JP3166094B2 - Coumarin derivatives and their uses - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to a novel coumarin derivative which selectively inhibits 12-lipoxygenase and a medicament containing these compounds as an active ingredient. A novel coumarin derivative having an action of selectively inhibiting the activity of 12-lipoxygenase in the lipoxygenase pathway, and prevention and treatment of various circulatory diseases such as arteriosclerosis and vasospasm containing the compound as an active ingredient. And a drug that selectively inhibits 12-lipoxygenase, which is useful as a drug for preventing metastasis of cancer (such as Lewis lung cancer). As used herein, the IC ₅₀ value is the molar concentration required for a substance to inhibit 5-lipoxygenase or 12-lipoxygenase activity by 50%.

[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, leukotriene B ₄ has a potent leukocyte chemotactic activity and is a mediator of inflammation, and leukotrienes C ₄ and D ₄ are mediators of asthma. (Prostaglandin and pathology, Tokyo Chemical 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).

[0008] Based on the above facts, substances which inhibit 12-lipoxygenase are useful for preventing or treating various circulatory diseases such as arteriosclerosis and vasospasm, or for preventing metastasis of certain cancers. It is expected that it can be used effectively.

As a substance having an inhibitory action on 12-lipoxygenase, baicalene, one of natural flavonoids, 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, coumarin derivatives are generally
The compound is chemically synthesized or separated from the natural world,
Purified but mentions lipoxygenase inhibitory action
As the prior art, for example, the following item 1) is known.
ing. 1) Escretin (6,7-dihydroxycoumarin)
[Biochimi eto biophysica acta (Biochimi
ca et Biophysica Acta), Volume 753, Issue 1, Issue 13
0-132, 1983].
And 5-lipoxygenase and 12-
IC of the compound against lipoxygenase ₅₀The values are
4 × 10 each^-6M and 2.5 × 10^-6Reported to be M
Have been.

However, as described later, the IC ₅₀ value of the compound is considerably larger than that of the compound of the present invention, and it is hard to say that the compound has selectivity for 12-lipoxygenase. In fact, even in comparative experiments performed by the present inventors, it was found that the 12-lipoxygenase inhibitory effect of esculetin was considerably weaker than that of the compound of the present invention, and no selectivity with 5-lipoxygenase inhibitory effect was observed. .

Further, as 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 Chemical Organic Chemistry (Journal of the Chemical Chemistry)
al Society. C. Organic Chemistry), Vol. 16, No. 2
069-2070, 1969, and Zhurnal Prikladn
oi Spektroskopii), Volume 8, Issue 6, 1063-1
066, 1968]

3) 7,8-dihydroxy-3-phenylcoumarin [Current Science,
Vol. 35, No. 22, pp. 557-559, 1966
Year, Zhurnal Prikladnoi Spektroskopii, Volume 8, Volume 6
No. 1063-1066, 1968, Proceedings of the Indian Academy of Sciences Section A
ndian Academy of Sciences. Section A), Volume 56,
71-85, 1962, Proceedings of the Indian Aca
demy of Sciences. Section A), Vol. 59, No. 3,
185-189, 1964, and Journal of Organic Chemistry
Chemistry), Vol. 19, pp. 1548-1552, 1
954]

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. Organic
Chemistry), Vol. 16, pp. 2069-2070, 19
69 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, 383
388 pages, 1971]

7) 6,7-dihydroxy-4-methyl-
3-Phenylcoumarin [Pharmaco Il Pavia
Edizione Scientifica (Farmaco, Il (P
avia), Edizione Scientifica), Volume 12, 691-
694, 1957, and Atti della accademia nazionale dei Linsay Rendi Conti Classe di Sciense Fischer Matematique e Naturali (Atti della accademia naziona)
le dei Lincei. Rendiconti, Classe di scienzefisich
e, matematiche e naturali), Volume 10, 230-
235, 1951]

8) 6,7-dihydroxy-3,4-diphenylcoumarin [Publicazioni del Centro di Studiodio per la Citogenetica Vegetare del Consiglio Nazionale delle Research (Pubblicazioni del centro di studio per la
citogenetica vegetale del consiglio nazionale dell
e ricerche), No. 182, pp. 350-387, 19
55 years, and Atti della accademia nazionale dei Lincei. (Atti della accademia nazionale dei Lincei.
Rendiconti, Classe di scienze fisiche, matematich
ee naturali), Vol. 16, pp. 645-649, 19
54 years]

9) 6,7-dihydroxy-3- (pyridin-3-yl) coumarin [Journal of the Chemical Society. C. Organic
Chemistry), Vol. 16, pp. 2069-2070, 19
69 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
It has never been known to have lipoxygenase inhibitory activity.

Further, although it is 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 (Biochemical and Biophy
sical Research Communications), Vol. 105, No. 3
No., 1909-095, 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 12) completely inhibited the production of 5-lipoxygenase metabolites in human peripheral blood leukocytes at a concentration of 10 μM, while the compound described in 12) showed a decrease in 12-lipoxygenase in platelets. Only 25% metabolite production at the same concentration
The compound was known to be selective for 5-lipoxygenase [Prostaglandins, Vol. 28, No. 6,
783-804, 1984]. 13)
For the compounds described, the 5-lipoxygenase inhibitory activity of the compounds on human peritoneal macrophages was IC
_In contrast to the ₅₀ value of 1-2 μM, 12
Lipoxygenase inhibitory activity is 16-20 μm in terms of IC ₅₀ value
M [International Journal of Tissue Reactions, No. 1,
1, No. 3, pp. 107-112, 1989].

The compound of the present invention has an IC ₅₀ as described below.
It has a very strong 12-lipoxygenase inhibitory activity, on the order of 10 ^{-9 to} 10 ^-8 mol. On the other hand, 5-
The IC ₅₀ value for lipoxygenase is 7-20 times greater than that for 12-lipoxygenase,
It 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.

[0027]

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.

Under these circumstances, the present inventors have found that baicalene, one of the natural flavonoids, is relatively strong.
-Focusing on lipoxygenase inhibitory activity, and having relatively high selectivity, using this compound as a lead compound, and modifying or modifying its partial structure to have strong and high selectivity We have succeeded in creating a 12-lipoxygenase inhibitory compound and have already filed a patent application (Japanese Patent Application No. 5-108766, hereinafter sometimes referred to as a prior application).

The invention of the prior application is as follows. The following general formula 7

[0031]

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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) No), Ar is a general formula of the following chemical formula 8, 9 or 10

[0033]

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[0034]

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[0035]

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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 coumarin derivative shown by these.

After filing the application for the prior application, the present inventors have conducted intensive studies on other compounds, and as a result, a coumarin derivative different from that of the prior application has an inhibitory activity equivalent to or higher than that of known baicalene, And found that it has excellent selectivity,
The present invention has been 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 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.

[0040]

Means for Solving the Problems A first invention of the present invention for solving the above-mentioned problems is represented by the following general formula (11):

[0041]

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Wherein R ² and R ³ represent a hydrogen atom or a hydroxyl group (however, R ² and R ³ are not simultaneously hydrogen atoms), and Ar is 1
General formula of 3

[0043]

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[0044]

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Wherein X represents an oxygen atom or a sulfur atom. A coumarin derivative represented by the formula:

According to a second aspect of the present invention for solving the above problems, the following general formula (14)

[0047]

Embedded image Wherein R ² and R ^{3 each} represent a hydrogen atom or a hydroxyl group (however, R ² and R ³ are not simultaneously hydrogen atoms); formula

[0048]

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[0049]

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Wherein X represents an oxygen atom or a sulfur atom. Or a mixture thereof as an active ingredient.

Next, the present invention will be described in detail. The method for producing the compound of the present invention is as follows. That is, the compound of the present invention can be synthesized by the step represented by the chemical formula (17).

[0052]

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(In the above formula, R ⁵ and R ⁶ are
A hydrogen atom or a methoxy group, and R ⁷ and R ^{8 each} represent a hydrogen atom or a hydroxyl group). That is, the methyl ether (a) of a salicylaldehyde derivative and the desired arylacetonitrile (a) are subjected to Knoevenagel condensation to obtain an α, β-diarylacrylonitrile derivative (c), which is then converted to, for example, pyridinium chloride or the like. The resulting imine (d) is treated with an acid such as hydrochloric acid and hydrolyzed to obtain the compound (e) of the present invention (step A).

Also, the chemical formulas of the following chemical formulas (18) and (19)

[0055]

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[0056]

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(In the above formula, R ⁷ and R ^{8 each} represent a hydrogen atom or a hydroxyl group, and R ⁹ and R ^{10 each} represent a hydrogen atom or an acetoxy group.)

Acetylsalicylic aldehyde derivative (G)
And the desired aryl acetic acid (H) are condensed under a reaction condition known as the Parkin reaction. That is, usually 12 hours in acetic anhydride in the presence of a base such as triethylamine.
By gently heating and refluxing at about 0 ° C. for 1 hour to several hours, compound (I) can be obtained (step B).

Acetylsalicylic aldehyde derivative (G)
Can be obtained by acetylating the corresponding salicylaldehyde derivative (f) with an acetylating agent such as acetic anhydride or acetyl chloride, and the salicylaldehyde derivative (f) is cooled on ice or at room temperature. Acetyl salicylaldehyde derivative produced by acetylation in acetic anhydride in the presence of a base such as triethylamine (G)
Can be directly led from the compound (f) to the compound (g) by directly transferring to the above-mentioned Parkin reaction conditions without isolation. In this case, the other raw material, aryl acetic acid (h), may be added at the time of transition to the Parkin reaction condition, but may be coexistent from the stage of acetylation of the compound (h), 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 (q) thus obtained can be hydrolyzed (or transesterified) under acidic conditions to lead to the compound (v) of the present invention. For example, the object is achieved by heating and refluxing for 30 minutes to several hours in a mixed solution of ethanol and hydrochloric acid (Step C).

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 compound is used as an active ingredient to treat or prevent various circulatory diseases such as arteriosclerosis and vasospasm caused by metabolites, and to prevent metastasis of certain cancers (such as Lewis lung cancer). It can be used effectively as a drug.

The compound of the present invention may be used alone 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 This test was performed to examine the inhibitory effect of the compound of the present invention on 12-lipoxygenase and 5-lipoxygenase. 1. Preparation of Sample 1) Test sample A test sample was prepared in the same manner as in Examples 1 to 4.
As a control, the following chemical formula

[0065]

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A known baicalene (manufactured by Wako Pure Chemical Industries, Ltd.) represented by the following formula:

[0067]

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A known esculetin (manufactured by Tokyo Chemical Industry Co., Ltd.) represented by

2) Preparation of Enzyme Solution for 12-Lipoxygenase Under ether anesthesia, approximately 1/10 volume of 3.8% (weight; the same applies hereinafter) sodium citrate solution was introduced from the abdominal aorta of a male Sprague Dawley rat. Blood is collected with a syringe, centrifuged at 180 g for 15 minutes at room temperature, platelet-rich plasma is separated, and centrifuged at 1,800 g for 10 minutes at 4 ° C., and the obtained precipitate is washed with a washing buffer (154 mM sodium chloride, 2 mM EDTA The platelets were washed with 50 mM Tris-HCl buffer (pH 7.4). The obtained platelets are re-suspended in 1/20 volume of the resuspended buffer (154
mM sodium chloride, 50 containing 5.5 mM glucose
mM Tris-HCl buffer: pH 7.4), sonicated, and centrifuged at 100,000 g for 30 minutes, and the supernatant was separated to prepare an enzyme solution.

3) 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.

2. Test method 1) Method for measuring enzyme activity of 12-lipoxygenase 1 μl of a 3 mM indomethacin ethanol solution and 1 μm of a 300 mM reduced glutathione solution were added to 300 μl of the enzyme solution prepared to have an enzyme activity of about 2 mU / ml with the resuspension buffer.
and 3 μl of an ethanol solution of the test substance at various concentrations were added, and the mixture was kept at 37 ° C. for 5 minutes. Then, 3 μl of a 2.5 mM ethanol solution of arachidonic acid was added, and the mixture was allowed to react at 37 ° C. for 5 minutes. Was added to stop the reaction. 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.

2) Method for measuring 5-lipoxygenase enzyme activity: 15 μl of the enzyme solution (equivalent to 40 mU / ml) was added to 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.

3) Measurement of Enzyme Activity As test substances, the enzyme activities of the compounds of the present invention, baicalene and esculetin, which were produced by the same method as in Examples 1 to 4, were measured at various concentrations by the above-mentioned method. From the measured values of the test substances, IC ₅₀ values for 12-lipoxygenase and 5-lipoxygenase were determined.

3. Test Results The results of this test are as shown in Table 1. As is clear from Table 1, the compounds of the present invention exhibited a very strong inhibitory effect on 12-lipoxygenase,
₅₀ value is of the order of approximately 10 ^-9 mol to 10 ^-8 mol early showed smaller than it (4.2 × 10 ^-8 mol) of a known Baikaren. On the other hand, the compounds of the present invention can also have an inhibitory effect on 5-lipoxygenase, its an IC ₅₀ value was a value of about 7 to 20 times higher than that for the 12-lipoxygenase. Therefore, the compound of the present invention was found to have a selective inhibitory effect on 12-lipoxygenase.

[0075]

[Table 1]

Now, the present invention will be described in further detail with reference to Examples for the production examples of the compounds of the present invention. However, the present invention is not limited to the following Examples. Table 2 shows the measured values of the nuclear magnetic resonance spectrum and the infrared absorption spectrum of the compound of the present invention produced in the following Examples. Further, the nuclear magnetic resonance spectrum [ ¹ H-NMR (500 MH
z)] is a heavy methyl sulfoxide (DMSO-d ₆₎ solvent using tetramethylsilane as an internal standard, the infrared absorption spectra, in KBr tablet method, were measured.

[0077]

[Table 2]

[0078]

【Example】

Example 1 931 mg of naphthalene-2-acetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.)
(5.00 mmol) and 771 mg of 2,3,4-trihydroxybenzaldehyde (manufactured by Aldrich)
(5.00 mmol) with acetic anhydride (Wako Pure Chemical Industries, Ltd.)
The suspension was suspended in 10 ml, and 5 ml of triethylamine (manufactured by Kokusan Chemical Co., Ltd.) was added thereto under ice cooling, followed by stirring for 1 hour under ice cooling. Then, the reaction mixture was heated and refluxed on an oil bath at 120 ° C. for 5 hours, and then air-cooled. The reaction mixture was added to 100 ml of 1N hydrochloric acid and stirred, and the precipitate was collected by filtration, sufficiently washed with water, and washed with ethanol ( Washed three times with Kokusan Chemical Co., Ltd. and twice with hexane (Kokusan Chemical Co., Ltd.), dried, and 1.52 g of cream-colored crystalline compound 7,8-diacetoxy-3- (naphthalen-2-yl) coumarin. (Yield: 78.4%).

The above-mentioned 7,8-diacetoxy-3- (naphthalen-2-yl) coumarin 388 mg (1.00 mmol)
l), ethanol (Kokusan Chemical Co., Ltd.) 8 ml, concentrated hydrochloric acid 1 m
A mixture of 1 ml of water and 1 ml of water was heated at reflux for 4 hours, and then air-cooled. The reaction mixture was added to 100 ml of water, and the precipitate was collected by filtration, thoroughly washed with water, and dried. The obtained reaction product was purified by silica gel column chromatography [eluent: ethyl acetate (manufactured by Kokusan Chemical Co., Ltd.): Hexane (manufactured by Kokusan Chemical Co., Ltd.) having a ratio of 1: 5 to 3: 1] was used. Formula 22

[0080]

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1045 mg of a yellow crystalline compound represented by the following formula:
(86.2% yield). The melting point of the obtained compound is
255-256 ° C.

Example 2 Naphthalene-2-acetonitrile (Aldrich)
836 mg (5.00 mmol) and 2,4,5-trimethoxybenzaldehyde (manufactured by Lancaster) 981 m
g (5.00 mmol) of ethanol (manufactured by Kokusan Chemical Co., Ltd.)
15 ml of the mixture was dissolved by heating, 2 drops of a 20% aqueous sodium hydroxide solution was added, and the mixture was stirred overnight while cooling, and the precipitated crystals were collected by filtration, and ethanol (manufactured by Kokusan Chemical) and hexane (manufactured by Kokusan Chemical). ) And dried, and the yellow crystalline compound α- (naphthalen-2-yl) -β- (2,4,5-
1.48 g of trimethoxyphenyl) acrylonitrile
(85.9% yield).

The above α- (naphthalen-2-yl) -β-
A mixture of 691 mg (2.00 mmol) of (2,4,5-trimethoxyphenyl) acrylonitrile and 3.5 g (30 mmol) of pyridinium chloride (manufactured by Wako Pure Chemical Industries, Ltd.) was melted on an oil bath previously heated to 220 ° C. Mix,
Stir for 1 hour, then air-cool and add 10 minutes to the solidified reaction mixture.
20 ml of hydrochloric acid was added and the mixture was pulverized and stirred for 30 minutes. The precipitate was collected by filtration, washed sufficiently with water, and dried. The obtained reaction product was purified by silica gel column chromatography [eluent was ethyl acetate (manufactured by Kokusan Chemical Co., Ltd.)].
The chemical formula of the following Chemical Formula 23

[0084]

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431 mg (yield: 70.8%) of a yellow crystal compound represented by the following formula: was obtained. The melting point of the obtained compound is 28
8-289 ° C.

Example 3 693 mg (4.00 mmol) of thianaphthene-3-acetonitrile (manufactured by Lancaster) and 785 m of 2,3,4-trimethoxybenzaldehyde (manufactured by Tokyo Kasei)
g (4.00 mmol) of ethanol (manufactured by Kokusan Chemical Co., Ltd.)
5 ml of the mixture was heated and dissolved, 2 drops of a 20% aqueous sodium hydroxide solution was added, and the mixture was stirred overnight while cooling, and the reaction mixture was added to 100 ml of 1N hydrochloric acid, extracted twice with ethyl acetate, and extracted with sodium bicarbonate water. , Saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the brown oily compound α- (thianaphthen-3-yl) -β- (2,
3,4-trimethoxyphenyl) acrylonitrile
41 g (quantitative yield) were obtained.

Α- (Naphthalen-2-yl) -β-
Instead of (2,4,5-trimethoxyphenyl) acrylonitrile, the above α- (thianaphthen-3-yl)-
In the same manner as in Example 2, except that 703 mg (2.00 mmol) of β- (2,3,4-trimethoxyphenyl) acrylonitrile was used,

[0088]

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343 mg of an ocher crystal compound represented by
(55.3% yield). The obtained compound did not show a clear melting point, turned black at around 140 ° C., and was decomposed (the measured values of the nuclear magnetic resonance spectrum and the infrared absorption spectrum of this compound are shown in Table 2).

Example 4 Instead of 2,3,4-trimethoxybenzaldehyde,
A yellow crystalline compound α- (thianaphthen-3-yl) -β was prepared in the same manner as in Example 3 except that 785 mg (4.00 mmol) of 2,4,5-trimethoxybenzaldehyde (manufactured by Lancaster) was used. − (2,4,5
-Trimethoxyphenyl) acrylonitrile 579 mg
(41.2% yield). However, unlike the case of Example 3, since the target product was precipitated as a crystal in the reaction system, the following treatment was performed in the same manner as in Example 2.

Α- (Naphthalen-2-yl) -β-
In place of (2,4,5-trimethoxyphenyl) acrylonitrile, the aforementioned α- (thianaphthen-3-yl) -β
422 mg (1.20 mmol) of-(2,4,5-trimethoxyphenyl) acrylonitrile was used and pyridinium chloride (manufactured by Wako Pure Chemical Industries, Ltd.) 2.1 g (18
mmol), and the same method as in Example 2 was carried out, except that

[0092]

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127 mg of a green-yellow crystalline compound represented by the following formula:
(34.1% yield). The obtained compound did not show a clear melting point, and was colored and decomposed at around 220 ° C.
Table 2 shows the measured values of the nuclear magnetic resonance spectrum and the infrared absorption spectrum of the compound. ).

Example 5 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 2 20.0 (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 Carboxymethylcellulose calcium ( (Nichirin Chemical Industry Co., Ltd.) 20.0

Example 6 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 2 20.0 (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

[0096]

As described in detail above, the present invention relates to coumarin derivatives and medicaments containing these compounds as active ingredients. 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 containing the compound of the present invention as an active ingredient is effective 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 useful 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 5-17-15 Higashihara, Zama City, Kanagawa Prefecture 407 Sagamino Sakura (72) Inventor Naoko Moriuchi 1-20-7 Hinominami, Konan-ku, Yokohama, Kanagawa Prefecture (56) References 15834 (JP, A) (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 ² and R ^{3 each} represent a hydrogen atom or a hydroxyl group (however, R ² and R ³ are not simultaneously hydrogen atoms), and Ar is a general formula of the following chemical formula 2 or 3 Formula 2 Embedded image Wherein X represents an oxygen atom or a sulfur atom. ] The coumarin derivative shown by these. 2. A general formula of the following chemical formula 4: Wherein R ² and R ³ represent a hydrogen atom or a hydroxyl group (provided that R ² and R ³ are not simultaneously hydrogen atoms), and Ar is a general formula of the following chemical formula 5 or 6 Formula Embedded image Wherein X represents an oxygen atom or a sulfur atom. 12-lipoxygenase inhibitor comprising, as an active ingredient, a compound selected from the group consisting of coumarin derivatives represented by the formula: 3. The general formula of Chemical formula 4 according to claim 2, wherein
Where R ^Two  And R ^Three  Represents a hydrogen atom or a hydroxyl group (only
Then R ^Two  And R ^Three  And are simultaneously hydrogen atoms What is
), Ar is a general formula of the formula (5) or (6)
Wherein X is an oxygen atom or a sulfur atom
Show. Selected from the group consisting of coumarin derivatives
Compound or mixture thereof as active ingredient
Have a selective inhibitory effect on 12-lipoxygenase activity.
A drug for inhibiting 12-lipoxygenase.