JPH0753554A - Coumarin derivative and its use - Google Patents

Abstract

PURPOSE:To obtain a new coumarin compound consisting of a 3-arylcoumarin derivative, cleaving and breaking the modified part in vivo to form a compound having selective 12-lipoxygenase inhibiting action and useful for the prevention, treatment, etc., of arteriosclerosis, etc. CONSTITUTION:This new coumarin derivative is expressed by formula I [R<1> is H or a lower alkyl; Z is H or R<5>CO (R<5> is a 1-20C alkyl or alkenyl); R<2> and R<3> are H, OZ (R<2> and R<3> are not H at the same time); Ar is substituted phenyl, substituted thienyl or substituted furyl]. The compound can be produced, e.g. by acetylating a salicylaldehyde derivative of formula II (R<17> and R<18> are H, OH) with acetic anhydride, etc., condensing with an arylacetic acid by Perkin reaction and optionally deprotecting the product. The modified part of the compound is cleaved and broken in vivo to form a compound capable of selectively inhibiting 12-lipoxygenae activity and accordingly the compound is effective for the prevention and treatment of arteriosclerosis and angiospasm and the prevention of the matastasis of Lewis lung cancer, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention contains novel coumarin derivatives capable of producing a substance which selectively cleaves / cleaves a modified portion in vivo to selectively inhibit 12-lipoxygenase, and these compounds as active ingredients. The present invention relates to a drug, and more specifically, the present invention relates to a 1-member of the 12-lipoxygenase pathway in which a modified portion is cleaved / cleaved in vivo.
A coumarin derivative that may be converted into a compound that selectively inhibits the activity of 2-lipoxygenase (hereinafter sometimes referred to as a precursor), and a cardiovascular system such as arteriosclerosis or vasospasm containing the precursor as an active ingredient The present invention relates to a drug that selectively inhibits 12-lipoxygenase, which is useful as a drug for the prevention and treatment of various diseases and the prevention of metastasis of certain cancers (Lewis lung cancer etc.). In the present specification, unless otherwise specified, the indication of percentage means a value by weight.

[0002]

BACKGROUND ART There is a metabolic pathway called 5-lipoxygenase pathway in the arachidonic acid cascade, and arachidonic acid acts on 5-hydroperoxyeicosatetraenoic acid (hereinafter referred to as 5-HPET) by the action of 5-lipoxygenase.
It is known that it is converted to E) (Murota Seiitsu, edited by “Prostaglandin and Pathology”, Tokyo Kagaku Dojin, 1984).

It is known that various leukotrienes are biosynthesized by using this compound as an intermediate (edited by Seiitsu Murota, “Prostaglandin and Pathology”, Tokyo Kagaku Dojin,
1984), among these leukotrienes, for example, leukotriene B4 has a strong leukocyte chemotactic activity and is a mediator of inflammation, and leukotrienes C4 and D4 are known to be asthma mediators. (Prostaglandin and Pathology, edited by Seito Murota, Tokyo Kagaku Dojin, 1984).

Therefore, if there is a drug capable of effectively inhibiting 5-lipoxygenase, which is the initial enzyme of the biosynthesis system of these leukotrienes, various diseases caused by overproduction of leukotrienes (for example, allergic diseases, From the viewpoint of promising preventive and therapeutic effects for bronchial asthma, edema, various inflammatory diseases, etc., a drug having an inhibitory action on 5-lipoxygenase has been extensively searched.

On the other hand, the arachidonic acid cascade has 12
-There is a metabolic pathway called the lipoxygenase pathway. 12-lipoxygenase is an enzyme that is often 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).

The physiological significance of metabolites in the 12-lipoxygenase pathway has not been clarified in the past as compared with that in the 5-lipoxygenase pathway, but recently, its major metabolite, 12-HP.
Various physiological activities of the metabolite have been clarified, centering on ETE and 12-HETE.

[0007] The physiological activities thereof are as follows. That is, it has been pointed out that metabolites of 12-lipoxygenase may be involved in arteriosclerosis by promoting function regulation of platelet aggregation, adhesion and the like, and migration of vascular smooth muscle cells (Modern Medicine, 21, Vol. 11, No. 3, pages 3109 to 3113, 1989), and it is suggested that 12-HPETE may be an initiator in the occurrence of vasospasm after subarachnoid hemorrhage (modern medicine). , Vol. 21, No. 11, 3127-313
0, 1989), and 12-HETE has been shown to promote adhesion and metastasis of certain cancer cells to vascular endothelial cells (Modern Medicine, Vol. 22, special issue, 56-5).
P. 7, 1990). From the above facts, substances that inhibit 12-lipoxygenase are effective as drugs for the purpose of preventing or treating various diseases of the circulatory system such as arteriosclerosis and vasospasm or preventing metastasis of certain cancers. Expected to be usable.

Under these circumstances, the inventors of the present invention created a compound having a strong 12-lipoxygenase inhibitory action, and filed a patent application therefor (Japanese Patent Application No. 5-108766).
May be referred to as the prior application). That is, the earlier application is
The following general formula

[0009]

[Chemical 11]

[Wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ⁶ and R ⁷ represent a hydrogen atom or a hydroxyl group (provided that R ⁶ and R ⁷ are not hydrogen atoms at the same time)] , Ar is a general formula of the following Chemical formula 12, Chemical formula 13 or Chemical formula 14

[0011]

[Chemical 12]

[0012]

[Chemical 13]

[0013]

[Chemical 14]

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 represented by the formula (hereinafter, these compounds may be collectively referred to as the compound of the prior application).

[0015]

Generally, when a compound is used as a medicine, for example, an oral preparation, it is an important requirement that the compound be efficiently absorbed in the body. As an important factor that affects its efficient absorption,
The compound has properties such as fat solubility and polarity.

By the way, the compounds of the prior application represented by the above general formula have various degrees of lipophilicity or polarity, as can be inferred from the variety of substituents. Therefore, when the compound of the prior application is used, for example, as an oral preparation, the compound does not always have properties such as fat solubility and polarity suitable for absorption from the intestinal tract and the like.

After the application of the prior application, the inventors of the present invention efficiently adsorbed various modified compounds of the compound of the prior application into the living body by imparting lipophilicity or polarity suitable as a drug, and after the absorption, in the living body. Due to the action of the enzyme present in the, the modified portion is cleaved quickly or gradually depending on the purpose.
As a result of the investigation of so-called prodrugs that can be cleaved to form a compound before modification, the monoacyl and diacyl catechol-type hydroxyl groups that the compounds of the prior application have in common are a group of compounds suitable for the above purpose. The present invention has been completed and the present invention has been completed.

The object of the present invention is to provide a novel compound having a use as a so-called prodrug, which can be efficiently absorbed in a living body and can be cleaved / cleaved at a modified portion in a living body to produce a substance which inhibits 12-lipoxygenase. To provide a coumarin derivative of

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

[0020]

The first invention of the present invention for solving the above-mentioned problems is a general formula of the following chemical formula 15.

[0021]

[Chemical 15]

[Wherein R ¹ represents a hydrogen atom or a lower alkyl group, and R ² and R ³ represent a hydrogen atom or OZ.
(Provided that R ² and R ³ are not hydrogen atoms at the same time), Ar is a compound represented by the following general formula 16, chemical formula 17 or chemical formula 18

[0023]

[Chemical 16]

[0024]

[Chemical 17]

[0025]

[Chemical 18] Wherein R ⁴ is a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a nitro group or a cyano group, and Z is independently a hydrogen atom or General formula of

[0026]

[Chemical 19]

## STR3 ## wherein R ⁵ is a group of 1 to 20 carbon atoms (however, not all are hydrogen atoms).
Is a linear or branched alkyl group or alkenyl group. ]
Is a coumarin derivative.

The second invention of the present invention which solves the above-mentioned problems is the following general formula:

[0029]

[Chemical 20]

[Wherein R ¹ represents a hydrogen atom or a lower alkyl group, and R ² and R ³ represent a hydrogen atom or OZ.
(However, R ² and R ³ are not hydrogen atoms at the same time), and Ar is a compound represented by the following chemical formula 21, chemical formula 22, or chemical formula 23:

[0031]

[Chemical 21]

[0032]

[Chemical formula 22]

[0033]

[Chemical formula 23]

Wherein R ⁴ is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a nitro group or a cyano group, and Z is independently hydrogen. Atom or the general formula

[0035]

[Chemical formula 24]

## STR3 ## where R ⁵ is a group of 1 to 20 carbon atoms (provided that all are not hydrogen atoms).
Is a linear or branched alkyl group or alkenyl group. ]
A drug containing as an active ingredient a compound selected from the group consisting of coumarin derivatives represented by:

Next, the present invention will be described in detail. The production method of the compound (precursor) of the present invention is illustrated below. That is, the compound of the present invention can be synthesized by the process shown in the following chemical formula.

[0038]

[Chemical 25]

(In the above chemical formula, R ⁸ represents a hydrogen atom or a lower alkyl group, R ⁹ and R ¹⁰ represent a hydrogen atom or a hydroxyl group, R ¹¹ and R ¹² represent a hydrogen atom or OZ, and Ar represents the following: General formula of Chemical formula 26, Chemical formula 27 or Chemical formula 28

[0040]

[Chemical formula 26]

[0041]

[Chemical 27]

[0042]

[Chemical 28]

Wherein R ¹³ is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a cyano group or a nitro group, and Z is independently a hydrogen atom. Or the following general formula

[0044]

[Chemical 29]

Wherein R ¹⁴ represents a straight chain or branched alkyl group or alkenyl group having 1 to 20 carbon atoms. Hereinafter, Ar may be simply referred to as Ar).

That is, the compound (a) of the present invention is obtained by reacting the hydroxycoumarin derivative (a) with an acylating agent such as a desired acid anhydride or acid chloride in the presence of a base such as triethylamine. You can
In this case, the partially acylated compound can also be obtained by adjusting the equivalence relationship of the acylating agent (step A).

When R ⁸ is a hydrogen atom, the starting hydroxycoumarin derivative (a) can be produced by the process represented by the following chemical formula.

[0048]

[Chemical 30]

(In the above chemical formula, R ¹⁵ and R ¹⁶ are
A hydrogen atom or a methoxy group, and R ⁹ and R ¹⁰ represent a hydrogen atom or a hydroxyl group). That is, a methyl ether of a salicylaldehyde derivative (c) and a desired arylacetonitrile (d) are subjected to Knoevenagel condensation to obtain a stilbene derivative (e), which is then demethylated with, for example, pyridinium chloride. The intermediate imine (mosquito) can be treated with an acid such as hydrochloric acid and hydrolyzed to obtain the hydroxycoumarin derivative (ki) (step B).

R of hydroxycoumarin (a) as a raw material
^{When 8} is a hydrogen atom or a lower alkyl group,
It can be manufactured by the process represented by the chemical formula 1.

[0051]

[Chemical 31]

An aryl group is introduced at the 3-position of the coumarin derivative (KU) by the arylation reaction of meavine. That is, a diazonium salt (ke) prepared from a desired aromatic amine and sodium nitrite under acidic conditions with hydrochloric acid and a coumarin derivative (cou) are reacted in the presence of cupric chloride to give a hydroxycoumarin derivative (a). Can be obtained (step C).

Further, the desired compound of the present invention is
In the general formula of, when Z is an acetyl group and R ¹ is a hydrogen atom, it can also be produced by the process represented by the following chemical formula (Formula 32) (process D).

[0054]

[Chemical 32]

(In the above chemical formula, R ¹⁷ and R ¹⁸ are
A hydrogen atom or a hydroxyl group, and R ¹⁹ and R ²⁰ represent a hydrogen atom or an acetoxy group). The acetylsalicylaldehyde derivative (SA) and the desired arylacetic acid (SI) are condensed under reaction conditions known as the Parkin reaction.
That is, the compound (su) can be obtained by gently heating and refluxing in acetic anhydride in the presence of a base such as triethylamine at about 120 ° C. for 1 hour to several hours.

Acetylsalicylaldehyde derivative (sa)
Can be obtained by acetylating the corresponding salicylaldehyde derivative (co) with an acetic anhydride or an acetylating agent such as acetyl chloride. The salicylaldehyde derivative (co) is cooled with ice or at room temperature. Acetylsalicylaldehyde derivative (sa) produced by acetylating acetic anhydride in the presence of a base such as triethylamine.
It is also possible to directly lead from the compound (co) to the compound (s) by directly shifting to the Parkin reaction conditions described above without isolation. In this case, the other raw material, arylacetic acid (shi), may be added at the time of shifting to Parkin reaction conditions, but may be allowed to coexist from the beginning of the acetylation of compound (co), that is, from the beginning. . Further, 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 (Su) of the present invention thus obtained is represented by the following chemical formula

[0058]

[Chemical 33]

For example, the hydroxycoumarin derivative (se) produced by deacetylation by heating under reflux in a mixed solution of ethanol and hydrochloric acid for 30 minutes to 4 hours can be used as a raw material in step A (step E).

As the acyl group as the modifying moiety of the compound of the present invention, those having various carbon numbers are used.
Various compounds such as diacyl compounds and triacyl compounds can be used to produce a compound having desired lipophilicity, polarity and the like. The acyl group is not particularly limited as long as the free acid that is absorbed in the living body, cleaved / cleaved, and is produced is medically and pharmaceutically acceptable. When it is bulky, a decrease in hydrolysis rate due to esterase or the like is observed. Therefore, using this fact,
It is also possible to control the in vivo cleavage / cleavage of the compound of the present invention by selecting various kinds of acyl groups as modifying moieties.

The compound of the present invention obtained as described above can be purified by a known purification method such as recrystallization and chromatography. The purified compound of the present invention is extremely stable and can exist for a long time without any change even when contacted with an aqueous solution having a pH of 1 to 8.

The compound of the present invention is absorbed in the living body, the acyl group is cleaved and cleaved by the action of the enzyme or the like existing in the living body, and the resulting compound is selected to have a strong 12-lipoxygenase inhibitory action. I have 1
It has an action of suppressing the production of 12-lipoxygenase metabolites such as 2-HPETE and 12-HETE, and is a therapeutic or prophylactic agent for various cardiovascular diseases such as arteriosclerosis and vasospasm caused by these metabolites. Further, it can be effectively used as a drug for preventing metastasis of certain cancers (Lewis lung cancer etc.).

The compound of the present invention may be used in the form of a tablet, capsule, injection, granule, suppository or the like as it is or after mixing with a known pharmaceutically acceptable carrier, excipient or the like. Can be used as The drug containing the compound of the present invention as an active ingredient can be administered orally or parenterally by injection, inhalation, application or the like. The dose of the drug containing the compound of the present invention as an active ingredient varies depending on the subject to be treated, symptoms, age, treatment period, etc., but it is usually about 0.1 mg to 50 mg once to 1 to 3 times a day. Administer about.

Next, the present invention will be described in more detail by showing test examples. Test Example 1 This test was carried out in order to investigate the 12-lipoxygenase inhibitory action of a compound produced by the compound of the present invention being absorbed in vivo and then deacylated. 1) Preparation of Enzyme Solution Under ether anesthesia, blood was drawn from the abdominal aorta of Sprague Dawley male rats with a syringe containing approximately 1/10 volume of 3.8% sodium citrate solution, and the blood was collected at room temperature, 18
Centrifuge at 0 g for 15 minutes to separate platelet rich plasma,
After centrifugation at 1,800 g for 10 minutes, the resulting precipitate was washed with a washing buffer (154 mM sodium chloride, 50 mM Tris-HCl buffer containing 2 mM EDTA: pH 7.4) to obtain platelets. The obtained platelets are collected at a volume of 20
Suspended in 1/10 volume of resuspension buffer (50 mM Tris-HCl buffer containing 154 mM sodium chloride 5.5 mM glucose: pH 7.4), ultrasonically disrupted, 100,
After centrifugation at 000 g for 30 minutes, the supernatant was separated to prepare an enzyme solution.

2) Method for measuring enzyme activity To 300 μl of the enzyme solution prepared to have an enzyme activity of about 2 mU / ml with the resuspension buffer, 1 μl of 3 mM indomethacin ethanol solution and 1 μm of 300 mM reduced glutathione solution
1 and various concentrations of test substances (compounds of the present invention produced in the same manner as in Example 1 and compounds of Comparative Examples 1 to 8) dimethyl sulfoxide solution (3 μl) was added, and the mixture was kept at 37 ° C. for 5 minutes, and then 2 3 μl of a 0.5 mM arachidonic acid ethanol solution was added, and the mixture was kept at 37 ° C. for 5 minutes for reaction, and then 600 μl of methanol was added to stop the reaction. The reaction solution was centrifuged at 10,000 g for 5 minutes, and the supernatant 1
2-Hydroxyeicosatetraenoic acid was separated by reverse phase high performance liquid chromatography using a C-18 column, and diene was quantified by absorption at 234 nm to measure enzyme activity. From the measured value of each test substance, the molar concentration showing a 12-lipoxygenase inhibition rate of 50% (hereinafter sometimes referred to as IC ₅₀ value) was determined.

3) Test Results The results of this test are shown in Table 1. Table 1 shows
The compounds of Examples 1 to 47, 18 and 20 to 22 of the present invention are absorbed in a living body and then deacylated, and baicalene (Wako Pure Chemical Industries) which is a known compound for comparison. The IC ₅₀ value of 12-lipoxygenase from Kogyo Co., Ltd.) is shown in comparison. As is clear from Table 1, the 12-lipoxygenase inhibitory action of the compounds of the respective examples of the present invention was found to be far superior to that of baicalen. The other compounds of the present invention were also tested, but almost the same results were obtained.

[0067]

[Table 1]

Test Example 2 In this test, when the compound of the present invention was treated with the same enzyme solution as in Test Example 1, it was determined whether or not a deacylated product was formed by the action of esterase present in this enzyme solution. Went to find out. 1) Preparation of enzyme solution It was prepared by the same method as in Test Example 1.

2) Test method 1.0 ml of the enzyme solution was diluted with 11 ml of the resuspension buffer solution, and 300 μl of the enzyme solution was diluted with 1.0 × 10 ⁻³ of the test substance.
3 μl of M dimethyl sulfoxide solution was added and kept at 37 ° C. for a certain period of time, and then 1 ml of acetonitrile was added to stop the reaction. 20 μl of this reaction solution was added to C-18
The amount of deacylated product was determined by performing reverse phase high performance liquid chromatography under the following conditions using a column. A similar test was conducted using 300 μl of the resuspension buffer instead of the enzyme solution as a control.

Conditions for reversed-phase high performance liquid chromatography Column: Superspher RP-18 (e) (manufactured by Merck), diameter 4.0 mm, length 125 mm Flow rate: 1.0 ml / min Dissolution solution: 50 mM NaClO ₄ And acetonitrile containing 50 mM orthophosphoric acid-water (55:45) Column temperature: 30 ° C Detection: Absorbance at 280 nm

3) Test Results Among the compounds of the present invention, the test results of the compounds of Example 4 (Chemical formula 43) and Example 21 (Chemical formula 74) will be illustrated. The compounds of Example 4 (Chemical Formula 43) and Example 21 (Chemical Formula 74) were both subjected to a deacylation reaction to produce the compound of Reference Example 2 (Chemical Formula 3).
Since it is presumed that 4) is produced, the retention time under the conditions of the reverse phase high performance liquid chromatography was confirmed using the standard of the compound of Reference Example 2 (retention time is 2.49).
It was a minute), and a calibration curve was prepared.

Next, Example 4 (Chemical Formula 43) and Example 21
As for the compound of (Chemical formula 74), the resuspension buffer was used instead of the enzyme solution to examine the possibility of deacylation. As a result, no deacylated compound (Chemical formula 34) was formed. .

Further, as a result of conducting a similar test using the above enzyme solution, as shown in Table 2, all the compounds were deacylated over time, and the deacylated product (Chemical formula 34) was added to the reaction solution. It was confirmed that it produced. As is clear from these results, the compound of the present invention was used in the enzyme solution prepared from rat platelets (in addition to 12-lipoxygenase,
It was found that the modified portion is cleaved relatively quickly and a deacylated product is produced by contact with a certain esterase).

On the other hand, the compound produced by the deacylation reaction (this compound is the same as the compound of the prior application) has an extremely strong 12-lipoxygenase inhibitory activity as shown in Test Example 1. There is. Therefore, the compound of the present invention has an effect as a precursor of a compound that inhibits 12-lipoxygenase activity, and can be used as a so-called prodrug. The other compounds of the present invention were tested in the same manner, but almost the same results were obtained.

[0075]

[Table 2]

[0076]

EXAMPLES Next, the present invention will be described in more detail with reference to Production Examples of compounds of the present invention and Reference Examples (production examples of intermediates for producing the compounds of the present invention) and Examples. ,
The present invention is not limited to the following examples. The measured values of the nuclear magnetic resonance spectrum and infrared absorption spectrum of the compound of the present invention produced in the following Reference Examples and Examples, and Reference Examples and Comparative Examples are shown in Tables 3 to 11. The nuclear magnetic resonance spectrum [ ¹ H-NMR (500 MHz)] was measured in a heavy dimethyl sulfoxide (DMSO-d ₆ ) solvent using tetramethylsilane as an internal standard, and the infrared absorption spectrum was measured by the KBr tablet method. .

[0077]

[Table 3]

[0078]

[Table 4]

[0079]

[Table 5]

[0080]

[Table 6]

[0081]

[Table 7]

[0082]

[Table 8]

[0083]

[Table 9]

[0084]

[Table 10]

[0085]

[Table 11]

Reference Example 1 [Production of α-cyano-3-chloro-2 ′, 4 ′, 5′-trimethoxystilbene] 3-chlorophenylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) 1.96 g (10.0 mmo)
1) and 2,4,5-trimethoxybenzaldehyde (manufactured by Lancaster) 1.96 mg (10.0 mmo)
l) and are dissolved by heating in 10 ml of ethanol (manufactured by Kokusan Kagaku), and 2 drops of 20% sodium hydroxide aqueous solution is added,
After stirring overnight, the precipitated crystals were crushed, filtered, washed twice with ethanol and then twice with hexane, dried, and α-
Cyano-3-chloro-2 ', 4', 5'-trimethoxystilbene (yellow crystals) 3.05 g (yield 92.5%)
Got

Reference Example 2 [Production of 3- (3-chlorophenyl) -6,7-dihydroxycoumarin] α-obtained by the same method as Reference Example 1
Cyano-3-chloro-2 ', 4', 5'-trimethoxystilbene 660 mg (2.00 mmol) and pyridinium chloride (manufactured by Wako Pure Chemical Industries, Ltd.) 3.5 g (30 mmo
l) and the mixture with 21) under argon gas atmosphere in advance.
Melt and mix in an oil bath heated to 0 ° C., stir at the same temperature for 1 hour, cool in air, and solidify the reaction product.
Was added and pulverized, and the mixture was stirred for 30 minutes, then the precipitate was filtered, washed with water three times and dried, and purified by silica gel short column (eluent was ethyl acetate). Chemical formula of

[0088]

[Chemical 34]

3- (3-chlorophenyl) -represented by
6,7-Dihydroxycoumarin (yellow crystals) 486 mg
(Yield 84.2%) was obtained.

Reference Example 3 [Production of 4-iodophenylacetonitrile] 4.36
g (20.0 mmol) of p-iodotoluene (manufactured by Tokyo Kasei), 3.9 g (22 mmol) of N-bromosuccinimide (manufactured by Tokyo Kasei) and 60 ml of carbon tetrachloride (manufactured by Wako Pure Chemical Industries). The mixture was heated under reflux for 4 hours under irradiation of an incandescent lamp to obtain 2.67 g (yield 45.0%) of 4-iodobenzyl bromide (white crystals). Next 5
1.48 g (5.00 mmol) of 4-iodobenzyl bromide was added to a 10 ml solution of 0.49 g (10 mmol) of sodium cyanide (Kokusan Kagaku Co., Ltd.) heated to 0 ° C. in dimethyl sulfoxide (Aldrich Co.). Then, the reaction product solidified was dissolved in water, extracted with hexane, hexane was distilled off, and 0.84 g of white crystals of 4-iodophenylacetonitrile (yield 68.9). %) Was obtained.

Reference Example 4 [Production of 4-ethylphenylacetonitrile] 2.72
50 g of 47% hydrobromic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added to g (20.0 mmol) of 4-ethylbenzyl alcohol (manufactured by Aldrich), and the mixture was vigorously stirred at room temperature for 30 minutes, and then hexane. The extract was extracted with to obtain 4.98 g of colorless oily 4-ethylbenzyl bromide. Next 5
To a solution of 1.96 g (40.0 mmol) of sodium cyanide (manufactured by Kokusan Kagaku Co., Ltd.) heated to 0 ° C. in 20 ml of dimethyl sulfoxide (manufactured by Aldrich Co.), 3.98 g of the above 4-ethylbenzyl bromide was added and released. After stirring for 3 hours under cooling, the solidified reaction product was dissolved in water, extracted with hexane, hexane was distilled off, and 2.70 g of 4-ethylphenylacetonitrile as a pale yellow oily substance (yield 93.1).
%) Was obtained.

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

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

Reference Example 6 [Production of 5-methylfuran-2-ylacetonitrile]
5-methylfuran-2-carboxaldehyde (manufactured by Wako Pure Chemical Industries, Ltd.) 5.51 g (50.0 mmol), Rhodanine (manufactured by Tokyo Kasei) 6.66 g (50.0 mmol),
Anhydrous sodium acetate (Kokusan Kagaku) 12.3 g (15
(0 mmol) and 35 ml of acetic acid (manufactured by Wako Pure Chemical Industries, Ltd.) were heated under reflux for 30 minutes, air-cooled and added to 500 ml of water, and the precipitated crystals were filtered and washed with water, ethanol and ether in that order. Dried, and orange-brown crystals of (5-methylfurfurylidene) rhodanin 10.04 g (yield 8
9.1%) was obtained.

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 filtered, washed with water and dried. And 3- (5-methylfuryl)
8.22 g of yellow crystals of 2-thioketopropionic acid were obtained.

45 ml of ethanol and 10.1 g of hydroxylamine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.) (1
46 mmol), and further sodium ethoxide (Aldrich, 21% denatured ethanol solution) 55
ml (147 mmol equivalent) is gradually added, and the temperature is 100 ° C.
Heated at rt for 1 h, cooled in air and concentrated under reduced pressure. 5 for residue
% Aqueous sodium hydroxide solution (20 ml) was added and suspended,
Under ice-cooling, 20 ml of 10% hydrochloric acid was added carefully, extraction was performed 3 times with ether, and the ether layer was washed with saturated brine,
After anhydrous sodium sulfate was added and dried, ether was distilled off.

The residue was dissolved in a small amount of ether, toluene was gradually added until white turbidity was generated, and the mixture was allowed to stand, and the precipitated crystals were collected, thoroughly washed with toluene, and dried to give 3- (5
4.55 g (yield 53.3%) of yellow crystals of -methyl-2-furyl) -2-hydroxyiminopropionic acid were obtained.

All of this was dissolved in 60 ml of benzene,
3.97 g (24.8 mmol) of 1,1′-carbonyldiimidazole (manufactured by Aldrich) was gradually added,
Heat at 70 ° C for 1 hour, cool with air, add to 50 ml of ice water, extract with benzene three times, and wash the benzene layer with sodium bicarbonate solution, saturated saline, 1% hydrochloric acid and water successively, and dry with anhydrous sodium sulfate. And the solvent was distilled off under reduced pressure to give 2.40 g of an oily substance.
Got This oily substance was purified by silica gel column chromatography (the eluent used was an ethyl acetate: hexane ratio of 1: 4), and 2.00 g of a colorless oily substance of 5-methylfuran-2-ylacetonitrile (yield 66 .6%) was obtained.

Reference Example 7 [3- (4-chlorophenyl) -4-methyl-6,7-
Production of dihydroxycoumarin] Concentrated hydrochloric acid 25 ml and ice 15
p-chloroaniline (manufactured by Tokyo Kasei)
3.83 g (30.0 mmol) was added, and 7 m of a 30% aqueous solution of sodium nitrite (manufactured by Wako Pure Chemical Industries, Ltd.) was added.
1 was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium acetate (Wako Pure Chemical Industries, Ltd.) was added to this mixture to adjust the pH to 4, and insoluble components were separated by filtration, and a filtrate was separately prepared. ) 5.7
7 g (30.0 mmol) of acetone in 90 ml of suspension was added, and cupric chloride dihydrate (manufactured by Kanto Chemical Co., Inc.)
0.8 g was added and stirred for 1 hour. The reaction product was concentrated under reduced pressure to remove most of the solvent, leaving a residue of 300 ml.
Ethyl acetate of was added and mixed well, the insoluble component (unreacted 4-methylesculetin) was filtered off, the organic layer was separated from the filtered solution, and the aqueous layer was extracted twice with ethyl acetate, The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane ratio 1: 1 for eluate. The eluate fraction containing the target compound was allowed to stand and the precipitated crystals were collected and dried.

[0100]

[Chemical 35]

3- (4-chlorophenyl) -represented by
533 mg (yield 5.9%) of 4-methyl-6,7-dihydroxycoumarin (pale yellow crystal) was obtained.

Reference Example 8 [Production of 3- (4-fluorophenyl) -7,8-dihydroxycoumarin] 356 mg (1.00 m) of the compound represented by the chemical formula of Chemical formula 44 obtained by the same method as in Example 5
mol) and 8 ml of ethanol (manufactured by Kokusan Kagaku), 2 ml of 6N hydrochloric acid was added, and the mixture was heated under reflux for 1 hour,
After air cooling, the reaction mixture was added to 60 ml of water and stirred,
Precipitated crystals are filtered, washed with water, dried, ethyl acetate-
It is recrystallized from hexane and has the following chemical formula

[0103]

[Chemical 36]

3- (4-fluorophenyl) represented by
-7,8-Dihydroxycoumarin (pale yellow crystal) 193
mg (yield 70.9%) was obtained.

Example 1 2,3,4-trihydroxybenzaldehyde (manufactured by Aldrich) 771 mg (5.00 mmol), 4-chlorophenylacetic acid (manufactured by Tokyo Kasei) 853 mg (5.0)
0 mmol) and acetic anhydride (Wako Pure Chemical Industries, Ltd.) 10 m
5 ml of triethylamine (manufactured by Kokusan Kagaku Co., Ltd.) was added to the mixture of 1 under ice-cooling, and the mixture was stirred for 1 hour while protecting the calcium chloride tube, and heated under reflux for 4 hours in an oil bath preheated to 120 ° C. Then, the mixture was air-cooled, the reaction product was added to 100 ml of ice-cooled 10% hydrochloric acid, and the mixture was vigorously stirred, the precipitated crystals were separated by filtration, washed with water and ethanol, and the obtained light brown crystals were washed with chloroform and ethanol. Recrystallization using the mixed solution, the following chemical formula

[0106]

[Chemical 37]

1.17 g (yield: 62.9%) of a white crystalline compound represented by was obtained. The melting point of the obtained compound is 18
It was 8.0-188.5 degreeC. (Comparative Example 1) Instead of the compound represented by the chemical formula of Chemical formula 44, the compound 37 represented by the chemical formula of Chemical formula 37 obtained in Example 1
By the same method as in Reference Example 8 except that 3 mg (1.00 mmol) was used, the following chemical formula

[0108]

[Chemical 38]

3- (4-chlorophenyl) -represented by
7,8-Dihydroxycoumarin (pale yellow crystal) 227m
g (yield 78.6%) was obtained.

Example 2 2,4,5-Trihydroxybenzaldehyde (manufactured by Lancaster) 154 mg (1.00 mmol), 4-chlorophenylacetic acid (manufactured by Tokyo Kasei) 171 mg (1.0)
0 mmol) and acetic anhydride (Wako Pure Chemical Industries, Ltd.) 2 ml
In a mixture of, under ice-cooling triethylamine (manufactured by Kokusan Kagaku)
1 ml was added, the mixture was stirred for 1 hour under protection of a calcium chloride tube, and heated under reflux for 4 hours in an oil bath preheated to 120 ° C. It was then air cooled and the reaction was cooled to 20 ml with ice cold 10%.
Add to hydrochloric acid, stir vigorously, filter the precipitated crystals,
It was washed with water, the obtained crystals were dissolved in ethyl acetate, the solvent was distilled off under reduced pressure after drying, and the residual crystals were recrystallized using a mixed solution of ethyl acetate and hexane.

[0111]

[Chemical Formula 39]

280 mg of a white crystalline compound represented by:
(Yield 75.1%) was obtained. The melting point of the obtained compound is
It was 211.5-212.5 degreeC.

(Comparative Example 2) Reference Example 8 except that 373 mg (1.00 mmol) of the compound of the chemical formula 39 obtained in Example 2 was used in place of the compound of the chemical formula 44. By the same method, the following chemical formula

[0114]

[Chemical 40]

3- (4-chlorophenyl) -represented by
6,7-Dihydroxycoumarin (pale yellow crystal) 233m
g (yield 80.6%) was obtained.

Example 3 Except that 853 mg (5.00 mmol) of 3-chlorophenylacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) was used in place of 4-chlorophenylacetic acid, and ethyl acetate-hexane was used as a recrystallization solvent. By the same method as in Example 1,
The following chemical formula

[0117]

[Chemical 41]

853 mg (yield: 45.8%) of a white crystalline compound represented by was obtained. The melting point of the obtained compound is 16
It was 5 to 167 ° C.

Comparative Example 3 Referential Example 8 except that 373 mg (1.00 mmol) of the compound of the chemical formula 41 obtained in Example 3 was used in place of the compound of the chemical formula 44. By the same method, the following chemical formula

[0120]

[Chemical 42]

3- (3-chlorophenyl) -represented by
7,8-Dihydroxycoumarin (pale yellow crystal) 268m
g (yield 92.8%) was obtained.

Example 4 87 mg of 3- (3-chlorophenyl) -6,7-dihydroxycoumarin obtained by the same method as in Reference Example 2 (0.
2 ml of methylene chloride (made by Kokusan Kagaku)
Suspended in water and triethylamine (manufactured by Kokusan Kagaku Co.) 0.09
ml was added and stirred, the obtained clear orange solution was ice-cooled, 0.05 ml of acetyl chloride (manufactured by Wako Pure Chemical Industries, Ltd.) was added, the mixture was stirred with ice-cooling, and further stirred at room temperature for 30 minutes.
30 ml of the obtained mixed solution of ethanol (made by Kokusan Kagaku)
Dilute with, filter the precipitated crystals, wash with ethanol and hexane sequentially, and dry.

[0123]

[Chemical 43]

96 mg (yield 86%) of a white crystalline compound represented by The melting point of the obtained compound is 194-1.
It was 95 ° C.

Example 5 771 mg (5.00 mm) of 4-fluorophenylacetic acid (manufactured by Lancaster) instead of 4-chlorophenylacetic acid
by the same method as in Example 1, except that

[0126]

[Chemical 44]

1.26 g (yield: 70.8%) of a white crystalline compound represented by: was obtained. The melting point of the obtained compound is 18
The temperature was 3.5 to 184.0 ° C.

Example 6 771 mg (5.00 mmol) of 4-bromophenylacetic acid (manufactured by Tokyo Kasei) instead of 4-chlorophenylacetic acid
By the same method as in Example 1, except that

[0129]

[Chemical formula 45]

1.02 g (yield 48.8%) of the white crystalline compound represented by was obtained. The melting point of the obtained compound is 20.
It was 1.5 to 202.5 ° C.

(Comparative Example 4) Reference Example 8 except that 417 mg (1.00 mmol) of the compound represented by the chemical formula of Chemical formula 45 obtained in Example 6 was used in place of the compound represented by the chemical formula of Chemical formula 44. By the same method, the following chemical formula

[0132]

[Chemical formula 46]

3- (4-bromophenyl) -represented by
7,8-Dihydroxycoumarin (yellow crystals) 300 mg
(Yield 90.2%) was obtained.

Example 7 Using 392 mg (2.00 mmol) of 2,4,5-trimethoxybenzaldehyde (manufactured by Lancaster), 3
-Iodophenylacetonitrile 48 obtained in the same manner as in Reference Example 3 instead of chlorophenylacetonitrile 48
[Alpha] -Cyano-4-iodo- by the same method as Reference Example 1 except that 6 mg (2.00 mmol) was used.
2 ', 4', 5'-Trimethoxystilbene was obtained. α
-Cyano-3-chloro-2 ', 4', 5'-trimethoxystilbene instead of α-cyano-4-iodo-
2 ', 4', 5'-trimethoxystilbene 421 mg
By the same method as in Reference Example 2, except that (1.00 mmol) was used, the following chemical formula

[0135]

[Chemical 47]

3- (4-iodophenyl) -represented by
6,7-Dihydroxycoumarin (yellow crystals) 566 mg
(Yield 74.4%) was obtained.

Instead of 3- (3-chlorophenyl) -6,7-hydroxycoumarin, 114 mg of the above-mentioned 3- (4-iodophenyl) -6,7-dihydroxycoumarin (0.
By the same method as in Example 4, except that 30 mmol) was used.

[0138]

[Chemical 48]

100 mg (yield: 72.1%) of a white crystalline compound represented by was obtained. The melting point of the obtained compound is 18
It was 9.0-190,0 degreeC.

Example 8 751 mg (5.00 mmol) of 4-methylphenylacetic acid (manufactured by Tokyo Kasei) instead of 4-chlorophenylacetic acid
By the same method as in Example 1, except that

[0141]

[Chemical 49]

626 mg (yield 35.3%) of white crystalline compound represented by the above formula was obtained. The melting point of the obtained compound is 19
It was 9-200 degreeC.

(Comparative Example 5) Reference Example 8 except that 352 mg (1.00 mmol) of the compound of the chemical formula 49 obtained in Example 8 was used in place of the compound of the chemical formula 44. Using the same method, the following chemical formula

[0144]

[Chemical 50]

3- (4-methylphenyl) -represented by
233 mg of 7,8-dihydroxycoumarin (yellow crystals)
(Yield 86.9%) was obtained.

Example 9 771 mg (5.00 mmol) of 3-methylphenylacetic acid (manufactured by Tokyo Kasei) instead of 4-chlorophenylacetic acid
Except that ethyl acetate-hexane was used as the recrystallization solvent, the following formula 51 was used.

[0147]

[Chemical 51]

684 mg (yield 38.88%) of a white crystalline compound represented by the above formula was obtained. The melting point of the obtained compound is 1
It was 55-156 degreeC.

(Comparative Example 6) Reference Example 8 except that 352 mg (1.00 mmol) of the compound represented by the chemical formula of Chemical formula 51 obtained in Example 9 was used instead of the compound represented by the chemical formula of Chemical formula 44. By the same method, the following chemical formula

[0150]

[Chemical 52]

3- (3-methylphenyl) -represented by
212 mg of 7,8-dihydroxycoumarin (yellow crystals)
(Yield 79.2%) was obtained.

Example 10 Using 628 mg (3.20 mmol) of 2,4,5-trimethoxybenzaldehyde (manufactured by Lancaster), 3
4-ethylphenylacetonitrile 46 obtained by the same method as in Reference Example 4 instead of chlorophenylacetonitrile 46
Α-Cyano-4-ethyl-by the same method as in Reference Example 1 except that 5 mg (3.20 mmol) was used.
2 ', 4', 5'-Trimethoxystilbene was obtained. α
-Cyano-3-chloro-2 ', 4', 5'-trimethoxystilbene instead of the above α-cyano-4-ethyl-
2 ', 4', 5'-trimethoxystilbene 485mg
Using the same method as in Reference Example 2 except that (1.50 mmol) was used, the following chemical formula

[0153]

[Chemical 53]

3- (4-ethylphenyl) -represented by
6,7-Dihydroxycoumarin (yellow crystals) 493 mg
(Yield 87.5%) was obtained. In place of 3- (3-chlorophenyl) -6,7-hydroxycoumarin, the above 3-
Except that 85 mg (0.30 mmol) of (4-ethylphenyl) -6,7-dihydroxycoumarin was used,
Using the same method as in Example 4, the following chemical formula

[0155]

[Chemical 54]

46 mg (yield 42%) of the white crystalline compound represented by the above formula was obtained. The melting point of the obtained compound is 161.5.
It was -162.0 ° C.

Example 11 By the same method as in Reference Example 1, except that 1.85 g (10.0 mmol) of 4-trifluoromethylphenylacetonitrile (manufactured by Aldrich) was used in place of 3-chlorophenylacetonitrile. α-cyano-4-
Trifluoromethyl-2 ', 4', 5'-trimethoxystilbene was obtained. α-cyano-3-chloro-2 ′,
Instead of 4 ', 5'-trimethoxystilbene, the above α-
Cyano-4-trifluoromethyl-2 ', 4', 5'-
Trimethoxystilbene 727 mg (2.00 mmo
By the same method as in Reference Example 2 except that l) was used, the following chemical formula

[0158]

[Chemical 55]

594 mg (yield 92.2%) of 3- (4-trifluoromethylphenyl) -6,7-dihydroxycoumarin (pale yellow crystal) represented by was obtained. 3- (3-
Instead of chlorophenyl) -6,7-hydroxycoumarin, the above 3- (4-trifluoromethylphenyl) -6,6 was used.
97 mg of 7-dihydroxycoumarin (0.30 mmo
By the same method as in Example 4, except that 1) was used, the following chemical formula

[0160]

[Chemical 56]

95 mg (yield: 77.8%) of a white crystalline compound represented by was obtained. The melting point of the obtained compound is 19
It was 6.5 to 197.5 ° C.

Example 12 Instead of 4-chlorophenylacetic acid, 4-methoxyphenylacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) 831 mg (5.00 mmo)
by the same method as in Example 1, except that 1) was used.

[0163]

[Chemical 57]

814 mg (yield 44.2%) of a white crystalline compound represented by: The melting point of the obtained compound is 17
It was 4.5 to 175.5 ° C.

Comparative Example 7 Reference Example 8 except that 368 mg (1.00 mmol) of the compound represented by the chemical formula 57 obtained in Example 12 was used in place of the compound represented by the chemical formula 44. By the same method as

[0166]

[Chemical 58]

3- (4-methoxyphenyl) represented by
-7,8-Dihydroxycoumarin (ocher crystals) 186
mg (yield 65.6%) was obtained.

Example 13 Instead of 4-chlorophenylacetic acid, 4-nitrophenylacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) 906 mg (5.00 mmol)
By the same method as in Example 1, except that

[0169]

[Chemical 59]

827 mg (yield 43.2%) of a yellow crystalline compound represented by were obtained. The melting point of the obtained compound is 22.
It was 7.5 to 228.5 ° C.

Comparative Example 8 Reference Example 8 except that 383 mg (1.00 mmol) of the compound of the chemical formula 59 obtained in Example 13 was used in place of the compound of the chemical formula 44. By the same method as

[0172]

[Chemical 60]

3- (4-nitrophenyl) -represented by
228 mg of 7,8-dihydroxycoumarin (orange crystal)
(Yield 76.2%) was obtained.

Example 14 Using 2,4,5-trimethoxybenzaldehyde (manufactured by Lancaster) 981 mg (5.00 mmol), 3
-Instead of chlorophenylacetonitrile, phenylacetonitrile (manufactured by Tokyo Kasei) 586 mg (5.00 mm)
.alpha.-cyano-2 ', 4', 5'-trimethoxystilbene was obtained by the same method as in Reference Example 1, except that α-cyano-3-chloro-2 ′, 4 ′,
Instead of 5'-trimethoxystilbene, the above-mentioned α-cyano-2 ', 4', 5'-trimethoxystilbene 591m.
Reference Example 2 except that g (2.00 mmol) was used
By the same method as

[0175]

[Chemical formula 61]

3-phenyl-6,7-dihydroxycoumarin (yellowish brown crystal) 444 mg (yield 87.
3%) was obtained. 3- (3-chlorophenyl) -6,7-
Instead of hydroxycoumarin, the above 3-phenyl-6,7
-Dihydroxycoumarin 76 mg (0.30 mmol)
Using the same method as in Example 4, except that

[0177]

[Chemical formula 62]

48 mg (yield 70%) of a white crystalline compound represented by the above formula was obtained. The melting point of the obtained compound is 195.0.
-195.5 ° C.

Example 15 1.23 g of thiophen-2-ylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd.) instead of 3-chlorophenylacetonitrile
Α- (2,4,5-Trimethoxybenzylidene) -thiophene-2-acetonitrile was obtained by the same method as in Reference Example 1 except that (10.0 mmol) was used. In place of α-cyano-3-chloro-2 ′, 4 ′, 5′-trimethoxystilbene, the above α- (2,4,5-trimethoxybenzylidene) -thiophene-2-acetonitrile (603 mg, 2.00 mmol) was added. By the same method as in Reference Example 2, except that the chemical formula:

[0180]

[Chemical formula 63]

3- (thiophen-2-yl) represented by
-6,7-Dihydroxycoumarin (yellow crystals) 274m
g (yield 52.6%) was obtained. In place of 3- (3-chlorophenyl) -6,7-hydroxycoumarin, the above 3-
By the same method as in Example 4, except that 78 mg (0.30 mmol) of (thiophen-2-yl) -6,7-dihydroxycoumarin was used, the following chemical formula

[0182]

[Chemical 64]

63 mg (yield 61%) of a light brown crystalline compound represented by was obtained. The melting point of the obtained compound is 222-
It was 224 ° C.

Example 16 Following the same procedure as in Reference Example 1 except that 711 g (5.00 mmol) of thiophen-3-acetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of 4-chlorophenylacetic acid.
Chemical formula of 5

[0185]

[Chemical 65]

960 mg of pale yellow crystalline compound represented by:
(Yield 55.8%) was obtained. The melting point of the obtained compound is
It was 159.5 to 160.5 ° C.

Comparative Example 9 Reference Example 8 except that 344 mg (1.00 mmol) of the compound represented by the chemical formula of Chemical formula 65 obtained in Example 16 was used in place of the compound represented by the chemical formula of Chemical formula 44. By the same method as

[0188]

[Chemical formula 66]

3- (thiophen-3-yl) represented by
-7,8-Dihydroxycoumarin (yellow crystal) 165m
g (yield 63.4%) was obtained.

Example 17 Using 385 mg (2.50 mmol) of 2,3,4-trihydroxybenzaldehyde (manufactured by Aldrich),
553 mg of 4-bromothiophene-2-acetic acid obtained by the same method as in Reference Example 5 instead of 4-chlorophenylacetic acid
Using the same method as in Example 1, except that (2.50 mmol) was used, the following chemical formula

[0191]

[Chemical formula 67]

756 mg of light brown crystalline compound represented by
(Yield 71.4%) was obtained. The melting point of the obtained compound is
It was 234.0 to 234.0 ° C.

Comparative Example 10 Reference Example 8 except that 423 mg (1.00 mmol) of the compound represented by the chemical formula of Chemical Formula 67 obtained in Example 17 was used in place of the compound represented by the chemical formula of Chemical formula 44. By the same method as
Chemical formula of

[0194]

[Chemical 68]

3- (4-bromothiophene-
There was obtained 310 mg (yield 91.4%) of 2-yl) -7,8-dihydroxycoumarin (yellow crystals).

Example 18 385 mg (2.50 mmol) of 2,4,5-trihydroxybenzaldehyde (manufactured by Lancaster) was used in place of 2,3,4-trihydroxybenzaldehyde, and a reference example was used instead of 4-chlorophenylacetic acid. 4-Bromothiophene-2-acetic acid 553 obtained by the same method as 5
By the same method as in Example 1 except that mg (2.50 mmol) was used, the following chemical formula

[0197]

[Chemical 69]

755 mg of a light brown crystalline compound represented by
(Yield 71.4%) was obtained. The melting point of the obtained compound is
It was 220.5 to 221.5 ° C.

Comparative Example 11 Reference Example 8 except that 423 mg (1.00 mmol) of the compound of the chemical formula 69 obtained in Example 18 was used in place of the compound of the chemical formula 44. In the same way as
Chemical formula of

[0200]

[Chemical 70]

3- (4-bromothiophene-represented by
287 mg (yield 84.6%) of 2-yl) -6,7-dihydroxycoumarin (yellow crystal) was obtained.

Example 19 Using 2,4,5-trimethoxybenzaldehyde (manufactured by Lancaster) 981 mg (5.00 mmol), 3
By the same method as in Reference Example 1, except that 1.21 g (5.00 mmol) of 5-methylfuran-2-ylacetonitrile obtained in the same manner as in Reference Example 6 was used instead of -chlorophenylacetonitrile. 5-methyl-α-
(2,4,5-Trimethoxybenzylidene) furan-2
-Acetonitrile was obtained. α-cyano-3-chloro-
Instead of 2 ', 4', 5'-trimethoxystilbene,
597 mg of 5-methyl-α- (2,4,5-trimethoxybenzylidene) furan-2-acetonitrile
Using the same method as in Reference Example 2 except that (2.00 mmol) was used, the following chemical formula

[0203]

[Chemical 71]

3- (5-methylfuran-2-) represented by
Ill) -6,7-dihydroxycoumarin (yellowish brown crystal)
241 mg (yield 46.7%) was obtained. Except that 77 mg (0.30 mmol) of 3- (5-methylfuran-2-yl) -6,7-dihydroxycoumarin was used in place of 3- (3-chlorophenyl) -6,7-hydroxycoumarin. Using the same method as in Example 4,
Chemical formula of 2

[0205]

[Chemical 72]

47 mg (yield 46%) of a pale yellow crystalline compound represented by was obtained. The melting point of the obtained compound was 199.
It was 5 to 200.0 ° C.

Example 20 3- (4-chlorophenyl) -4-methyl-6,7-dihydroxycoumarin 1 obtained by the same method as in Reference Example 7
00 mg (0.33 mmol) was suspended in 2 ml of methylene chloride (Kokusan Kagaku), 0.11 ml of triethylamine (Kokusan Kagaku) was added and stirred, and the resulting clear orange solution was ice-cooled to obtain acetyl. Chloride (made by Wako Pure Chemical Industries, Ltd.)
0.06 ml was added, and the mixture was stirred with ice cooling and further stirred at room temperature for 30 minutes. Ethyl acetate was added to the obtained mixed solution,
The organic layer was separated, washed successively with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue crystals were recrystallized from ethyl acetate-hexane. The following chemical formula

[0208]

[Chemical formula 73]

104 mg of a pale yellow crystalline compound represented by:
(Yield 81.3%) was obtained. The melting point of the obtained compound is
It was 151.5 to 152.5 ° C.

Example 21 577 mg of 3- (3-chlorophenyl) -6,7-dihydroxycoumarin obtained by the same method as in Reference Example 2
(2.00 mmol) methylene chloride (made by Kokusan Kagaku)
Suspend in 10 ml, triethylamine (Kokusan Kagaku)
0.69 ml was added and stirred, the resulting clear orange solution was ice-cooled, and propionyl chloride (manufactured by Tokyo Kasei)
0.44 ml was added, and the mixture was stirred with ice cooling and further stirred at room temperature for 30 minutes. Ethyl acetate was added to the obtained mixed solution,
The organic layer was separated, washed successively with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue crystals were recrystallized from ethyl acetate-hexane. The chemical formula of the following chemical formula 74

[0211]

[Chemical 74]

671 mg of pale yellow crystalline compound represented by:
(Yield 83.7%) was obtained. The melting point of the obtained compound is
It was 163-165 degreeC.

Example 22 By the same method as in Example 21 except that 0.52 ml of butyryl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) was used in place of propionyl chloride, the following chemical formula

[0214]

[Chemical 75]

673 mg (yield: 78.4%) of a white crystalline compound represented by The melting point of the obtained compound is 13
It was 5 to 136 ° C.

Example 23 A mixture having the following composition per tablet was prepared and tableted by a tablet machine according to a conventional method to produce a medicine which selectively inhibits 12-lipoxygenase of the present invention. Compound obtained in Example 1 20.0 (mg) Lactose (manufactured by Iwaki Pharmaceutical Co., Ltd.) 40.0 Corn 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 24 A mixture having the following composition per capsule was prepared and filled in a gelatin capsule by a conventional method to prepare a medicine for selectively inhibiting 12-lipoxygenase of the present invention. Compound obtained in Example 1 20.0 (mg) Lactose (manufactured by Iwaki Pharmaceutical Co., Ltd.) 40.0 Fine powder cellulose (manufactured by Nippon Soda Co., Ltd.) 30.0 Magnesium stearate (manufactured by Taihei Chemical Co., Ltd.) 3.0

[0218]

INDUSTRIAL APPLICABILITY As described above in detail, according to the present invention, the modified portion is cleaved / cut by the action of an enzyme or the like in the living body.
The present invention relates to a coumarin derivative that is a novel compound that can produce a substance that selectively inhibits lipoxygenase, and a pharmaceutical that can selectively inhibit 12-lipoxygenase containing these compounds as an active ingredient. The effects that can be achieved are as follows. 1) The compound of the present invention has an action capable of inhibiting 12-lipoxygenase with a strong and high selectivity by cleaving / cleaving a modified portion by the action of an enzyme or the like in vivo. 2) The medicament containing the compound of the present invention as an active ingredient is useful for the prevention and treatment of various diseases of the circulatory system such as arteriosclerosis and vasospasm, and the prevention of metastasis of certain cancers. 3) The compound of the present invention has low toxicity, few side effects, and is effective as an active ingredient of a drug capable of selectively inhibiting 12-lipoxygenase. 4) Cleavage / cleavage of the compound of the present invention in vivo can be controlled by selecting various kinds of acyl groups as modifying moieties of the compound of the present invention.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location C07D 409/04 311 (72) Inventor Shigehiro Mori 5-chome 1-15, Higashihara, Zama City, Kanagawa 407 Sagamino Sakura (72) Inventor Naoko Moriuchi 1-20-7 Hinominami, Konan-ku, Yokohama-shi, Kanagawa

Claims (2)

[Claims] 1. A general formula of the following chemical formula 1 [Wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ² and R ³ represent a hydrogen atom or OZ (provided that R ² and R ³ are not simultaneously a hydrogen atom),
Ar is a general formula of the following Chemical formula 2, Chemical formula 3 or Chemical formula 4 [Chemical 3] [Chemical 4] Wherein R ⁴ is a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a nitro group or a cyano group, and Z is independently a hydrogen atom or the following chemical formula 5 The general formula of In the formula, R ⁵ represents a straight chain or branched alkyl group or alkenyl group having 1 to 20 carbon atoms. ] The coumarin derivative shown by these. 2. A general formula of the following chemical formula 6 [Wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ² and R ³ represent a hydrogen atom or OZ (provided that R ² and R ³ are not simultaneously a hydrogen atom),
Ar is a general formula of the following Chemical formula 7, Chemical formula 8 or Chemical formula 9 [Chemical 8] [Chemical 9] Wherein R ⁴ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a nitro group or a cyano group, and Z is a hydrogen atom or A general formula of the chemical formula 10 In the formula, R ⁵ represents a straight chain or branched alkyl group or alkenyl group having 1 to 20 carbon atoms. ] The pharmaceutical which contains the compound selected from the group which consists of the coumarin derivative shown by these as an active ingredient.