JP5305418B2 - Platelet aggregation inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new inhibitor for arachidonic acid metabolism, ameliorating or preventing various symptoms caused by abnormal arachidonic acid metabolism, in particular a readily available inhibitor of arachidonic acid metabolism which can be readily produced in a large scale. <P>SOLUTION: The inhibitor for arachidonic acid metabolism includes at least one plant extract chosen from Foeniculum vulgare fruit, Myristica fragrans seed, Barosma betulina leaf and Artemisia dracunculus as an active ingredient. A blood flow improving agent, an antithrombotic agent, an antiinflammatory agent or an antiallergic agent includes the inhibitor for arachidonic acid metabolism as an active ingredient. <P>COPYRIGHT: (C)2011,JPO&amp;INPIT

Description

  The present invention relates to an arachidonic acid metabolism inhibitor. Furthermore, the present invention relates to a blood flow improving agent, an antithrombotic agent, an anti-inflammatory agent and the like by suppressing the metabolism of arachidonic acid.

  Various prostaglandins and thromboxanes are known to be biosynthesized using arachidonic acid as a starting material. While these arachidonic acid metabolites are known to be involved in various regulatory mechanisms in the living body, it is also known to be deeply involved in inflammation and thrombus generation. In recent years, there has been an increasing interest in improving various inflammations, including blood fluidity and allergic properties, and attention has been focused on methods for alleviating various symptoms by controlling the metabolic pathway of arachidonic acid. ing. For example, inhibition of arachidonic acid metabolism by quinolylmethoxyphenylacetic acid and its derivatives (Patent Document 1), treatment of abnormal arachidonic acid metabolism by mulberry bark, licorice extract or its components (Patent Document 2), morgin or its derivatives There have been proposed a method for inhibiting arachidonic acid metabolism (Patent Document 3), a method for inhibiting arachidonic acid metabolizing enzyme with citrus peel extract (Patent Document 4), and the like.

  In addition, capsaicin and pepper extract are known to have a blood flow promoting effect, but their use is limited because of their strong irritation, and there are restrictions on the administration method and dose.

Japanese Patent Laid-Open No. 06-157463 Japanese Patent Application Laid-Open No. 07-017859 Japanese Patent Laid-Open No. 08-113536 Japanese Patent Application Laid-Open No. 08-245412

  The present invention provides a novel arachidonic acid metabolism inhibitor that can reduce or prevent various symptoms of adverse effects on the living body caused by arachidonic acid metabolism, and is particularly easily available. Another object of the present invention is to provide an arachidonic acid metabolism inhibitor that can be easily mass-produced.

  The present invention provides the following formula 1

（式中Ｒ１は水素原子、水酸基および／または炭素数１〜３のアルキル基が結合してもよいフェニル基またはメチルフェニル基またはエチルフェニル基、水酸基で置換されてもよい炭素数１〜１０の直鎖まはた分岐鎖もしくは環を形成してもよい飽和または不飽和の炭素鎖を示す）で表されるアンゲリカ酸およびそのエステルを有効成分として含有するアラキドン酸代謝抑制剤である。また、本発明はさらに、該アラキドン酸代謝抑制剤を有効成分とする、血流改善剤、抗血栓剤、抗炎症剤または抗アレルギー剤である。

(In the formula, R1 represents a hydrogen atom, a hydroxyl group and / or a phenyl group, a methylphenyl group, an ethylphenyl group or a hydroxyl group which may be substituted by a hydroxyl group and / or a hydroxyl group having 1 to 3 carbon atoms. An arachidonic acid metabolism inhibitor containing angelic acid represented by a straight chain or a branched chain or a saturated or unsaturated carbon chain which may form a ring and an ester thereof as an active ingredient. The present invention is further a blood flow improving agent, antithrombotic agent, anti-inflammatory agent or antiallergic agent comprising the arachidonic acid metabolism inhibitor as an active ingredient.

  ADVANTAGE OF THE INVENTION According to this invention, the metabolic disorder of arachidonic acid can be improved and the effect of blood-flow promotion, thrombus prevention, prevention of various inflammations, and allergic symptoms, and an alleviation effect can be acquired.

  The following formula 1 of the present invention

（式中Ｒ１は水素原子、水酸基および／または炭素数１〜３のアルキル基が結合してもよいフェニル基またはメチルフェニル基またはエチルフェニル基、水酸基で置換されてもよい炭素数１〜１０の直鎖まはた分岐鎖もしくは環を形成してもよい飽和または不飽和の炭素鎖を示す）で表されるアンゲリカ酸およびそのエステル類として具体的には例えば、アンゲリカ酸、２−メチル−２−ブテニルアンゲレート、３−ヘキセニルアンゲレート、２−ヒドロキシ−２−メチル−３−ブテニルアンゲレート、２−メチル−２−プロぺニルアンゲレート、２−メチルブチルアンゲレート、３−ヒドロキシ−２−メチリデンブチルアンゲレート、３−メチルペンチルアンゲレート、ベンジルアンゲレート、ブチルアンゲレート、エチルアンゲレート、ゲラニルアンゲレート、ヘプチルアンゲレート、ヘキシルアンゲレート、イソブチルアンゲレート、イソペンチルアンゲレート、イソプロピルアンゲレート、ノニルアンゲレート、オクチルアンゲレート、ペンチルアンゲレート、フェネチルアンゲレート、プロピルアンゲレート、セカンダリブチルアンゲレート、ターシャリブチルアンゲレートが挙げられる。これら化合物の内、３−メチルペンチルアンゲレート、ブチルアンゲレート、イソブチルアンゲレート、２−メチルブチルアンゲレートが入手がより容易であるためより好ましい。これらの化合物は、特開昭５７−１１２３４８号公報に記載された方法などで容易に製造することができる。また、一般に市販されているものを使用することもできる。

(In the formula, R1 represents a hydrogen atom, a hydroxyl group and / or a phenyl group, a methylphenyl group, an ethylphenyl group or a hydroxyl group which may be substituted by a hydroxyl group and / or a hydroxyl group having 1 to 3 carbon atoms. Specific examples of angelic acid and esters thereof represented by a straight chain or a branched chain or a saturated or unsaturated carbon chain that may form a ring include angelic acid, 2-methyl-2 -Butenyl angelate, 3-hexenyl angelate, 2-hydroxy-2-methyl-3-butenyl angelate, 2-methyl-2-propenyl angelate, 2-methylbutyl angelate, 3- Hydroxy-2-methylidenebutyl angelate, 3-methylpentyl angelate, benzyl angelate, butyl angelate, ethyl angelate, Ranyl angelate, heptyl angelate, hexyl angelate, isobutyl angelate, isopentyl angelate, isopropyl angelate, nonyl angelate, octyl angelate, pentyl angelate, phenethyl angelate , Propyl angelate, secondary butyl angelate, and tertiary butyl angelate. Among these compounds, 3-methylpentyl angelate, butyl angelate, isobutyl angelate, and 2-methylbutyl angelate are more preferable because they are easier to obtain. These compounds can be easily produced by the method described in JP-A No. 57-112348. Moreover, what is generally marketed can also be used.

  Furthermore, the angelic acid esters in the compound are included as characteristic components of the essential oil of Roman chamomile (Anthemis nobilis L.), a perennial of the family Asteraceae, and these essential oils can also be used. As a plant generally called chamomile, German chamomile (chamomile) is used industrially in addition to roman chamomile. However, although Roman chamomile and German chamomile are similar in shape, they are not so closely related species, and it is known that there are significant differences in components such as essential oils. The angelic acid esters of the present invention are contained in roman chamomile, but are not contained in german chamomile.

  In the arachidonic acid metabolism inhibitor of the present invention, the above compounds may be used alone or in combination of two or more.

  The arachidonic acid metabolism inhibitor of the present invention is a solvent such as ethanol, water, propylene glycol, glycerin, edible fats and oils or a mixed solution thereof, salts applicable to pharmaceuticals and foods, sugars, sugar alcohols, enhancers, depending on applications. Shapes, solubilizers, emulsifiers, dispersants, stabilizers, antioxidants, pigments, fragrances and the like can be appropriately blended.

  In the arachidonic acid metabolism inhibitor of the present invention, the content of the compound group is not particularly limited, but is preferably 0.0001 to 100% by mass.

  The form of the arachidonic acid metabolism inhibitor of the present invention is not particularly limited. For example, it may remain in a liquid state, and can be appropriately selected depending on the application, such as emulsification, dispersion, and powderization by a known method.

  The arachidonic acid metabolism inhibitor of the present invention can be used in combination with nutrition enhancing agents such as vitamins, minerals and amino acids, antioxidants, antibacterial agents and other agents. The arachidonic acid metabolism inhibitor of the present invention may be used in combination with other arachidonic acid metabolism inhibitors.

  When formulating the arachidonic acid metabolism inhibitor of the present invention as a pharmaceutical or quasi-drug, a stabilizer, a coloring agent, a flavoring agent, a fragrance, an excipient, a solvent, a surfactant, Add emulsifiers, preservatives, solubilizers, isotonic agents, buffers, humectants, binders, coatings, lubricants, disintegrants, transdermal agents, etc., liquids, powders, powders, granules, tablets , Sugar coatings, capsules, suspensions, suppositories, baths, ointments, creams, gels, patches, injections, eye drops, and the like, but the arachidonic acid metabolism of the present invention can be selected. Since the inhibitor is particularly suitable for the purpose of health support due to its mild action, a dosage form particularly suitable for oral intake is preferred.

  Since many of the active ingredients used in the arachidonic acid metabolism inhibitor of the present invention are compounds that have been used mainly as fragrances, they can be added to foods and drinks, cosmetics, and the like. For example, beverages such as milk drinks, soft drinks, taste drinks, alcoholic drinks, chocolate, candy, tablet confectionery, gum, snack confectionery, cookies, cakes, other baked confectionery, frozen confectionery such as ice confectionery, ice cream, and instant Add to foods such as noodles, retort foods, frozen foods, seasonings, dietary supplements and other foods to add health maintenance functions such as promoting blood flow, preventing blood clots, reducing inflammation, and reducing allergic symptoms can do.

  The food / beverage product can be marked with a blood flow improvement and / or an anti-inflammatory effect. Specific embodiments of the display in the present invention include food and beverage packaging, containers, storefront display media, advertising media, and the like.

  When adding the arachidonic acid metabolism inhibitor of this invention to food-drinks, there is no restriction | limiting of the addition amount in particular, However, It is preferable that it is 0.001-5 mass%.

  The method for adding the arachidonic acid metabolism inhibitor of the present invention to a food or drink is not particularly limited, but an emulsifier, a dispersant, a stabilizer and the like can be added as necessary.

  When the arachidonic acid metabolism inhibitor of the present invention is added to foods and drinks, nutrition enhancers such as vitamins, minerals, amino acids, antioxidants, antibacterial agents, dietary fiber, blood flow promoters other than arachidonic acid metabolism inhibitors, Other functional components such as thrombotic agents and antiallergic agents can be used in combination as long as they do not inhibit the function of the arachidonic acid metabolism inhibitor of the present invention.

  The arachidonic acid metabolism inhibitor of the present invention is a body wash such as perfumes, lotions, foundations, lipsticks, creams, lotions, emulsions, gels, packs, sunscreens, sun oils, soaps, body shampoos, face wash Agent, shampoo, rinse, hair treatment agent, hair conditioner, hair dye, permanent agent, hair cosmetics such as hair nourishing agent, shaving foam, shaving cream, after shave lotion, toothpaste, mouthwash, powder detergent, liquid detergent, bleaching agent It can be added to cosmetics such as softeners, bath preparations, hygiene products, and contraceptives.

  Also, for the purpose of alleviating contact dermatitis and allergic symptoms, dyes, pigments, paints, rubber, plastics, silicon products, paper products, non-woven fabrics, textile products, concrete, films, polishes, adhesives, metal surfaces It can also be added to products that come into contact with the skin, such as coating agents applied to wood surfaces and the like.

  When adding the arachidonic acid metabolism inhibitor of this invention to cosmetics, there is no restriction | limiting in particular in addition amount, However, It is preferable that it is 0.001-15 mass%.

  The method for adding the arachidonic acid metabolism inhibitor of the present invention to cosmetics is not particularly limited, but emulsifiers, dispersants, stabilizers, excipients and the like may be added as necessary.

  When adding the arachidonic acid metabolism inhibitor of the present invention to cosmetics, antioxidants, vitamins, minerals, amino acids, moisturizers, UV absorbers, antibacterial agents, antifungal agents, melanin production inhibitors, hair nourishing agents, cooling sensations Other functional substances such as blood flow promoters, antithrombotic agents, and antiallergic agents other than drugs, warming agents, absorption promoters, and arachidonic acid metabolism inhibitors, as long as the functions of the arachidonic acid metabolism inhibitor of the present invention are not inhibited. It can also be used together.

(Test method)
A 3.8% sodium citrate solution was added to human blood to a concentration of 10%, this blood was centrifuged at 1000 rpm for 10 minutes, and the upper layer was collected, and this was used as platelet-rich plasma (PRP). Further, the lower layer was centrifuged at 3000 rpm for 15 minutes, and platelet poor plasma (PPP) was collected from the upper layer, which was used as a control when measuring the platelet aggregation ability.

  When a platelet aggregation measuring device (Kowa PA-20) manufactured by Kowa Co., Ltd. is used as the measuring device, the maximum aggregation rate with respect to the target aggregation curve without adding the test substance and adding only the aggregation-inducing agent is 100%. The maximum aggregation rate at each sample concentration step was determined.

  A test substance was placed in a measurement container, and further 270 μl of PRP was added to the measurement apparatus and incubated at 37 ° C. with stirring for 30 seconds. Subsequently, 2 μL of a methanol solution of arachidonic acid adjusted to 0.2 M was added as an agglutination-inducing agent within 30 seconds, and the agglomeration rate was measured after 7 minutes from the installation of the measurement container.

Arachidonic acid metabolism inhibitory activity was evaluated by determining the platelet aggregation inhibition rate by the following calculation method.
(Platelet aggregation inhibition rate calculation method)
A is the maximum aggregation rate when only the PRP + aggregation inducing agent is added.
Let B be the maximum aggregation rate when test substance + PRP + arachidonic acid is added.
When the aggregation inhibition rate (%) is C, C = 100−B / A × 100

(Test results)
In the test method, the platelet aggregation inhibitory activity was measured under the condition where 100 μg of the test substance was added. Furthermore, about the thing with comparatively high activity, the platelet aggregation inhibitory activity on the conditions which added 50 micrograms of test substances and 10 micrograms was measured.

  The test results of the arachidonic acid metabolism inhibitor of the present invention are shown in Table 1 as a comparative example using a commercially available chili tincture with a known platelet aggregation inhibitory activity and a pine bark extract with a known blood flow improving effect. Show.

  As shown in Table 1, the compounds of the present invention were confirmed to have an activity equal to or higher than that of chili tincture and pine bark extract.

  Next, the test result of the plant extract in this invention is shown. Commercially available essential oil was used for the plant extract used for the test. In addition, Table 2 shows the results of testing the Roman chamomile oil containing the angelic acid esters of the present invention and the results of testing the extract of the Roman chamomile flower extracted with hot water.

  The hot water extract of Roman chamomile flowers was extracted by adding 200 g of hot water to 2 g of dried flowers and stirring for 3 minutes, followed by solid-liquid separation to obtain an extract. The obtained extract was concentrated under reduced pressure to obtain 0.42 g of extract with respect to the dry flowers of the raw material, and this was used as a test substance.

  As shown in Table 2, the plant extract of the present invention showed the same effect as capsicum tincture and pine bark extract. Moreover, even when the amount of roman chamomile oil was reduced to 50 μg, the effect was equal to or better than that of the pine bark extract, and the hot water extract obtained by extracting the water-soluble component of roman chamomile did not provide a high effect.

  An example of a preparation example of the arachidonic acid metabolism inhibitor of the present invention is shown below.

Tablet formulation example (mass ratio)
──────────────────────
Arachidonic acid metabolism inhibitor of the present invention 5.0
6% HPC lactose 80.0
Magnesium stearate 4.0
Potato starch 6.0
──────────────────────

Ointment formulation example (mass ratio)
─────────────────────────
White petrolatum 20.0
Stearyl alcohol 22.0
Propylene glycol 12.0
Sodium lauryl sulfate 1.5
Paraben 0.2
Arachidonic acid metabolism inhibitor of the present invention 5.0
Purified water 39.3
─────────────────────────

Bath salt formulation example (mass ratio)
――――――――――――――――――――――――
Sodium bicarbonate 50.0
Sodium sulfate 45.0
Roman chamomile oil 0.5
p-methoxyphenethyl methyl ether
0.3
Fragrance 0.7
Dye 3.0
───────────────────────

  An example of the formulation of the arachidonic acid metabolism inhibitor of the present invention in a food is shown below.

Beverage formulation example (mass ratio)
―――――――――――――――――――――――― ──
Fructose glucose liquid sugar 60.0
Apple transparent fruit juice 4.3
Citric acid 2.3
Trisodium citrate 0.8
Ascorbic acid 0.2
Sucralose 0.03
Acesulfame potassium 0.02
Perfume 0.99
Roman chamomile oil 0.009
Isobutyl angelate 0.001
Water 31.0
―――――――――――――――――――――――― ──

Chewing gum formulation example (mass ratio)
――――――――――――――――――――――――
Gum base 20.0
Sugar 60.0
Glucose 10.0
Minamata 8.0
Glycerin 5.0
Fragrance 0.7
Roman chamomile oil 0.2
Isobutyl angelate 0.1
───────────────────────

  The arachidonic acid metabolism inhibitor of the present invention is a compound that has been used as a fragrance and has very little irritation and can be widely added to foods and drinks and cosmetics. In addition, since the compound group of the present invention can be easily synthesized, mass production is possible.

Claims (4)

Formula 1 below

(In the formula, R1 represents a hydrogen atom, a hydroxyl group and / or a phenyl group, a methylphenyl group, an ethylphenyl group or a hydroxyl group which may be substituted by a hydroxyl group and / or a hydroxyl group having 1 to 3 carbon atoms. A platelet aggregation inhibitor containing, as an active ingredient, at least one selected from angelic acid represented by a linear or branched chain or a saturated or unsaturated carbon chain that may form a ring) and an ester thereof . A platelet aggregation inhibitor comprising as an active ingredient at least one compound selected from 3-methylpentyl angelate, butyl angelate, isobutyl angelate, and 2-methylbutyl angelate. A blood flow improving agent comprising the platelet aggregation inhibitor according to claim 1 as an active ingredient. An antithrombotic agent comprising the platelet aggregation inhibitor according to claim 1 as an active ingredient.