JP2007045717A - 5-lipoxygenase inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a 5-lipoxygenase inhibitor suitably useful in the field of food, medicine, quasi-medicine, cosmetic, etc. <P>SOLUTION: The 5-lipoxygenase inhibitor comprises a compound represented by general formula (1) [R<SP>1</SP>is a 1-18C alkyl group which may be branched; R<SP>2</SP>is a hydrogen atom or a 1-4C alkyl group; R<SP>3</SP>is a 1-4C alkyl group which may be branched; A is a 1-4C alkylene group] or a compound represented by general formula (2) [R<SP>1</SP>is a 1-18C alkyl group which may be branched; R<SP>2</SP>is a hydrogen atom or a 1-4C alkyl group; R<SP>3</SP>is a 1-4C alkyl group which may be branched; A is a 1-4C alkylene group]. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a 5-lipoxygenase inhibitor that can be suitably used in the fields of foods, pharmaceuticals, quasi drugs, cosmetics and the like.

  Arachidonic acid, an unsaturated fatty acid that exists in various tissues in the living body and constitutes the cell membrane, generates metabolites such as prostaglandins and leukotrienes (LT) by metabolic enzymes involving cyclooxygenase or lipoxygenase, respectively.

The presence of a plurality of lipoxygenases such as 5-lipoxygenase, 8-lipoxygenase, 12-lipoxygenase, and 15-lipoxygenase has been confirmed in lipoxygenases. For example, 5-lipoxygenase is mainly involved in inflammatory diseases and allergic diseases. As its metabolic process, 5-lipoxygenase expresses enzyme activity by stimulating cytokines, etc., and oxidizes the 5-position of the substrate arachidonic acid to produce 5-hydroperoxyeicosatetraenoic acid (5-HPTEE). . From this 5-HPETE, LTA ₄ is produced, and then LTB ₄ or LTC ₄ is produced. Further LTD ₄ and LTE ₄ are produced from LTC _4.

The pharmacological action of LT has various actions such as an airway resistance increasing action, a tracheal mucosal secretion promoting action, and other inflammatory reaction systems such as a vascular permeability enhancing action and a leukocyte migration action (Non-Patent Documents 1 to 3). For example, a slow reacting substance of anaphylaxis (abbreviated as SRS-A) composed of LTC ₄ , LTD ₄ , LTE ₄ and the like is said to be involved in the development of allergic diseases such as bronchial asthma and anaphylaxis. . LTB ₄ is known to have biological activities that cause degranulation, enhanced vascular permeability, enhanced migration, calcium transport, and the like for leukocytes at low concentrations. These effects of LTB ₄ are considered to be causes of rheumatism, spondyloarthritis, gout, psoriasis, ulcerative colitis, respiratory diseases and the like (Patent Document 1).

Thus, 5-lipoxygenase plays an important role in the biosynthesis of mediators of arthritis, psoriasis, allergies, asthma and inflammation, and drugs that block or suppress the activity of 5-lipoxygenase are diseases derived from these leukotrienes. It is known to be useful in the treatment of
In arteriosclerosis, it has been said that 12- or 15-lipoxygenase is involved in the art. Recently, lipoxygenase present in arteriosclerotic lesions has been reported to be mostly 5-lipoxygenase, which inhibits 5-lipoxygenase. This suggests the possibility of suppressing inflammation and arteriosclerosis (Non-patent Documents 4 and 5).

  Specific examples of substances exhibiting an inhibitory action on 5-lipoxygenase include AA-861 (Patent Document 2), nordihydroguaiaretic acid (Non-Patent Document 6), hydroxamic acid (Patent Documents 3 and 4), cafe Examples include acids.

  On the other hand, gingerol is a major component of ginger extract along with gingerol, for example, blood circulation promoting action (Patent Document 5), body odor suppressing effect (Patent Document 6), antioxidant effect (Non-Patent Document 7), moisturizing effect. (Non-patent document 8), it is known to have a prostaglandin production inhibitory effect (non-patent documents 9 to 11).

  The present inventors have previously reported that a compound having a chemical structure similar to gingerol has a tyrosinase activity inhibitory action (Patent Document 7), a lipid peroxide production inhibitory action (Patent Document 8), and a cyclooxygenase inhibitory action (Patent Document 9). Heading to show.

JP-A-8-143529 (Claims) US Pat. No. 4,393,075 US Pat. No. 4,608,390 US Pat. No. 4,623,661 JP-A-6-183959 (Claims) US Pat. No. 6,264,928 JP 2003-342224 A (Claims) International Publication No. WO03 / 099752 (Claims) JP 2003-279606 A (Claims) Adams G. K., Lichtenstein L. M., J. Immunol., 122, 555-562 (1979) Watanabe-Kohno S., Yasui K. et.al., Jpn. J. Pharmacol., 60, 209-216 (1992) Coles s S. J., Neill K. H. et. Al., Prostaglandins, 25, 155-170 (1983) Lotzer K., Habenicht A. J., Arterioscler Thromb Vasc Biol., 23, E32-36 (2003) Spanbroek R., Grabner R., Proc. Natl. Acad. Sci. USA, 100, 1238-1243 (2003) Corey, E. J. et. Al., J. Am. Chem. Soc., 106, 1503 (1984) Kikuzaki, H. et al., J. Food Sci., 58, 6, 1407-1410 (1993) Supervised by Masato Suzuki, “New Functional Cosmetic Material 300, Volume 1”, 311-312 pages, CM Publishing (2002) Kiuchi, F., Shibuya, M., Sankawa, U., Chem. Pharm. Bull., 30, 754 (1982) Mikawa Ushio, History of Medicine, 126, 867-874 (1983) Mamoru Suekawa and 7 others, Journal of Japanese Pharmacology, 88, 263-269 (1986)

  The object of the present invention is to provide a 5-lipoxygenase inhibitor useful in the fields of foods, pharmaceuticals, quasi-drugs, cosmetics and the like in view of the above situation.

  As a result of intensive studies to solve the above problems, the present inventors have found that a gingerol-like compound represented by the following general formula (1) or a gingerdiol-like compound represented by (2) has an excellent 5-lipoxygenase inhibitory effect. The present invention was completed.

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.

  The gingerol-like compound and gingerdiol-like compound of the present invention have an excellent 5-lipoxygenase inhibitory effect and can be used in the fields of foods, pharmaceuticals, quasi drugs and cosmetics.

○ for compounds of formula (1) or (2) in formula (1) or (2), R ¹ represents an optionally branched alkyl group having 1 to 18 carbon atoms, a methyl group, an 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 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 Formula (1) or (2), 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 Formula (1) or (2), R ³ is an alkyl group that may have 1 to 4 carbon atoms, preferably a methyl group or an ethyl group.
In the formula (1) or (2), 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 compound represented by the general formula (1) and the compound represented by the general formula (2) are disclosed in, for example, Japanese Patent Application Laid-Open No. 2003-342224, International Publication No. WO 03/099752 and Japanese Patent Application Laid-Open No. 2003-279606. It can be produced according to the method described.

  Since the compound represented by the general formula (1) and the compound represented by the general formula (2) have a 5-lipoxygenase inhibitory action, as will be apparent from the examples described later, foods, pharmaceuticals, and quasi drugs. It can be used by blending it into prescriptions such as cosmetics.

  When used as a pharmaceutical, the compound of the present invention is used alone or in combination with pharmaceutically acceptable excipients or carriers and other additives in various preparation forms. Their proportions and properties are determined by the solubility and chemical nature of the chosen compound, the chosen route of administration and standard pharmaceutical practice. A vaginal or carrier can be a solid, semi-solid, or liquid material, which can serve as a vehicle or carrier for the active ingredient. Suitable excipients or carriers are common in the pharmaceutical field. The pharmaceutical composition can be adapted for oral or parenteral use and can be administered to a patient in the form of tablets, capsules, suppositories, solutions, suspensions, and the like.

  The pharmaceutical composition can be administered orally, for example with an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral administration, the compounds of the invention can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. Tablets, troches, capsules and the like can contain one or more auxiliaries. Auxiliaries include binders (eg microcrystalline cellulose, tragacanth gum, gelatin), glazes (eg starch, lactose), disintegrants (eg alginic acid, primogel, corn starch), lubricants (eg magnesium stearate). , Sterotex), lubricants (eg, colloidal silicon dioxide), sweeteners (eg, sucrose, saccharin), and flavoring agents (eg, peppermint, methyl salicylate, orange flavor), and the like. When the dosage unit form is a capsule, it can contain a liquid carrier (eg, polyethylene glycol, aliphatic oil) in addition to the above types of substances. Other dosage unit systems can contain other substances (eg, coatings) that alter the physical form of the dosage unit. Thus, tablets or suppositories can be coated with sugar, shellac or other enteric coatings. In addition to the active ingredient, syrups can contain sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

  For parenteral administration, the compounds of the invention can be incorporated into a solution or suspension. Solutions or suspensions can contain one or more auxiliaries. Auxiliary agents are sterile diluents (eg, water for injection, aqueous salt solution, non-volatile oil, polyethylene glycols, glycerin, propylene glycol, other synthetic solvents), antibacterial agents (eg, benzyl alcohol, methyl parapenes), antioxidants (E.g., ascorbic acid, sodium bisulfite), chelating agents (e.g., ethylenediaminetetraacetic acid), buffers (e.g., acetate, citrate, phosphate), and agents for preparing toxicity (e.g., Sodium chloride, dextrose) and the like. The parenteral preparation can be enclosed in ampoules, disposable injections or multiple dose vials made of glass or plastic.

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 (Compound 4) protected with benzoyl group Compound 3 was prepared using Compound 1 and Compound 2. Further, Compound 4 was synthesized by de-Ts-converting Compound 3 in the presence of a palladium catalyst.
A specific synthesis method is shown below.

[Compound 1]

[Compound 2]

[Compound 3]

[Compound 4]

  3.46 g (13.7 mmol) of Compound 1 was dissolved in 50 ml of tetrahydrofuran and cooled to −78 ° C. with dry ice / acetone. To this solution, 9.10 ml (13.7 mmol) of a 1.50 M n-butyllithium / n-hexane solution was added dropwise. After stirring for 20 minutes at the same temperature, a solution of 3.49 g (13.0 mmol) of Compound 2 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. 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 the 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). In addition, the wave number (cm-1) absorbed in the infrared absorption spectrum (KBr pellet method) is 3520,2950,2930,2870,1740,1600,1510,1450,1280,1260,1200,1140, 1120,1080 1060,1020,710. The results of elemental analysis were as follows: carbon 69.22% and hydrogen 6.55%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 3.

  1.31 g (2.51 mmol) of Compound 3 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, 39.5 mg of triphenylphosphine ( 0.151 mmol) and 87.0 mg (0.0753 mmol) of tetrakistriphenylphosphine palladium 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 resulting 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 results of CHN elemental analysis of this product were 75.56% carbon and 7.70% hydrogen.
Based on the above analysis, it was confirmed that the obtained compound was the compound 4.

<Synthesis Example 2>
Synthesis of Gingerol Analogue Compound (Compound 5) Compound 5 was synthesized by adding methanol to compound 4 obtained in Synthesis Example 1 described above in the presence of sodium hydroxide and removing the benzoyl group.

[Compound 5]

  After dissolving 330 mg (0.867 mmol) of Compound 4 in 2 ml of isopropyl alcohol, 8 ml of methanol and 0.9 ml of 1N aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 2 hours, and then 2 ml of 0.5N hydrochloric acid was added to react. Stopped. 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 ¹ H-NMR spectrum measured in deuterochloroform of this product are 0.89 (3H, t), 1.20-1.83 (8H, 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. The results of elemental analysis of this product were 69.80% carbon and 8.98% hydrogen.
Based on the above analysis, it was confirmed that the obtained compound was the compound 5.

<Synthesis Example 3>
Synthesis of Gingerdiol Analogue Compound (Compound 6) Compound 6 was synthesized by reducing Compound 5 obtained in Synthesis Example 2.

[Compound 6]

A solution of 154 mg (0.5 mmol) of Compound 5 dissolved in 5 ml of tetrahydrofuran was added dropwise to 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). In addition, 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, It was 1030. The results of elemental analysis of this product were 69.74% carbon and 9.47% hydrogen.
Based on the above analysis, it was confirmed that the obtained compound was the compound 6.

<Example 1>
The 5-lipoxygenase inhibitory activity was measured for Compound 5 obtained in Synthesis Example 2 and Compound 6 obtained in Synthesis Example 3.
Rat basophilic leukemia cells (RBL-1) were used as the 5-lipoxygenase source, and the conversion rate from arachidonic acid to 5-HETE was calculated as the enzyme activity. Activity measurement was performed as follows.
To 5 μL of the test sample dissolved in dimethyl sulfoxide aqueous solution, 10 μL of 200 mM calcium chloride aqueous solution and 10 μL of 20 mg / mL arachidonic acid-methanol solution were added and preincubated at 37 ° C. for 5 minutes. An RBL-1 cell suspension dispersed at 1.5 × 10 ⁷ cells / mL in 50 mM phosphate buffer (pH 7.4) containing 0.25 M sucrose, 1.0 mM EDTA, and 2 mM glutathione. 475 μL was added and stirred, and reacted at 37 ° C. for 3 minutes. Thereafter, 500 μL of methanol was added to stop the reaction, and this solution was centrifuged at 4 ° C. and 4000 rpm for 20 minutes. 400 μL of this supernatant was collected and analyzed by high performance liquid chromatography (HPLC). HPLC analysis, Hitachi pump L6200, using a Hitachi detector L4000UV, and Nacalai Tesque column COSMOSIL 5C ₁₈ -MS (inner diameter 4.6 × length 150 mm), 60% acetonitrile containing 0.04% acetic acid Development with an aqueous solution and measurement of the peak area at a detection wavelength of 235 nm.

As a control, 5 μL of 6-shogaol dissolved in an aqueous dimethylsulfoxide solution or nordihydroguaiaretic acid (NDGA) was used instead of 5 μL of the test sample. The conversion rate from arachidonic acid to 5-HETE was calculated in comparison with the peak area when no test sample was added, and {100% -conversion rate (%)} was defined as the conversion inhibition rate (%).
From the relationship between the conversion inhibition rate and the test sample concentration, the concentration (IC ₅₀ ) that inhibits the conversion to 5-HETE by 50% was calculated, and the results are shown in Table 1.

  Although compound 5 and compound 6 did not reach NDGA, they showed 5-lipoxygenase inhibitory activity in a concentration-dependent manner.

The compound represented by the general formula (1) or (2) of the present invention has an excellent 5-lipoxygenase inhibitory effect and can be used in the fields of foods, pharmaceuticals, quasi drugs and cosmetics.

Claims (1)

A 5-lipoxygenase inhibitor comprising a gingerol-like compound represented by the following general formula (1) or a gingerdiol-like compound represented by (2):

[R ¹ in 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 carbon number. The alkyl group which may have a 1-4 branch is shown, A shows a C1-C4 alkylene group. ]

[R ¹ in Formula (2) 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 carbon number. The alkyl group which may have a 1-4 branch is shown, A shows a C1-C4 alkylene group. ]