.0Hz, 2H), 2.47 (t, J = 7.5Hz, 2H), 2.58 (t, J = 7.5Hz, 2
H), 2.77 (t, J = 7.0Hz, 2H), 3.78 (s, 3H), 4.09 (t, J = 7.0Hz,
2H), 6.53 (s, 1H), 7.20 (dd, J = 5.5,8.0Hz, 1H), 7.49 (dt, J
= 1.5,8.0Hz, 1H), 7.79 (s, 1H), 8.40 (bs, 2H) Example 27 (E) -3- (2,3-dihydro-5-hydroxy-4)
-Methoxy-6-benzofuranyl) -2- [5- (3-
Pyridyl) pentyl] acrylic acid

[0149]

[Chemical 58]

(E) -3- [2,3-dihydro-5-
From 1.0 g of ethyl (methoxymethoxy) -4-methoxy-6-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate, 230 mg of the title compound was obtained as slightly yellow crystals in the same manner as in Example 18. It was

Melting point: 157 to 159 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm; 1.26 (tt, J =
7.5,7.5Hz, 2H), 1.45 (tt, J = 7.5,7.5Hz, 2H), 1.51 (tt, J =
7.5,7.5Hz, 2H), 2.35 (t, J = 7.5Hz, 2H), 1.53 (t, J = 7.5Hz, 2
H), 3.27 (t, J = 8.5Hz, 2H), 3.78 (s, 3H), 4.44 (t, J = 8.5Hz,
2H), 6.31 (s, 1H), 7.26 (dd, J = 5.0,8.0Hz, 1H), 7.56 (dt, J
= 1.5,8.0Hz, 1H), 7.63 (s, 1H), 8.36 (bs, 1H), 8.48 (bs, 1
H) Example 28 (E) -3- (2,3-dihydro-5-hydroxy-4)
-Methyl-6-benzofuranyl) -2- [5- (3-pi
Lysyl) pentyl] acrylic acid

[0152]

[Chemical 59]

(E) -3- [2,3-dihydro-5-
100 mg of the title compound was obtained as a brown oil from 500 mg of ethyl (methoxymethoxy) -4-methyl-6-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate by the same method as in Example 18. ..

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.31 (tt, J = 7.0,7.0Hz, 2H), 1.50 ~ 1.65 (m, 4H), 2.18 (s,
3H), 2.46 (t, J = 7.0Hz, 2H), 2.59 (t, J = 7.0Hz, 2H), 3.14
(t, J = 8.5Hz, 2H), 4.56 (t, J = 8.5Hz, 2H), 6.48 (s, 1H), 7.2
0 ~ 7.28 (m, 1H), 7.53 (bd, J = 8.0Hz, 1H), 7.74 (s, 1H), 8.3
8 to 8.45 (m, 2H) Example 29 (E) -3- (2,3-dihydro-5-hydroxy-4)
-Methoxy-7-methyl-6-benzofuranyl) -2-
[5- (3-pyridyl) pentyl] ethyl acrylate

[0155]

[Chemical 60]

(E) -3- [2,3-dihydro-5-
(Methoxymethoxy) -4-methoxy-7-methyl-6
-Benzofuranyl] -2- [5- (3-pyridyl) pentyl] ethyl acrylate (200 mg) to (18) of Example 18
By a method similar to the above, 140 mg of the title compound was obtained as a brown oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.26 (tt, J = 7.5,7.5Hz, 2H), 1.34 (t, J = 7.5Hz, 3H), 1.40
~ 1.49 (m, 4H), 1.99 (s, 3H), 2.21 (t, J = 7.5Hz, 2H), 2.47
(t, J = 7.5Hz, 2H), 3.33 (t, J = 8.5Hz, 2H), 3.88 (s, 3H), 4.2
6 (q, J = 7.5Hz, 2H), 4.52 (t, J = 8.5Hz, 2H), 7.17 (dd, J = 5.0,
8.0Hz, 1H), 7.40 (dt, J = 1.5,8.0Hz, 1H), 7.42 (s, 1H), 8.3
5 (d, J = 1.5Hz, 1H), 8.34 (dd, J = 1.5,5.0Hz, 1H) Example 30 (E) -3- (2,3-dihydro-5-hydroxy-4)
-Methoxy-7-methyl-6-benzofuranyl) -2-
[5- (3-pyridyl) pentyl] acrylic acid

[0158]

[Chemical formula 61]

(E) -3- [2,3-dihydro-5-
(Methoxymethoxy) -4-methoxy-7-methyl-6
350 mg of the title compound was obtained as a brown oil from 500 mg of ethyl-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate by the same method as in Example 18.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.20 ~ 1.28 (m, 2H), 1.40 ~ 1.50 (m, 4H), 2.00 (s, 3H), 2.2
4 (t, J = 7.5Hz, 2H), 2.49 (t, J = 7.5Hz, 2H), 3.29 (t, J = 8.5H
z, 2H), 3.84 (s, 3H), 4.49 (t, J = 8.5Hz, 2H), 7.24 (bs, 1H),
7.48 (d, J = 8.0Hz, 1H), 7.52 (s, 1H), 8.45 (bs, 2H) Example 31 (E) -3- [2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -7-benzofuranyl] -2-
[5- (3-pyridyl) pentyl] acrylic acid

[0161]

[Chemical formula 62]

From 1.1 g of ethyl (E) -3- [2,3-dihydro-6-methoxy-5- (methoxymethoxy) -7-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate. By a method similar to that of Example 18, (1), 1.0 g of the title compound was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.24 to 1.33 (m, 2H), 1.49 to 1.60 (m, 4H), 2.33 (t, J = 7.5H
z, 2H), 2.55 (t, J = 7.5Hz, 2H), 3.16 (t, J = 8.5Hz, 2H), 3.53
(s, 3H), 3.75 (s, 3H), 4.52 (t, J = 8.5Hz, 2H), 5.12 (s, 2H),
7.02 (s, 1H), 7.21 (dd, J = 5.0,8.0Hz, 1H), 7.48 (dt, J = 1.
5,8.0Hz, 1H), 7.57 (s, 1H), 8.43 (dd, J = 1.5,5.0Hz, 1H),
8.44 (d, J = 1.5Hz, 1H) Example 32 (E) -3- (2,3-dihydro-5-hydroxy-6)
-Methoxy-7-benzofuranyl) -2- [5- (3-
Pyridyl) pentyl] acrylic acid

[0164]

[Chemical 63]

(E) -3- [2,3-dihydro-5-
800 mg of the title compound was obtained as milk-white crystals from 1.0 g of (methoxymethoxy) -6-methoxy-7-benzofuranyl) -2- [5- (3-pyridyl) pentyl] acrylic acid in the same manner as in Example 18, (2). Got as.

Melting point: 115 to 117 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm; 1.19 to 1.27 (m,
2H), 1.49 ~ 1.59 (m, 4H), 2.35 (t, J = 7.5Hz, 2H), 2.56 (t, J
= 7.5Hz, 2H), 3.14 (t, J = 8.5Hz, 2H), 3.72 (s, 3H), 4.50 (t,
J = 8.5Hz, 2H), 6.83 (s, 1H), 7.23 (dd, J = 5.0,8.0Hz, 1H),
7.49 (dt, J = 1.5,8.0Hz, 1H), 7.59 (s, 1H), 8.43 (dd, J = 1.
5,5.0Hz, 1H), 8.45 (d, J = 1.5Hz, 1H) Example 33 (Z) -3- (2,3-dihydro-5-hydroxy-6)
-Methoxy-7-benzofuranyl) -2- [5- (3-
Pyridyl) pentyl] acrylic acid

[0167]

[Chemical 64]

(Z) -3- [2,3-dihydro-5-
The title compound was obtained as white crystals from ethyl (methoxymethoxy) -6-methoxy-7-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate by the same method as in Example 18.

Melting point: 150 to 151 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm; 1.42 to 1.44 (m,
2H), 1.60 to 1.70 (m, 4H), 2.48 (t, J = 7.5Hz, 2H), 2.63 (t, J
= 7.5Hz, 2H), 3.09 (t, J = 8.5Hz, 2H), 3.68 (s, 3H), 4.47 (t,
J = 8.5Hz, 2H), 6.58 (s, 1H), 6.75 (s, 1H), 7.24 (dd, J = 5.0,
8.0Hz, 1H), 7.55 (bd, J = 8.0Hz), 8.42 (dd, J = 1.5,5.0Hz, 1
H), 8.45 (d, J = 1.5Hz, 1H) Example 34 (E) -3- (6-ethoxy-2,3-dihydro-5-
Hydroxy-7-benzofuranyl) -2- [5- (3-
Pyridyl) pentyl] acrylic acid

[0170]

[Chemical 65]

From 6.5 g of ethyl (E) -3- [6-ethoxy-2,3-dihydro-5- (methoxymethoxy) -7-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate. By a method similar to that in Example 18, 1.7 g of the title compound was obtained as a yellow amorphous substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.23 to 1.33 (m, 5H), 1.49 to 1.56 (m, 4H), 2.36 (t, J = 7.0H
z, 2H), 2.55 (t, J = 7.0Hz, 2H), 3.13 (t, J = 8.5Hz, 2H), 3.92
(q, J = 7.0Hz, 2H), 4.50 (t, J = 8.5Hz, 2H), 6.83 (s, 1H), 7.2
5 (dd, J = 5.0,8.0Hz, 1H), 7.49 (bd, J = 8.0Hz, 1H), 7.60 (s, 1
H), 8.43 to 8.45 (m, 2H) Example 35 (E) -3- (2,3-dihydro-5-hydroxy-6)
-Propoxy-7-benzofuranyl) -2- [5- (3
-Pyridyl) pentyl] acrylic acid

[0173]

[Chemical 66]

(E) -3- [2,3-dihydro-5-
From 7.1 g of ethyl (methoxymethoxy) -6-propoxy-7-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate, 1.5 g of the title compound was obtained as a yellow oil in the same manner as in Example 18. Obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
0.98 (t, J = 7.5Hz, 3H), 1.23〜1.27 (m, 2H), 1.50〜1.55
(m, 4H), 1.72 (tt, J = 7.5,7.5Hz, 2H), 2.37 (t, J = 7.5Hz, 2
H), 2.55 (t, J = 7.5Hz, 2H), 3.13 (t, J = 8.5Hz, 2H), 3.80 (t,
J = 7.5Hz, 2H), 4.50 (t, J = 8.5Hz, 2H), 6.82 (s, 1H), 7.24 (d
d, J = 5.0,8.0Hz, 1H), 7.50 (bd, J = 8.0Hz, 1H), 7.61 (s, 1H),
8.43-8.45 (m, 2H) Example 36 (E) -3- (6-heptyloxy-2,3-dihydro
-5-Hydroxy-7-benzofuranyl) -2- [5-
(3-Pyridyl) pentyl] acrylic acid

[0176]

[Chemical 67]

(E) -3- [6-heptyloxy-2,
1.1 g of the title compound was obtained as a yellow oil from 1.5 g of ethyl 3-dihydro-5- (methoxymethoxy) -7-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate by the same method as in Example 18. I got it as a thing.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
0.86 (t, J = 7.0Hz, 3H), 1.20〜1.42 (m, 10H), 1.46〜1.58
(m, 4H), 1.69 (tt, J = 7.5,7.5Hz, 2H), 2.36 (t, J = 7.5Hz, 2
H), 2.55 (t, J = 7.5Hz, 2H), 3.13 (t, J = 8.5Hz, 2H), 3.83 (t,
J = 7.0Hz, 2H), 4.49 (t, J = 8.5Hz, 2H), 6.83 (s, 1H), 7.22 (d
d, J = 5.0,8.0Hz, 1H), 7.48 (dt, J = 1.5,8.0Hz, 1H), 7.60 (s,
1H), 8.43 (dd, J = 1.5,5.0Hz, 1H), 8.45 (d, J = 1.5Hz, 1H) Example 37 (E) -3- [2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -4-methyl-7-benzofurani
] -2- [5- (3-pyridyl) pentyl] acrylic
acid

[0179]

[Chemical 68]

(E) -3- [2,3-Dihydro-6-methoxy-5- (methoxymethoxy) -4-methyl-7-
The title compound was obtained from ethyl benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate by the same method as in Example 18, (1).

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.24 to 1.33 (m, 2H), 1.45 to 1.65 (m, 4H), 2.23 (s, 3H), 2.3
3 (t, J = 7.5Hz, 2H), 2.56 (t, J = 7.5Hz, 2H), 3.09 (t, J = 8.5H
z, 2H), 3.59 (s, 3H), 3.71 (s, 3H), 4.54 (t, J = 8.5Hz, 2H),
5.01 (s, 2H), 7.23 (bs, 1H), 7.48 (d, J = 9.0Hz, 1H), 7.57
(s, 1H), 8.45 (bs, 2H) Example 38 (E) -3- (2,3-dihydro-5-hydroxy-6)
-Methoxy-4-methyl-7-benzofuranyl) -2-
[5- (3-pyridyl) pentyl] acrylic acid

[0182]

[Chemical 69]

(E) -3- [2,3-dihydro-5-
(Methoxymethoxy) -6-methoxy-4-methyl-7
The title compound was obtained from -benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylic acid in the same manner as in Example 18, (2).

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.21 to 1.31 (m, 2H), 1.44 to 1.64 (m, 4H), 2.19 (s, 3H), 2.3
7 (t, J = 7.5Hz, 2H), 2.56 (t, J = 7.5Hz, 2H), 3.09 (t, J = 7.5H
z, 2H), 3.70 (s, 3H), 4.51 (t, J = 8.5Hz, 2H), 7.22 (dd, J = 5.
0,7.5Hz, 1H), 7.48 (bd, J = 7.5Hz, 1H), 7.60 (s, 1H), 8.42
~ 8.46 (m, 2H) Example 39 (E) -3- (2,3-dihydro-5-hydroxy-6)
-Methoxy-4-methyl-7-benzofuranyl) -2-
[5- (3-pyridyl) hexyl] acrylic acid

[0185]

[Chemical 70]

(E) -3- [2,3-dihydro-5-
(Methoxymethoxy) -6-methoxy-4-methyl-7
In the same manner as in Example 18, the title compound (410 mg) was obtained as yellow crystals from 1.5 g of ethyl -benzofuranyl] -2- [5- (3-pyridyl) hexyl] acrylate.

Melting point: 145 to 146 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm; 1.23 to 1.29 (m,
4H), 1.43 to 1.60 (m, 4H), 2.20 (s, 3H), 2.36 (t, J = 7.0Hz, 2
H), 2.57 (t, J = 7.0Hz, 2H), 3.10 (t, J = 8.5Hz, 2H), 3.69 (s,
3H), 4.52 (t, J = 8.5Hz, 2H), 7.24 (dd, J = 5.0,8.0Hz, 1H),
7.50 (dt, J = 1.5,8.0Hz, 1H), 7.59 (s, 1H), 8.44 ~ 8.46 (m,
2H) Example 40 4-{[3,4-dihydro-6- (methoxymethoxy)
-5- (3-pyridylmethyl) -2H-1-benzopyra
N-7-yl] oxy} butyric acid

[0188]

[Chemical 71]

Ethyl 4-{[3,4-dihydro-6- (methoxymethoxy) -5- (3-pyridylmethyl) -2H-1-benzopyran-7-yl] oxy} butyrate prepared in Example 3 From 1.4 g, 860 mg of the title compound was obtained as white crystals by a method similar to that in Example 18, (1).

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.89 (tt, J = 7.0,7.0Hz, 2H), 2.16 (tt, J = 7.5,7.5Hz, 2H),
2.41 (t, J = 7.5Hz, 2H), 2.57 (t, J = 7.0Hz, 2H), 3.44 (s, 3
H), 4.00 ~ 4.05 (m, 4H), 4.08 (s, 2H), 5.01 (s, 2H), 6.37
(s, 1H), 7.24 (bs, 1H), 7.5 (bd, J = 8.0Hz, 1H), 8.45 (bs, 2
H) Example 41 4-{[3,4-dihydro-6-hydroxy-5- (3
-Pyridylmethyl) -2H-1-benzopyran-7-i
[Oxy] butyric acid

[0191]

[Chemical 72]

4-{[3,4-dihydro-6- (methoxymethoxy) -5- (3-pyridylmethyl) -2H-1
From 860 mg of -benzopyran-7-yl] oxy} butyric acid,
320 mg of the title compound was prepared in the same manner as in Example 18, (2)
Was obtained as white crystals.

Melting point: 140 to 142 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm; 1.80 (tt, J =
7.0,7.0Hz, 2H), 1.91 (tt, J = 7.5,7.5Hz, 2H), 2.41 ~ 2.53
(m, 4H), 3.89 ~ 3.93 (m, 6H), 6.28 (s, 1H), 7.20 ~ 7.28
(m, 1H), 7.46 (bd, J = 8.0Hz, 1H), 8.28 to 8.44 (m, 2H) Example 42 (E) -3- [3,4-dihydro-6- (methoxymeth)
Xy) -5- (3-pyridylmethyl) -2H-1-ben
Zopyran-7-yl] acrylic acid

[0194]

[Chemical 73]

(E) -3- [3,4-dihydro-6-
(Methoxymethoxy) -5- (3-pyridylmethyl)-
2H-1-benzopyran-7-yl] ethyl acrylate
From 1.0 g, the title compound (900 mg) was obtained as white crystals by a method similar to that in Example 18 (1).

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.94 (tt, J = 7.0,7.0Hz, 2H), 2.55 (t, J = 7.0Hz, 2H), 3.52
(s, 3H), 4.09 (t, J = 7.0Hz, 2H), 4.09 (s, 2H), 4.89 (s, 2H),
6.41 (d, J = 15.0Hz, 1H), 7.03 (s, 1H), 7.22 (dd, J = 5.0,8.0
Hz, 1H), 7.42 (dt, J = 1.5,8.0Hz, 1H), 8.02 (d, J = 15.0Hz, 1
H), 8.45 (dd, J = 1.5,5.0Hz, 1H), 8.49 (d, J = 1.5Hz, 1H) Example 43 (E) -3- [3,4-dihydro-6-hydroxy-5
-(3-Pyridylmethyl) -2H-1-benzopyran-
7-yl] acrylic acid

[0197]

[Chemical 74]

(E) -3- [3,4-dihydro-6-
(Methoxymethoxy) -5- (3-pyridylmethyl)-
2H-1-benzopyran-7-yl] acrylic acid,
The title compound was obtained as white crystals by a method similar to that in Example 18, (2).

Melting point: 195 to 197 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm; 1.82 (tt, J =
7.0,7.0Hz, 2H), 2.54 (t, J = 7.0Hz, 2H), 3.95 (t, J = 7.0Hz, 2
H), 3.98 (s, 2H), 6.36 (d, J = 15.0Hz, 1H), 6.96 (s, 1H), 7.
25 (dd, J = 5.0,8.0Hz, 1H), 7.43 (dt, J = 1.5,8.0Hz, 1H), 7.9
0 (d, J = 15.0Hz, 1H), 8.34 (dd, J = 1.5,5.0Hz, 1H), 8.37 (d,
J = 1.5 Hz, 1H), 8.73 (bs, 1H) Example 44 (E) -3- [3,4-dihydro-6-hydroxy-7
-Methyl-5- (3-pyridylmethyl) -2H-1-be
Nzopyran-8-yl] acrylic acid

[0200]

[Chemical 75]

(E) -3- [3,4-dihydro-6-
In the same manner as in Example 18, from 200 g of ethyl (methoxymethoxy) -7-methyl-5- (3-pyridylmethyl) -2H-1-benzopyran-8-yl] acrylate, 200 mg of the title compound was obtained as white crystals. Obtained.

Melting point: 259 to 261 ° C. ¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) δ ppm; 1.95
(tt, J = 7.0,7.0Hz, 2H), 2.33 (s, 3H), 2.60 (t, J = 7.0Hz, 2
H), 4.06 (s, 2H), 4.11 (t, J = 7.0Hz, 2H), 6.50 (d, J = 15.0H
z, 1H), 7.18 (dd, J = 5.0,8.0Hz, 1H), 7.45 (dt, J = 1.5,8.0H
z, 1H), 7.86 (d, J = 15.0Hz, 1H), 8.37 (dd, J = 1.5,5.0Hz, 1
H), 8.45 (d, J = 1.5Hz, 1H) Example 45 4-{[3,4-dihydro-6-hydroxy-7-
[(E) -2- (3-pyridyl) -1-vinyl] -2H
-1-Benzopyran-5-yl] oxy} butyric acid

[0203]

[Chemical 76]

4-{[3,4-dihydro-6- (methoxymethoxy) -7-[(E) -2- (3-pyridyl)-]
260 mg of the title compound was obtained as a yellow amorphous phenotype from 560 mg of ethyl 1-vinyl] -2H-1-benzopyran-5-yl] oxy} butyrate in the same manner as in Example 18.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm;
1.94 (tt, J = 7.0, 7.0 Hz, 2H),
2.10 (tt, J = 7.5, 7.5 Hz, 2H),
2.54 (t, J = 7.5 Hz, 2H), 2.74
(T, J = 7.0 Hz, 2H), 3.96 (t, J =
7.5 Hz, 2 H), 4.08 (t, J = 7.0 Hz,
2H), 6.38 (s, 1H), 6.54 (d, J
= 13.0 Hz, 1H), 6.72 (d, J = 13.0)
Hz, 1H), 7.21 (dd, J = 5.0, 8.0
Hz, 1H), 7.63 (dt, J = 1.5, 8.0H
z, 1H), 8.34 (dd, J = 1.5, 5.0H
z, 1H), 8.45 (d, J = 1.5Hz, 1H)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07D 405/06 213 8829-4C 405/12 213 8829-4C // (C07D 405/06 213: 00 6701-4C 311: 00) 7729-4C (C07D 405/06 213: 00 6701-4C 307: 00) 7729-4C (C07D 405/12 213: 00 6701-4C 311: 00) 7729-4C (72) Invention Katsuya Tagami 2-20-12 Umezono Tsukuba, Ibaraki Prefecture MK Heights 203 (72) Inventor Hirotoshi Numata 3-18-7 Namiki, Tsukuba City, Ibaraki Prefecture East Avenue B201 (72) Masanobu Shinoda 4 Kasuga, Tsukuba City, Ibaraki Prefecture −19−13 Shiyama Dormitory 203 (72) Inventor Tetsuya Kawahara 2-23-5 Amakubo, Tsukuba City, Ibaraki Prefecture 304 Maison Gakuen 304 (72) Isao Yamazu 3605-669 Kashida, Ushiku City, Ibaraki

Claims (9)

[Claims] 1. A compound represented by the general formula (I): {In the formula, R ¹ , R ² and R ³ are the same or different hydrogen atom, hydroxyl group or the formula: [In the formula, A represents a hydrogen atom or a heteroarylalkyl group. B means a hydrogen atom, a carboxyl group or a protected carboxyl group. Y is the formula (In the formula, p means 0 or an integer of 1 to 6), a group represented by the formula: (Wherein q represents 0 or an integer of 1 to 6) or a group represented by the formula: Means a group represented by. ] It means the group shown by.
X means a hydroxyl group or a protected hydroxyl group. n means an integer of 2 or 3. } The chroman derivative or dihydrobenzofuran derivative shown by these, or those pharmacologically acceptable salts. 2. A 5-lipoxygenase inhibitor comprising the chroman derivative or dihydrobenzofuran derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 3. A thromboxane synthase inhibitor containing the chroman derivative or dihydrobenzofuran derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 4. The 5-lipoxygenase inhibitor according to claim 2, which is a leukotriene production inhibitor. 5. The thromboxane synthase inhibitor according to claim 3, which is a thromboxane synthase inhibitor. 6. A preventive / therapeutic agent for a disease for which a leukotriene production inhibitor containing the chroman derivative or dihydrobenzofuran derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient is effective. 7. A prophylactic / therapeutic agent for diseases for which a thromboxane synthesis inhibitor containing the chroman derivative or dihydrobenzofuran derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient is effective. 8. The preventive / therapeutic agent according to claim 6, wherein the disease for which the leukotriene production inhibitor is effective is asthma or liver disease. 9. The preventive / therapeutic agent according to claim 7, wherein the disease for which the thromboxane synthesis inhibitor is effective is asthma or liver disease.