JP3166092B2 - Coumarin derivatives and their uses - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a coumarin derivative which selectively inhibits 12-lipoxygenase and a medicament containing these compounds as an active ingredient. More specifically, the present invention relates to 12-lipoxygenase A coumarin derivative having an action of selectively inhibiting the activity of 12-lipoxygenase in the pathway, and prevention and treatment of various circulatory diseases such as arteriosclerosis and vasospasm containing the compound as an active ingredient, and certain cancers ( 12 useful as a drug for the prevention of metastasis of Lewis lung cancer, etc.
A drug that selectively inhibits lipoxygenase. In this specification, the expression of percentage means a value by weight, unless otherwise specified.

[0002]

2. Description of the Related Art The arachidonic acid cascade has a metabolic pathway called the 5-lipoxygenase pathway, and arachidonic acid is converted to 5-hydroperoxyeicosatetraenoic acid (hereinafter referred to as 5-HPET) by the action of 5-lipoxygenase.
It is known that it may be converted to E (may be described as E).

[0003] It is known that various leukotrienes are biosynthesized using this compound as an intermediate ("Prostaglandin and pathology", edited by Makoto Murota, Tokyo Kagaku Dojin,
1984), among these leukotrienes, for example, it is known that leukotriene B4 has a potent leukocyte chemotactic activity and is a mediator of inflammation, and that leukotrienes C4 and D4 are mediators of asthma. (Prostaglandin and pathology, Tokyo Kagaku Dojin, 1984).

[0004] Therefore, if there is a drug capable of effectively inhibiting 5-lipoxygenase, which is the first enzyme of the biosynthesis system of leukotrienes, various diseases caused by overproduction of leukotrienes (for example, allergic diseases, From the viewpoint that the effects of preventing and treating bronchial asthma, edema, various inflammatory diseases, etc.) can be expected, drugs having an inhibitory effect on 5-lipoxygenase have been widely searched.

On the other hand, the arachidonic acid cascade contains 12
There is a metabolic pathway called the lipoxygenase pathway. 12-lipoxygenase is an enzyme abundantly present in platelets and the like, and acts on arachidonic acid to produce 12-hydroperoxyeicosatetraenoic acid (hereinafter 12-HPETE).
This compound is reduced to 12-hydroxyeicosatetraenoic acid (hereinafter sometimes referred to as 12-HETE).

Although the physiological significance of metabolites in the 12-lipoxygenase pathway has not been clarified in comparison with that in the 5-lipoxygenase pathway, recently, its major metabolite, 12-HP
Various physiological activities of the metabolites have been elucidated mainly on ETE and 12-HETE.

The following are examples of their physiological activities. In other words, it has been pointed out that metabolites of 12-lipoxygenase may be involved in arteriosclerosis by promoting the regulation of platelet aggregation and adhesion and other functions, and the promotion of vascular smooth muscle cell migration (Hyundai Medical Co., Ltd. 21, No. 11, pp. 3109-3113, 1989), and it has been suggested that 12-HPETE may be any initiator in the occurrence of vasospasm after subarachnoid hemorrhage (modern medicine) , Volume 21, Issue 11, 3127-313
0, 1989), and furthermore, it has been shown that 12-HETE promotes adhesion and metastasis of certain cancer cells to vascular endothelial cells (Hyundai Medical, Vol. 22, extra edition, 56-5-5).
7, p. 1990). From the above facts, a substance that inhibits 12-lipoxygenase can be effectively used as a drug aimed at preventing or treating various diseases of the circulatory system such as arteriosclerosis and vasospasm, or preventing metastasis of certain cancers. It is expected to be usable.

[0008] As a substance having an inhibitory action on 12-lipoxygenase, baicalene, a kind of natural flavonoid, is known [Biochemical and Co., Ltd.].
Biophysical Research Communications (B
iochemical and BiophysicalResearch Communication
s), Vol. 105, No. 3, pp. 1090-1095, 1
982]. Other hydroxamic acid derivatives (Japanese Unexamined Patent Publication No.
JP-A-216961, JP-A-2-752, JP-A-2-196767, etc.), caffeic acid derivatives (JP-A-1-275552, JP-A-2-235852)
And the like are known.

On the other hand, with respect to coumarin derivatives, generally, the compounds are chemically synthesized or separated from the natural world,
Although it has been purified, the following 1) is known as a conventional technique that mentions the lipoxygenase inhibitory action.

1) Esculetin (6,7-dihydroxycoumarin) [Biochimica et Biophysica Acta, Vol. 753, No. 1
No. 130-132, 1983], the compound is known to be effective against 5-lipoxygenase and 12-lipoxygenase of mast cell tumor cells.
It was reported that they exhibited IC ₅₀ values of 4 × 10 ⁻⁶ M and 2.5 × 10 ⁻⁶ M, respectively.

However, as will be described later, the compound has a significantly higher IC ₅₀ value than that of the compound of the present invention, and it cannot be said that the compound has selectivity for 12-lipoxygenase. In fact, in comparative experiments performed by the present inventors, it was also found that the 12-lipoxygenase inhibitory effect of esculetin was considerably weaker than that of the compound of the present invention, and that there was no selectivity with 5-lipoxygenase inhibitory effect.

As the coumarin derivatives similar to the compounds of the present invention, for example, the following compounds 2) to 10) are known.

2) 6,7-dihydroxy-3-phenylcoumarin [Journal of the Chemical Society C. Organic Chemistry]
he Chemical Society. C. Organic Chemistry), 1st
6, 2069-2070, 1969, and Zarnal Prikladnoy Spectroscopy (Zhur
nal Prikladnoi Spektroskopii), Vol. 8, No. 6, pp. 1063-1066, 1968]

3) 7,8-dihydroxy-3-phenylcoumarin [Current Scienc
e), Vol. 35, No. 22, pp. 557-559, 19
66, Zhurnal Prikladnoi Spektroskopii, 8th
Vol. 6, No. 1063-1066, 1968,
Proceeding of the Indian Academy of Sciences Section A (Proceeding
s of the Indian Academy of Sciences. Section A),
56, 71-85, 1962, Proceedings of the Indian Academy of Sciences Section A
dian Academy of Sciences. Section A), Vol. 59,
No. 3, pages 185-189, 1964, and Journal of Organic Chemistry (Journal
of Organic Chemistry), Volume 19, 1548-15
52 pages, 1954]

4) 6,7-dihydroxy-3- (furan-2-yl) coumarin and 7,8-dihydroxy-3
-(Fran-2-yl) coumarin [Zhurnal Prikladnoi S
pektroskopii), Volume 8, Issue 6, 1063-106
6, 1968]

5) 6,7-dihydroxy-3- (3-nitrophenyl) coumarin [Journal of the Chemical Society C.A. -Organic Chemistry (Journal of the Chemical Society. C. Organic Chem)
istry), Vol. 16, pp. 2069-2070, 196
9 years]

6) 7,8-dihydroxy-4-methyl-
3- (4-nitrophenyl) coumarin [Anales de.
La Societe Scientifique Series 1 (Annales de la Societe Scientifique d
e Bruxelles. Series 1), Vol. 84, No. 3, 38
3-388, 1971]

7) 6,7-dihydroxy-4-methyl-
3-Phenylcoumarin [Pharmaco il Pavia Edizione Scientifica (Farmaco, Il
(Pavia), Edizione Scientifica), Vol. 12, 691
Pp. 694, 1957, and Atti della accademia nazionale dei Linsei Lendi Conti Classe di Sciense Fischer Matematique et Naturali (Atti della accademia naz)
ionale dei Lincei.Rendiconti, Classe di scienze f
isiche, matematiche e naturali), Vol. 10, No. 2
30-235, 1951]

8) 6,7-dihydroxy-3,4-diphenylcoumarin [Pubricazioni del Centro di Studio di Pa Sitogenetica Vegetare del Consiglio Nazionale delle
Research (Pubblicazioni delcentro di studio per la
citogenetica vegetale del consiglio nazionale del
le ricerche), No. 182, pp. 350-387, 1
955, and Atti della accademia nazionale dei Lin (Atti della accademia nazionale dei Lin)
cei. Rendiconti, Classe di scienze fisiche, matema
tiche e naturali), Volume 16, 645-649
P. 1954]

9) 6,7-dihydroxy-3- (pyridin-3-yl) coumarin [Journal of the Chemical Society C.I. -Organic Chemistry (Journal of the Chemical Society. C. Organic Chem)
istry), Vol. 16, pp. 2069-2070, 196
9 years]

10) 7,8-dihydroxy-4-phenylcoumarin (US Pat. No. 2,809,201)

However, these compounds not only have 12-lipoxygenase inhibitory activity, but also have 5-
It has never been known to have lipoxygenase inhibitory activity.

Further, although not a coumarin derivative, it is relatively similar to the compound of the present invention, and mentions 12-lipoxygenase or 5-lipoxygenase inhibitory activity. )
Compounds such as １３ to 13) are known.

11) Baicalen (5,6,7-trihydroxyflavone) [Biochemical and Biophysical Research Communications (Biochemic)
al andBiophysical Research Communications), 1st
05, No. 3, pp. 1090-095, 1982]

12) 4 ', 6,7-trihydroxyisoflavan [Prostaglandins,
Vol. 28, No. 6, pp. 783-804, 1984]

13) 4 ', 7,8-Trihydroxyisoflavan and 6,7-dihydroxy-3', 4'-dimethoxyisoflavan [International Journal of Tissue Reactions (Internatio
nal Journal of Tissue Reactions), Volume 11, Volume 3
No. 107-112, 1989]

Among them, the compound described in the above item 12) completely inhibited the production of 5-lipoxygenase metabolites in human peripheral blood leukocytes at a concentration of 10 μM, whereas the compound described in item 12) showed 12-lipoxygenase in platelets. Only 25% metabolite production at the same concentration
However, the compound is known to be 5-lipoxygenase selective (Prostaglandins, Vol. 28, No. 6, pp. 783-804, 1984). In addition, for the compound described in 13), the 5-lipoxygenase inhibitory activity of the compound in human peritoneal macrophages was 1-2 μM in terms of IC ₅₀ value, whereas the 12-lipoxygenase inhibitory activity of the compound was in IC ₅₀ value. Was reported to be 16-20 μM [International Journal of Tissue Reactions (Inte
rnational Journal of Tissue Reactions), eleventh
Vol. 3, No. 107-112, 1989].

The compound of the present invention has an IC ₅₀ as described below.
Value of 10 ^{-9 to} 10 ^-8 M order, extremely strong 12
-Has a lipoxygenase inhibitory action. On the other hand, the IC ₅₀ value for 5-lipoxygenase is 10 to 60 times greater than that for 12-lipoxygenase,
-Has a lipoxygenase-selective inhibitory action. The fact that the compound of the present invention has such an action can hardly be conceived from conventional knowledge.

[0029]

By the way, 12-lipoxygenase is a related enzyme of 5-lipoxygenase, and a substance that inhibits one of the enzymes may inhibit the other. In fact, a substance that has been reported to have 5-lipoxygenase inhibitory activity and that also exhibits 12-lipoxygenase inhibitory activity is known, and most hydroxamic acid derivatives are examples.

Regarding the selectivity of such inhibitory activity,
Although depending on the purpose of use, 12-lipoxygenase metabolites are mainly used for prevention and treatment of diseases that are considered to be caused by 12-lipoxygenase metabolites, such as the above-mentioned circulatory diseases and cancer metastasis.
-Substances which potently and selectively inhibit lipoxygenase are desirable.

Based on such a situation, the present inventors,
Paying attention to the fact that baicalene, one of the natural flavonoids, has relatively strong 12-lipoxygenase inhibitory activity and relatively high selectivity, using this compound as a lead compound, modifying its partial structure, or By carrying out the modification, a 12-lipoxygenase inhibitory compound having strong and high selectivity was successfully created, and the present invention was completed.

An object of the present invention is to provide a compound capable of inhibiting 12-lipoxygenase with high potency and high selectivity.

Another object of the present invention is to prevent and treat various circulatory diseases such as arteriosclerosis and vasospasm caused by metabolites of 12-lipoxygenase, and to prevent the metastasis of certain cancers. It is an object of the present invention to provide a medicament which is useful as a modified drug, has low toxicity, and selectively inhibits 12-lipoxygenase having few side effects.

[0034]

Means for Solving the Problems A first invention of the present invention for solving the above-mentioned problems is a general formula of the following chemical formula 9.

[0035]

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Wherein R ¹ represents a hydrogen atom or a lower alkyl group, and R ² and R ³ represent a hydrogen atom or a hydroxyl group (provided that R ² and R ³ are both hydrogen atoms at the same time) Ar) is a compound represented by the following chemical formula 10, chemical formula 11, or chemical formula 12.
General formula

[0037]

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[0038]

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[0039]

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Wherein R ⁴ represents a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group or a cyano group. A coumarin derivative represented by the formula:

According to a second aspect of the present invention which solves the above-mentioned problems, the following general formula (13)

[0042]

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Wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ² and R ³ represent a hydrogen atom or a hydroxyl group (provided that R ² and R ³ are both hydrogen atoms at the same time) Ar) is the following chemical formula 14, chemical formula 15, or chemical formula 16
General formula

[0044]

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[0045]

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[0046]

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Wherein R ⁴ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a cyano group or a nitro group. Or a mixture thereof as an active ingredient.

Next, the present invention will be described in detail. The compound of the present invention has the following general formula:

[0049]

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A coumarin derivative having at least two catechol-type hydroxyl groups at positions 6, 7, and 8 of the coumarin ring and having an aromatic substituent at the 3-position of the coumarin ring. It is a derivative and its production method is as follows.

The following general formula:

[0052]

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(In the above formula, R ³ and R ⁴ are
Ar represents a hydrogen atom or a hydroxyl group;
Or the general formula of

[0054]

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[0055]

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[0056]

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Wherein R ⁴ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a cyano group or a nitro group. The compound of the present invention represented by the following formula (hereinafter, Ar may be simply referred to as Ar) can be synthesized by the steps represented by the following chemical formulas (22) and (23).

[0058]

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[0059]

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(In the above formula, R ¹ and R ² are
Represents a hydrogen atom or an acetoxy group, and R ³ and R ⁴ represent a hydrogen atom or a hydroxyl group).

Acetyl salicylaldehyde derivative (I
I) and the desired arylacetic acid (III) are condensed under a reaction condition known as the Parkin reaction. That is, the compound (IV) can be obtained by gently heating and refluxing in acetic anhydride in the presence of a base such as triethylamine at about 120 ° C. for 1 hour to several hours (Step I).

Acetyl salicylaldehyde derivative (I
I) is the corresponding salicylaldehyde derivative (I)
It can be obtained by acetylation using an acetylating agent such as acetic anhydride or acetyl chloride. The salicylaldehyde derivative (I) is cooled on ice or at room temperature,
Acetylation in acetic anhydride in the presence of a base such as triethylamine, and the resulting acetylsalicylic aldehyde derivative (II) can be directly transferred to the above-mentioned parkin reaction conditions without isolation to directly produce compound (I).
To the compound (IV). In this case, the other raw material, aryl acetic acid (III), may be added at the time of shifting to the Parkin reaction condition, but may be coexistent from the stage of acetylation of compound (I), that is, from the beginning. . In the above reaction, an alkali metal salt of arylacetic acid or the like can be used instead of a base such as triethylamine.

The compound (IV) thus obtained can be hydrolyzed (or transesterified) under acidic conditions or basic conditions to lead to the compound (V) of the present invention. First, when deacetylation is performed under acidic conditions, the object is achieved by, for example, heating and refluxing for 30 minutes to 2 hours in a mixed solution of ethanol and hydrochloric acid (Step II).

On the other hand, when deacetylation is performed under basic conditions, a mixture of ethanol and water or the like is used as a solvent.
The reaction is carried out at room temperature for 1 to 3 hours together with a base such as sodium hydroxide or lithium hydroxide. At this time, it is considered that the coumarin ring is open, but the compound (V) can be obtained by re-closing the ring by adding hydrochloric acid or the like and subjecting it to acid treatment (step III).

The compound of the present invention represented by the above general formula (I) can also be synthesized by the steps shown in the following chemical formulas (I) and (II).

[0066]

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(In the above formula, R ⁵ and R ⁶ represent a hydrogen atom or a methoxy group.)

[0068]

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(In the above formula, R ⁵ and R ⁶ represent a hydrogen atom or a methoxy group, and R ³ and R ⁴ represent a hydrogen atom or a hydroxyl group.)

The salicylaldehyde derivative methyl ether (VI) and the desired arylacetonitrile (VI
Is condensed under a reaction condition known as the Knoevenagel reaction. That is, for example, compound (VIII) can be obtained by heating and dissolving both with ethanol or the like as a solvent, adding a catalytic amount of a base such as sodium hydroxide or piperidine and stirring the mixture (step IV). Next, the compound of the present invention is obtained by reacting the compound (VIII) with a demethylating agent such as pyridinium chloride and treating the imine (IX), which is considered to be formed in the middle, with an acid such as hydrochloric acid and hydrolyzing it. (V) can be obtained (step V).

In the case where the arylacetonitrile (VII) used in the condensation reaction has relatively high reactivity, the compound of the present invention represented by the above general formula (I) can be used.

[0072]

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(Wherein R ³ and R ^{4 each} represent a hydrogen atom or a hydroxyl group) by condensation with a salicylaldehyde derivative (I) by a Knoevenagel reaction to directly form the intermediate (IX). Through this, the compound (V) of the present invention can be obtained (Step VI).

Further, the following general formula

[0075]

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(In the above chemical formula, R ¹ represents a hydrogen atom or a lower alkyl group, and R ² and R ^{3 each} represent a hydrogen atom or a hydroxyl group.) A compound represented by the following formula: Can be synthesized.

[0077]

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(In the above formula, R ¹ represents a hydrogen atom or a lower alkyl group, and R ² and R ³ represent a hydrogen atom or a hydroxyl group.)

An aryl group is introduced at the 3-position of the coumarin derivative (X) by the arylation reaction of meavine. That is, a diazonium salt (XI) prepared from a desired aromatic amine and sodium nitrite under acidic conditions of hydrochloric acid is reacted with a coumarin derivative (X) in the presence of cupric chloride to give the compound of the present invention ( XII) can be obtained.

The compound of the present invention obtained as described above can be purified by a known purification method such as recrystallization and chromatography.

Since the compound of the present invention has a selective inhibitory action on 12-lipoxygenase activity, it inhibits the production of 12-lipoxygenase metabolites such as 12-HPETE and 12-HETE in vivo. Have
The medicament for selectively inhibiting 12-lipoxygenase of the present invention containing the compound as an active ingredient is used as a therapeutic or prophylactic for various diseases of the circulatory system such as arteriosclerosis and vasospasm caused by these metabolites. Further, it can be effectively used as a drug for preventing metastasis of certain types of cancer (such as Lewis lung cancer).

The compound of the present invention may be used as it is or as a mixture with known pharmaceutically acceptable carriers, excipients, etc., in the form of tablets, capsules, injections, granules and suppositories. Can be used as

Pharmaceuticals containing the compound of the present invention as an active ingredient include:
It can be administered orally or parenterally by injection, inhalation, application or the like.

The above-mentioned compound (12) containing the compound of the present invention as an active ingredient
-The dose of a drug that selectively inhibits lipoxygenase varies depending on the subject to be treated, symptoms, age, treatment period, etc., but is preferably about 0.1 mg to 50 m / time.
g is administered about 1 to 3 times a day.

Next, the present invention will be described in more detail with reference to test examples. Test Example 1 This test was performed to examine the 12-lipoxygenase inhibitory activity of various compounds.

1) Preparation of Enzyme Solution Under ether anesthesia, blood was collected from an abdominal aorta of a male Sprague Dawley rat using a syringe containing about 1/10 volume of 3.8% sodium citrate solution. 18
Centrifuge at 0 g for 15 minutes to separate platelet-rich plasma,
The mixture was centrifuged at 1800 g for 10 minutes, and the obtained precipitate was washed with a washing buffer (50 mM Tris-HCl buffer containing 154 mM sodium chloride and 2 mM EDTA: pH 7.4) to obtain platelets. The obtained platelets are mixed with a resuspension buffer (154 mM sodium chloride,
Suspended in 50 mM Tris-HCl buffer containing 5.5 mM glucose: pH 7.4), sonicated, and
The mixture was centrifuged at 000 g for 30 minutes, the supernatant was separated, and an enzyme solution was prepared.

2) Method for Measuring Enzyme Activity To 300 μl of the enzyme solution prepared to have an enzyme activity of about 2 mU / ml with the above resuspended buffer, add 1 μl of a 3 mM indomethacin ethanol solution and 1 μm of a 300 mM reduced glutathione solution.
After adding 3 μl of an ethanol solution of the test substance having various concentrations and the test substance at 37 ° C. for 5 minutes, 3 μl of a 2.5 mM arachidonic acid ethanol solution was added thereto, and the mixture was reacted at 37 ° C. for 5 minutes. The reaction was stopped by adding 600 μl of methanol. The reaction solution was centrifuged at 10,000 g for 5 minutes, the supernatant 12-hydroxyeicosatetraenoic acid was separated by reversed-phase high-performance liquid chromatography using a C-18 column, and the diene was quantified by absorption at 234 nm.
Enzyme activity was measured.

As the test substances, the compound of the present invention prepared by the same method as in Examples 4, 5 and 8, the compound prepared by the same method as Comparative Examples 1 to 5, and the following compounds as controls: Chemical formula of Chemical formula 29

[0089]

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A test was conducted at various concentrations using a known esculetin (manufactured by Tokyo Chemical Industry Co., Ltd.), and the concentration showing a 50% 12-lipoxygenase inhibition rate (hereinafter referred to as IC ₅₀ value) was determined from the measured value of each test substance. May be described).

3) Test results The results of this test are as shown in Table 1. Table 1 shows the compounds of Examples 4, 5, and 8 of the present invention and Comparative Examples 3 to 5.
Of 12-lipoxygenase of esculetin (manufactured by Tokyo Chemical Industry Co., Ltd.) which is a known compound for comparison
₅₀ value, and compares an IC ₅₀ value could not be determined Example 1 and 2
12-lipoxygenase inhibition rate for the compound of Example 1.

[0092]

[Table 1]

[0093] 12-lipoxygenase inhibitory effects of Example 4 and the compound prepared in the same way as in Example 8 of the present invention, each 7.6 × 10 ^-9 M and 7.0 × with IC ₅₀ values
In contrast to 10 ^-9 M, the compound prepared by the same method as that of Comparative Examples 1 and 2 showed that its compound was similar to the compound of the present invention even though its chemical structure was similar to that of the compound of the present invention.
Lipoxygenase inhibitory action is very weak or absent,
Even at a concentration of 10 ^-5 M, it showed only less than 10% inhibition.

This result indicates that the compound of the present invention has a strong 12
-It has been suggested that it is essential to have at least two catechol-type hydroxyl groups at positions 6 to 8 of the coumarin ring in order to exhibit a lipoxygenase inhibitory action. In addition, the 12-lipoxygenase inhibitory effect of esculetin, which is a known compound used for comparison and has already been reported on 12-lipoxygenase inhibitory activity, was 4.4 × 10 ⁻⁶ M in terms of IC ₅₀ value. In contrast, the 12-lipoxygenase inhibitory activity of the compounds produced by the same method as in Examples 4 and 8 of the present invention was 10 ^−9.
It shows an IC ₅₀ value on the M order and is extremely powerful.

The compound of the present invention is characterized by having an aryl group at the 3-position of the coumarin ring. In contrast,
The 12-lipoxygenase inhibitory activity of the compound prepared by the same method as in Comparative Example 3 having an aryl group at the 4-position was as follows:
Although the IC ₅₀ value is relatively strong at 2.6 × 10 ⁻⁷ M, this is not a ratio of the 12-lipoxygenase inhibitory action of the compound of the present invention.

[0096] Although not shown in Table 1, 5-lipoxygenase inhibitory action of the compounds prepared by Esculetin and Comparative Example 3 in the same manner, each 4 with an IC ₅₀ value.
It was 3 × 10 ⁻⁷ M and 6.4 × 10 ⁻⁷ M, and no selectivity was observed in the inhibitory effect on 12-lipoxygenase and 5-lipoxygenase. In contrast, the compounds of the present invention selectively inhibit 12-lipoxygenase as described below. Therefore, in order for the compound of the present invention to exert a strong 12-lipoxygenase selective inhibitory action, it is essential that the compound has an aryl group at the 3-position of the coumarin ring.

Next, as an example of a compound having an aryl group at any of the 3-position and 4-position of the coumarin ring, the compound produced by the same method as in Comparative Example 4 has an IC ₅₀ -inhibiting effect of 12 ₅₀ -lipoxygenase. The value was 1.2 × 10 ⁻⁷ M. On the other hand, in addition to the compounds produced by the same method as in Examples 4 and 8, the 12-lipoxygenase inhibitory activity of the compound of Example 5 having a methyl group at the 4-position of the coumarin ring is also 9.50 in terms of IC ₅₀ value. It showed a very strong value of 2 × 10 ⁻⁹ M. This result indicates that the compound of the present invention has potent 12
In order to exhibit a lipoxygenase inhibitory action, it is suggested that the 4-position of the coumarin ring is unsubstituted or a sterically small substituent such as a lower alkyl group is preferred.

As will be described later, the aryl group at the 3-position of the coumarin ring of the compound of the present invention is characterized in that the aryl group has a substituent having a certain height at the para-position or meta-position. Those having a tendency to show stronger 12-lipoxygenase inhibitory action than those having no substitution were observed. Among them, preferred substituents will be described later, but as shown in the example of the compound produced by the same method as in Comparative Example 5, when the para- or meta-substituent of the aryl group is a hydroxyl group, 12 The lipoxygenase inhibitory action is significantly reduced.

Test Example 2 This test was conducted to examine the selectivity of the compound of the present invention for inhibiting 12-lipoxygenase.

1) Preparation of Enzyme Solution Preparation of 5-lipoxygenase enzyme solution Rat basophil leukemia cells (Rat Basophil)
ic Leukemia Cell: RBL-1. AT
CC CRL1378) was cultured in a Dulbecco's modified Eagle's medium containing 10% newborn calf serum by a conventional method,
Washed twice with 50 mM Tris-HCl buffer (pH 7.4, hereinafter referred to as TBS) containing 4 mM sodium chloride,
The cells were suspended in the same buffer at a rate of 4 × 10 ⁷ cells / ml, the cells were disrupted by ultrasonication, centrifuged at 10,000 g for 10 minutes, and the supernatant was separated to prepare an enzyme solution. Preparation of 12-lipoxygenase enzyme solution Prepared by the same method as in Test Example 1.

2) Method for measuring enzyme activity Method for measuring 5-lipoxygenase enzyme activity To 15 μl of the enzyme solution (equivalent to 40 mU / ml) was added TBS.
185 μl, 2 mM adenosine triphosphate TBS 50 μl
1, 12 mM calcium chloride TBS 50 μl, 3 mM indomethane 1 μl, 300 mM reduced glutathione aqueous solution 1 μl and various concentrations of test substance ethanol solution 3 μl
1 and hold at 37 ° C. for 5 minutes, then add 2.5 mM
After adding 3 μl of an arachidonic acid ethanol solution and keeping the mixture at 37 ° C. for 2 minutes to react, 600 μl of methanol was added to stop the reaction. 10,000 g of the reaction solution
For 5 minutes, and the supernatant, 5-hydroxyeicosatetraenoic acid, was separated by reversed-phase high-performance liquid chromatography using a C-18 column, quantified by absorption at 234 nm, and the enzyme activity was measured.

As the test substance, Examples 1 to 30
Compounds of the present invention prepared in the same manner as in Examples 33 to 36, and as a control, the following chemical formula

[0103]

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Using known baicalene (manufactured by Wako Pure Chemical Industries, Ltd.), the test was conducted at various concentrations to determine the IC ₅₀ value.

Method for measuring 12-lipoxygenase enzyme activity: The measurement was performed in the same manner as in Test Example 1 except that the same test substance as that used for the method for measuring 5-lipoxygenase enzyme activity was used. The IC ₅₀ value was determined in the same manner as in the method for measuring the enzyme activity.

3) Test results The results of this test are as shown in Table 2. As is clear from Table 2, the compound of the present invention exhibited a very strong inhibitory effect on 12-lipoxygenase,
_{The 50} values were of the order of 10 ⁻⁹ M, which was equal to or higher than that of known baicalen. On the other hand, the compounds of the present invention can also have an inhibitory effect on 5-lipoxygenase, the IC ₅₀ values were equal to or greater than the 10-60 times than that for 12-lipoxygenase. Therefore, the compound of the present invention was found to have a selective inhibitory effect on 12-lipoxygenase.

Among the compounds of the present invention, compounds having a certain size of substituent on the aryl group at the 3-position of the coumarin ring tend to show stronger 12-lipoxygenase inhibitory action. The position of the group is desirably para-position or meta-position, and as the type of substituent, a halogen atom is a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and an alkyl group is a methyl group and an ethyl group. The group showed a particularly pronounced 12-lipoxygenase inhibitory effect.

[0108]

[Table 2]

In the following Reference Examples (Examples for producing intermediates for producing the compounds of the present invention), Comparative Examples (Examples for producing known compounds for comparison with the compounds of the present invention) and Examples, The nuclear magnetic resonance spectrum and infrared absorption spectrum of the compounds synthesized in Examples and Examples are shown in Tables 3 to 10.
Are shown together. Incidentally, a nuclear magnetic resonance spectrum ^[1 H-
NMR (500 MHz)] was measured in a heavy DMSO solvent, and the infrared absorption spectrum was measured by a KBr tablet method.

[0110]

[Table 3]

[0111]

[Table 4]

[0112]

[Table 5]

[0113]

[Table 6]

[0114]

[Table 7]

[0115]

[Table 8]

[0116]

[Table 9]

[0117]

[Table 10]

Reference Example 1 1.96 g (10.0 mmo)
l) 2,4,5-Trimethoxybenzaldehyde (manufactured by Lancaster) and 1.96 g (10.0 mmol) of 4-bromophenylacetonitrile (manufactured by Tokyo Chemical Industry) in 5 ml of ethanol (manufactured by Kokusan Chemical) , And 2 drops of a 20% aqueous sodium hydroxide solution were added thereto with stirring, and the mixture was stirred overnight while being left to cool. Ethanol was added to the solidified reaction product, and the mixture was pulverized by adding ethanol. The crystals were separated by filtration, washed twice with ethanol and twice with hexane and dried, and then 3.58 g (yield 95.6%). Of α-cyano-4-bromo-2 ′, 4 ′, 5′-trimethoxystilbene (yellow crystals).

Reference Example 2 771 mg (5.0 mmo)
l) 2,3,4-trihydroxybenzaldehyde (manufactured by Aldrich) and 853 mg (5.0 mmol)
1) with 4-chlorophenylacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.)
5 ml of acetic anhydride (Wako Pure Chemical Industries, Ltd.) mixture under ice-cooling.
ml of triethylamine (manufactured by Kokusan Chemical Co., Ltd.)
After stirring for 1 hour while protecting the calcium chloride tube, 12
The mixture was refluxed for 4 hours in an oil bath heated to 0 ° C. After air cooling,
The reaction product was added to 100 ml of ice-cooled 10% hydrochloric acid and stirred vigorously, and the precipitated crystals were separated by filtration and washed with water. The obtained brown crystals were pulverized well in ethanol, and the crystals were filtered off and washed with ethanol. The obtained light brown crystals were recrystallized using a mixed solution of chloroform and ethanol, and 1.17 g (62.9% yield) of 7,8-diacetoxy-3- (4-chlorophenyl) coumarin (light brown) Crystal) was obtained.

Reference Example 3 [Synthesis of 4-iodophenylacetonitrile] 4.36
g (20.0 mmol) of p-iodotoluene (Tokyo Kasei), 3.92 g (22.0 mmol) of N-bromosuccinimide (Tokyo Kasei) and 60 ml of carbon tetrachloride (Wako Pure Chemical Industries, Ltd.) Was heated and refluxed for 4 hours under irradiation of an incandescent lamp, and 2.67 g (yield 45.0%) of 4
-Iodobenzyl bromide (white crystals) was obtained. Then 0.49 g (10.0 mmol) preheated to 50 ° C
Of sodium cyanide (Kokusan Chemical Co., Ltd.) in 10 ml of dimethyl sulfoxide (Aldrich)
1.48 g of iodobenzyl bromide (5.0 mmo
l) was added thereto, and the mixture was stirred under cooling for 3 hours. The solidified reaction product was dissolved in water, extracted with hexane, hexane was distilled off, and white crystals of 4-iodophenylacetonitrile were added.
84 g (68.9% yield) was obtained.

Reference Example 4 [Synthesis of 4-ethylphenylacetonitrile] 2.72
g (20.0 mmol) of 4-ethylbenzyl alcohol (manufactured by Aldrich), 50 ml of 47% hydrobromic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was vigorously stirred at room temperature for 30 minutes. To give 3.98 g of colorless oily 4-ethylbenzyl bromide. Then 5
To a solution of 1.96 g (40.0 mmol) of sodium cyanide (manufactured by Kokusan Chemical Co., Ltd.) in 20 ml of dimethyl sulfoxide (manufactured by Aldrich) heated to 0 ° C., 3.98 g of the above-mentioned 4-ethylbenzyl bromide was added, and the solution was released. The mixture was stirred for 3 hours under cooling, and the solidified reaction product was dissolved in water, extracted with hexane, and hexane was distilled off. 2.70 g of 4-ethylphenylacetonitrile as a pale yellow oil (yield 93.1)
%).

Reference Example 5 [Synthesis of 4-bromothiophene-2-acetic acid] 1.20 g
In a 12 ml anhydrous dioxane (Aldrich) suspension of sodium hydride (equivalent to 30 mmol) (60% oily, manufactured by Wako Pure Chemical Industries, Ltd.) was added 9.94 g (30.0 mm).
ol) of tetraethyldimethylaminomethylene diphosphonate (manufactured by Lancaster) in 9 ml of anhydrous dioxane, and the mixture was stirred at room temperature for 10 minutes. Then 5.7
9 ml of 3 g (30.0 mmol) of 4-bromo-2-thiophenecarboxaldehyde (manufactured by Aldrich)
An anhydrous dioxane solution was added and the mixture was stirred at 60 ° C. for 1 hour. After air cooling, the reaction mixture was added to 100 ml of water, extracted three times with ether, dried over anhydrous sodium sulfate, and evaporated to obtain 14.85 g of a black oil.

After adding 15 ml of concentrated hydrochloric acid to the oily substance and heating under reflux for 15 minutes, the reaction mixture was added to 100 ml of cold water and extracted three times with ether. The extract was back-extracted twice with a 2N sodium hydroxide solution, adjusted to pH 1 with 6N hydrochloric acid, and then extracted again three times with ether.
After washing with a saturated saline solution, it was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a brown oily substance. This oily product was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1: 1) to give 4
1.29 g of yellow-white crystals of -bromothiophene-2-acetic acid
(19.5% yield).

Reference Example 6 Synthesis of 5-methylfuran-2-ylacetonitrile
5.51 g (50.0 mmol) of 5-methylfuran-2-carboxaldehyde (manufactured by Wako Pure Chemical Industries, Ltd.), 6.66 g (50.0 mmol) of rhodanine (manufactured by Tokyo Chemical Industry),
12.3 g of anhydrous sodium acetate (manufactured by Kokusan Chemical Co., Ltd.) (15
A mixture of 0 mmol) and 35 ml of acetic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was heated under reflux for 30 minutes, air-cooled, added to 500 ml of water, and the precipitated crystals were collected by filtration, washed successively with water, ethanol and ether. , Dried, 10.04 g of orange-brown crystals of (5-methylfurfurylidene) rhodanine (yield 8
9.1%). The whole amount was suspended in 65 ml of a 15% aqueous sodium hydroxide solution and heated at 100 ° C. for 30 minutes.
After air cooling, the mixture was added to 500 ml of 10% hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, dried, and yellow crystals of 3- (5-methylfuryl) -2-thioketopropionic acid 8.22.
g was obtained.

To this total amount, 45 ml of ethanol and 10.1 g of hydroxylamine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.) were added.
Sodium ethoxide (Aldrich, 21% denatured ethanol solution) 55
ml (equivalent to 147 mmol) is gradually added,
For 1 hour, air-cooled, and concentrated under reduced pressure. 5 for residue
20% aqueous sodium hydroxide solution and suspended.
20 ml of 10% hydrochloric acid was carefully added under ice-cooling, and the mixture was extracted three times with ether.
After adding anhydrous sodium sulfate and drying, ether was distilled off. The residue was dissolved in a small amount of ether, and toluene was gradually added until cloudiness occurred, and the mixture was allowed to stand. The precipitated crystals were collected, sufficiently washed with toluene, dried, and dried in 3- (5-
4.55 g (yield 53.3%) of yellow crystals of methyl-2-furyl) -2-hydroxyiminopropionic acid were obtained.

The whole amount was dissolved in 60 ml of benzene,
3.97 g (24.8 mmol) of 1,1'-carbonyldiimidazole (manufactured by Aldrich) was gradually added,
The mixture was heated at 70 ° C. for 1 hour, air-cooled, added to 50 ml of ice water, extracted three times with benzene, and the benzene layer was washed successively with aqueous sodium bicarbonate, saturated saline, 1% hydrochloric acid and water, and dried over anhydrous sodium sulfate. And the solvent was distilled off under reduced pressure to obtain 2.40 g of an oily substance.
I got This oily product was purified by silica gel column chromatography (eluent: ethyl acetate: hexane ratio 1: 4) to give 2.00 g of 5-methylfuran-2-ylacetonitrile as a colorless oil (yield 66). 0.6%).

(Comparative Example 1) 150 mg of a compound represented by the chemical formula of Chemical Formula 52 (0.
A mixture of 59 mmol) and 3 ml of acetone (manufactured by Kanto Chemical Co., Ltd.) was previously well pulverized into 207 mg (1.5 mmol
l) anhydrous potassium carbonate (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.14 ml (equivalent to 1.5 mmol) of dimethyl sulfate (manufactured by Tokyo Chemical Industry Co., Ltd.) were added.
Reflux with heating for hours. After air cooling, the reaction product was added to 20 ml of ice-cooled dilute hydrochloric acid, and the precipitated crystals were separated by filtration.
The obtained filtered material is thoroughly washed with water, washed with a small amount of ethanol, dried, and subjected to the following chemical formula.

[0128]

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130 mg of a white crystalline compound represented by the following formula:
(Yield: 78.1%) was obtained. The melting point of the obtained compound is
147-148 ° C.

Comparative Example 2 691 mg (5.0 mmol) instead of 2,3,4-trihydroxybenzaldehyde
l) 988 mg of white crystals of 7-acetoxy-3- (4-chlorophenyl) coumarin were obtained in the same manner as in Reference Example 2 except that 2,4-dihydroxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) was used. 62.8%). Same as Example 2, except that 314 mg (1.0 mmol) of the 7-acetoxy-3- (4-chlorophenyl) coumarin was used instead of 7,8-diacetoxy-3- (4-fluorophenyl) coumarin The following chemical formula

[0131]

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236 mg of a pale yellow crystalline compound represented by the following formula:
(86.5% yield). The melting point of the obtained compound is
296-297 ° C.

Comparative Example 3 1.26 g (10.0 mmol)
l) pyrogallol (manufactured by Tokyo Chemical Industry Co., Ltd.) and 1.92 g (1
0.0 mmol) of ethyl benzoylacetate (manufactured by Tokyo Chemical Industry Co., Ltd.) and 10 ml of 75% sulfuric acid were added in advance to 55%.
The mixture was heated and stirred overnight in an oil bath heated to ℃. After air cooling, 15 ml of ice water was added to the reaction mixture and the mixture was stirred, and the solidified reaction mixture was pulverized, filtered, and washed with water. The obtained tan powder was dissolved in ethyl acetate and dried over anhydrous sodium sulfate. Activated carbon was added to the filtrate, heated, and then concentrated under reduced pressure. The residue was dissolved by heating in ethyl acetate, hexane was added, and the mixture was stirred under cooling. The precipitated crystals are collected and dried, and have the following chemical formula

[0134]

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916 mg of a brown crystalline compound represented by the following formula:
(36% yield). The melting point of the obtained compound was 19
1.5-192.5 ° C.

(Comparative Example 4) 821 mg (5.0 mmo)
To a solution of l) ethyl phenylacetate (manufactured by Tokyo Kasei) in 2 ml of ethanol (manufactured by Kokusan Chemical), a solution of 0.8 g of sodium hydroxide dissolved in 2 ml of water was added, and the mixture was stirred at room temperature for 2 hours. did. To this, 30 ml of about 10% hydrochloric acid was added and extracted three times with ether. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 1.15 g (5.0 mmol) of 2,2 was added to the residue.
3,4-Trihydroxybenzophenone (manufactured by Tokyo Chemical Industry Co., Ltd.) and 10 ml of acetic anhydride (manufactured by Wako Pure Chemical Industries, Ltd.) were added, and 5 ml of triethylamine (manufactured by Kokusan Chemical) was added while stirring under ice-cooling. And stirred for 1 hour. The reaction was then heated at reflux for 2 hours in an oil bath previously heated to 120 ° C. After air cooling, the reaction mass is 100m
of ice-cold 10% hydrochloric acid, stirred for a while, and extracted three times with methylene chloride. The organic layer was washed with aqueous sodium hydrogen carbonate and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1: 2) to give 7,8-
823 mg (yield 39.8%) of white crystals of diacetoxy-3,4-diphenylcoumarin were obtained. 250mg
(0.6 mmol) of the 7,8-diacetoxy-3,
8 ml ethanol and 1 m in 4-diphenyl coumarin
l of water and 1 ml of concentrated hydrochloric acid were added, and the mixture was heated under reflux for 4 hours. After air cooling, the reaction product was added to 60 ml of water, and the precipitated crystals were separated by filtration, washed with water, and dried, and the following chemical formula

[0137]

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165 mg of a white crystalline compound represented by the following formula:
(82.8% yield). The melting point of the obtained compound is
281 to 282 ° C.

Comparative Example 5 The same method as in Reference Example 2 was used except that 761 mg (5.0 mmol) of 4-hydroxyphenylacetic acid (manufactured by Tokyo Chemical Industry) was used instead of 4-chlorophenylacetic acid. 7,8-diacetoxy-3
1.45 g (yield: 73.0%) of milky white crystals of-(4-acetoxyphenyl) coumarin were obtained. Example 1 was repeated except that 396 mg (1.0 mmol) of the above 7,8-diacetoxy-3- (4-acetoxyphenyl) coumarin was used instead of 7,8-diacetoxy-3- (4-fluorophenyl) coumarin. By the same method as 2, the following chemical formula

[0140]

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189 mg of a compound of ocher crystals represented by
(70.0% yield). The melting point of the obtained compound is
295 ° C (decomposition).

[0142]

EXAMPLES Next, the present invention will be described in more detail by way of examples, but the present invention is not limited to the following examples. Example 1 α-cyano-4-bromo-2 ′, 4 ′, 5′-trimethoxystilbene 74 obtained by the same method as in Reference Example 1.
8 mg (2.0 mmol) and 3.47 g (30.0 m
(mol.) of pyridinium chloride (manufactured by Aldrich) was melt-mixed on an oil bath previously heated to 210 ° C. under an argon gas atmosphere, and stirred at the same temperature for 1 hour. Then, the reaction mixture was air-cooled, and the solidified reaction product was added with 20 ml of 2N hydrochloric acid and pulverized well. After stirring for 30 minutes, the precipitate was separated by filtration, washed three times with water and dried. This was purified by silica gel column chromatography (eluent was ethyl acetate), and the following chemical formula was used.

[0143]

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551 mg (yield: 82.7%) of a yellow crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound is 28
7-288 ° C.

Example 2 771 mg (5.0 m) instead of 4-chlorophenylacetic acid
mol) of 4-fluorophenylacetic acid (manufactured by Lancaster), except that 356 mg (1.0 mmol) of 7,8-diacetoxy-3- (4-fluorophenyl) coumarin obtained by the same method as in Reference Example 2 was used. ) And 8ml
Of ethanol (manufactured by Kokusan Chemical Co., Ltd.) was added with 2 ml of 6N hydrochloric acid, and the mixture was heated under reflux for 1 hour. After air cooling, the reaction product was added to 60 ml of water and stirred, and the precipitated crystals were separated by filtration and washed with water. After drying, recrystallized using a mixed solution of ethyl acetate and hexane, the following chemical formula

[0146]

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193 mg of a pale yellow crystalline compound represented by the following formula:
(70.9% yield). The melting point of the obtained compound is
248-249 ° C.

Example 3 751 mg (5.0) instead of 4-chlorophenylacetic acid
mmol) of 3-methylphenylacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.)
352 mg (1.0 mmol) of 7,8-diacetoxy-3- (3-methylphenyl) coumarin obtained by the same method as in Reference Example 2 except that was used in 8 ml of ethanol (manufactured by Kokusan Chemical Co., Ltd.). The suspension was added with a solution of 168 mg (4.0 mmol) of lithium hydroxide monohydrate (manufactured by Kokusan Chemical) dissolved in 4 ml of water, and the mixture was stirred at room temperature for 1 hour. Then add 4 ml of about 10%
After adding hydrochloric acid to make it acidic, it was concentrated to dryness under reduced pressure.
Ethyl acetate and water were added to the reaction product, and the organic layer was separated. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The liquid obtained by filtering off sodium sulfate was purified by silica gel column chromatography (eluent was ethyl acetate), and the following chemical formula was used.

[0149]

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203 mg (yield: 75.7%) of a yellow crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound is 18
5.5-186.5 ° C.

Example 4 771 mg (5.0 mmol) of 2,3,4-trihydroxybenzaldehyde (manufactured by Aldrich) and 75%
To a mixture of 8 mg (5.0 mmol) of 4-chlorophenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) in 10 ml of ethanol (manufactured by Kokusan Chemical), 0.54 ml of piperidine (manufactured by Wako Pure Chemical Industries) was added, and the mixture was heated under reflux for 6 hours. . After air cooling, the reaction product was added to 100 ml of 1 N hydrochloric acid and stirred, and the precipitate was separated by filtration and washed with water. The obtained filtrate was dissolved in ethyl acetate, washed twice with a 20% aqueous sodium bisulfite solution and then once with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. About 300m
g was obtained. This was subjected to silica gel column chromatography (eluent: ethyl acetate: hexane at a ratio of 1: 5 to 3: 5).
With the following chemical formula

[0152]

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227 mg of a pale yellow crystalline compound represented by the following formula:
(15.7% yield). The melting point of the obtained compound is
239-241 ° C.

EXAMPLE 5 3.83 was added to a mixture of 25 ml of concentrated hydrochloric acid and 15 g of ice.
g (30.0 mmol) of p-chloroaniline (manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and 7 ml of an aqueous solution of 30% sodium nitrite (manufactured by Wako Pure Chemical Industries) was added thereto, followed by stirring at room temperature for 1 hour. . To this mixture was added a saturated aqueous solution of sodium acetate (manufactured by Wako Pure Chemical Industries, Ltd.) to adjust the pH to 4, and the insoluble components were filtered off. This filtrate was separately prepared in 5.77 g (30
mmol) of 4-methylesculetin (manufactured by Tokyo Chemical Industry Co., Ltd.)
Was added to 90 ml of acetone suspension, and 0.8 g of cupric chloride dihydrate (manufactured by Kanto Chemical Co., Ltd.) was further added, followed by stirring for 1 hour. After the reaction was concentrated under reduced pressure to remove most of the solvent, 300 ml of ethyl acetate was added to the residue and mixed well. After filtering off insoluble components (unreacted 4-methylesculetin), the organic layer was separated from the filtrate, the aqueous layer was further extracted twice with ethyl acetate, and the combined organic layers were washed with saturated saline. Then, it was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate: hexane ratio: 1: 1), and the effluent fraction containing the desired product was allowed to stand. The crystals that precipitate are collected and dried, and the following chemical formula

[0155]

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533 mg of a pale yellow crystalline compound represented by the following formula:
(5.9% yield). The melting point of the obtained compound is 1
74-175 ° C.

Example 6 586 mg instead of 4-bromophenylacetonitrile
Α-cyano-2 ′, 4 ′, 5′-trimethoxystilbene was obtained by the same method as in Reference Example 1 except that (5.0 mmol) of phenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) was used. α-cyano-4-bromo-2 ′,
591m instead of 4 ', 5'-trimethoxystilbene
g (2.0 mmol) of the α-cyano-2 ′, 4 ′,
By the same method as in Example 1, except that 5'-trimethoxystilbene was used, the following chemical formula

[0158]

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444 mg of a tan crystalline compound represented by the following formula:
(87.3% yield). The melting point of the obtained compound is
251 to 253 ° C.

Example 7 1.35 g instead of 4-bromophenylacetonitrile
Reference Example 1 except that (10.0 mmol) of 4-fluorophenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) was used.
Α-cyano-4-fluoro-
2 ', 4', 5'-Trimethoxystilbene was obtained. α
599 mg (2.0 mmol) of the above α-cyano-4-fluoro-2 ′, 4 ′, 5′-trimethoxystilbene instead of cyano-4-bromo-2 ′, 4 ′, 5′-trimethoxystilbene The following chemical formula was obtained in the same manner as in Example 1 except that

[0161]

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364 mg of a yellow-brown crystalline compound represented by the following formula:
(66.9% yield). The melting point of the obtained compound is
287-288 ° C.

Example 8 1.52 g instead of 4-bromophenylacetonitrile
(10.0 mmol) of 4-chlorophenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.), except that α-cyano-4-chloro-2 ′,
4 ', 5'-Trimethoxystilbene was obtained. Instead of α-cyano-4-bromo-2 ′, 4 ′, 5′-trimethoxystilbene, 660 mg (2.0 mmol) of α
In the same manner as in Example 1 except that -cyano-4-chloro-2 ', 4', 5'-trimethoxystilbene was used, the following chemical formula was obtained.

[0164]

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435 mg of a yellow crystalline compound represented by the following formula:
(Yield 75.3%). The melting point of the obtained compound is
289-291 ° C.

Example 9 1.52 g instead of 4-bromophenylacetonitrile
Except that (10.0 mmol) of 3-chlorophenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) was used, α-cyano-3-chloro-2 ′,
4 ', 5'-Trimethoxystilbene was obtained. Instead of α-cyano-4-bromo-2 ′, 4 ′, 5′-trimethoxystilbene, 660 mg (2.0 mmol) of α
In the same manner as in Example 1 except that -cyano-3-chloro-2 ', 4', 5'-trimethoxystilbene was used, the following chemical formula was obtained.

[0167]

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Compound 290 mg of pale yellow crystals of the formula
(50.2% yield). The melting point of the obtained compound is
279-281 ° C.

Example 10 Using 392 mg (2.0 mmol) of 2,4,5-trimethoxybenzaldehyde (manufactured by Lancaster), 4
486 mg instead of bromophenylacetonitrile
In the same manner as in Reference Example 1, except that (2.0 mmol) of 4-iodophenylacetonitrile obtained by the method of Reference Example 3 was used, α-cyano-4-iodo-
2 ', 4', 5'-Trimethoxystilbene was obtained. α
421 mg (1.0 mmol) of the above α-cyano-4-iodo-2 ′, 4 ′, 5′-trimethoxystilbene instead of cyano-4-bromo-2 ′, 4 ′, 5′-trimethoxystilbene The following chemical formula was obtained in the same manner as in Example 1 except that

[0170]

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566 mg of a yellow crystalline compound represented by the following formula:
(74.4% yield). The melting point of the obtained compound is
273-276 ° C.

Example 11 1.31 g instead of 4-bromophenylacetonitrile
(10.0 mmol) of 4-methylphenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.), except that α-cyano-4-methyl-2 ′,
4 ', 5'-Trimethoxystilbene was obtained. 619 mg (2.0 mmol) of the α-cyano-4-bromo-2 ′, 4 ′, 5′-trimethoxystilbene
In the same manner as in Example 1 except that -cyano-4-methyl-2 ', 4', 5'-trimethoxystilbene was used, the following chemical formula was obtained.

[0173]

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435 mg of a yellow crystalline compound represented by the following formula:
(81.0% yield). The melting point of the obtained compound is
252.5-253 ° C.

Example 12 1.31 g instead of 4-bromophenylacetonitrile
(10.0 mmol) of 3-methylphenylacetonitrile (manufactured by Aldrich) except that α-cyano-3-methyl- was used in the same manner as in Reference Example 1.
2 ', 4', 5'-Trimethoxystilbene was obtained. α
619 mg (2.0 mmol) of the above α-cyano-3-methyl-2 ′, 4 ′, 5′-trimethoxystilbene instead of cyano-4-bromo-2 ′, 4 ′, 5′-trimethoxystilbene The following chemical formula was obtained in the same manner as in Example 1 except that

[0176]

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493 mg of a yellow crystalline compound represented by the following formula:
(91.8% yield). The melting point of the obtained compound is
216-218 ° C.

Example 13 Using 628 mg (3.20 mmol) of 2,4,5-trimethoxybenzaldehyde (manufactured by Lancaster),
465mg instead of 4-bromophenylacetonitrile
(3.20 mmol) of 4-
According to the same method as in Reference Example 1 except that ethylphenylacetonitrile was used, α-cyano-4-ethyl-
2 ', 4', 5'-Trimethoxystilbene was obtained. α
485 mg (1.5 mmol) of the above α-cyano-4-ethyl-2 ′, 4 ′, 5′-trimethoxystilbene instead of cyano-4-bromo-2 ′, 4 ′, 5′-trimethoxystilbene The following chemical formula was obtained in the same manner as in Example 1 except that

[0179]

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493 mg of a yellow crystalline compound represented by the following formula:
(87.5% yield). The melting point of the obtained compound is
232-234 ° C.

Example 14 1.85 g instead of 4-bromophenylacetonitrile
(10.0 mmol) of 4-trifluoromethylphenylacetonitrile (manufactured by Aldrich) was used, except that α-cyano-4- was used in the same manner as in Reference Example 1.
Trifluoromethyl-2 ', 4', 5'-trimethoxystilbene was obtained. α-cyano-4-bromo-2 ′,
727m instead of 4 ', 5'-trimethoxystilbene
g (2.0 mmol) of the above α-cyano-4-trifluoromethyl-2 ′, 4 ′, 5′-trimethoxystilbene, except that
The following chemical formula

[0182]

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594 mg of a pale yellow crystalline compound represented by the following formula:
(Yield 92.2%). The melting point of the obtained compound is
257-258 ° C.

Example 15 1.23 g instead of 4-bromophenylacetonitrile
Reference Example 1 except that (10.0 mmol) thiophen-2-ylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) was used.
Α- (2,4,5-trimethoxybenzylidene) thiophene-2-acetonitrile was obtained in the same manner as described above. Instead of α-cyano-4-bromo-2 ′, 4 ′, 5′-trimethoxystilbene, 603 mg (2.0 mmol
l) According to the same method as in Example 1 except that α- (2,4,5-trimethoxybenzylidene) thiophen-2-acetonitrile was used, the following chemical formula

[0185]

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274 mg of a yellow crystalline compound represented by the following formula:
(52.6% yield). The melting point of the obtained compound is
273 ° C (decomposition).

Example 16 1.23 g instead of 4-bromophenylacetonitrile
Reference Example 1 except that (10.0 mmol) thiophen-3-ylacetonitrile (Tokyo Kasei) was used.
Α- (2,4,5-trimethoxybenzylidene) thiophene-3-acetonitrile was obtained in the same manner as described above. Instead of α-cyano-4-bromo-2 ′, 4 ′, 5′-trimethoxystilbene, 603 mg (2.0 mmol
l) According to the same method as in Example 1 except that the above α- (2,4,5-trimethoxybenzylidene) thiophen-3-acetonitrile was used, the following chemical formula was obtained.

[0188]

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315 mg of a yellow crystalline compound represented by the following formula:
(60.5% yield). The melting point of the obtained compound is
249-250 ° C.

Example 17 In place of 2,4,5-trimethoxybenzaldehyde, 1.96 g (10.0 mmol) of 2,3,4-trimethoxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) was used.
1.17 g of bromophenylacetonitrile (1
Α-cyano-2 ′, 3 ′, 4′-trimethoxystilbene was obtained in the same manner as in Reference Example 1 except that 0.0 mmol) of phenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) was used. α-cyano-4-bromo-2 ′, 4 ′,
591 mg instead of 5'-trimethoxystilbene
(2.0 mmol) of the α-cyano-2 ′, 3 ′,
In the same manner as in Example 1 except that 4'-trimethoxystilbene was used, the following chemical formula was obtained.

[0191]

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474 mg of a compound as yellow crystals represented by the following formula:
(93.2% yield). The melting point of the obtained compound is
209-210 ° C.

Example 18 In place of 2,4,5-trimethoxybenzaldehyde, 1.96 g (10.0 mmol) of 2,3,4-trimethoxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) was used.
Instead of bromophenylacetonitrile, 1.31 g (1
0.0 mmol) of 4-methylphenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.), except that α-cyano-4-methyl-2 ′, 3 ′,
4'-Trimethoxystilbene was obtained. α-cyano-4
Using 619 mg (2.0 mmol) of the above α-cyano-4-methyl-2 ′, 3 ′, 4′-trimethoxystilbene in place of -bromo-2 ′, 4 ′, 5′-trimethoxystilbene By the same method as in Example 1 except for the following chemical formula

[0194]

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481 mg of a yellow crystalline compound represented by the following formula:
(89.7% yield). The melting point of the obtained compound is
226-227 ° C.

Example 19 In place of 2,4,5-trimethoxybenzaldehyde, 1.96 g (10.0 mmol) of 2,3,4-trimethoxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) was used.
1.45 g instead of bromophenylacetonitrile
(10.0 mmol) of 4-
According to the same method as in Reference Example 1 except that ethylphenylacetonitrile was used, α-cyano-4-ethyl-
2 ', 3', 4'-Trimethoxystilbene was obtained. α
-Instead of cyano-4-bromo-2 ', 4', 5'-trimethoxystilbene, 647 mg (2.0 mmol) of the above α-cyano-4-ethyl-2 ', 3', 4'-trimethoxystilbene The following chemical formula was obtained in the same manner as in Example 1 except that

[0197]

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436 mg of a yellow crystalline compound represented by the following formula:
(Yield: 77.2%). The melting point of the obtained compound is
188.5-190 ° C.

Example 20 In place of 2,4,5-trimethoxybenzaldehyde, 1.96 g (10.0 mmol) of 2,3,4-trimethoxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) was used.
1.85 g of bromophenylacetonitrile (1
Α-cyano-4-trifluoromethyl-2 ′, 3 ′, 4 by the same method as in Reference Example 1 except that 0.0 mmol) of 4-trifluoromethylphenylacetonitrile (manufactured by Aldrich) was used. '-Trimethoxystilbene was obtained. α-cyano-4-bromo-2 ′,
727m instead of 4 ', 5'-trimethoxystilbene
g (2.0 mmol) of the above α-cyano-4-trifluoromethyl-2 ′, 3 ′, 4′-trimethoxystilbene, except that
The following chemical formula

[0200]

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205 mg of a yellow crystalline compound represented by the following formula:
(31.8% yield). The melting point of the obtained compound is
234 to 234.5 ° C.

Example 21 In place of 2,4,5-trimethoxybenzaldehyde, 1.96 g (10.0 mmol) of 2,3,4-trimethoxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) was used.
Instead of bromophenylacetonitrile, 1.23 g (1
0.0-mmol) thiophen-3-ylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) except that α- (2,3,4-trimethoxybenzylidene) thiophen-3- Acetonitrile was obtained. α
Using 603 mg (2.0 mmol) of the above α- (2,3,4-trimethoxybenzylidene) thiophene-3-acetonitrile in place of -cyano-4-bromo-2 ', 4', 5'-trimethoxystilbene In the same manner as in Example 1 except that

[0203]

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376 mg of a yellow crystalline compound represented by the following formula:
(72.3% yield). The melting point of the obtained compound is
243-245.5 ° C.

Example 22 Instead of 4-chlorophenylacetic acid, 853 mg (5.0
mmol) of 3-chlorophenylacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.)
By using the same method as in Reference Example 2, except that
7,8-Diacetoxy-3- (3-chlorophenyl) coumarin was obtained. Instead of 7,8-diacetoxy-3- (4-fluorophenyl) coumarin, 373 mg (1.0 m
mol) of the above 7,8-diacetoxy-3- (3-chlorophenyl) coumarin in the same manner as in Example 2 except that the following chemical formula was used.

[0206]

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268 mg of a compound of pale yellow crystal represented by the following formula:
(92.8% yield). The melting point of the obtained compound is
281 to 282 ° C.

Example 23 Instead of 4-chlorophenylacetic acid, 906 mg (5.0 mg)
mmol) of 4-nitrophenylacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.)
By using the same method as in Reference Example 2, except that
7,8-Diacetoxy-3- (4-nitrophenyl) coumarin was obtained. Instead of 7,8-diacetoxy-3- (4-fluorophenyl) coumarin, 383 mg (1.0 m
mol) of 7,8-diacetoxy-3- (4-nitrophenyl) coumarin, except that the following chemical formula was used.

[0209]

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228 mg of an orange crystalline compound represented by the following formula:
(Yield: 76.2%). The melting point of the obtained compound is
303-304 ° C (decomposition).

Example 24 In the same manner as in Reference Example 2, 7,8-diacetoxy-
3- (4-Chlorophenyl) coumarin was obtained. 7,8-
Instead of diacetoxy-3- (4-fluorophenyl) coumarin, 373 mg (1.0 mmol) of the 7,8-
Except that diacetoxy-3- (4-chlorophenyl) coumarin was used, the following chemical formula was prepared in the same manner as in Example 2.

[0212]

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242 mg of a yellow crystalline compound represented by the following formula:
(83.9% yield). The melting point of the obtained compound is
240-241 ° C. NMR and IR spectra were identical to those of the compound obtained in Example 4.

Example 25 Instead of 4-chlorophenylacetic acid, 1075 mg (5.
7,8-diacetoxy-3- (4-bromophenyl) coumarin was obtained in the same manner as in Reference Example 2 except that 0 mmol) of 4-bromophenylacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) was used. 7,8-diacetoxy-3- (4
-Fluorophenyl) coumarin instead of 417mg
(1.0 mmol) of the above 7,8-diacetoxy-3-
Except for using (4-bromophenyl) coumarin,
By the same method as in Example 2, the following chemical formula

[0215]

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Compound 300 mg of a yellow crystal represented by the following formula:
(90.2% yield). The melting point of the obtained compound is
262-264 ° C.

Example 26 751 mg (5.0) instead of 4-chlorophenylacetic acid
mmol) of 4-methylphenylacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.)
By using the same method as in Reference Example 2, except that
7,8-Diacetoxy-3- (4-methylphenyl) coumarin was obtained. Instead of 7,8-diacetoxy-3- (4-fluorophenyl) coumarin, 352 mg (1.0 m
mol) of the above 7,8-diacetoxy-3- (4-methylphenyl) coumarin, except that the following chemical formula was used.

[0218]

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233 mg of a yellow crystalline compound represented by the following formula:
(86.9% yield). The melting point of the obtained compound is
226-227 ° C. NMR and IR spectra gave the same spectra as those obtained in Example 18.

Example 27 Instead of 4-chlorophenylacetic acid, 831 mg (5.0
7,8-diacetoxy-3- (4-methoxyphenyl) coumarin was obtained in the same manner as in Reference Example 2 except that (mmol) 4-methoxyphenylacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) was used. 7,8-diacetoxy-3- (4
368mg instead of -fluorophenyl) coumarin
(1.0 mmol) of the 7,8-diacetoxy-3-
Except that (4-methoxyphenyl) coumarin was used, the following chemical formula was obtained in the same manner as in Example 2.

[0221]

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186 mg of an ocher crystal compound represented by the following formula:
(65.5% yield). The melting point of the obtained compound is
245-246 ° C.

Example 28 Reference Example 2 was repeated except that 771, mg (5.0 mmol) of 2,4,5-trihydroxybenzaldehyde (manufactured by Lancaster) was used instead of 2,3,4-trihydroxybenzaldehyde. 6,7 by the same method as
-Diacetoxy-3- (4-chlorophenyl) coumarin was obtained. 373 mg (1.0 mmol) instead of 7,8-diacetoxy-3- (3-methylphenyl) coumarin
In the same manner as in Example 3, except that the above 6,7-diacetoxy-3- (4-chlorophenyl) coumarin was used, the following chemical formula

[0224]

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176 mg of a yellow crystalline compound represented by the following formula:
(60.9% yield). The melting point of the obtained compound is
290-291 ° C. NMR and IR spectra gave the same spectra as obtained in Example 8.

Example 29 616 mg instead of 4-chlorophenylacetonitrile
(5.0 mmol) thiophen-2-ylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.), except that the following chemical formula was used in the same manner as in Example 4.

[0227]

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264 mg of a yellow crystalline compound represented by the following formula:
(20.3% yield). The melting point of the obtained compound is
246-247 ° C.

Example 30 Instead of p-chloroaniline, 3.89 g (30.0 mm
ol) aniline hydrochloride (manufactured by Wako Pure Chemical Industries)
By the same method as in Example 5, the following chemical formula

[0230]

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153 mg of a yellow crystalline compound represented by the following formula:
(1.9% yield). The melting point of the obtained compound is 1
61-162 ° C.

Example 31 A mixture having the following composition was prepared per tablet, and the mixture was tableted by a tablet machine according to a conventional method to produce a medicament for selectively inhibiting 12-lipoxygenase of the present invention. Compound obtained in Example 1 30.0 (mg) Lactose (manufactured by Iwaki Pharmaceutical Co., Ltd.) 40.0 Maize starch (manufactured by Yoshida Pharmaceutical Co., Ltd.) 15.0 Magnesium stearate (manufactured by Taihei Chemical Co., Ltd.) 0.4 Carboxymethyl cellulose calcium ( (Nichirin Chemical Industry Co., Ltd.) 20.0

Example 32 A mixture having the following composition per capsule was prepared and filled in a gelatin capsule according to a conventional method to produce a medicament for selectively inhibiting 12-lipoxygenase of the present invention. Compound obtained in Example 5 30.0 (mg) Lactose (Iwaki Pharmaceutical Co., Ltd.) 40.0 Finely powdered cellulose (Nippon Soda Co., Ltd.) 30.0 Magnesium stearate (Taipei Chemical Co., Ltd.) 3.0

Example 33 Using 385 mg (2.5 mmol) of 2,3,4-trihydroxybenzaldehyde (manufactured by Aldrich),
553 mg (2.5 m) instead of 4-chlorophenylacetic acid
mol) of 4-bromothiophene-2-acetic acid, except that 7,8-diacetoxy-3- (4-bromothiophene-
756 mg (yield 71.4%) of 2-yl) coumarin was obtained.

Instead of 7,8-diacetoxy-3- (4-fluorophenyl) coumarin, 423 mg (1.0 mm
ol) except that the 7,8-diacetoxy-3- (4-bromothiophen-2-yl) coumarin was used.
By the same method as in Example 2, the following chemical formula

[0236]

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There were obtained 310 mg (yield: 91.4%) of a yellow crystalline compound represented by the following formula: The melting point of the obtained compound was 291.
° C (decomposition).

Example 34 Using 385 mg (2.5 mmol) of 2,4,5-trihydroxybenzaldehyde (manufactured by Lancaster),
553 mg (2.5 m) instead of 4-chlorophenylacetic acid
mol) of 4-bromothiophene-2-acetic acid, except that pale brown crystals of 6,7-diacetoxy-3- (4-bromothiophene-
755 mg (71.4% yield) of 2-yl) coumarin were obtained.

Instead of 7,8-diacetoxy-3- (4-fluorophenyl) coumarin, 423 mg (1.0 mm
ol) except that the 6,7-diacetoxy-3- (4-bromothiophen-2-yl) coumarin was used.
By the same method as in Example 2, the following chemical formula

[0240]

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287 mg (yield: 84.6%) of a yellow crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound is 300
° C or higher.

Example 35 Using 0.98 g (5.0 mmol) of 2,3,4-trimethoxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) instead of 2,4,5-trimethoxybenzaldehyde, 4-bromophenylacetonitrile 1.21 g (5.
0 mmol) of 5-methyl-α- (2,3,4-trimethoxybenzylidene) furan-2 in the same manner as in Reference Example 1 except that 5-methylfuran-2-ylacetonitrile was used. -Acetonitrile 703m
g (47.1% yield).

Α-cyano-4-bromo-2 ′, 4 ′,
597 mg instead of 5'-trimethoxystilbene
(2.0 mmol) of the 5-methyl-α- (2,3,
4-Trimethoxybenzylidene) furan-2-acetonitrile, except that the following chemical formula was used in the same manner as in Example 1.

[0244]

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241 mg (yield: 46.7%) of a yellow crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound is 24.
6.5-247.0 ° C.

Example 36 Using 0.98 g (5.0 mmol) of 2,4,5-trimethoxybenzaldehyde, instead of 4-bromophenylacetonitrile, 1.21 g (5.0 mmol) of 5
-Methylfuran-2-ylacetonitrile was used in the same manner as in Reference Example 1 to obtain yellow crystals of 5-
687 mg of methyl-α- (2,4,5-trimethoxybenzylidene) furan-2-acetonitrile (yield 4
6.1%).

Α-cyano-4-bromo-2 ′, 4 ′,
597 mg instead of 5'-trimethoxystilbene
(2.0 mmol) of the 5-methyl-α- (2,4,
5-Trimethoxybenzylidene) furan-2-acetonitrile, except that the following chemical formula was used in the same manner as in Example 1.

[0248]

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140 mg of a yellow-brown crystalline compound represented by the following formula:
(Yield 27.0%). The melting point of the obtained compound is 2
78 ° C (decomposition).

[0250]

As described in detail above, the present invention provides a 12-
Coumarin derivatives that selectively inhibit lipoxygenase,
The present invention also relates to a medicament for selectively inhibiting 12-lipoxygenase containing these compounds as active ingredients, and the effects of the present invention are as follows. 1) The compound of the present invention has a potent and highly selective inhibitory action on 12-lipoxygenase. 2) The medicament comprising the compound of the present invention as an active ingredient is useful for prevention and treatment of various circulatory diseases such as arteriosclerosis and vasospasm, and prevention of metastasis of certain cancers. 3) The compound of the present invention has low toxicity, has few side effects, and is effective as an active ingredient of a drug that selectively inhibits 12-lipoxygenase.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 35/04 A61P 35/04 43/00 111 43/00 111 C07D 407/04 C07D 407/04 409/04 409/04 (72 ) Inventor Shigehiro Mori 5-1-1, Higashihara, Zama City, Kanagawa Prefecture 407 Sakura Sakura (72) Inventor Naoko Moriuchi 1-20-7 Hino Minami, Konan-ku, Yokohama, Kanagawa Prefecture (56) References 15834 (JP, A) Chim. Acta Turc. (1992), Volume data 1991, 19 (1), pages 17-26 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 311/06-311/20 A61K 31/00-31 / 80 C07D 407/04 C07D 409/04 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A general formula of the following chemical formula 1. Wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ² and R ³ represent a hydrogen atom or a hydroxyl group (provided that R ² and R ³ are not hydrogen atoms at the same time), Ar is a general formula of the following chemical formula 2, chemical formula 3, or chemical formula 4 Embedded image Embedded image Wherein R ⁴ represents a lower alkyl group, a halogen atom, a trifluoromethyl group or a cyano group. ] The coumarin derivative shown by these. 2. A general formula of the following chemical formula 5 Wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ² and R ³ represent a hydrogen atom or a hydroxyl group (provided that R ² and R ³ are not hydrogen atoms at the same time), Ar is a general formula of the following Chemical Formula 6, Chemical Formula 7, or Chemical Formula 8: Embedded image Embedded image Wherein R ⁴ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a cyano group or a nitro group. 12-lipo containing a compound selected from the group consisting of coumarin derivatives represented by the following formulas or a mixture thereof as an active ingredient:
Xigenase inhibitors. 3. The general formula of Chemical formula 5 according to claim 2, wherein
In the formula, R1 represents a hydrogen atom or a lower alkyl group;
And R3 represent a hydrogen atom or a hydroxyl group (provided that R2
And R3 are not simultaneously hydrogen atoms), Ar is
It is represented by the general formula of Chemical formula 6, Chemical formula 7, or Chemical formula 8 according to claim 2.
Wherein R 4 is a hydrogen atom, a lower alkyl group,
Grade alkoxy group, halogen atom, trifluoromethyl
Group, shea A nitro group or a nitro group. Kumari shown by]
Or a compound selected from the group consisting of
A mixture of 12-lipoxygena
12-lipoxyge having a selective inhibitory action on lipase activity
A drug for inhibiting an enzyme.