JP2004315498A - New phenol compound, and antioxidant or cyclooxygenase inhibitor containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new phenol compound useful in fields of a food, medicine, quasi drug, cosmetic, etc., and also an excellent antioxidant and cyclooxygenase inhibitor, especially cyclooxygenase-2 inhibitor. <P>SOLUTION: This new phenol compound is expressed by general formula (1) (wherein, R<SP>1</SP>is a 1-18C alkyl which may have branches; and R<SP>2</SP>is H, a 1-4 C alkyl or a protecting group for phenolic hydroxy group). The antioxidant and cyclooxygenase inhibitor consist of the compound. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a novel phenolic compound which can be suitably used as an antioxidant in the fields of foods, pharmaceuticals, quasi-drugs, cosmetics, etc., and further as an antioxidant and a cyclooxygenase inhibitor by the compound. About the use of.

  In recent years, it has become clear that reactive oxygen species and free radicals cause various diseases. Reactive oxygen is originally generated in the body's immune system and has the function of attacking pathogens and the like that have entered from the outside. However, if active oxygen is excessively generated and remains, it reacts with constituents in the living body, that is, lipids, proteins, DNA, and the like, and has an adverse effect. Above all, unsaturated fatty acids, which are constituents of biological membranes and the like, are easily oxidized and generate lipid peroxides via free radical intermediates. This lipid peroxide is known to induce arteriosclerosis, hypertension, liver dysfunction and the like, and is also said to be closely related to the aging phenomenon. Recently, oxidative decomposition products of unsaturated fatty acids have been raised as a cause of armpit odor (for example, see Non-Patent Document 1). In addition, foods, pharmaceuticals, cosmetics, and the like containing unsaturated fatty acids that are easily oxidized also have a problem that the quality tends to deteriorate during storage.

  In order to prevent the oxidation of such unsaturated fatty acids, it is necessary to use an antioxidant. Many compounds are known as antioxidants, specifically, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tocopherols, ascorbic acid and its derivatives, ubiquinone and its derivatives, flavone derivatives, Examples thereof include gallic acid derivatives and polyphenols (for example, see Non-Patent Documents 2 and 3). However, the above synthetic chemicals such as BHT and BHA are not safe for the human body and have limitations in application, and natural antioxidants are one step short in performance or difficult to obtain. there were.

Prostaglandins (PGs), which are typical mediators of inflammation, are synthesized from arachidonic acid, which is an unsaturated fatty acid in the living body. That is, when arachidonic acid is released from phospholipids in a biological membrane in response to a stimulus from outside the cell, it is converted into PGG2 and PGH2 by the action of cyclooxygenase (COX), a kind of fatty acid oxidase. Then, four kinds of physiologically important PGs (PGD2, PGE2, PGF2a, and PGI2) and thromboxane A2 are synthesized by specific synthetic enzymes present in various cells.
As COX, two types of isozymes (COX-1 and COX-2) are known (for example, see Non-Patent Document 4). COX-1 is a constituent enzyme present in the gastrointestinal tract such as stomach and intestine, kidney, ovary, seminal vesicle, platelets, etc., and PG synthesized therefrom has a physiological role in gastric secretion, diuresis, platelet aggregation and the like. Is responsible for. On the other hand, COX-2 is an inducible enzyme newly produced by stimulation of cytokines, tumor promoters, hormones and the like, and PG synthesized therefrom is used for inflammatory reaction, angiogenesis, apoptosis, carcinogenesis, ovulation, parturition, and bone resorption. (For example, see Non-Patent Document 5).
Regarding the relationship between COX and disease, there have been many reports that rheumatism and arthritis are caused by COX-2. Recent research has also revealed the relationship with human cancer cells. For example, enhanced expression of COX-2 in colon cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, hepatocellular carcinoma, pancreatic cancer, and squamous cell carcinoma of the head and neck and the like has been reported. Further, Alzheimer's disease has been reported as a disease state related to COX-2 (for example, see Non-Patent Document 6).

COX inhibitors can be used as therapeutics for these diseases and for improving / suppressing the disease states. It is known that inhibition of COX-1 also inhibits the synthesis of PG required for physiological functions, and thus may cause various side effects such as gastrointestinal tract disorders.
Therefore, as a means for solving the above problem, a drug that selectively inhibits only COX-2 without inhibiting COX-1 has attracted attention. That is, a selective inhibitor of COX-2 can be expected to have an effect of suppressing cancer growth, metastasis, inflammation and the like with few side effects. Representative examples thereof include Cellecoxib, Rofecoxib, JTE-522, and the like, and further others are being vigorously developed (for example, see Patent Documents 1, 2, and 3). .

  On the other hand, Non-Patent Literature 7 and Non-Patent Literature 8 describe phenol compound 1 and phenol compound 2 represented by the following chemical formulas.

・ Phenol compound 1

・ Phenol compound 2

R in phenol compound 2 is CH (CH ₃ ) CH ₂ CH ₃ or CH ₂ CH (CH ₃ ) ₂ .

  However, Non-Patent Document 7 only describes a method for synthesizing phenolic compound 1, but does not describe its performance or use. Non-Patent Document 8 only discloses that phenolic compound 2 has a prostaglandin production inhibitory ability with respect to the property of phenolic compound 2.

JP 2003-176264 A (claims, p9) JP-A-2003-160554 (claims, p15) JP-A-2002-080453 (Claims, p2) Satoru Iida, et al., "Analysis and management of body odor generation mechanism", Proc. Of the 51st SCCJ Research Symposium, 2002, p. 64-67 Kenji Fukuzawa, "Pharmacology of Free Radical Defense and Perspectives on Drug Development", Japanese Clinical Laboratory, October 1988, 46, 10, p. 2269-2276 Sies, H., et al., "Antioxidant Functions of Vitamins", Annals New York Academy of Sciences, 1992, 669, p. 7-20 Yukio Hirata, Ikuo Morita, "COX-1 and COX-2", Medical Review, 1996, p. 105-118. Hideo Nakamura, Journal of Pharmaceutical Sciences, 2001, 118, pp. 219-230 M. Murota and S. Yamamoto, Ed., “38. New Developments in Prostaglandin Research, Hyundai Chemistry Special Edition”, Tokyo Kagaku Dojin, 2001 Choi, Y.H., 4 others, Tetrahedron Lett., 1995, 36, 1871-1874 Xin-Sheng, 3 others, Tetrahedron Lett., 1983, 24, 3247-3250

  An object of the present invention is to provide a novel phenol compound useful in the fields of foods, pharmaceuticals, quasi-drugs, cosmetics, and the like in view of the circumstances described above, and to provide an excellent antioxidant and cyclooxygenase inhibitor containing them. Agents, especially cyclooxygenase-2 inhibitors.

  The present inventors have conducted intensive studies to solve the above problems, and as a result, a novel phenol compound can be easily synthesized, and further, the compound has an excellent free radical scavenging effect and a cyclooxygenase inhibitory effect. And completed the present invention.

  That is, the present invention relates to a compound represented by the following general formula (1), and an antioxidant and a cyclooxygenase inhibitor comprising the compound.

R ¹ in the formula (1) represents an alkyl group having 1 to 18 carbon atoms which may have a branch, and R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a protecting group for a phenolic hydroxyl group. Show.

  The novel phenolic compound of the present invention has an excellent antioxidant effect and a cyclooxygenase inhibitory effect, and can be used in the fields of foods, pharmaceuticals, quasi-drugs, cosmetics, and the like.

○ About the novel phenol compound R ¹ of the compound represented by the formula (1) (hereinafter referred to as “new phenol compound”) is an alkyl group having 1 to 18 carbon atoms, and the alkyl group may be a branched or unbranched alkyl group. There may be. Specific examples of such an alkyl group include methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, lauryl. And a stearyl group. More preferred alkyl groups are straight-chain alkyl groups, and specifically include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl groups. Can be
In the general formula (1), R ² is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a protecting group for a phenolic hydroxyl group. Examples of the alkyl group having 1 to 4 carbon atoms for R ² include a methyl group, an ethyl group and a propyl group. As the protecting group for the phenolic hydroxyl group of the R ^2, methoxymethyl group, tetrahydropyranyl group, ether protecting groups such as benzyl and 4-methoxybenzyl groups, such as trimethylsilyl group and t- butyldimethylsilyl group Examples include silyl-based protecting groups, and ester-based protecting groups such as acetyl group, propionyl group, butyroyl group, isobutyroyl group, pivaloyl group, benzoyl group, and trioil group, and preferably ester-based protecting groups. R ^{2 in the} general formula (1) is preferably a methyl group or an ethyl group, and more preferably a methyl group.
The phenol in the general formula (1) may have a protecting group for a phenolic hydroxyl group bonded thereto. Examples of the protecting group for the phenolic hydroxyl group include those described above.

-Synthesis of new phenol compound The new phenol compound can be prepared, for example, by reacting a compound represented by the following formula (2) (hereinafter referred to as a compound of the formula (2)) in the presence of a basic compound.

R ¹ in the formula (2) represents an alkyl group having 1 to 18 carbon atoms which may have a branch, and R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a protecting group for a phenolic hydroxyl group. R ³ represents a hydrogen atom or a protecting group for a phenolic hydroxyl group. X represents a benzenesulfonyl group or a toluenesulfonyl group.

When synthesizing the compound of the formula (1), the compound of the formula (2) reacts with the basic compound to produce the compound of the formula (3) in which the double bond is isomerized. Then, it is presumed that elimination of the HX group occurs from the compound of the formula (3) to form a furan ring (see the following scheme). When R ² and R ^{3 in} the formula (2) are phenolic hydroxyl-protecting groups that can be removed under basic conditions, deprotection of the protecting group also occurs.

R ¹ in the above formula (3) represents an alkyl group having 1 to 18 carbon atoms which may have a branch, and R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a protecting group for a phenolic hydroxyl group. And X represents a benzenesulfonyl group or a toluenesulfonyl group.

When R ² and R ^{3 in} the formula (2) are protecting groups for a phenolic hydroxyl group, a protecting group that can be easily removed when the need for the protecting group is eliminated is preferable. Is exemplified by silyl-type protecting groups and acyl-type protecting groups.
Specifically, a trimethylsilyl group, a t-butyldimethylsilyl group, an acetyl group, a propionyl group, a butyroyl group, an isobutyroyl group, a pivaloyl group, a benzoyl group, and a toluoyl group can be preferably used, and more preferably an acetyl group and a propionyl group , Butyroyl, isobutyroyl, pivaloyl, benzoyl or toluoyl groups.

Examples of the basic compound used in the reaction from the compound of the formula (2) to the novel phenol compound include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, and alkoxides (eg, sodium methoxide, sodium ethoxide, potassium t- Butoxide), n-butyllithium, s-butyllithium, t-butyllithium and the like, and preferably sodium hydride.
The amount of the basic compound used in the reaction with the compound of the formula (2) varies depending on the structures of R ² and R ³ in the formula (2) and the kind of the basic substance, but is suitably 2 to 10 chemical equivalents. Preferably it is 3-5 chemical equivalents.

  In this reaction, a solvent may be used, and methanol, isopropyl alcohol, n-butyl alcohol, s-butyl alcohol, t-butyl alcohol, tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, N, N-dimethylformamide, hexamethylphosphoric triamide, N, N-dimethylpropyleneurea, a mixed solvent thereof and the like can be suitably used.

  This reaction temperature is 0 ° C to 100 ° C, preferably 25 ° C to 80 ° C. When the reaction temperature is too low, the reaction progresses slowly, and when the reaction temperature is too high, side reactions may progress. The reaction time varies depending on conditions, but is usually several tens minutes to several hours. After completion of the reaction, a novel phenol compound can be obtained by a known method such as solvent extraction and column chromatography.

○ Synthesis of compound of formula (2) The compound of formula (2) is produced, for example, by oxidizing a compound represented by the following formula (4) (hereinafter referred to as a compound of formula (4)) with an oxidizing agent such as hydrogen peroxide. it can. Further, the compound of the formula (4) is prepared by reacting a compound represented by the following general formula (5) (hereinafter referred to as a compound of the formula (5)) with an electrophile such as phenylselenyl chloride to give a compound of the formula (5) It can be synthesized by forming a five-membered ring ether with the terminal hydroxyl group of the chain.

R ¹ , R ² , R ³ and X in the formula (4) are the same as those in the formula (2), and R ⁴ represents an alkyl group having 1 to ⁴ carbon atoms or a substituted or unsubstituted aryl group. Is a methyl group or a phenyl group, and Y represents a sulfur atom or a selenium atom.

  The oxidizing agent for synthesizing the compound of the formula (2) from the compound of the formula (4) is not particularly limited, but may be hydrogen peroxide, peracetic acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperoxide. Peracids and peroxides such as benzoic acid and t-butyl hydroperoxide can be suitably used. The amount of the peracid or peroxide used in this reaction is 1 to 10 chemical equivalents, preferably 1.1 to 2 chemical equivalents.

  This oxidation reaction may use a solvent, such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, acetonitrile, toluene, water, and a mixed solvent thereof. Can be suitably used.

  The temperature of this oxidation reaction is from -20C to 100C, preferably from 0C to 80C. When the reaction temperature is too low, the progress of the reaction is slow, and when the reaction temperature is too high, a side reaction may proceed. The reaction time varies depending on the conditions, but is usually several tens minutes to several hours. After completion of the reaction, the compound of the formula (2) can be obtained by a known method such as solvent extraction or column chromatography.

-Synthesis of compound of formula (4) As described above, the compound of formula (4) can be synthesized, for example, by cyclizing the following formula (5).

R ¹ , R ² , R ³ and X in the formula (5) are the same as those in the formula (2).

  In the reaction for obtaining the compound of formula (4) from the compound of formula (5), phenylselenyl chloride and dimethyl (methylthio) sulfonium tetrafluoroborate can be used as reaction partners of the compound of formula (5). The amount of the compound to be used is 1 to 5 chemical equivalents, preferably 1.1 to 1.5 chemical equivalents. In the above cyclization reaction, an appropriate amount of an amine such as diisopropylethylamine or a weakly basic compound such as molecular sieves can be used in addition to the above compound.

  This cyclization reaction may be carried out using a solvent, preferably in an aprotic polar solvent, and is preferably performed in tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, hexamethylphosphoric triamide, N, N-dimethylpropyleneurea, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, a mixed solvent thereof and the like can be suitably used.

  The temperature of this cyclization reaction is 0 ° C to 100 ° C, preferably 25 ° C to 80 ° C. When the reaction temperature is too low, the progress of the reaction is slow, and when the reaction temperature is too high, a side reaction may proceed. The reaction time varies depending on the conditions, but is usually several tens minutes to several hours. After completion of the reaction, the compound of the formula (4) can be obtained by a known method such as solvent extraction or column chromatography.

○ Synthesis of compound of formula (5) The compound of formula (5) is obtained by reacting a compound represented by the following formula (6) (hereinafter referred to as a compound of formula (6)) with a strongly basic compound, and a substituent X is bonded thereto. The compound can be synthesized by reacting an anion obtained by extracting a hydrogen atom from a carbon atom with a carbon atom of a carbonyl group in a compound represented by the following formula (7) (hereinafter referred to as an aldehyde of the formula (7)).

R ¹ , R ² , R ³ and X in the formula (6) are the same as those in the formula (2).

R ¹ -CHO (7)
R ¹ in the formula (7) is the same as in the formula (5).

  As the strong basic compound which acts on the compound of the formula (6) to generate an anion, an alkyl metal compound, an alkali metal or the like can be used. Specifically, alkyllithium compounds such as n-butyllithium, s-butyllithium, t-butyllithium and phenyllithium, and n-butylmagnesium chloride, s-butylmagnesium chloride, t-butylmagnesium chloride, n-butylmagnesium Grignard compounds such as bromide, s-butylmagnesium bromide and t-butylmagnesium bromide. Specific examples of the alkali metal include lithium metal and sodium metal. Preferred examples of the strong basic compound include n-butyllithium, n-butylmagnesium chloride and n-butylmagnesium bromide. The preferred use amount of the strong basic compound is preferably 0.7 to 1.3 chemical equivalents, more preferably 0.9 to 1.1 chemical equivalents, with respect to the compound of the formula (6).

  The reaction between the compound of formula (6) and the strongly basic compound is preferably carried out in an aprotic solvent, and includes tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, hexamethylphosphoric Amide, N, N-dimethylpropylene urea, a mixed solvent thereof and the like can be suitably used. The reaction temperature is preferably from -100C to 25C, more preferably from -80C to 0C. The reaction time varies depending on the conditions, but is usually several minutes to several tens of minutes.

  The aldehyde of the formula (7) is added to a reaction vessel containing an anion formed by the reaction between the compound of the formula (6) and the strongly basic compound. The reaction temperature at that time is preferably from -100 ° C to 25 ° C, and more preferably from -80 ° C to 0 ° C. The reaction time varies depending on the conditions, but is usually several minutes to several tens of minutes. After completion of the reaction, the compound of the formula (5) can be isolated and purified by a known method such as solvent extraction or column chromatography.

  The compound of the formula (6) can be synthesized, for example, by substituting the hydroxyl group of the compound represented by the following formula (8) with a toluenesulfonyl group or a benzenesulfonyl group by a known method.

R ² and R ³ in the formula (8) are the same as those in the formula (2).

  The novel phenolic compound of the present invention has free radical scavenging activity and cyclooxygenase inhibitory activity. Accordingly, it can be used as an antioxidant or a cyclooxygenase inhibitor in formulations of foods, pharmaceuticals, quasi-drugs, cosmetics and the like.

<Example>
Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples. Ts represents a p-toluenesulfonyl group.

<Synthesis example 1>
O Synthesis of Compound 2 First, Compound 2 was synthesized using Compound 1 below as a starting material.

・ Compound 1

・ Compound 2

14.4 g (79.9 mmol) of compound 1, 22.3 mL (160 mmol) of triethylamine and 976 mg (7.99 mmol) of N, N-dimethylaminopyridi were dissolved in 350 mL of tetrahydrofuran, and pivaloyl chloride was dissolved in ice under cooling with ice. 7 mL (160 mmol) was added dropwise. After stirring at room temperature for 16 hours, the mixture was washed twice with 100 mL of saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
Next, the obtained residue was dissolved in 270 mL of tetrahydrofuran and 90 mL of methanol, and 15.7 g (87.9 mmol) of sodium p-toluenesulfinate and 923 mg (0.799 mmol) of tetrakistriphenylphosphine palladium (0) were added thereto for 4 hours. Refluxed. After the reaction, 90 mL of distilled water was added and stirred, and then left at 4 ° C. The generated crystals were collected by filtration. After the filtrate was concentrated, it was extracted with 200 mL of ethyl acetate, and the organic layer was washed with 100 mL of distilled water. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and recrystallized from a mixed solvent of ethyl acetate-hexane. The obtained crystals were combined with the above-mentioned crystals to obtain 20.3 g (yield: 63%) of a yellow crystalline compound.
The chemical shift values of the ¹ H-NMR spectrum of this product measured in deuterated chloroform were 1.36 (9H, s), 2.44 (3H, s), 3.80 (3H, s), and 3.93. (2H, d), 6.06 (1H, dt), 6.33 (1H, d), 6.83-6.94 (3H, m), 7.33 (2H, d), 7.75 ( 2H, d).
The wave numbers (cm ⁻¹ ) at which absorption was observed in the infrared absorption spectrum (KBr pellet method) were 2980, 1747, 1600, 1508, 1480, 1465, 1420, 1399, 1343, 1314, 1304, 1289, and 1269. Was.
Furthermore, the result of CHN elemental analysis was 65.65% of carbon and 6.51% of hydrogen.
From the above analysis, it was confirmed that the obtained compound was the compound 2.

-Synthesis of compound 3 Subsequently, compound 3 was synthesized by reacting compound 2 with propionaldehyde.

・ Compound 3

4.45 g (7.45 mmol) of Compound 2 was dissolved in a mixed solvent of 50 mL of tetrahydrofuran and 10 mL of 1,3-dimethyl-2-imidazolinone, and cooled to -78 ° C with dry ice / acetone. To this solution, 7.4 mL (11.8 mmol) of a 1.6 M t-butyllithium / pentane solution was added dropwise. After stirring at the same temperature for 5 minutes, 0.87 mL (12.1 mmol) of propionaldehyde was added dropwise. After the dropwise addition, the mixture was stirred at the same temperature for 10 minutes, and then gradually heated. When the temperature of the reaction solution reached −30 ° C., the reaction was stopped by adding a 2 mL solution of methanol containing 1 g of citric acid. 60 mL of saturated saline, 20 mL of distilled water and 20 mL of ethyl acetate were added to the reaction mixture, and after stirring, the organic layer was separated. The aqueous layer was extracted with 20 mL of ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer, and purification was performed by silica gel column chromatography to obtain 3.72 g (yield 73%) of a pale yellow highly viscous liquid compound.
The chemical shift values of the ¹ H-NMR spectrum of this product measured in deuterated chloroform were 0.97 to 1.01 (3H, m), 1.24 to 1.44 (11H, m), 2.43 ( 3H, s), 3.71 (1H, t), 3.80 (3H, s), 4.30-4.32 (1H, m), 5.72 (1H, dd), 6.16 (1H) , D), 6.78-6.80 (2H, m), 6.93 (1H, d), 7.31 (2H, d), and 7.71 (2H, d).
In addition, wave numbers (cm ⁻¹ ) at which absorption was observed in an infrared absorption spectrum (KBr pellet method) were 3511, 2972, 1753, 1598, 1509, 1268, and 1124.
Furthermore, the result of CHN elemental analysis was 65.19% of carbon and 7.00% of hydrogen.
From the above analysis, it was confirmed that the obtained compound was the compound 3.

○ Synthesis of Compound 4 Subsequently, Compound 3 was reacted with phenylselenyl chloride to effect cyclization, whereby Compound 4 was synthesized.

・ Compound 4

9.03 g (19.6 mmol) of compound 3 was dissolved in 50 mL of acetonitrile, 2 g of molecular sieves 3A and 4.36 g (22.8 mmol) of phenylselenyl chloride were added, and the mixture was stirred at room temperature for 2 hours. This reaction mixture was washed twice with 100 mL of saturated saline, and the obtained organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer, and the residue was purified by silica gel column chromatography to obtain 10.9 g (yield 90%) of a pale yellow highly viscous liquid compound.
The chemical shift values of the ¹ H-NMR spectrum of this product measured in deuterated chloroform were 1.07-1.11 (3H, m), 1.24-1.38 (11H, m), and 2.37 ( 3H, s), 3.50 (1H, dd), 3.73 (1H, dd), 3.79-3.89 (4H, m), 4.68 (1H, d), 6.87-7 .55 (12H, m).
The wave numbers (cm ^-1 ) at which absorption was observed in the infrared absorption spectrum (KBr pellet method) were 2971, 1754, 1598, 1509, 1478, 1463, 1274, and 1118. Further, the result of mass spectrometry was M ⁺ = 617.
From the above analysis, it was confirmed that the obtained compound was the compound 4.

○ Synthesis of Compound 5 Subsequently, Compound 4 was oxidized to prepare Compound 5.

・ Compound 5

9.93 g (16.1 mmol) of the compound 4 was dissolved in 200 mL of dichloromethane. On the other hand, a solution prepared by dissolving 4.18 g (24.2 mmol) of m-chloroperbenzoic acid in 50 mL of dichloromethane was added dropwise under ice cooling. After stirring at the same temperature for 30 minutes, 200 mL of a 10% aqueous sodium thiosulfate solution was added to the reaction mixture to stop the reaction. The organic layer was separated from the reaction solution and dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer, and the residue was purified by silica gel column chromatography to obtain 7.26 g (yield 98%) of a pale yellow highly viscous liquid compound.
The chemical shift values of the ¹ H-NMR spectrum of this product measured in deuterated chloroform were 0.91 to 0.95 (3H, m), 1.24 to 1.38 (11H, m), and 2.36 ( 3H, s), 3.78 (3H, s), 4.97 (1H, m), 5.79 (1H, d), 6.67 (1H, s), 6.83 (1H, d), 6.89 (1H, d), 6.98 (1H, d), 7.37 (2H, d), 7.80 (2H, d).
In addition, wave numbers (cm ⁻¹ ) at which absorption occurred in an infrared absorption spectrum (KBr pellet method) were 2,973, 1754, 1508, 1458, 1321, 1304, and 1283. Furthermore, the result of CHN elemental analysis was 65.48% of carbon and 6.59% of hydrogen.
From the above analysis, it was confirmed that the obtained compound was the compound 5.

O Synthesis of Compound 6 By reacting Compound 5 obtained in Synthesis Example 1 with sodium hydride in an alcohol solvent, R ^{1 in} the general formula (1) of the present invention is an ethyl group and R Compound 6 in which ² corresponds to a methyl group was synthesized.

・ Compound 6

That is, 1.49 g (3.25 mmol) of Compound 5, was dissolved in 30 mL of t-butyl alcohol. On the other hand, a solution prepared by dissolving 390 mg (9.75 mmol) of sodium hydride prepared in advance in 20 mL of t-butyl alcohol was added dropwise. After the reaction solution was stirred at 40 ° C. for 2 hours, an appropriate amount of 1 M / L hydrochloric acid was added to stop the reaction. After evaporating the solvent from the reaction solution, 100 mL of ethyl acetate was added for extraction, and the organic layer was washed twice with 50 mL of saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer, and the residue was purified by silica gel column chromatography to obtain 420 mg (59% yield) of a pale yellow highly viscous liquid compound.
The chemical shift value of the ¹ H-NMR spectrum of this product measured in deuterated chloroform was 1.24 to 1.29 (3H, m), 2.70 (2H, dd), and 3.94 (3H, s). 5.62 (1H, s), 6.03 (1H, d), 6.40 (1H, d), 6.91 (1H, d), 7.13-7.16 (2H, m) there were.
The wave numbers (cm ⁻¹ ) at which absorption was observed in the infrared absorption spectrum (KBr pellet method) were 3510, 2974, 2362, 1506, 1254, and 1209. Further, the result of CHN elemental analysis was 71.54% of carbon and 6.47% of hydrogen.
From the above analysis, it was confirmed that the obtained compound was the compound 6.

<Synthesis Example 2>
-Synthesis of compound 7 Compound 2 was reacted with 1-heptanal to synthesize compound 7.

・ Compound 7

4.45 g (11.4 mmol) of Compound 2 was dissolved in a mixed solvent of 50 mL of tetrahydrofuran and 10 mL of 1,3-dimethyl-2-imidazolinone, and the mixture was cooled to -78 ° C with dry ice / acetone. To this solution, 7.4 mL (11.8 mmol) of a 1.6 M t-butyllithium / pentane solution was added dropwise. After the reaction solution was stirred at the same temperature for 5 minutes, 1.6 mL (11.5 mmol) of 1-heptanal was added dropwise. After the dropwise addition, the mixture was stirred at the same temperature for 10 minutes, and then gradually heated. When the temperature of the reaction solution reached −30 ° C., the reaction was stopped by adding a 2 mL solution of methanol containing 1 g of citric acid. 60 mL of saturated saline, 20 mL of distilled water, and 20 mL of ethyl acetate were added to the reaction mixture, and the mixture was stirred, and then the organic layer was separated. The aqueous layer was extracted with 20 mL of ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer, and purification was performed by silica gel column chromatography to obtain 4.15 g (72%) of a pale yellow highly viscous liquid compound.
The chemical shift values of the ¹ H-NMR spectrum of this product measured in deuterated chloroform were 0.84-0.87 (3H, m), 1.9-1.36 (19H, m), 2.42 ( 3H, s), 3.57 (1H, d), 3.81 (3H, s), 4.50-4.61 (1H, m), 5.72 (1H, dd), 6.18 (1H) , D), 6.29 (1H, dd), 6.79 (1H, d), 6.88 (1H, s), 6.91 (1H, d), 7.31 (2H, d), 7 .71 (2H, d).
The wave numbers (cm ⁻¹ ) at which absorption was observed in the infrared absorption spectrum (KBr pellet method) were 3510, 2933, 2337, 1755, 1508, and 1268. Furthermore, the result of CHN elemental analysis was as follows: carbon was 67.41% and hydrogen was 7.80%.
From the above analysis, it was confirmed that the obtained compound was the compound 7.

-Synthesis of Compound 8 Subsequently, Compound 7 was reacted with phenylselenyl chloride to cyclize and Compound 8 was synthesized.

・ Compound 8

3.43 g (6.71 mmol) of the compound 7 was dissolved in 50 mL of acetonitrile, 1 g of Molecular Sieves 3A and 1.35 g (7.05 mmol) of phenylselenyl chloride were added thereto, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with 50 mL of ethyl acetate and washed twice with 50 mL of saturated saline, and the obtained organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer, and the residue was purified by silica gel column chromatography to obtain 4.14 g (yield 92%) of a pale yellow highly viscous liquid compound.
The chemical shift values of the ¹ H-NMR spectrum of this product measured in deuterated chloroform were 0.84-0.89 (3H, m), 1.4-1.38 (19H, m), and 2.36 ( 3H, s), 3.51 (1H, dd), 3.72 (1H, dd), 3.86 (3H, s) 3.92-3.97 (1H, m), 4.67 (1H, d), 6.89-7.55 (12H, m).
In addition, wave numbers (cm ⁻¹ ) at which absorption was observed in an infrared absorption spectrum (KBr pellet method) were 2932, 1755, 1508, 1464, and 1274. Further, the result of mass spectrometry was M ⁺ = 673.
From the above analysis, it was confirmed that the obtained compound was the compound 8.

O Synthesis of Compound 9 Subsequently, Compound 8 was oxidized to prepare Compound 9.

・ Compound 9

4.29 g (6.36 mmol) of compound 8 was dissolved in 100 mL of dichloromethane. On the other hand, a solution prepared by dissolving 1.65 g (9.58 mmol) of m-chloroperbenzoic acid in 25 mL of dichloromethane was added dropwise under ice cooling. After stirring the reaction solution at the same temperature for 30 minutes, 100 mL of a 10% aqueous solution of sodium thiosulfate was added to stop the reaction. The organic layer was separated from the reaction solution and dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer, and the residue was purified by silica gel column chromatography to obtain 2.84 g (yield 87%) of a pale yellow highly viscous liquid compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product were 0.83-0.87 (3H, m), 1.18-1.36 (19H, m), and 2.46 ( 3H, s), 3.77 (3H, s), 5.01 (1H, m), 5.79 (1H, d), 6.66 (1H, s), 6.82 (1H, d), 6.88 (1H, d), 6.98 (1H, d), 7.37 (2H, d), and 7.80 (2H, d).
In addition, wave numbers (cm ⁻¹ ) at which absorption was observed in an infrared absorption spectrum (KBr pellet method) were 2,935, 1755, 1599, 1510, 1321, and 1283. Further, the result of CHN elemental analysis was 67.68% of carbon and 7.44% of hydrogen.
From the above analysis, it was confirmed that the obtained compound was the compound 9.

O Synthesis of Compound 10 By reacting Compound 9 obtained in Synthesis Example 2 with sodium hydride in an alcohol solvent, R ^{1 in} the general formula (1) of the present invention has a hexyl group and R Compound 10 in which ² corresponds to a methyl group was synthesized.

-Compound 10

In 41 mL of t-butyl alcohol, 1.41 g (2.74 mmol) of Compound 9 was dissolved. On the other hand, a solution prepared by dissolving 548 mg (13.7 mmol) of sodium hydride in 30 mL of t-butyl alcohol was added dropwise. After stirring the reaction solution at 40 ° C. for 4.5 hours, an appropriate amount of 1 M / L hydrochloric acid was added to stop the reaction. After the solvent was distilled off from the reaction solution, 50 mL of ethyl acetate was added for extraction, the organic layer was washed twice with 25 mL of saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer, and the residue was purified by silica gel column chromatography to obtain 540 mg (yield: 72%) of a pale yellow highly viscous liquid compound.
The chemical shift values of the ¹ H-NMR spectrum of this product measured in deuterated chloroform were 0.88-0.91 (3H, m), 1.25-1.39 (8H, m), 2.66 ( 2H, t), 3.95 (3H, s), 5.59 (1H, s), 6.02 (1H, d), 6.39 (1H, d), 6.80 (1H, d), 7.13-7.16 (2H, m). In addition, wave numbers (cm ⁻¹ ) at which absorption occurred in an infrared absorption spectrum (KBr pellet method) were 3,532, 2931, 1505, 1254, and 1212. Furthermore, the result of CHN elemental analysis was 74.42% for carbon and 8.08% for hydrogen.
From the above analysis, it was confirmed that the obtained compound was the compound 10.

○ DPPH radical scavenging activity Compound 6 obtained in Example 1, compound 10 obtained in Example 2 and dl-α-tocopherol (manufactured by Tokyo Chemical Industry) were used to prepare DPPH (1,1-diphenyl-2-picrylhydrazyl). ) A radical scavenging test was performed. The specific test procedure is as follows.
1 ml of a 200 μM ethanol solution of DPPH was added to 800 μl of a 100 mM Tris-HCl buffer (pH = 7.4) and 200 μl of an ethanol solution of the compound 6 (final concentration: 10 μg / mL), and the mixture was thoroughly stirred. After allowing this to stand at room temperature in a dark place for 20 minutes, the absorbance at 517 nm was measured (absorbance of the sample solution).
The same operation was performed for compound 10 and dl-α-tocopherol.
As a control, the same operation was carried out using 800 μl of 100 mM Tris-HCl buffer (pH = 7.4), 200 μl of ethanol and 1 ml of 200 μM ethanol solution of DPPH, and the absorbance was measured (absorbance of control solution).
The same measurement was performed three times for each compound, and the average value was substituted into the following equation to calculate the DPPH radical scavenging rate. The results are shown in Table 1.
DPPH radical scavenging rate (%) =
[1- (absorbance of sample solution / absorbance of control solution)] × 100

  As a result of the test, it was found that Compound 6 and Compound 10 had a free radical scavenging effect higher than dl-α-tocopherol.

O Cyclooxygenase inhibitory activity Sheep seminal vesicle gland microsomes (manufactured by Caiman Chemical Co., Ltd.) were used as COX-1, and sheep placenta-derived purified COX-2 product (manufactured by Caiman Chemical Co., Ltd.) was used as COX-2. The conversion rate to E2 was defined as the enzyme activity. The activity was measured as follows.
To 70 μL of a 143 mM Tris buffer (pH 7.5) containing 2.9 mM phenol and 1.4 mM hematin, 10 μL of each concentration of compound 6 or compound 10 dissolved in a 10% aqueous dimethyl sulfoxide solution was added, and then 2 units. Of COX-1 or COX-2 was added and mixed. This was pre-incubated at 37 ° C. for 2 minutes. Next, 10 μL (0.14 μCi) of radiolabeled [1- ¹⁴ C] arachidonic acid (manufactured by Amersham Pharmacia Biotech) adjusted to a concentration of 25.5 μM with 100 mM Tris buffer was added and mixed. This was reacted at 37 ° C. for 2 minutes and immediately cooled on ice.
The COX activity was calculated with reference to the method of Yanagi and Komatsu (Biochem. Pharmacol., 25, 937-941 (1976)). That is, 0.4 mL of a mixed solution of n-hexane / ethyl acetate (2: 1) was added to the reaction solution, stirred for 30 seconds, and centrifuged to remove an unreacted organic layer containing arachidonic acid. After repeating the same extraction operation twice, 50 μL of ethanol was added to the aqueous layer, followed by stirring for 30 seconds. After centrifugation at 2000 G for 1 minute, 0.1 mL of the aqueous layer was transferred to a vial for a liquid scintillation counter. To this, 2 mL of Clearsol 1 (manufactured by Nacalai Tesque) as a scintillator was added to obtain a prostaglandin E2 fraction cocktail. Radioactivity was measured with a liquid scintillation counter (LSA-1000, manufactured by ALOKA), and the ratio of radioactivity was calculated to be the conversion rate of prostaglandin E2.
From the relationship between the conversion rate of prostaglandin E2 and the test sample concentration, the concentration (IC ₅₀ ) at which the conversion to prostaglandin E2 was inhibited by 50% was calculated, and the results are shown in Table 2.

  The novel phenolic compound of the present invention has an excellent antioxidant effect and a cyclooxygenase inhibitory effect, and can be used in the fields of foods, pharmaceuticals, quasi-drugs, cosmetics, and the like.

Claims (3)

A compound represented by the following general formula (1).

(1)
(R ¹ in the formula (1) represents an alkyl group having 1 to 18 carbon atoms which may have a branch, and R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a protecting group for a phenolic hydroxyl group. Is shown.)   An antioxidant comprising the compound represented by the general formula (1) according to claim 1.   A cyclooxygenase inhibitor comprising the compound represented by the general formula (1) according to claim 1.