JP2007045716A - 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 hydrogen atom, a lower alkyl group or a phenolic hydroxy-protecting group; A is a 1-4C alkylene group; B is a 1-12C alkylene group; R<SP>2</SP>is a -COOR<SP>3</SP>(R<SP>3</SP>is a 1-18C substituted or branched alkyl group), a carboxy group or -CH<SB>2</SB>OH; Z is -CO-CH=CH- or the like, a ketal derivative of -CO-CH=CH- or a ketal derivative of -CO-CH<SB>2</SB>CH<SB>2</SB>-; R<SP>4</SP>is a lower alkyl 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 is present in various tissues in the body and constitutes the cell membrane, produces 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 caused by these leukotrienes. It is known to be useful in the treatment of
In arteriosclerosis, 12- or 15-lipoxygenase has been said to be involved in the past, but 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 and gingerol are the main components of ginger extract. 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), known to have a prostaglandin production inhibitory effect (non-patent documents 9 to 11). In addition, metabolic pathways of gingerol and gingerol in vivo have been studied, and the structure of metabolites has also been reported (Non-patent Documents 12 and 13).
The present inventors have already reported the manufacturing method which mass-produces gingerol (patent document 8). Further, compounds having a structure similar to that of gingerol have also been found to have a tyrosinase activity inhibitory action and an antioxidant action (Patent Documents 7 and 8). Furthermore, a tyrosinase activity inhibitory action and an antioxidant action have also been found for its related compounds that have improved the poor water solubility of gingerol and gingerol (Patent Document 9).

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 2003-327574 A (Claims) Japanese Patent Application No. 2003-086818 (Claims) International Publication No. WO 2004/085373 (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 Pharmacology, 88, 263-269 (1986) Takahashi, H. et al., Phytochemistry, 34, 1497-1500 (1993) Lee, S.S., Arch. Pharm. Res., 18, 136-137 (1995)

  An 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 the compound represented by the following general formula (1) has an excellent 5-lipoxygenase inhibitory effect and completed the present invention. did.

R ¹ in formula (1) is a hydrogen atom, a lower alkyl group or a protecting group for a phenolic hydroxyl group, A is an alkylene group having 1 to 4 carbon atoms, and B is an alkylene group having 1 to 12 carbon atoms. , R ² is —COOR ³ (wherein R ³ is an alkyl group having 1 to 18 carbon atoms which may be substituted or branched), a carboxyl group or —CH ₂ OH, and Z is —CO—. CH = CH -, - CHOH- CH = CH -, - CHOH-1,2- epoxy _{-, - CO-CH 2 CH} 2 -, - CHOH-CH 2 CH 2 -, - CO-CH 2 CHOH -, - _{CHOH-CH 2 CHOH -, -} CO-CH 2 CHOR 4 -, - CHOH-CH 2 CHOR 4 -, - CO-CH = CH- ketal derivative or -CO-CH ₂ CH _2, - there in the ketal derivative , R ⁴ is a lower alkyl group.

  The lower alkyl group in formula (1) is an alkyl group having 1 to 4 carbon atoms, preferably a methyl group. Moreover, —CHOH-1,2-epoxy— in the formula (1) is represented by the following formula (2).

  The ketal derivative in formula (1) is an acyclic ketal or a cyclic ketal, preferably a cyclic ketal. Examples of the cyclic ketal include those obtained from ethylene glycol, 1,3-propanediol or 2,2-dimethyl-1,3-propanediol with respect to the carbonyl group.

O About compound represented by general formula (1) In general formula (1), R ¹ is a hydrogen atom or a lower alkyl group. The protecting group for the phenolic hydroxyl group of R ¹ is preferably easy to introduce and remove the protecting group, and examples thereof include a silyl-type protecting group, an acyl-type protecting group, a benzyl-type protecting group, and an ether-type protecting group. . Specifically, t-butyldimethylsilyl group, propionyl group, butyroyl group, isobutyroyl group, pivaloyl group, benzoyl group, toluoyl group, benzyl group, tetrahydropyranyl group, and methoxymethyl group are preferable.
In General formula (1), A is a C1-C4 alkylene group, Preferably it is an ethylene group or a butylene group, More preferably, it is an ethylene group.
In General formula (1), B is a C1-C12 alkylene group, Preferably it is a C1-C9 alkylene group, More preferably, it is a C2-C6 alkylene group.

In the general formula (1), R ² is —COOR ³ (wherein R ³ is an alkyl group having 1 to 18 carbon atoms which may be substituted or branched), a carboxyl group, or —CH ₂ OH. . R ³ is preferably a methyl group, an ethyl group, a propyl group, an iso-propyl group, a butyl group or a benzyl group. More preferred is a methyl group or an ethyl group.
In the general formula (1), Z represents —CO—CH═CH—, —CHOH—CH═CH—, —CHOH-1,2-epoxy—, —CO—CH ₂ CH ₂ —, —CHOH—CH ₂ CH. _{2 -, - CO-CH 2} CHOH -, - CHOH-CH 2 CHOH -, - CO-CH 2 CHOR 5 -, - CHOH-CH 2 CHOR 4 -, - CO-CH = CH- ketal derivatives or, - It is a ketal derivative of CO—CH ₂ CH ₂ —, and R ⁴ is a lower alkyl group.

  The compound represented by the general formula (1) can be produced, for example, according to the method described in International Publication WO 2004/085373.

  Among the compounds represented by the general formula (1), there are compounds having one or two asymmetric carbons. These are usually obtained as a racemic mixture. If necessary, one optical activity can be obtained by a method of synthesizing only one optically active compound by asymmetric synthesis or a method such as high performance liquid chromatography using an optically active column. It is also possible to use only the body separately.

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

  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>
Compound 5 was prepared via Compound 2 and Compound 3 using Compound 1 as a starting material.

[Compound 1]

[Compound 2]

[Compound 3]

[1] First, a conversion reaction of ethyl 6-bromohexanoate to ethyl 6-iodohexanoate was performed.
That is, 39.1 g (175 mmol) of ethyl 6-bromohexanoate was dissolved in 250 ml of acetone, 29.1 g (175 mmol) of potassium iodide was added, and the mixture was heated to reflux for 20 hours. Next, the reaction solution was allowed to cool to room temperature, the solvent was distilled off, and the residue was extracted with 150 ml of ethyl acetate. The obtained organic layer was washed with 50 ml of distilled water and then dried over anhydrous magnesium sulfate. The solvent was distilled off and dried under reduced pressure to obtain 47.4 g of a crude product. As a result of 1H-NMR analysis, it was found that the crude product contained 90% ethyl 6-iodohexanoate in molar fraction. This crude product was directly used in the next step.
Next, a solution obtained by dissolving 30.5 g (155 mmol) of Compound 1 in 450 ml of tetrahydrofuran was cooled to −78 ° C. with dry ice / acetone. To this solution, 100 ml (156 mmol) of a 1.56 M n-butyllithium / n-hexane solution was added dropwise. And after stirring for 45 minutes at the same temperature, the solution which melt | dissolved the crude product of the ethyl 6-iodohexanoate prepared as mentioned above in 50 ml of tetrahydrofuran was dripped. 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., 50 ml of 5% aqueous citric acid solution was added to stop the reaction. The reaction mixture was partitioned by adding 100 ml 10% aqueous sodium thiosulfate, 150 ml saturated brine and 50 ml ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and purification by silica gel column chromatography was performed to obtain 49.5 g (yield 94%) of a pale yellow low-viscosity liquid compound.

Chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.20-1.70 (9H, m), 2.03-2.15 (2H, m), 2.23-2.35 (2H, m), 2.44 (3H , s), 3.43-3.55 (1H, m), 4.11 (2H, q), 5.04 (1H, d), 5.25-5.35 (1H, m), 5.53-5.68 (1H, m), 7.32 (2H, d ), 7.70 (2H, d). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2930, 2860, 1730, 1600, 1300, 1290, 1180, 1140, 940, 670. The results of elemental analysis were as follows: carbon 64.09% and hydrogen 7.87%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 2.

[2] Next, conversion from Compound 2 to Compound 3 was performed.
49.5 g (146 mmol) of Compound 2 was dissolved in 360 ml of tetrahydrofuran and 120 ml of methanol, and 3.38 g (2.92 mmol) of tetrakistriphenylphosphine palladium was added. The reaction solution was heated to reflux for 16 hours. Next, the reaction solution was allowed to cool to room temperature, and then the solvent was distilled off, followed by purification by silica gel column chromatography to obtain 47.1 g (95%) of a light brown low-viscosity liquid compound. As a result of 1H-NMR analysis, infrared absorption spectrum analysis, and elemental analysis shown below, this product contains 73% of Compound 3 by mole fraction, and the remaining 27% is carbon-carbon in Compound 3. It was confirmed that the double bond was a geometric isomer arranged in a cis form.

The chemical shift values of ¹ H-NMR spectrum of Compound 3 measured in deuterated chloroform are 1.20-1.33 (7H, m), 1.50-1.60 (2H, m), 1.99 (2H, t), 2.20-2.30 (2H , m), 2.45 (3H, s), 3.73 (2H, d), 4.08-4.15 (2H, q), 5.35-5.55 (2H, m), 7.34 (2H, d), 7.72 (2H, d) there were. The wave numbers (cm ⁻¹ ) absorbed by the infrared absorption spectrum (KBr pellet method) were 2930, 2860, 1730, 1600, 1320, 1150, 1090, 1030, 820, 740. The results of elemental analysis were as follows: carbon 64.03% and hydrogen 7.57%.

<Synthesis Example 2>
Compound 5 was prepared using compounds 3 and 4 obtained in Synthesis Example 1 as raw materials.

[Compound 4]

[Compound 5]

  A solution of 11.9 g (35.2 mmol) of Compound 3 in 100 ml of tetrahydrofuran was cooled to -78 ° C. with dry ice / acetone. To this solution, 26.0 ml (36.4 mmol) of a 1.40 M t-butyllithium / heptane solution was added dropwise. Then, after stirring at the same temperature for 10 minutes, a solution of 9.00 g (34.0 mmol) of Compound 4 dissolved in 50 ml of tetrahydrofuran was added. After dropping, the mixture was stirred at the same temperature for 5 minutes and then gradually heated. When the temperature of the reaction solution reached −5 ° C., 30 ml of 10% aqueous citric acid solution was added to stop the reaction. The reaction mixture was partitioned by adding 60 ml of saturated brine. The organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 6.03 g (yield 29%) of a pale yellow medium viscosity liquid compound.

The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.17-2.30 (24H, m), 2.45 (3H, s), 2.56-2.92 (2H, m), 3.15-4.58 (8H m), 4.95-5.83 (2H, m), 6.65-6.94 (3H, m), 7.29-7.38 (2H, m), 7.63-7.77 (2H, m). The wave number (cm-1) absorbed in the infrared absorption spectrum (KBr pellet method) was 3510, 2970, 2940, 2860, 1750, 1730, 1600, 1510, 1280, 1200, 1120, 1030, 670. It was. The results of elemental analysis were as follows: carbon 65.51% and hydrogen 7.45%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 5.

<Synthesis Example 3>
Compound 6 was prepared using Compound 5 obtained in Synthesis Example 2 as a raw material.

[Compound 6]

  To a solution of 6.00 g (9.95 mmol) of compound 5 in 60 g of 1,2-dichloroethane and 15 g of methanol was added 2.10 ml (15.1 mmol) of triethylamine, 130 mg (0.496 mmol) of triethylamine. Phenylphosphine and 575 mg (0.498 mmol) of tetrakistriphenylphosphine palladium were added, and the mixture was stirred at a bath temperature of 100 ° C. for 16 hours. After allowing to cool and concentrate, 50 ml of saturated brine and 50 ml of ethyl acetate were added and partitioned. The organic layer was separated and washed with 10 ml of saturated brine. The combined aqueous layer was extracted with 30 ml of ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 936 mg (yield 21%) of a pale yellow medium viscosity liquid compound.

The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.25 (3H, t), 1.29-1.52 (15H, m), 1.57-1.68 (2H, m), 2.16-2.33 (4H m), 2.82-2.96 (4H, m), 3.80 (3H, s), 4.13 (2H, q), 6.10 (1H, d), 6.70-6.94 (4H, m). The wave number (cm ^-1 ) absorbed in the infrared absorption spectrum (KBr pellet method) was 2970, 2930, 2860, 1750, 1740, 1670, 1630, 1610, 1510, 1270, 1200, 1120, 1040. It was. The results of elemental analysis were as follows: carbon 70.17% and hydrogen 8.80%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 6.

<Synthesis Example 4>
Compound 8 was prepared using Compound 3 and Compound 7 as raw materials.

[Compound 7]

[Compound 8]

From 1.19 g (3.52 mmol) of compound 3 and 851 mg (3.40 mmol) of compound 7 according to the method of Synthesis Example 2, 663 mg (yield 32%) of compound 8 was obtained as a pale yellow medium-viscosity compound. It was.
The chemical shift value of the ¹ H-NMR spectrum of Compound 8 measured in deuterated chloroform is 1.22-1.60 (18H, m), 1.99-2.2.45 (4H, m), 2.78 (3H, s), 2.77-2.84. (2H, m), 2.94 (1H, t), 3.71-3.80 (4H, m), 4.12 (2H, q), 5.37-5.5.43 (1H, m), 5.47-5.53 (1H, m), 6.74 -6.94 (3H, m), 7.30-7.35 (2H, m), 7.72-7.77 (2H, m). The wave numbers (cm ^-1 ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3510, 2970, 2940, 2860, 1750, 1730, 1600, 1510, 1280, 1200, 1120, 1030, 670. It was. The results of elemental analysis were as follows: carbon 65.28% and hydrogen 7.53%.

<Synthesis Example 5>
Compound 9 was prepared using Compound 8 obtained in Synthesis Example 4 as a raw material.

[Compound 9]

According to the method of Synthesis Example 3, 936 mg (yield 21%) of Compound 9 was obtained from 6 g (9.95 mmol) of Compound 8 as a pale yellow medium viscosity liquid compound.
The chemical shift values of ¹ H-NMR spectrum of Compound 9 measured in deuterated chloroform are 1.23-1.73 (17H, m), 2.18-2.31 (4H, m), 2.79-2.93 (5H, m), 3.79 (3H , s), 4.12 (2H, q), 6.09 (1H, d), 6.75-6.83 (3H, m), 6.91 (1H, d). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2979, 1760, 1732, 1668, 1603, 1512, 1468, 1369, 1267, 1150, 1127, 1038. The results of elemental analysis were as follows: carbon 69.42% and hydrogen 8.39%.

<Synthesis Example 6>
Compound 11 was prepared using Compound 3 and Compound 10 as raw materials.

[Compound 10]

[Compound 11]

That is, in a solution of 49.1 g (145 mmol) of compound 3 and 4.70 ml (14.7 mmol) of tris [2- (2-methoxyethoxy) ethyl] amine in 300 ml of tetrahydrofuran, 1.0 M at −78 ° C. 145 ml of a lithium hexamethyldisilazane / tetrahydrofuran solution was added dropwise. After stirring at the same temperature for 60 minutes, 32.6 g (145 mmol) of Compound 10 was added. After stirring for 5 minutes at the same temperature, the temperature was gradually raised. At −10 ° C., 100 ml of 20% aqueous citric acid solution was added to stop the reaction.
Subsequently, 300 ml of saturated brine was added, and after partitioning, the organic layer was separated. The aqueous layer was extracted with 100 ml of ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 60.1 g (74%) of a pale yellow medium viscosity liquid compound.

The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.05-1.32 (7H, m), 1.40-1.72 (4H, m), 1.78-2.00 (2H, m), 2.18-2.31 (2H, m), 2.45 (3H, s), 2.53-2.85 (2H, m), 3.10-3.38 (1H, m), 3.51 (3H, s), 3.86 (3H, s), 4.13 (2H, q ), 4.22-4.60 (1H, m), 5.03-5.78 (4H, m), 6.61-6.75 (2H, m), 7.00-7.09 (1H, m), 7.29-7.38 (2H, m), 7.64-7.73 (2H, m). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3520, 2940, 1730, 1600, 1510, 1290, 1140, 1080 and 1000. The results of elemental analysis were as follows: carbon 64.03% and hydrogen 7.54%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 11.

<Synthesis Example 7>
Compound 12 was prepared using Compound 11 obtained in Synthesis Example 6 as a raw material.

[Compound 12]

  According to the method of Synthesis Example 3, 5.64 g (51%) of Compound 12 was obtained from 16.0 g (28.4 mmol) of Compound 11 as a pale yellow medium viscosity liquid compound.

The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.27 (3H, t), 1.30-1.40 (4H, m), 1.42-1.52 (2H, m), 1.58-1.68 (2H , m), 2.20 (2H, dd), 2.29 (2H, t), 2.82-2.93 (4H, m), 3.51 (3H, s), 3.87 (3H, s), 4.13 (2H, q), 5.12 ( 2H, s), 6.10 (1H, d), 6.66-6.86 (3H, m), 7.06 (1H, d). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2930, 1730, 1670, 1630, 1510, 1370, 1260, 1160, and 990. The results of elemental analysis were as follows: carbon 67.96% and hydrogen 8.43%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 12.

<Synthesis Example 8>
Compound 13 was prepared using Compound 12 obtained in Synthesis Example 7 as a raw material.

[Compound 13]

  That is, 5 ml of 1N hydrochloric acid was added to a solution in which 7.73 g (20.0 mmol) of Compound 12 was dissolved in 50 ml of tetrahydrofuran and stirred. After 5 hours at 55 ° C., the mixture was neutralized by adding 5 ml of 1N aqueous sodium hydroxide solution. The organic layer was recovered by adding 20 ml of saturated brine and partitioning. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.64 g (36%) of a pale yellow medium viscosity liquid compound.

The chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.25 (3H, t), 1.30-1.38 (4H, m), 1.40-1.50 (2H, m), 1.58-1.68 (2H , m), 2.16-2.24 (2H, m), 2.29 (2H, t), 2.79-2.90 (4H, m), 3.87 (3H, s), 4.12 (2H, q), 5.52 (1H, s), They were 6.08 (1H, d), 6.65-6.73 (2H, m), 6.75-6.85 (2H, m). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3440, 2940, 1730, 1670, 1630, 1520, 1370, 1270, 1200, 1030, and 980. The results of elemental analysis were as follows: carbon 69.59% and hydrogen 8.34%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 13.

<Synthesis Example 9>
Compound 9 obtained in Synthesis Example 5 was ketalized to obtain Compound 14.

[Compound 14]

  This reaction was performed in a nitrogen atmosphere. To a solution of 11 μl (0.0614 mmol) trimethylsilyl trifluoromethanesulfonate and 0.9 ml (3.69 mmol) 1,2-bistrimethylsiloxyethane in 6 ml dichloromethane was added 133 mg (0.307 mmol) under ice cooling. A solution of the compound 9 in 1 ml of dichloromethane was added dropwise. After stirring for 50 minutes, triethylamine was added to the reaction mixture to stop the reaction. Next, 5 ml of saturated aqueous sodium hydrogen carbonate and 5 ml of chloroform were added and partitioned. The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel thin layer chromatography to obtain 114 mg (78%) of a pale yellow, medium-viscous liquid compound.

The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.23-1.64 (17H, m), 1.98-2.06 (4H, m), 2.28 (2H, t), 2.67-2.71 (2H , m), 2.80-2.84 (1H, m), 3.79 (3H, s), 3.91-3.98 (4H, m), 4.12 (2H, q), 5.38 (1H, d), 5.81 (1H, dt), 6.74-6.78 (2H, m), 6.89 (1H, d). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2924, 1758, 1737, 1608, 1510, 1466, 1420, 1127, and 1042. The results of elemental analysis were as follows: carbon 68.04% and hydrogen 8.46%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 14.

<Synthesis Example 10>
Compound 14 obtained in Synthesis Example 9 was reduced with lithium aluminum hydride to obtain Compound 15.

[Compound 15]

  To a solution of 159 mg (0.334 mmol) of compound 14 dissolved in 6 ml of tetrahydrofuran, 50.0 mg (1.33 mmol) of lithium aluminum hydride was added under ice cooling. After stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction mixture to stop the reaction. Next, 5 ml of saturated saline was added, and extraction with 5 ml of ethyl acetate was repeated three times. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel thin layer chromatography to obtain 121 mg (99%) of a yellow medium viscosity liquid compound.

The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.26-1.55 (10H, m), 1.96-2.06 (4H, m), 2.62-2.66 (2H, m), 3.62 (2H , t), 3.86 (3H, s), 3.91-3.99 (4H, m), 5.38 (1H, d), 5.61 (1H, s), 5.81 (1H, dt), 6.66-6.69 (2H, m), 6.82 (1H, d). The results of elemental analysis were as follows: carbon 69.20% and hydrogen 8.85%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 15.

<Synthesis Example 11>
The ketal of compound 15 obtained in Synthesis Example 10 was removed to obtain compound 16.

[Compound 16]

  To a solution of 122 mg (0.335 mmol) of compound 15 dissolved in 2 ml of acetone and 2 ml of distilled water, 8.4 mg (0.0335 mmol) of pyridinium p-toluenesulfonate was added. The reaction solution was heated to reflux for 3 hours. Next, the reaction solution was allowed to cool to room temperature, the solvent was distilled off, 5 ml of saturated brine was added to the resulting residue, and extraction with 5 ml of ethyl acetate was repeated three times. The combined organic layers were dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel thin layer chromatography to obtain 85.2 mg (80%) of a pale yellow, medium-viscous compound.

The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.30-1.58 (10H, m), 2.17 (2H, dd), 2.81-2.86 (4H, m), 3.63 (2H, t ), 3.86 (3H, s), 5.73 (1H, s), 6.08 (1H, dt), 6.67-6.71 (2H, m), 6.78-6.83 (2H, m). The results of elemental analysis were as follows: carbon 71.22% and hydrogen 8.81%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 16.

<Synthesis Example 12>
Compound 6 obtained in Synthesis Example 3 was catalytically hydrogenated to obtain Compound 17.

[Compound 17]

  To a solution of 1.00 g (2.24 mmol) of compound 6 in 25 ml of ethanol, 100 mg of palladium-carbon was added. After the reaction system was stirred for 3.5 hours under a hydrogen atmosphere, the reaction solution was filtered through Celite to separate the palladium catalyst. The filtrate was concentrated under reduced pressure to obtain 0.97 g (yield 97%) of a pale yellow medium viscosity liquid compound.

The chemical shift values of ¹ H-NMR spectrum measured in deuterated chloroform of this product are 1.23-1.61 (24H, m), 2.28 (2H, t), 2.37 (2H, t), 2.71 (2H, t), They were 2.87 (2H, t), 3.78 (3H, s), 4.12 (2H, q), 6.72-6.77 (2H, m), 6.89 (1H, d). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2930, 1760, 1730, 1639, 1511, 1452, 1419, 1369, 1267, 1183, 1126. The results of elemental analysis were as follows: carbon 69.61% and hydrogen 8.99%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 17.

<Synthesis Example 13>
Compound 17 obtained in Synthesis Example 12 was ketalized to obtain Compound 18.

[Compound 18]

According to the method of Synthesis Example 9, 200 mg (78%) of Compound 18 was obtained from 234 mg (0.522 mmol) of Compound 17 as a pale yellow medium viscosity liquid compound.
The chemical shift values of ¹ H-NMR spectrum of Compound 18 measured in deuterated chloroform are 1.23-1.35 (22H, m), 1.59-1.64 (4H, m), 1.90-1.94 (2H, m), 2.28 (2H , t), 2.64-2.68 (2H, m), 3.78 (3H, s), 3.98 (4H, s), 4.12 (2H, q), 6.74-6.78 (2H, m), 6.88 (1H, d) there were. The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 2936, 1755, 1735, 1606, 1511, 1464, 1418, 1266, 1203, 1117, and 1036. The results of elemental analysis were as follows: carbon 68.54% and hydrogen 8.63%.

<Synthesis Example 14>
Compound 18 obtained in Synthesis Example 13 was reduced with lithium aluminum hydride to obtain Compound 19.

[Compound 19]

According to the method of Synthesis Example 10, from 186 mg (0.378 mmol) of Compound 18, 137 mg (99%) of Compound 19 was obtained as a yellow medium viscosity liquid compound.
The chemical shift value of the ¹ H-NMR spectrum of Compound 19 measured in deuterated chloroform is 1.24-1.70 (16H, m), 1.88-1.93 (2H, m), 2.59-2.63 (2H, m), 3.64 (2H , t), 3.87 (3H, s), 3.98 (4H, s), 5.50 (1H, br), 6.67-6.70 (2H, m), 6.82 (1H, d).
The results of elemental analysis were as follows: carbon 69.20% and hydrogen 8.85%.

<Synthesis Example 15>
The ketal of compound 19 obtained in Synthesis Example 14 was removed to obtain compound 20.

[Compound 20]

According to the method of Synthesis Example 11, 120 mg (99%) of Compound 20 was obtained from 137 mg (0.377 mmol) of Compound 19 as a colorless crystalline compound.
The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of Compound 20 is 1.20-1.51 (14H, m), 2.29 (2H, t), 2.62 (2H, t), 2.75 (2H, t), 3.59 (2H, t), 3.81 (3H, s), 5.47 (1H, s), 6.64-6.67 (2H, m), 6.80 (1H, d). The wave numbers (cm ^-1 ) absorbed in the infrared absorption spectrum (KBr pellet method) are 3415, 2920, 1705, 1611, 1520, 1463, 1455, 1365, 1278, 1236, 1151, 1122, 1064, 1028. Met.
The results of elemental analysis were as follows: carbon 70.77% and hydrogen 9.38%.

<Synthesis Example 16>
Compound 6 obtained in Synthesis Example 3 was reduced with lithium aluminum hydride to obtain Compound 21.

[Compound 21]

  To a solution of 594 mg (1.33 mmol) of compound 6 dissolved in 40 ml of tetrahydrofuran, 202 mg (5.32 mmol) of lithium aluminum hydride was added under ice cooling. After stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction mixture to stop the reaction. Next, 15 ml of distilled water was added, and extraction with 20 ml of ethyl acetate was repeated twice. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain 315 mg (73%) of a colorless medium viscosity liquid compound.

The chemical shift value of ¹ H-NMR spectrum measured in deuterochloroform of this product is 1.23-1.83 (12H, m), 2.02 (2H, m), 2.56-2.69 (2H, m), 3.61 (2H, t ), 3.84 (3H, s), 4.04 (1H, dd), 5.45-5.49 (1H, m), 5.58-5.66 (1H, m), 6.65-6.67 (2H, m), 6.79 (1H, d) there were. The wave numbers (cm ^-1 ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3349, 2930, 1666, 1602, 1516, 1464, 1453, 1431, 1368, 1273, 1236, 1154, 1036. It was. The results of elemental analysis were as follows: carbon 70.77% and hydrogen 9.38%.
Based on the above analysis, it was confirmed that the obtained compound was the compound 21.

<Synthesis Example 17>
Compound 9 obtained in Synthesis Example 5 was reduced by catalytic hydrogenation to obtain Compound 22.

[Compound 22]

According to the method of Synthesis Example 12, 148 mg (yield 91%) of Compound 22 was obtained as a pale yellow, medium-viscosity liquid compound from 161 mg (0.379 mmol) of Compound 9.
The chemical shift value of ¹ H-NMR spectrum of Compound 22 measured in deuterated chloroform is 1.23-1.71 (21H, m), 2.28 (2H, t), 2.38 (2H, t), 2.43-2.45 (1H, m ), 2.72 (2H, t), 2.87 (2H, t), 3.79 (3H, s), 4.12 (2H, q), 6.72-6.78 (2H, m), 6.90 (1H, d). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) are 2930, 1760, 1730, 1639, 1511, 1452, 1419, 1369, 1267, 1183, 1126, 1098, 1029, 1015. Met. The results of elemental analysis were as follows: carbon 69.10% and hydrogen 8.81%.

<Synthesis Example 18>
Compound 22 obtained in Synthesis Example 17 was reduced with lithium aluminum hydride to obtain Compound 23.

[Compound 23]

According to the method of Synthesis Example 16, 97.4 mg (91%) of Compound 23 was obtained as a colorless crystalline compound from 148 mg (0.330 mmol) of Compound 22.
The chemical shift value of ¹ H-NMR spectrum of Compound 23 measured in deuterated chloroform is 1.26-1.72 (18H, m), 2.54-2.61 (1H, m), 2.66-2.70 (1H, m), 3.54-3.73 (3H, m), 3.85 (3H, s), 6.66 to 6.68 (2H, m), 6.80 (1H, d). The wave numbers (cm ^-1 ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3426, 2930, 1607, 1515, 1481, 1468, 1437, 1365, 1268, 1239, 1155, 1124, 1039. It was. The results of elemental analysis were as follows: carbon 70.3% and hydrogen 9.94%.

<Example 1>
Compound 13 obtained in Synthesis Example 8, Compound 16 obtained in Synthesis Example 11, Compound 20 obtained in Synthesis Example 15, Compound 21 obtained in Synthesis Example 16, and Compound 23 obtained in Synthesis Example 18 The 5-lipoxygenase inhibitory activity was measured.
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.

  Compound 13, Compound 16, Compound 20, Compound 21, and Compound 23 exhibited 5-lipoxygenase inhibitory activity in a concentration-dependent manner, although they did not reach NDGA.

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

(R ¹ in Formula (1) is a hydrogen atom, a lower alkyl group or a protecting group for a phenolic hydroxyl group, A is an alkylene group having 1 to 4 carbon atoms, and B is an alkylene group having 1 to 12 carbon atoms. R ² is —COOR ³ (wherein R ³ is an alkyl group which may have 1 to 18 carbon atoms substituted or branched), a carboxyl group or —CH ₂ OH, and Z is —CO 2 -CH = CH -, - CHOH- CH = CH -, - CHOH-1,2- epoxy _{-, - CO-CH 2 CH} 2 -, - CHOH-CH 2 CH 2 -, - CO-CH 2 CHOH-, _{-CHOH-CH 2 CHOH -, -} CO-CH 2 CHOR 4 -, - CHOH-CH 2 CHOR 4 -, - CO-CH = CH- ketal derivative or -CO-CH ₂ CH _2, - with the ketal derivative There, R ⁴ is a lower alkyl group.