JP3180127B2 - Stilbene derivatives and stilbene homolog derivatives and their uses - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to stilbene derivatives and stilbene homolog derivatives which selectively inhibit 12-lipoxygenase, and to medicaments containing these compounds as active ingredients. Are stilbene derivatives and stilbene homolog derivatives having an action of selectively inhibiting the activity of 12-lipoxygenase in the 12-lipoxygenase pathway, and various diseases of the circulatory system, such as arteriosclerosis and vasospasm, containing the compound as an active ingredient. The present invention relates to a medicament for selectively inhibiting 12-lipoxygenase, which is useful as a drug for the purpose of preventing and treating cancer, preventing the metastasis of certain cancers, and the like. 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 centering 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, as for stilbene derivatives, generally, the compounds are chemically synthesized or separated from the natural world,
Although purified, compounds similar to the compounds of the present invention, for example, the following compounds 1) to 6) are known.

1) α-[(3,4-dihydroxyphenyl) methylene] -4-nitrobenzeneacetonitrile [Journal of the Society of Daysers and Colorists
ty of Dyers and Colorists, Vol. 92, No. 1, p. 14, p. 1976] 2) α-[(3,4-dihydroxy-5-nitrophenyl) methylene] -2-pyrimidineacetonitrile [Journal of・ Journal of Computer-Aided Molecular Design
Design), Vol. 6, No. 3, p. 253, 1992]

3) α-[(3,4-dihydroxyphenyl) methylene] -3,4-dihydroxybenzeneacetonitrile (US Pat. No. 4,015,017)

4) 2- (p-azidophenyl) -3-
(3,4-dihydroxyphenyl) -acrylonitrile (French Patent No. 1,513,907) 5) α'-cyano-3 ', 4'-dihydroxy-4-stilbenecarboxylic acid (U.S. Pat. 6) α- (diphenylmethylene) -3,4-dihydroxy-benzeneacetonitrile (West German Patent Publication No. 2,5)
01,443)

However, conventionally, these compounds are
It is not known at all that it has 2-lipoxygenase inhibitory activity.

[0014]

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 strongly and selectively inhibit lipoxygenase are desirable.

In view of such circumstances, the present inventors have:
Focusing on the fact that baicalene, one of the natural flavonoids, has relatively strong 12-lipoxygenase inhibitory activity and relatively high selectivity, this compound was used as a lead compound, and the modification or modification of its partial structure was carried out. As a result, the present inventors succeeded in creating a 12-lipoxygenase inhibitory compound having high potency and high selectivity, and completed the present invention.

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 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.

[0019]

Means for Solving the Problems A first invention of the present invention for solving the above-mentioned problems has the following general formula:

[0020]

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Wherein R ¹ represents a hydrogen atom or a hydroxyl group, R ² and R ³ represent a hydrogen atom or a cyano group (provided that R ² and R ³ are different), and Ar is The following general formula of Chemical Formula 10, Chemical Formula 11, or Chemical Formula 12

[0022]

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[0023]

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[0024]

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[0025] a group represented by the formula in R ⁴ represents a lower alkyl group, a lower alkoxy group, a halogen atom, or a trifluoromethyl group. A stilbene derivative or a stilbene homolog derivative.

According to a second aspect of the present invention for solving the above-mentioned problems, the following general formula:

[0027]

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Wherein R ¹ represents a hydrogen atom or a hydroxyl group, R ² and R ³ represent a hydrogen atom or a cyano group (provided that R ² and R ³ are different), and Ar is The following general formula of Chemical formula 14, Chemical formula 15, or Chemical formula 16

[0029]

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[0030]

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[0031]

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[0032] a group represented by the formula in R ⁴ is lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, or a nitro group. A 12-lipoxygenase inhibitor comprising, as an active ingredient, a compound selected from the group consisting of stilbene derivatives and stilbene homolog derivatives ,
12 having a selective inhibitory effect on lipoxygenase activity
-A drug for inhibiting lipoxygenase .

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

[0034]

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A stilbene homologue of a stilbene or a heterocyclic-substituted derivative of one of the benzene rings thereof, having at least two catechol-type hydroxyl groups on the A ring, having no hydroxyl group on the B ring, And a stilbene derivative or a stilbene homolog derivative having a cyano group bonded to any carbon of a double bond connecting to the ring B.

The production method of the compound according to the present invention is as follows. The following general formula

[0037]

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(In the above chemical formula, R is a hydrogen atom or a hydroxyl group, and Ar is a general formula of the following chemical formula 19, 20 or 21)

[0039]

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[0040]

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[0041]

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[0042] a group represented by the formula in R ⁴ is lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, or a nitro group. Hereinafter, Ar is simply described as Ar). The compound represented by the following formula can be synthesized by a process represented by the following chemical formula.

[0043]

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(In the above chemical formula, R represents a hydrogen atom or a hydroxyl group, and R ′ represents a hydrogen atom or OMe.)

The desired benzaldehyde derivative (I) and arylacetonitrile (II) are condensed under a reaction condition known as Knebena gel condensation to give the compound (II)
I) can be obtained (step I). The compound is then converted to, for example, boron tribromide, trimethylsilane iodide,
The desired compound can be obtained by reacting with a demethylating reagent such as pyridinium chloride (Step II).

When the arylacetonitrile (II) used in the condensation reaction is relatively reactive, the following chemical formula

[0047]

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The desired compound can be obtained by subjecting hydroxybenzaldehyde (IV) to Kneevenagel condensation reaction in the step shown in (3).

Also, the following general formula

[0050]

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The compound represented by the above formula (R is hydrogen or a hydroxyl group) can be synthesized by the process represented by the following formula.

[0052]

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(In the above formula, R represents a hydrogen atom or a hydroxyl group, and R ′ represents a hydrogen atom or OMe.)

The desired phenylacetonitrile derivative (V) and the aromatic aldehyde (VI) can be condensed under a reaction condition known as Knebena gel condensation to obtain the compound (VII) (Step IV). Next, this compound is demethylated in the same manner as in Step II to obtain the desired compound (Step V).

The compound of the present invention obtained as described above can be purified by a known purification method such as recrystallization, chromatography and the like. In addition, the compound of the present invention includes
There are cis and trans geometric isomers, both of which are included in the compounds of the present invention.

Since the compounds of the present invention selectively have an inhibitory action on 12-lipoxygenase,
The medicine which has an action of suppressing the production of 12-lipoxygenase metabolites such as TE and 12-HETE and selectively inhibits 12-lipoxygenase of the present invention containing the compound as an active ingredient is useful for these metabolites. It can be effectively used as an agent for treating or preventing various circulatory diseases such as arteriosclerosis and vasospasm caused by the disease, and as an agent for preventing metastasis of certain cancers.

The compound of the present invention may be used as it is or as a mixture with known pharmaceutically acceptable carriers, excipients and the like, and may be in any form such as tablets, capsules, injections, granules and suppositories. Can be used as The medicament containing the compound of the present invention as an active ingredient can be administered orally or parenterally by injection, inhalation, application and the like. The dose of a drug containing the compound of the present invention as an active ingredient varies depending on the subject to be treated, symptoms, age, treatment period, and the like, but is preferably about 0.1 mg to 50 mg per dose 1 to 3 times a day. Dose.

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 5.
Suspended in 50 mM Tris-HCl buffer containing 5 mM glucose: pH 7.4), sonicated, and
The mixture was centrifuged at 00 g for 30 minutes, the supernatant was separated, and an enzyme solution was prepared.

2) Method of measuring enzyme activity [0060] To 300 µl of the enzyme solution prepared to have an enzyme activity of about 2 mU / ml with the above resuspended buffer, 1 µl of a 3 mM indomethacin ethanol solution and 1 µl of a 300 mM reduced glutathione solution
and 3 μl of an ethanol solution of the test substance (compounds of the present invention and compounds of Comparative Examples 1 to 8 produced by the same method as in Example 1) and various concentrations were added, and kept at 37 ° C. for 5 minutes. After adding 3 μl of a 5 mM ethanol solution of arachidonic acid and keeping the mixture at 37 ° C. for 5 minutes to react,
The reaction was stopped by adding 1 liter of methanol. The reaction solution was centrifuged at 10,000 g for 5 minutes, and the 12-hydroxyeicosatetraenoic acid in the supernatant was separated by reversed-phase high-performance liquid chromatography using a C-18 column.
The enzyme activity was measured by quantification based on nm absorption. From the measured value of each test substance, a concentration (hereinafter, sometimes referred to as an IC ₅₀ value) showing a 50% 12-lipoxygenase inhibition rate was determined.

3) Test results The results of this test are as shown in Tables 1 and 2.
Table 1 shows Comparative Example 1 in which the IC ₅₀ value could not be determined.
12 to lipoxygenase inhibition rate of the compounds of Examples 1 to 4 of the present invention for comparison, and Table 2
The compound of Comparative Example 5-9 was able to obtain the C ₅₀ values are shown in comparison with the compounds of the present invention (Example 1).

As is clear from Tables 1 and 2, the 12-lipoxygenase inhibitory activity of the compound of Example 1 of the present invention was 97% at a concentration of 10 ^-5 M, and was 10 ^-8 M.
Is 73%, whereas the compounds of Comparative Examples 1-4 have a 12-lipoxygenase inhibitory effect of 1 despite the fact that the chemical structure is similar to the compound of the present invention.
At a concentration of 0 ^-5 M, the inhibition was found to be only 10% or less.

This result indicates that the compound of the present invention has a strong 12
-To express a lipoxygenase inhibitory action, the following general formula

[0064]

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It is suggested that it is essential to have at least two catechol-type hydroxyl groups on the ring A shown by In addition, a compound having no cyano group in the double bond connecting Ring A and Ring B (Comparative Example 5), a compound having an ethoxycarbonyl group instead of a cyano group (Comparative Example 6), and a hydroxyl group or a carboxyl group in Ring B (Comparative Examples 7 to
It was found that the 12-lipoxygenase IC ₅₀ inhibitory effect of Comparative Example 9) was significantly weaker than the compound of the present invention (Example 1). In addition, other compounds of the present invention were tested, and almost the same results were obtained.

[0066]

[Table 1]

[0067]

[Table 2]

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 Enzyme Solution for 12-Lipoxygenase 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.

The test substance of the present invention produced by the same method as in Examples 1 to 6, 6, 9 and 13 and 17 and 20 to 27 was used as the test substance. The compound, and as a control, the following chemical formula

[0073]

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Using a 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: Measurement was carried out in the same manner as in Test Example 1 except that the same test substance used in 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 3. As is clear from Table 3, the compounds of the present invention exhibited a very strong inhibitory effect on 12-lipoxygenase,
_{The 50} values were on the order of 10 ^-9 moles, which was equal to or greater than that of known baicalene. 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 10-30 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 substituent of a certain size on the B ring tend to show a stronger 12-lipoxygenase inhibitory action. A compound having a substituent is desirable, and in the case of a thiophene ring or a furan ring, a compound having a substituent at the m-position with respect to the substitution position of the double bond connecting to the A ring is desirable.

The substituent is a chlorine atom or a bromine atom in the case of a halogen atom, a methyl group or an ethyl group in the case of an alkyl group, a methoxy group in the case of an alkoxy group, and particularly exhibits a remarkable 12-lipoxygenase inhibitory action. Was. In addition, other compounds of the present invention were tested, and almost the same results were obtained.

[0079]

[Table 3]

Test Example 3 This test was performed to examine the nuclear magnetic resonance spectrum and the infrared absorption spectrum of the compound of the present invention and the compound for comparison.

1) Preparation of Samples The compounds of the present invention were prepared in Examples 1 to 17 and 2
0 to 29 were prepared in the same manner as in Example 29, and compounds for comparison were prepared in the same manner as in Comparative Examples 1 to 9.

2) Test method Nuclear magnetic resonance spectrum [ ¹ H-NMR (500 MH
z)] in a solvent prepared by adding 2-3 drops of heavy methanol (CD ₃ OD) to heavy chloroform (CDCl ₃ ), and the infrared absorption spectrum was measured by a KBr tablet method.

3) Test results The results of this test were as shown in Tables 4 to 11.

[0084]

[Table 4]

[0085]

[Table 5]

[0086]

[Table 6]

[0087]

[Table 7]

[0088]

[Table 8]

[0089]

[Table 9]

[0090]

[Table 10]

[0091]

[Table 11]

Comparative Example 1 Instead of 3,4-dihydroxybenzaldehyde, 611 mg (5.0 mmol) of 3
-The following chemical formula was obtained in the same manner as in Example 1 except that hydroxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) was used.

[0093]

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551 mg (yield 43.1%) of a yellow crystalline compound represented by the following formula was obtained. The melting point of the obtained compound was 11
4.5-116.5 ° C.

Comparative Example 2 Instead of 3,4-dihydroxybenzaldehyde, 611 mg (5.0 mmol) of 4
-The following chemical formula was obtained in the same manner as in Example 1 except that hydroxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) was used.

[0096]

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975 mg (yield: 76.2%) of a yellow crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound is 20
0-202 ° C.

Comparative Example 3 Instead of 3,4-dihydroxybenzaldehyde, 761 mg (5.0 mmol) of 3
In the same manner as in Example 1 except that -hydroxy-4-methoxybenzaldehyde (manufactured by Janssen) was used, the following chemical formula was used.

[0099]

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488 mg of a pale yellow crystalline compound represented by the following formula:
(97.6% yield). The melting point of the obtained compound is
139-140 ° C.

Comparative Example 4 761 mg (5.0 mmol) of 4 instead of 3,4-dihydroxybenzaldehyde
Except for using -hydroxy-3-methoxybenzaldehyde (manufactured by Tokyo Kasei Co., Ltd.), the following chemical formula was obtained in the same manner as in Example 1.

[0102]

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481 mg (yield: 68.7%) of a yellow crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound is 12
2-123 ° C.

(Comparative Example 5) 4.33 g (10 mmol)
10 ml of lithium bistrimethylsilylamide (1.0 M tetrahydrofuran solution, manufactured by Aldrich) was added dropwise to a suspension of benzyltriferphosphonium bromide (manufactured by Lancaster) in 12 ml of tetrahydrofuran (manufactured by Aldrich) at room temperature, and the addition was completed. Later, 3 more
The mixture was stirred for 0 minutes, a solution of 1.5 g (9 mmol) of 3,4-dimethoxybenzaldehyde (manufactured by Tokyo Chemical Industry) in 6 ml of tetrahydrofuran was added dropwise, and the mixture was further stirred for 2.5 hours. Next, methanol was added to stop the reaction, and the crude product obtained after the usual treatment was subjected to silica gel column chromatography (ethyl acetate-hexane) to obtain a mixture of trans and cis isomers of 3,4-dimethoxystilbene. . This mixture was fractionally recrystallized from hexane-ethyl acetate (30: 1) to give 680 mg of the trans form (yield 31.0%).
%).

222 mg (0.93 mmol) of the above trans-3,4-dimethoxystilbene and 1.5 g
(13 mmol) of pyridinium chloride (manufactured by Wako Pure Chemical Industries, Ltd.) at 200 ° C. under an argon gas atmosphere.
The mixture was melt-stirred for 5 minutes, air-cooled, treated with 50 ml of 2N-hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to thin layer chromatography (ethyl acetate-hexane = 1: 1).
1), the following chemical formula

[0106]

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100 mg (yield: 50.0%) of a white crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound is 170.
-171 ° C.

(Comparative Example 6) 821 mg (5.0 mmo)
l) ethyl phenylacetate (Tokyo Kasei) and 69
To a mixture of 1 mg (5.0 mmol) of 3,4-dihydroxybenzaldehyde (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, Ltd.) was added, and the mixture was heated. The mixture was stirred for 24 hours under reflux, and the air-cooled reaction product was added to 100 ml of 1N hydrochloric acid and stirred, and the precipitate was separated by filtration and washed with water. The obtained precipitate was dissolved in ethyl acetate, washed twice with a 20% aqueous sodium bisulfite solution and then once with saturated saline, and the residue was subjected to silica gel column chromatography (ethyl acetate:
Purification is performed with a hexane ratio of 10: 1 to 10: 4), and the following chemical formula

[0109]

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499 mg of a pale yellow crystal represented by the following formula (yield: 3)
5.1%). The melting point of the obtained compound is 153 to
154.5 ° C.

Comparative Example 7 1.47 g (10 mmol) of 4-methoxyphenylacetonitrile (manufactured by Aldrich) was used instead of 3,4-dimethoxyphenylacetonitrile, and 1.6 was used instead of 4-chloroshibenzaldehyde.
Example 2 except that 6 g (10 mmol) of 3,4-dimethoxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) was used.
2.61 g (yield: 88.0%) of α-cyano-3 ′, 4,4′-trimethoxystilbene (white crystals) was obtained in the same manner as described above. Except that 0.74 g (2.5 mmol) of the α-cyano-3 ′, 4,4′-trimethoxystilbene and 3.47 g (30 mmol) of pyridinium chloride (Wako Pure Chemical Industries) were used. Example 2
By the same method as

[0112]

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588 mg of a yellow crystal represented by the following formula (yield: 9)
3.0%). The melting point of the obtained compound is 229-
231 ° C.

Comparative Example 8 The same procedure as in Example 2 was carried out except that 1.66 g (10 mmol) of 3,4-dimethoxybenzaldehyde (manufactured by Tokyo Kasei) was used instead of 4-chlorobenzaldehyde. 2.99 g (92.0% yield) of α-cyano-3,3 ′, 4,4′-tetramethoxystilbene (yellow crystals) was obtained. 0.81g
(2.5 mmol) of the α-cyano-3 ′, 3,4
4'-tetramethoxystilbene and 3.47 g (30
mmol) of pyridinium chloride (manufactured by Wako Pure Chemical Industries, Ltd.) in the same manner as in Example 2, except that the following chemical formula was used.

[0115]

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138 mg of a yellow crystal represented by the following formula (yield: 2)
0.5%). The melting point of the obtained compound is from 238 to
239 ° C.

(Comparative Example 9) 475 mg (2.68 mmol)
l) 3,4-dimethoxyphenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) and 402 mg (2.68 mmol) of 4
Heating and dissolving 5 ml of anhydrous ethanol mixture of formyl benzoic acid (manufactured by Tokyo Chemical Industry Co., Ltd.), adding 2.0 ml of a 2.68 M denatured alcohol solution of sodium ethoxide (manufactured by Aldrich), and reacting; The mixture was further left for 1 hour, 30 ml of water was added, and the mixture was stirred to dissolve. The insoluble components were filtered off and washed with water. 30 ml of the obtained crystals
The mixture was added to normal hydrochloric acid, stirred, and the precipitated crystals were collected by filtration, washed sufficiently with water, and dried to obtain α′-cyano-3 ′, 4′-dimethoxy-4-stilbenecarboxylic acid yellow crystals (605 m).
g (73.0% yield).

309 mg (1.0 mmol) of the α ′
A mixture of -cyano-3 ', 4'-dimethoxy-4-stilbenecarboxylic acid and 1.73 g (15 mmol) of pyridinium chloride (manufactured by Wako Pure Chemical Industries, Ltd.) was melt-stirred at 200 ° C for 1 hour in an argon gas atmosphere. Thereafter, the reaction mixture was air-cooled, and the solidified reaction mixture was pulverized by adding 2N hydrochloric acid,
Stir, filter, and wash with water. The obtained crystals were dissolved in ethanol, dried to dryness under reduced pressure, ethanol was added again to dryness under reduced pressure, and the residue was recrystallized from ethanol-hexane to give the following chemical formula.

[0119]

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198 mg of a yellow crystal represented by the following formula (yield: 7
0.4%). The melting point of the obtained compound is 285-
287 ° C.

[0121]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to the following Examples (however, Example 16 is a reference example).
) . Example 1 758 mg (5.0 mmol) of 4-chlorophenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) and 691 mg (5.0 mmol)
(mmol) of 3,4-dihydroxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) in 10 ml of ethanol (manufactured by Kokusan Chemical Co., Ltd.), and 0.54 ml of piperidine (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto, followed by heating under reflux for 6 hours. After air cooling, the reaction product was added to 100 ml of 1N hydrochloric acid and stirred. The precipitate was separated by filtration, washed with water, dissolved in ethyl acetate (manufactured by Kokusan Chemical Co., Ltd.), and twice with a 20% aqueous sodium bisulfite solution. Then, it was washed once with a saturated saline solution and dried over anhydrous sodium sulfate (manufactured by Wako Pure Chemical Industries, Ltd.). Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent was hexane: ethyl acetate at a ratio of 5: 1 to 5: 2).

[0122]

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919 mg (yield 67.6%) of a yellow crystalline compound represented by the following formula was obtained. The melting point of the obtained compound was 16
0-162 ° C.

Example 2 1.77 g (10.0 mmol) of 3,4-dimethoxyphenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.), 1.41 g
(10.0 mmol) of 4-chlorobenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) and 5 ml of ethanol (manufactured by Kokusan Chemical) are dissolved by heating, 2 drops of a 20% aqueous sodium hydroxide solution are added, and the mixture is stirred overnight. The precipitated crystals were pulverized in ethanol, filtered, washed with ethanol and then with hexane, dried, and dried to give 2.39 g (yield: 79.7).
%) Α-cyano-3,4-dimethoxy-4′-chlorostilbene (yellow-green crystals).

0.75 g (2.5 mmol) of the α-
A mixture of cyano-3,4-dimethoxy-4'-chlorostilbene and 2.31 g (20.0 mmol) of pyridinium chloride (manufactured by Wako Pure Chemical Industries, Ltd.) was preheated to 210 ° C. in an argon gas atmosphere in an oil bath. The mixture was melted and stirred at the same temperature for 1 hour. Then, the mixture was air-cooled, and 2N hydrochloric acid and ethyl acetate (manufactured by Kokusan Chemical Co., Ltd.) were added to the solidified reaction product.
The solvent layer was separated, the aqueous layer was extracted with ethyl acetate, added to the solvent layer, washed with saturated saline, and dried over anhydrous sodium sulfate (manufactured by Wako Pure Chemical Industries, Ltd.).

Then, the solvent was distilled off under reduced pressure, the residue was dissolved in a small amount of ethyl acetate, hexane was added until the mixture became slightly turbid, and the mixture was stirred.

[0127]

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455 mg (yield: 67.0%) of a yellow crystalline compound represented by the following formula was obtained. The melting point of the obtained compound is 17
1-172 ° C.

Example 3 676 mg instead of 4-chlorophenylacetonitrile
(5.0 mmol) of 4-fluorophenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) except that the following chemical formula was used in the same manner as in Example 1.

[0130]

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405 mg of a pale yellow crystalline compound represented by the following formula:
(31.7% yield). The melting point of the obtained compound is
184-186 ° C.

Example 4 980 mg instead of 4-chlorophenylacetonitrile
(5.0 mmol) of 4-bromophenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.), except that the following chemical formula was used in the same manner as in Example 1.

[0133]

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1.14 g of a pale yellow crystalline compound represented by the following formula:
(Yield: 72.2%). The melting point of the obtained compound is
172-175 ° C.

Example 5 In the same manner as in Example 1 except that 4-chlorophenylacetonitrile was replaced by 1.22 g (5.0 mmol) of 4-iodophenylacetonitrile synthesized by the following method. The following chemical formula

[0136]

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1.39 g (yield: 76.4%) of a yellow crystalline compound represented by the following formula was obtained. The melting point of the obtained compound was 19
7-198 ° C.

[Synthesis of 4-iodophenylacetonitrile] 4.36 g (20 mmol) of p-iodotoluene (manufactured by Tokyo Chemical Industry Co., Ltd.) and 3.92 g (22 mmol) of N-
A mixture of bromosuccinimide (manufactured by Tokyo Chemical Industry Co., Ltd.) and 60 ml of carbon tetrachloride (manufactured by Wako Pure Chemical Industries, Ltd.) was heated and refluxed under incandescent lamp irradiation for 4 hours, and 2.67 g (45.0% yield) was obtained.
Of 4-iodobenzyl bromide (white crystals) was obtained. Then 0.49 g (10 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.

Example 6 656 mg instead of 4-chlorophenylacetonitrile
(5.0 mmol) of p-tolylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) except that the following chemical formula was used in the same manner as in Example 1.

[0140]

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515 mg (yield: 41.0%) of a yellow crystalline compound represented by the following formula was obtained. The melting point of the obtained compound was 16
4-165 ° C.

Example 7 656 mg instead of 4-chlorophenylacetonitrile
(5.0 mmol) of m-tolylacetonitrile (manufactured by Aldrich), except that the following chemical formula was used in the same manner as in Example 1.

[0143]

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360 mg of a pale yellow crystalline compound represented by the following formula:
(28.7% yield). The melting point of the obtained compound is
144-145 ° C.

Example 8 736 mg instead of 4-chlorophenylacetonitrile
(5.0 mmol) of 4-methoxyphenylacetonitrile (manufactured by Aldrich), except that the following chemical formula was used in the same manner as in Example 1.

[0146]

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214 mg of a pale yellow crystalline compound represented by the following formula:
(16.0% yield) was obtained. The melting point of the obtained compound is
197-198 ° C.

Example 9 586 mg instead of 4-chlorophenylacetonitrile
(5.0 mmol) of phenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.), except that the following chemical formula was used in the same manner as in Example 1.

[0149]

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890 mg of a pale yellow crystalline compound represented by the following formula:
(Yield 75.0%) was obtained. The melting point of the obtained compound is
148-150 ° C.

Example 10 926 mg instead of 4-chlorophenylacetonitrile
(5.0 mmol) of 4-trifluoromethylphenylacetonitrile (manufactured by Aldrich) except that the following chemical formula was used in the same manner as in Example 1.

[0152]

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657 mg (yield: 87.4%) of a yellow crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound was 16
8-169 ° C.

Example 11 The following method was used in the same manner as in Example 1 except that 726 mg (5.0 mmol) of 4-ethylphenylacetonitrile synthesized by the following method was used instead of 4-chlorophenylacetonitrile. Chemical formula

[0155]

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281 mg of a pale yellow crystalline compound represented by the following formula:
(21.2% yield). The melting point of the obtained compound is
137-138 ° C.

[Synthesis of 4-ethylphenylacetonitrile] To 2.72 g (20 mmol) of 4-ethylbenzyl alcohol (manufactured by Aldrich) were added 50 ml of 47%
Add hydrobromic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and add
After vigorously stirring for 0 minutes, the mixture was extracted with hexane to obtain 3.98 g of colorless oily 4-ethylbenzyl bromide. Then, 1.96 g (40 mmol) of sodium cyanide (manufactured by Kokusan Chemical Co., Ltd.) in 20 ml of dimethyl sulfoxide (manufactured by Aldrich) preliminarily heated to 50 ° C. was added to the above 4
-Ethylbenzyl bromide (3.98 g) was added, 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 4-ethylphenylacetonitrile was pale yellow oil 2.70 g (yield 93.
1%).

Example 12 616 mg instead of 4-chlorophenylacetonitrile
(5.0 mmol) of 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 1.

[0159]

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281 mg (yield: 21.2%) of a yellow crystalline compound represented by the following formula was obtained. The melting point of the obtained compound is 18
0.5-181.5 ° C.

Example 13 The same as Example 1 except that instead of 4-chlorophenylacetonitrile, 1.01 g (5.0 mmol) of 4-bromothiophen-2-ylacetonitrile synthesized by the following method was used. The following chemical formula

[0162]

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1.05 g (yield: 65.0%) of a yellow crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound is 22
2-224 ° C.

[Synthesis of 4-bromothiophen-2-ylacetonitrile] A mixture of 9.55 g (50 mmol) of 4-bromothiophen-2-carboxaldehyde (manufactured by Aldrich) and 100 ml of ethanol (manufactured by Kokusan Chemical). While cooling in an ice bath with 3.78 g (1
(00 mmol) of sodium borohydride (manufactured by Yoneyama Pharmaceutical Co., Ltd.) was gradually added, and the whole was added. After stirring at room temperature for 1.5 hours, the mixture was acidified with hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in water and extracted with ether. 9.29 g of oily 4-bromothiophen-2-ylmethanol (yield: 96)
%).

Next, 63 m was added to 4.83 g (25 mmol) of the 4-bromothiophen-2-ylmethanol.
l of 47% hydrobromic acid (manufactured by Wako Pure Chemical Industries, Ltd.)
The mixture was stirred vigorously at room temperature for 30 minutes and extracted with pentane (manufactured by Kokusan Chemical Co., Ltd.) to obtain 5.31 g (82.8% yield) of 2-bromomer-4-bromothiophene as a pale yellow oil. The obtained 2-bromomer-4-bromothiophene 5.12
g, using α, α-bis [(4-bromothiophen-2-yl) methyl] by-produced by reacting with sodium cyanide in the same manner as in the synthesis of 4-iodophenylacetonitrile in Example 5 using g. 4-Bromothiophene acetonitrile was removed by fractional recrystallization, and white crystals of 4-
Bromothiophen-2-ylacetonitrile 1.50 g
(37.0% yield).

Example 14 Same as Example 1 except that 4-chlorophenylacetonitrile was replaced by 1.01 g (5.0 mmol) of 5-bromothiophen-2-ylacetonitrile synthesized by the following method. The following chemical formula

[0167]

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216 mg (yield 13.4%) of a yellow crystalline compound represented by the following formula was obtained. The melting point of the obtained compound is 18
5-186 ° C.

[Synthesis of 5-bromothiophen-2-ylacetonitrile] Except that 5-bromothiophen-2-carboxaldehyde (manufactured by Aldrich) was used and purification was performed by high performance liquid chromatography. The compound was synthesized by the same method as that of Example 13 for synthesizing 4-bromothiophen-2-ylacetonitrile.

Example 15 Instead of 3,4-dihydroxybenzaldehyde 771
mg (5.0 mmol) of 3,4,5-trihydroxybenzaldehyde (manufactured by Aldrich) except that the following chemical formula was used in the same manner as in Example 1.

[0171]

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344 mg of a pale yellow crystalline compound represented by the following formula:
(23.9% yield). The melting point of the obtained compound is
240-243 ° C.

Example 16 In place of 4-chlorophenylacetonitrile, 355 mg (2.5 mmol) of cyanophenylacetonitrile synthesized by the following method was replaced with 345 mg (2.5 mmol) of 3,4-dihydroxibenzaldehyde (manufactured by Aldrich). In the same manner as in Example 1, except that 5 ml of ethanol and 0.27 ml of piperidine (manufactured by Wako Pure Chemical Industries, Ltd.) were used and stirring was performed at room temperature for 6 hours, the following chemical formula was used.

[0174]

Embedded image 558 mg (yield 85.1) of a yellow crystalline compound represented by
%). The melting point of the obtained compound was 263-265.
° C.

[Synthesis of 4-cyanophenylacetonitrile] The procedure of Example 5 was repeated except that 2.34 g (20 mmol) of p-tolunitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) was used.
According to the same method as that for synthesizing iodophenylacetonitrile, 2.0 g (yield: 51.0%) of 4-bromomethylbenzonitrile (white crystals) was obtained. Then 1.76 g
(9.0 mmol) of 4-bromomethylbenzonitrile was used, and the purification was performed by silica gel column chromatography and recrystallization, and the same method as that of Example 5 for synthesizing 4-iodophenylacetonitrile was used. According to the method, 438 mg (yield: 34.2%) of pale yellow crystals of 4-cyanophenylacetonitrile were obtained.

Example 17 811 mg instead of 4-chlorophenylacetonitrile
Example 1 was the same as Example 1 except that (5.0 mmol) of 4-nitroacetonitrile (manufactured by Aldrich) was used, stirring was performed at room temperature for 4 hours, and purification was performed by a recrystallization method from ethanol-water. By the same method, the following chemical formula

[0177]

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1.18 g (yield: 82.3%) of an orange crystal compound represented by the following formula was obtained. The melting point of the obtained compound was 26.
0-262 ° C.

Example 18 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 the medicament 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 19 A mixture having the following composition per capsule was prepared and filled in a gelatin capsule by a conventional method to produce the medicament 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 20 Instead of 4-chlorobenzaldehyde, 1.06 g (1
0.02 mmol) of benzaldehyde (manufactured by Wako Pure Chemical Industries, Ltd.), and 2.62 g (yield 98.9%) of α-cyano-3,
4-Dimethoxystilbene (yellow crystals) was obtained. Identical to Example 2 except that instead of α-cyano-3,4-dimethoxy-4′-chlorostilbene, 530 mg (2.0 mmol) of the α-cyano-3,4-dimethoxystilbene were used. Depending on the method, the following chemical formula

[0182]

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253 mg (yield 53.4%) of a yellow crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound is 17
2.5-173.0 ° C.

Example 21 In place of 4-chlorobenzaldehyde, 1.24 g (1
2.33 g (82.2% yield) of α-cyano-3,4 by the same method as in Example 2 except that 0.0 mmol) of 4-fluorobenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) was used. -Dimethoxyfluorostilbene (white crystals)
I got 567 mg (2.0 mmol) instead of α-cyano-3,4-dimethoxy-4′-chlorostilbene
In the same manner as in Example 2, except that the above α-cyano-3,4-dimethoxy-4′-fluorostilbene was used, the following chemical formula

[0185]

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432 mg (yield: 84.6%) of a white crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound is 17
5.5-176.0 ° C.

Example 22 In place of 4-chlorobenzaldehyde, 1.41 g (1
0.035 mmol) of 3-chlorobenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.), and 2.35 g (yield: 78.3%) of α-cyano-
3,4-Dimethoxy-3'-chlorostilbene (yellow crystals) was obtained. α-cyano-3,4-dimethoxy-4′-
600mg (2.0mmo) instead of chlorostilbene
l) In the same manner as in Example 2, except that the above α-cyano-3,4-dimethoxy-3'-chlorostilbene was used, the following chemical formula was obtained.

[0188]

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436 mg (yield: 80.2%) of a white crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound is 18
9-190 ° C.

Example 23 Instead of 4-chlorobenzaldehyde, 1.85 g (1
0.07 mmol) of 4-bromobenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.), and 3.17 g (yield 92.1%) of α-cyano-
3,4-Dimethoxy-4'-bromostilbene (yellow crystals) was obtained. α-cyano-3,4-dimethoxy-4′-
Instead of chlorostilbene, 688 mg (2.0 mmol
l) In the same manner as in Example 2 except that the above α-cyano-3,4-dimethoxy-4'-bromostilbene was used, the following chemical formula was obtained.

[0191]

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544 mg (yield: 86.0%) of a white crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound is 17
1.0-171.5 ° C.

Example 24 Instead of 4-chlorobenzaldehyde, 1.20 g (1
0.020 mmol) of 4-methylbenzaldehyde (manufactured by Wako Pure Chemical Industries, Ltd.), and 2.20 g (yield 78.8%) of α-cyano-3 by the same method as in Example 2. There was obtained 4,4-dimethoxy-4'-methylstilbene (yellow crystals). α-cyano-3,4-dimethoxy-
Instead of 4'-chlorostilbene, 559 mg (2.0
mmol) of the α-cyano-3,4-dimethoxy-
Example 2 except that 4'-methylstilbene was used.
By the same method as

[0194]

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438 mg (yield: 87.1%) of a white crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound was 16
2.5-163.0 ° C.

Example 25 In place of 4-chlorobenzaldehyde, 1.20 g (1
1.46 g (52.3% yield) of α-cyano- by the same method as in Example 2 except that 0.0 mmol) of 3-methylbenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) was used.
3,4-Dimethoxy-3'-methylstilbene (yellow crystals) was obtained. α-cyano-3,4-dimethoxy-4′-
Instead of chlorostilbene, 559mg (2.0mmo
l) In the same manner as in Example 2, except that the above α-cyano-3,4-dimethoxy-3'-methylstilbene was used, the following chemical formula was obtained.

[0197]

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294 mg (yield 58.5%) of a yellow crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound was 11
0-111 ° C.

Example 26 Instead of 4-chlorobenzaldehyde, 1.34 g (1
0.079) of 4-ethylbenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.), except that 1.79 g (61.0% yield) of α-cyano-
3,4-Dimethoxy-4'-ethylstilbene (pale yellow crystal) was obtained. α-cyano-3,4-dimethoxy-4 ′
-Instead of chlorostilbene, 587 mg (2.0 mm
ol) of the above α-cyano-3,4-dimethoxy-4′-
By the same method as in Example 2 except that ethylstilbene was used, the following chemical formula

[0200]

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448 mg (yield: 84.4%) of a yellow crystalline compound represented by the following formula: was obtained. The melting point of the obtained compound was 14
0.5 to 141.0 ° C.

Example 27 In place of 4-chlorobenzaldehyde, 1.26 g (1
0.0mmol) of 5-methylthiophene-2-carboxaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.)
According to the same method as that of Example 2, 2.36 g (yield: 82.
7%) of α- (3,4-dimethoxyphenyl) -β-
(5-Methylthiophen-2-yl) acrylonitrile (pale yellow crystal) was obtained. Instead of α-cyano-3,4-dimethoxy-4′-chlorostilbene, 571 mg
Except that (2.0 mmol) of the α- (3,4-dimethoxyphenyl) -β- (5-methylthiophen-2-yl) acrylonitrile was used, the following chemical formula was obtained in the same manner as in Example 2.

[0203]

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There was obtained 400 mg (yield: 77.7%) of an orange crystal compound represented by the following formula: The melting point of the obtained compound is 18
3.0 to 183.5 ° C.

Example 28 In place of 4-chlorobenzaldehyde, 1.10 g (1
0.0mmol) of 5-methylfuran-2-carboxaldehyde (manufactured by Wako Pure Chemical Industries, Ltd.)
According to the same method as that of Example 2, 2.16 g (yield 80.
2%) α- (3,4-dimethoxyphenyl) -β-
(5-Methylfuran-2-yl) acrylonitrile (yellow crystals) was obtained. α-cyano-3,4-dimethoxy-
Instead of 4'-chlorostilbene, 539 mg (2.0
mmol) of the α- (3,4-dimethoxyphenyl)
By the same method as in Example 2, except that -β- (5-methylfuran-2-yl) acrylonitrile was used.
The following chemical formula

[0206]

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320 mg (yield: 66.3%) of an orange crystal compound represented by the following formula was obtained. The melting point of the obtained compound is 15
0.5 to 151.0 ° C.

Example 29 5.51 g (50 mmol) of 5-methylfuran-2-carboxaldehyde (manufactured by Wako Pure Chemical Industries, Ltd.), 6.66 g (50 mmol) of rhodanine (manufactured by Tokyo Chemical Industry), anhydrous sodium acetate (domestic) 12.3 g (150 mm)
ol) and 35 ml of acetic acid (manufactured by Wako Pure Chemical Industries, Ltd.) were 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 and 10.04 g of orange-brown crystals of (5-methylfurfurylidene) rhodanine (yield 89.1).
%). The whole amount was suspended in 65 ml of a 15% aqueous sodium hydroxide solution, heated at 100 ° C. for 30 minutes, air-cooled, added to 500 ml of 10% hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, dried and dried. -(5-methylfuryl)
8.22 g of yellow crystals of -2-thioketopropionic acid were obtained.

To this total amount was added 45 ml of ethanol and 10.1 g of hydroxylamine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.).
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.

This 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 The oil was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give 5-
2.00 g (yield 66.6%) of a colorless oily product of methylfuran-2-ylacetonitrile was obtained.

606 mg (5.0 mmol) of 5-methylfuran-2-ylacetonitrile and 831 mg of 3,4-dimethoxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.)
419 mg (yield: 31.1%) of 5-, by the same method as in Example 2 except that (5.0 mmol) was used.
Methyl-α- (3,4-dimethoxybenzylidene) furan-2-acetonitrile (yellow crystals) was obtained. Instead of α-cyano-3,4-dimethoxy-4′-chlorostilbene, 323 mg (1.2 mmol) of the above 5-methyl-α- (3,4-dimethoxybenzylidene) furan-2
-In the same manner as in Example 2 except that acetonitrile and 1.73 g (15 mmol) of pyridinium chloride (manufactured by Wako Pure Chemical Industries, Ltd.) were used, the following chemical formula was used.

[0212]

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140 mg (yield: 48.4%) of an orange crystal compound represented by the following formula: was obtained. The melting point of the obtained compound is 15
3.0-153.5 ° C.

[0214]

As described in detail above, the present invention provides a 12-
Stilbene derivatives and stilbene homolog derivatives that selectively inhibit lipoxygenase, and pharmaceuticals that selectively inhibit 12-lipoxygenase containing these compounds as an active ingredient, the effects provided by the present invention, It is 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 A61K 31/38 A61K 31/38 C07C 43/23 C07C 43/23 C 255/36 255/36 255/53 255/53 C07D 307 / 54 C07D 307/54 333/24 333/24 (72) Inventor Shigehiro Mori 5-1-15-407 Higashihara, Zama City, Kanagawa Prefecture Sagamino Sakura (72) Inventor Naoko Moriuchi 1-20 Hino Minami, Konan-ku, Yokohama, Kanagawa Prefecture -7 (56) References US Patent 2,681,359 (US, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 39/21 C07C 43/23 C07C 255/36 C07C 255/53 C07D 307 / 54 C07D 333/24

Claims (3)

(57) [Claims] 1. The following general formula: Wherein R ¹ represents a hydrogen atom or a hydroxyl group;
² and R ³ represent a hydrogen atom or a cyano group (provided that
R ² and R ³ are different from each other), and Ar is a general formula of the following chemical formula 2, chemical formula 3, or chemical formula 4 Embedded image Embedded image In a group represented, wherein R ⁴ represents lower alkyl group, a lower alkoxy group, a halogen atom, or a trifluoromethyl group. Or a stilbene homolog derivative. 2. The following general formula: Wherein R ¹ represents a hydrogen atom or a hydroxyl group;
² and R ³ represent a hydrogen atom or a cyano group (provided that
R ² and R ³ are different from each other), and Ar is
Or the general formula of Embedded image Embedded image In a group represented, wherein R ⁴ is lower alkyl group, a lower alkoxy group, a halogen atom, trifluoromethyl
Group, or a nitro group. As an active ingredient, a compound selected from the group consisting of stilbene derivatives and stilbene homolog derivatives represented by
12-Ripokishigena peptidase inhibitors. 3. The general formula according to claim 2. [However, in the formula, R ¹  Represents a hydrogen atom or a hydroxyl group;
^Two  And R ^Three  Represents a hydrogen atom or a cyano group (provided that
R ^Two  And R ^Three And Ar is the same as in the above formulas (6) and (7).
Or a group represented by the general formula: ^Four  Is low
Lower alkyl group, lower alkoxy group, halogen atom, tri
Indicates a fluoromethyl group or a nitro group. ]
Consists of stilbene derivatives and stilbene homolog derivatives
A compound selected from the group or a mixture thereof as an active ingredient
Inhibition of 12-lipoxygenase activity contained as
A drug for inhibiting 12-lipoxygenase having a harmful effect.