JP4419465B2 - Cyclooxygenase inhibitor - Google Patents

Description

  The present invention relates to the use of a novel compound having a chemical structure similar to gingerol, which is useful in the fields of foods, pharmaceuticals, quasi drugs and cosmetics, and the compound exhibits excellent performance as a cyclogenase activity inhibitor. And can be used by adding to the food, medicine, quasi-drug, cosmetics, etc.

Prostaglandins (PGs) are bioactive substances synthesized from arachidonic acid and are one of the representative mediators of inflammation. This PG is produced by the so-called “arachidonic acid cascade”. That is, arachidonic acid is released from phospholipids in the biological membrane by the action of phospholipase A2 in response to various stimuli from the outside of the cell. Using this released arachidonic acid as a substrate, it is converted to PGG2 and PGH2 by the action of cyclooxygenase (COX), which is a fatty acid oxidase, and is further physiologically important by specific synthetic enzymes present in various cells. Types of PGs (PGD2, PGE2, PGF2a, and PGI2) and thromboxane A2 are synthesized. Therefore, many COX inhibitors represented by aspirin have been developed as anti-inflammatory agents and / or antipyretic analgesics.
In the 1990s, it was revealed that this COX is composed of two types of isozymes (COX-1 and COX-2) (for example, see Non-Patent Document 1). COX-1 is a constitutive enzyme that is constantly present in cells, and COX-2 is an inductive enzyme that is newly produced by inflammatory substances such as cytokines and other stimuli. That is, COX-1 is present in the digestive tract such as the stomach and intestine, kidneys, ovaries, seminal vesicles, and platelets, and PG synthesized therefrom plays a physiological role such as gastric juice secretion, diuresis, and platelet aggregation. ing. On the other hand, COX-2 is induced in macrophages, fibroblasts, vascular endothelial cells, cancer cells and the like by stimulation of cytokines, tumor promoters, hormones, etc., and PG synthesized therefrom becomes an inflammatory reaction, angiogenesis, apoptosis, It is involved in carcinogenesis, ovulation, parturition, bone resorption, and the like (see, for example, Non-Patent Document 2).

  As a 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 has been reported in colon cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, hepatocellular carcinoma, pancreatic cancer, squamous cell carcinoma such as head and neck. The relationship between COX-2 and carcinogenesis is supported by the significantly low incidence of colorectal cancer and breast cancer among nonsteroidal antiinflammatory drugs (NSAIDs) such as aspirin and indomethacin. (For example, see Non-Patent Document 1). Furthermore, it has been pointed out that PG produced by COX-2 is involved in promoting the growth of cancer tissues by inducing the formation of tumor blood vessels that supply nutrients to cancer cells (eg, non-patented). Reference 3 and Non-Patent Document 4). COX-2 expression level in primary and metastatic cancers correlates with tumor angiogenesis level, malignancy of cancer, resistance to apoptosis, systemic immunosuppression, etc. Increased expression is also associated with poor prognosis in cancer (see, for example, Non-Patent Document 5). Furthermore, Alzheimer's disease has been reported as a pathological condition related to COX-2 (see, for example, Non-Patent Document 6).

The COX inhibitor can be used for a therapeutic agent for these diseases, and for improvement / suppression of the disease state. For example, NSAIDs having a COX inhibitory effect have been used as therapeutic agents for arthritis and chronic rheumatism. In addition to inhibition of growth of cancer cells and tumors (for example, see Non-Patent Document 3 and Non-Patent Document 4), inhibition of COX-2 has been reported to enhance the anticancer effect by combined use with an anticancer agent (for example, Non-patent document 5). In an experimental model of angiogenesis using rat cornea, it has been reported that corneal neovascularization was suppressed by a COX-2 inhibitor. From this, it can be expected as an inhibitor of intraocular neovascularization in diabetic retinopathy and age-related macular degeneration, for example. Furthermore, it has been found in a large-scale clinical trial in Germany that the incidence of Alzheimer's disease is reduced by up to 80% when NSAID is taken for a long time (see, for example, Non-Patent Document 7).
Since inhibition of COX-1 also inhibits the synthesis of PG necessary for physiological functions, it is known that there is a risk of causing various side effects such as gastrointestinal disorders. Therefore, as a means for solving the above problems, 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 suppress cancer growth, metastasis, inflammation and the like with few side effects. Typical examples of this are Celecoxib, Rofecoxib, JTE-522, and others, and others have been vigorously developed (see, for example, Patent Document 1, Patent Document 2, and Patent Document 3). .

JP 2003-176264 A (Claims, p9) JP2003-160554A (Claims, p15) JP 2002-080453 A (Claims, p2) Hirata Yukio, Morita Ikuo, “COX-1 and COX-2”, Medical Review, 1996, p105-118 Hideo Nakamura, Journal of Japanese Pharmacology, 2001, 118, p219-230 Leahy, K .; M.M. 5 others, Cancer Res, 2002, 62, 3, p625-631 Masferrer, J.M. L. 7 others, Cancer Res, 2000, 60, 5, p1306-1311 Blanke, C.I. D. , Oncology (Huntingt), 2002, 16 (4 Suppl 3), p17-21. Murota Seigo and Yamamoto Shozo, “Modern Chemistry Special Issue 38 New Developments in Prostaglandin Research”, Tokyo Chemical Doujin, 2001 Veld, B.M. A. 7 others, New Engl. J. et al. Med. 2001, 345, 1515-1521

  This invention is providing the compound which acts as a cyclooxygenase inhibitor, especially a cyclogenase-2 activity inhibitor used for a foodstuff, a pharmaceutical, a quasi-drug, cosmetics, etc.

  As a result of diligent research, the present inventors have found that gingerol analogs and / or gingerdiol analogs have excellent cyclooxygenase inhibitory activity, and therefore can be used as cyclooxygenase inhibitors, and further cyclogenase-2 activity inhibitors. As a result, the present invention has been completed.

That is, the present invention, among the gingerol analogues represented by the following formula (1), a compound represented by the formula (11), and / or of Jingejioru analogues represented by the following formula (2), the formula (12) It is a cyclooxygenase inhibitor characterized by comprising the compound shown .

R ¹ in the formula (1) represents an alkyl group which may have 1 to 18 carbon atoms, R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ³ represents 1 carbon atom. The alkyl group which may have a -4 branch is shown, A shows a C1-C4 alkylene group.

R ¹ in Formula (2) represents an alkyl group that may have a branch having 1 to 18 carbon atoms, R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ³ represents 1 carbon atom. The alkyl group which may have a -4 branch is shown, A shows a C1-C4 alkylene group.

  Since the gingerol analog and / or gingerdiol analog of the present invention has an excellent cyclooxygenase inhibitory action, it is added to foods, pharmaceuticals, quasi drugs, cosmetics, etc., and symptoms such as inflammation and allergy Can be suppressed or treated.

○ About gingerol analog represented by formula (1) In formula (1), R ¹ is an alkyl group which may have 1 to 18 carbon atoms, and is a methyl group, an ethyl group, a propyl group or a butyl group. , Isobutyl group, pentyl group, hexyl group, peptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, lauryl group, and stearyl group. As the alkyl group, a straight-chain alkyl group is preferable, and considering the structure of gingerol existing in nature, it is preferable that R ¹ has an even number of carbon atoms. Specifically, an ethyl group, a butyl group, a hexyl group, an octyl group, and a decyl group can be illustrated as preferable examples.
In the formula (1), R ² is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, preferably a methyl group or an ethyl group, and more preferably a methyl group.
In the formula (1), R ³ is an alkyl group which may have 1 to 4 carbon atoms, and is preferably a methyl group or an ethyl group.
In the formula (1), A is an alkylene group having 1 to 4 carbon atoms, preferably an ethylene group or a butylene group, and more preferably an ethylene group.

  The gingerol analog represented by the formula (1) can be easily prepared, for example, by adding an alcohol such as methanol or ethanol to the gingerol represented by the chemical synthesis or naturally derived formula (3). .

R ¹ in Formula (3) represents an alkyl group which may have 1 to 18 carbon atoms, and R ² and R ⁴ each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or phenolic. A hydroxyl protecting group is shown, and A represents an alkylene group having 1 to 4 carbon atoms. However, R ² and R ⁴ are not simultaneously an alkyl group having 1 to 4 carbon atoms.

The protecting group for the phenolic hydroxyl group in R ² and R ⁴ of formula (3) can be removed in the presence of an alkali catalyst used as a catalyst for the addition reaction of alcohol such as methanol or ethanol to formula (3) described below. Preferred protecting groups are preferred. Examples of such protecting groups include silyl-type protecting groups and acyl-type protecting groups. Specific examples include trimethylsilyl group, t-butyldimethylsilyl group, acetyl group, propionyl group, butyroyl group, isobutyroyl group, pivaloyl group, benzoyl group, and toluoyl group. Considering raw material costs, introduction of protecting groups, simplicity of deprotection reaction, etc., the protecting group of the phenolic hydroxyl group is preferably an acetyl group, propionyl group, butyroyl group, isobutyroyl group, pivaloyl group, benzoyl group, or toluoyl group. .

The addition reaction of alcohol such as methanol or ethanol to formula (3) is preferably carried out in the presence of a catalyst, especially sodium hydroxide, potassium hydroxide, alkoxide (for example, sodium methoxide or sodium ethoxide). And / or an alkali catalyst such as sodium hydride can be suitably used. The amount of catalyst used varies depending on the structure of R ² and R ⁴ in formula (3) and the type of catalyst, but is preferably 0.05 to 10 chemical equivalents, more preferably 0.1 to 5 chemical equivalents. When the amount of the catalyst used is too small, the progress of the reaction may be delayed, and when the amount used is too large, a large amount of neutralizing agent may be required for the treatment after the reaction.

  In this addition reaction, a solvent may be used, tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, N, N-dimethylformamide, hexamethylphosphoric triamide, N, N-dimethylpropylene urea. , Water, and a mixed solvent thereof can be preferably used. In addition, as a solvent of this addition reaction, you may use the alcohol added to Formula (3) as a solvent.

The temperature of this addition reaction is preferably -20 to 100 ° C, more preferably 0 to 80 ° C. When the reaction temperature is too low, the reaction may proceed slowly, and when the reaction temperature is too high, a side reaction may proceed.
Although this addition reaction time varies depending on conditions, it is usually several tens of minutes to several hours.
After the completion of this reaction from formula (3) to formula (1), the gingerol analog represented by formula (1) can be obtained by a known purification method such as solvent extraction or column chromatography.

The compound represented by the formula (3) is prepared by using a compound represented by the following formula (4) and a compound represented by the following formula (5) as raw materials, and further preparing a compound represented by the formula (6) ) From “HX”.
X—CH ₂ —CH═CH—R ¹ (4)
In the formula (4), R ¹ is an alkyl group which may have a branch having 1 to 18 carbon atoms, and X is a benzenesulfonyl group or a toluenesulfonyl group.

R ² and R ⁴ in the formula (5) correspond to R ² and R ⁴ in the formula (3), and A also corresponds to A in the formula (3).

R ² and R ⁴ in the formula (6) correspond to R ² and R ⁴ in the formula (3), and A also corresponds to A in the formula (3). R ¹ is an alkyl group which may have 1 to 18 carbon atoms, and X is a benzenesulfonyl group or a toluenesulfonyl group.

The compound represented by the formula (4) is K.I. Inomata, et al. , Chem. Lett. , 931 (1985) and the like.
R ^{1 in} Formula (4) is an alkyl group that may have a branch having 1 to 18 carbon atoms. This alkyl group is an alkyl group which may have 1 to 18 carbon atoms from the ease of raw material availability and the synthesis yield of the compound represented by formula (4), and is preferably linear carbon. It is an alkyl group of formula 1 to 18. Specifically, methyl group, ethyl group, propyl group, butyl group, isobutyl group, pentyl group, hexyl group, peptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, lauryl group, and Examples include stearyl groups. Furthermore, considering the structure of gingerols existing in nature, it is preferable that the number of carbon atoms in R ¹ is an even number. Specific examples include an ethyl group, a butyl group, a hexyl group, an octyl group, and a decyl group.

The compound represented by the formula (5) is G.I. Solladie, et al. , J .; Org. Chem. , 58 , 2181 (1993) and the like.

R ² and R ^{4 in} the formula (5) each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a protecting group for a phenolic hydroxyl group. These may be the same or different.
The alkyl group of R ² and carbon atoms R ⁴ 1 to 4 of formula (5), preferably 1 to 3 carbon atoms, more preferably methyl group.
Examples of the protecting group for the phenolic hydroxyl group of R ² and R ^{4 in} the formula (5) include acetyl group, propionyl group, butyroyl group, isobutyroyl group, pivaloyl group, benzoyl group, toluoyl group, benzyl group, allyl group, trimethylsilyl group, And t-butyldimethylsilyl group and the like.
In view of the introduction of a protective group to the phenolic hydroxyl group and the simplicity of the deprotection reaction and the raw material cost, an acetyl group, a propionyl group, a butyroyl group, an isobutyroyl group, a pivaloyl group, a benzoyl group, or a toluoyl group are preferred. An isobutyroyl group or a benzoyl group is preferred.
A in Formula (5) is an alkylene group having 1 to 4 carbon atoms, preferably an ethylene group or a butylene group, and more preferably an ethylene group.

  The compound represented by the formula (6) can be synthesized by reacting the compound represented by the formula (4) with an alkyl metal compound and further reacting the compound represented by the formula (5). That is, the alkyl metal compound attacks the compound represented by the formula (4) and extracts a hydrogen atom from the carbon to which the substituent -X is bonded, thereby generating a carbon anion based on the compound represented by the formula (4). To do. Thereafter, when the compound represented by the formula (5) is added to the reaction system, the carbon anion reacts with the aldehyde group in the compound represented by the formula (4) to synthesize the compound represented by the formula (6). .

  Examples of the alkyl metal compounds include alkyl lithium compounds such as n-butyllithium, s-butyllithium, t-butyllithium, and phenyllithium, n-butylmagnesium chloride, s-butylmagnesium chloride, t-butylmagnesium chloride, n Examples include Grignard compounds such as butylmagnesium bromide, s-butylmagnesium bromide, and t-butylmagnesium bromide, and alkali metals such as metal lithium and metal sodium, and n-butyllithium and n-butylmagnesium chloride. Or n-butylmagnesium bromide can be preferably used.

  The amount of the alkyl metal compound used is basically preferably 0.7 to 1.3 chemical equivalents, more preferably 0.9 to 1.1 chemical equivalents, relative to the compound represented by the formula (4). is there.

  The reaction between the compound represented by formula (4) and the alkyl metal compound is preferably carried out in an aprotic solvent, such as tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, hexamethyl. Phosphoric triamide, N, N-dimethylpropylene urea, a mixed solvent thereof and the like can be preferably used.

The reaction temperature between the compound of formula (4) and the alkyl metal compound is preferably −100 to 25 ° C., more preferably −80 to 0 ° C. If the reaction temperature is too low, it is costly to maintain the temperature, and if the reaction temperature is too high, side reactions may proceed.
The reaction time varies depending on the conditions, but is usually from several minutes to several tens of minutes.

  Next, when the compound represented by the formula (5) is added to the reaction solution obtained by reacting the compound represented by the formula (4) with the alkyl metal compound, the compound represented by the formula (6) can be prepared. it can.

The temperature of the reaction system when adding the compound represented by the formula (5) to the reactant is preferably −100 to 25 ° C., and preferably −80 to 0 ° C. If the reaction temperature is too low, it is costly to maintain the temperature, and if the reaction temperature is too high, side reactions may proceed.
Although this reaction time varies depending on conditions, it is usually several minutes to several tens of minutes.
After completion of this reaction, the compound represented by the formula (6) can be isolated and purified by a known purification method such as solvent extraction or column chromatography.

  The compound represented by the formula (3) can be produced using the compound represented by the formula (6) produced by the above method or the like as a starting material. That is, by reacting the ethylenically unsaturated bond in the compound represented by the formula (6) with a metal catalyst that forms a π-allyl complex, and reacting the obtained π-allyl complex with a basic compound, the formula (6) The compound represented by 3) can be synthesized. That is, in the π-allyl complex formed of the compound represented by the formula (6) and the metal catalyst, the hydrogen atom bonded to the carbon to which the hydroxyl group is bonded is activated, and the basicity coexisting in the reaction system. As a result of being easily extracted by the compound, the π-allyl complex is decomposed to produce a compound represented by the formula (3).

  As a metal catalyst for forming a π-allyl complex, a palladium complex can be preferably used. Specifically, tetrakistriphenylphosphine palladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform addition Products, palladium (II) chloride / triphenylphosphine mixture, palladium (II) acetate / tributylphosphine mixture, and the like. 0.0001-1 mol is preferable with respect to 1 mol of compounds represented by Formula (6), and, as for the usage-amount of the said metal catalyst, More preferably, it is 0.001-0.1 mol.

  As the basic compound for producing the compound represented by the formula (3), tertiary amines such as triethylamine, diisopropylethylamine, N-methylimidazole, and pyridine are preferable. It is 0.9 mol or more with respect to 1 mol of the compound represented by 6), and the range of 1-10 mol is suitable. Such a basic compound may be used as a solvent.

  The above reaction is preferably carried out in the presence of a solvent. Tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, hexamethylphosphoric triamide , N, N-dimethylpropylene urea, methanol, ethanol, isopropyl alcohol, ethylene glycol, glycerin, and mixed solvents thereof can be used, and among them, a mixture of 1,2-dichloroethane and alcohols is preferable. .

The reaction temperature for obtaining the compound represented by Formula (6) from Formula (6) is preferably from room temperature to 150 ° C, and more preferably from 50 to 120 ° C.
The reaction time is suitably several hours to several tens of hours.
After completion of the reaction for obtaining the compound represented by the formula (3), the compound represented by the formula (3) can be obtained by a known purification method such as solvent extraction or column chromatography.

  The synthesis of Formula (1) from Formula (3) can use a general reaction in which an O alkyl group is added to the double bond adjacent to the carbonyl group. That is, it can be prepared by reacting with a corresponding alcohol in the presence of a basic compound or by acting an alkoxide of an alcohol to be added. Examples of the alcohol include methanol, ethanol, n-propanol, i-propanol, n-butanol, and 2-methyl-1-propanol. Preferred examples include primary alcohols (methanol, ethanol, n-propanol, n-butanol, and 2-methyl-1-propanol), and methanol or ethanol is more preferred. Examples of basic compounds include lithium hydride, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, n-butyllithium, s-butyllithium, and t-butyllithium. Examples of the alkoxide include those corresponding to the alcohol to be added such as sodium methoxide and sodium ethoxide.

○ About the gingerdiol analog represented by the formula (2) The compound represented by the formula (2) can be synthesized, for example, by reducing the carbonyl group of the gingerol analog represented by the formula (1) to a hydroxyl group. .

The reducing agent for reducing the carbonyl group of formula (1) to a hydroxyl group is not particularly limited, but metal hydrides such as lithium aluminum hydride, lithium borohydride, and sodium borohydride are preferably used. Can be used. A suitable amount of the metal hydride to be used varies depending on the kind of the metal hydride and the structure of R ² in the formula (1). For example, when R ² in formula (1) is an alkyl group having 1 to 4 carbon atoms and lithium aluminum hydride is used as a reducing agent, lithium hydride is used with respect to 1 mol of gingerol analog represented by formula (1). It is preferred to use 0.5 to 3 moles of aluminum. When R ² is a hydrogen atom, the reducing agent is preferably increased by about 1 chemical equivalent.

  In this reaction for reducing the carbonyl group of formula (1) to a hydroxyl group, a solvent may be used, and tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, diglyme, and a mixed solvent thereof are preferable. Can be used for

The reaction temperature in the case of using metal hydrides as the reducing agent is preferably -30 to 100 ° C, and preferably -10 to 80 ° C. If the reaction temperature is too low, the reaction time may be long, and if the reaction temperature is too high, side reactions may proceed.
This reaction time for reducing the carbonyl group of formula (1) to a hydroxyl group varies depending on the conditions, but is usually from several tens of minutes to several hours.

  After completion of the reduction reaction, the gingerdiol analog represented by the formula (2) can be obtained by a known purification method such as solvent extraction or column chromatography.

The gingerol analog represented by the formula (11) and the gingerdiol analog represented by the formula (12) have cyclogenase activity inhibitory activity, so that they are used as a therapeutic agent, symptom improving agent, inhibitor or the like for PG-related diseases. can do. For example, the compound represented by the formula (11) and / or the formula (12) can be used for treatment of inflammation, symptom improvement or onset suppression. Further, the compound represented by the formula (11) and / or the formula (12) can be used for treatment of allergy, symptom improvement or suppression of onset.

The gingerol analog represented by the formula (11) and the gingerdiol analog represented by the formula (12) can be used by blending them with foods, pharmaceuticals, quasi drugs, cosmetics and the like.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples. Ts represents a p-toluenesulfonyl group.

<Synthesis Example 1>
Synthesis of [6] -shogaol (Formula (10)) with Benzoyl Group Protection The following formula (9) compound was prepared using the following formula (7) compound and the following formula (8) compound. Furthermore, the compound represented by the following formula (10) was synthesized by de-Ts-converting the compound of the above formula (9) in the presence of a palladium catalyst.
A specific synthesis method is shown below.

3.46 g (13.7 mmol) of the compound of formula (7) was dissolved in 50 ml of tetrahydrofuran and cooled to −78 ° C. with dry ice / acetone. To this solution, 9.1 ml (13.7 mmol) of a 1.5 M n-butyllithium / n-hexane solution was added dropwise. After stirring for 20 minutes at the same temperature, a solution of 3.49 g (13 mmol) of the compound of formula (8) dissolved in 50 ml of tetrahydrofuran was added dropwise. After dropping, the mixture was stirred for 10 minutes at the same temperature and then gradually heated. When the temperature of the reaction solution reached −10 ° C., 2 ml of methanol was added to stop the reaction. 30 ml of saturated brine was added to this reaction mixture and stirred, and then the organic layer was separated. The aqueous layer was extracted with 30 ml of ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off, and purification by silica gel column chromatography was performed to obtain 5.79 g (yield 79%) of a pale yellow, highly viscous liquid compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product are 0.72-0.89 (3H, m), 0.98-1.24 (4H, m), 1.52- 2.04 (4H, m), 2.45 (3H, s), 2.82-2.94 (2H, m), 3.16-3.64 (1H, m), 3.79 (3H, s), 4.04-4.65 (2H, m), 5.03-5.85 (2H, m), 6.70-6.84 (2H, m), 6.96-7.05 ( 1H, m), 7.32 (2H, d), 7.45-7.75 (5H, m), and 8.20 (2H, d).
The wave number (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) of this product is 3520, 2950, 2930, 2870, 1740, 1600, 1510, 1450, 1280, 1260, 1200, 1140, 1120, 1080, 1060, 1020, 710.
Furthermore, the results of elemental analysis of this product were carbon 69.22% and hydrogen 6.55%.
Based on the above analysis, it was confirmed that the obtained compound was the compound of the formula (9).

1.31 g (2.51 mmol) of the compound of formula (9) was dissolved in a mixed solvent of 39 g of 1,2-dichloroethane, 13 g of isopropyl alcohol and 13 g of glycerin, and 1.05 ml (7.53 mmol) of triethylamine, 39 0.5 mg (0.151 mmol) and tetrakistriphenylphosphine palladium 87.0 mg (0.0753 mmol) were added, and the mixture was stirred at a bath temperature of 100 ° C. for 18 hours. Next, after distilling off the solvent and the like, 50 ml of distilled water, 20 ml of saturated saline and 50 ml of acetic acid ethyl ester were added and distributed, and the organic layer was separated. The aqueous layer after this extraction was re-extracted with 20 ml of acetic acid ethyl ester. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The obtained reaction mixture was purified by silica gel column chromatography and then recrystallized with a mixed solvent of ethyl acetate and n-hexane to obtain 603 mg of colorless crystalline compound (yield 63%).
The chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product are 0.91 (3H, t), 1.25-1.60 (6H, m), 2.21 (2H, q). 2.85-3.00 (4H, m), 3.82 (3H, s), 6.16 (1H, d), 6.79-6.94 (3H, m), 7.05 (1H) , D), 7.45-7.68 (3H, m), 8.20 (2H, d).
The wave number (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) of this product is 2950, 2930, 2870, 1730, 1660, 1600, 1510, 1470, 1450, 1420, 1270, 1200, 1150, 1060, 710.
Furthermore, the result of CHN elemental analysis of this product was 75.56% carbon and 7.70% hydrogen.
From the above analysis, it was confirmed that the obtained compound was a compound represented by the above formula (10).

<Synthesis Example 2>
Synthesis of gingerol analog formula (11) Gingerol of the present invention was prepared by adding methanol to the compound represented by formula (10) obtained in Synthesis Example 1 in the presence of sodium hydroxide and removing the benzoyl group. The following formula (11), which is an example of an analog, was synthesized.

After dissolving 330 mg (0.867 mmol) of the compound represented by the formula (10) in 2 ml of isopropyl alcohol, 8 ml of methanol and 0.9 ml of 1N sodium hydroxide aqueous solution were added and stirred at room temperature for 2 hours, and then 2 ml of 0.5N hydrochloric acid. To stop the reaction. After methanol in the reaction solution was distilled off, 25 ml of saturated brine was added, and the mixture was extracted twice with 25 ml of ethyl acetate. These ethyl acetates were combined, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel thin layer chromatography to obtain 191 mg (71%) of a colorless liquid compound.
The chemical shift values of the ¹ H-NMR spectrum measured in deuterated chloroform of this product are 0.89 (3H, t), 1.20-1.83 (8 H, m), 2.34-2.89 ( 6H, m), 3.28 (3H, s), 3.57-3.70 (1H, m), 3.86 (3H, s), 5.49 (1H, s), 6.63-6 .73 (2H, m), 6.81 (1H, d).
The wave number (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) of this product is 3400, 2930, 2860, 1710, 1600, 1510, 1460, 1450, 1430, 1370, 1270, 1230, 1090, 1030.
Furthermore, the result of elemental analysis of this product was 69.80% carbon and 8.98% hydrogen.
Based on the above analysis, it was confirmed that the obtained compound was the compound of the formula (11).

<Synthesis Example 3>
Synthesis of Zingediol Analogue Formula (12) The compound of formula (11) obtained in Synthesis Example 2 was reduced to synthesize another type of gingerdiol analog represented by the following formula (12).

A solution of 154 mg (0.5 mmol) of the compound of formula (11) in 5 ml of tetrahydrofuran was dropped into a solution of 19 mg (0.5 mmol) of lithium aluminum hydride in 1 ml of tetrahydrofuran and stirred at room temperature for 16 hours. Next, 5 ml of distilled water and 2 ml of 0.5N hydrochloric acid were added dropwise, and extracted three times with 10 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and purified by silica gel thin layer chromatography to obtain 146 mg (94%) of a colorless liquid compound.
The chemical shift values of ¹ H-NMR spectrum measured in deuterochloroform of this product are 0.89 (3H, t), 1.20-1.87 (12H, m), 2.52-2.81 ( 2H, m), 3.30-3.55 (4H, m), 3.72-4.00 (4H, m), 5.55 (1H, s), 6.65-6.75 (2H, m), 6.81 (1H, d). The wave number (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) of this product is 3390, 2930, 2860, 1600, 1510, 1460, 1450, 1430, 1370, 1270, 1230, 1080, 1030.
Furthermore, the result of elemental analysis of this product was 69.74% carbon and 9.47% hydrogen.
Based on the above analysis, it was confirmed that the obtained compound was the compound of the formula (12).

○ Cyclooxygenase inhibitory activity test Using the sheep seminal vesicle microsomes (manufactured by Caiman Chemical Co.) as COX-1 and the COX-2 purified product of sheep placenta (manufactured by Caiman Chemical Co.) as COX-2 The conversion rate to gin E2 was defined as the enzyme activity. Activity measurement was performed as follows.
Test samples of various concentrations dissolved in 10% dimethyl sulfoxide aqueous solution in 70 μL of 143 mM Tris buffer (pH 7.5) containing 2.9 mM phenol and 1.4 mM hematin (described in Table 1. In addition, 6-gingerol is After adding 10 μL of a commercially available product (using Matsuura Pharmaceutical Co., Ltd.), 10 μL of 2 units of COX-1 or COX-2 solution was added and mixed. This was preincubated at 37 ° C. for 2 minutes. Then, radiolabeled [1- ¹⁴ C] arachidonic acid was adjusted to a concentration of 25.5μM in 100mM Tris buffer (Amersham Pharmacia Biotech) was added and mixed 10μL (0.14μCi). This was reacted at 37 ° C. for 2 minutes and immediately cooled on ice.
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 then centrifuged to remove the organic layer containing unreacted arachidonic acid. After the same extraction operation was repeated twice, 50 μL of ethanol was added to the aqueous layer and stirred for 30 seconds. The mixture was centrifuged at 2000 G for 1 minute, and 0.1 mL of the aqueous layer was transferred to a liquid scintillation counter vial. To this was added 2 mL of clear sol 1 (manufactured by Nacalai Tesque) as a scintillator to prepare a prostaglandin E2 fraction cocktail. The radioactivity was measured with a liquid scintillation counter (ALSCA LSC-1000), and the ratio of radioactivity was calculated as the prostaglandin E2 conversion rate.
From the relationship between the conversion rate of prostaglandin E2 and the test sample concentration, the concentration (IC ₅₀ ) that inhibits the conversion by 50% was calculated, and the results are shown in Table 1.

  The gingerol analog and / or gingerdiol analog of the present invention can be added to foods, pharmaceuticals, quasi drugs, cosmetics, and the like to suppress or treat symptoms such as inflammation and allergies. In addition, the onset of inflammation and allergies can be prevented.

Claims (1)

A cyclooxygenase inhibitor comprising a gingerol analog represented by the formula ( 11 ) and / or a gingerdiol analog represented by the formula ( 12 ).