JP2007169245A - Arachidonic acid metabolism inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new arachidonic acid metabolism inhibitor that alleviates or prevents various symptoms by arachidonic acid metabolic disorder, especially an arachidonic acid metabolism inhibitor that is more simply obtained and is easily mass-produced. <P>SOLUTION: The arachidonic acid metabolism inhibitor comprises dihydrojasmon and/or dihydrojasmonate or its ester as an active ingredient. The blood flow ameliorant, the antithrombotic medicine, the anti-inflammatory agent or the antiallergic agent comprises the arachidonic acid metabolism inhibitor as an active ingredient. <P>COPYRIGHT: (C)2007,JPO&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), morgine 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. Further, Non-Patent Document 1 reports that carvacrols, eugenol, and jasmon have an ability to suppress the aggregation reaction of sputum platelets caused by arachidonic acid. However, jasmon does not have a sufficient inhibition rate, and carvacrol analogs and eugenol have a characteristic aroma and are not always easy to use depending on the application.
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 Bulletin of Faculty of Agriculture, Shinshu University 1996, 33 (1/2), 1-8

  The present inventor has provided a novel arachidonic acid metabolism inhibitor capable of reducing or preventing various adverse effects on the living body caused by arachidonic acid metabolism. An object of the present invention is to provide an arachidonic acid metabolism inhibitor that can be easily mass-produced.

  The present invention relates to general formula 1

で表されるジヒドロジャスモン、および一般式２

Dihydrojasmon represented by the general formula 2

（式中Ｒは水素または炭素数１から３のアルキル基を表す）で示されるジヒドロジャスモネートおよびそのエステルから選ばれる少なくとも１つ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, R represents hydrogen or an alkyl group having 1 to 3 carbon atoms) An arachidonic acid metabolism inhibitor containing as an active ingredient at least one selected from dihydrojasmonate and esters thereof. 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 the relief can be acquired.

  The arachidonic acid metabolism inhibitor of the present invention has the general formula 1

で表されるジヒドロジャスモン、および一般式２

Dihydrojasmon represented by the general formula 2

（式中Ｒは水素または炭素数１から３のアルキル基を表す）で示されるジヒドロジャスモネートおよびそのエステルから選ばれる少なくとも１つを有効成分として含有することを特徴とするものである。

(Wherein R represents hydrogen or an alkyl group having 1 to 3 carbon atoms) and at least one selected from dihydrojasmonate and an ester thereof as an active ingredient.

  Formula 1 used as an arachidonic acid metabolism inhibitor of the present invention

で表されるジヒドロジャスモンは、従来から香料として使用されている公知の化合物であって、既に製法が確立され、人体への安全性も確認されているものである。本発明では、香料として製造されている該化合物をそのまま利用することもでき、また必要に応じて公知の方法により、さらに精製して使用することもできる。

The dihydrojasmon represented by the formula is a known compound that has been conventionally used as a fragrance, and has already been established and has been confirmed to be safe for the human body. In this invention, this compound manufactured as a fragrance | flavor can also be utilized as it is, and can further refine | purify and use it by a well-known method as needed.

  General formula 2 used in the present invention

で示される化合物としては、メチルジヒドロジャスモネートが香料化合物として市販されており、容易に入手することができる。本発明では、市販されているメチルジヒドロジャスモネートをそのまま使用してもよく、公知の方法により合成することもできる。また、公知の方法でエステル交換により、一般式のＲ部分をエチル基またはプロピル基に変換することもできる。また、市販のメチルジヒドロジャスモネートを加水分解してジヒドロジャスモネートとして使用することもできる。

As the compound represented by the formula, methyl dihydrojasmonate is commercially available as a fragrance compound and can be easily obtained. In the present invention, commercially available methyl dihydrojasmonate may be used as it is, or it can be synthesized by a known method. Further, the R moiety of the general formula can be converted into an ethyl group or a propyl group by transesterification by a known method. Also, commercially available methyl dihydrojasmonate can be hydrolyzed and used as dihydrojasmonate.

  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 beverages, soft drinks, taste beverages, alcoholic beverages, chocolate, candy, tablet confectionery, gum, snack confectionery, cookies, cakes, other confectionery such as baked confectionery, frozen confectionery such as ice confectionery and ice cream, 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.

  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.

  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 the surface of wood or wood.

  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.

  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 46.0
Arachidonic acid metabolism inhibitor of the present invention 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.

Ice cream formulation example (mass ratio)
────────────────────────
Whole fat condensed milk 10.0
Fresh cream 9.4
Unsalted butter 2.0
Nonfat dry milk 3.4
Sugar 12.0
Stabilizer 0.3
Emulsifier 0.2
pH adjuster 0.1
Caramel pigment 0.1
Arachidonic acid metabolism inhibitor of the present invention 0.01
Fragrance 0.01
Water 49.0
────────────────────────

Cookie dough formulation example (mass ratio)
────────────────────────
Soft flour 62.5
Whole grain 37.5
Shortening 30.0
Whole egg 30.0
Sugar 20.0
Minamata 1.0
Nonfat dry milk 5.0
Salt 1.2
Edible oils and fats 30.0
Sodium bicarbonate 1.0
Ammonium bicarbonate 1.0
Arachidonic acid metabolism inhibitor of the present invention 0.01
Fragrance 0.3
Water 11.0
────────────────────────

Chocolate formulation example (mass ratio)
─────────────────────────
Cocoa liquor 12.0
Cocoa butter 24.0
Sucrose 33.0
Full cream milk powder 19.0
Skim milk powder 11.4
Lecithin 0.5
Arachidonic acid metabolism inhibitor of the present invention 0.01
Fragrance 0.1
─────────────────────────

Non-oil dressing formulation example (mass ratio)
─────────────────────────
Dark soy sauce 10.0
Brewing vinegar 6.0
Apple cider vinegar 5.0
Lemon juice 4.0
Liquid sugar 7.0
Salt 2.0
Seasoning 7.0
Arachidonic acid metabolism inhibitor of the present invention 0.01
Fragrance 0.2
Water 50.0
─────────────────────────

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
Arachidonic acid metabolism inhibitor of the present invention 0.01
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
Arachidonic acid metabolism inhibitor of the present invention 0.3
───────────────────────

  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. Moreover, since the compound group of this invention can be obtained easily, mass production is possible.

Claims (6)

The following general formula 1

Dihydrojasmon represented by the general formula 2

An arachidonic acid metabolism inhibitor containing, as an active ingredient, at least one selected from dihydrojasmonate represented by (wherein R represents hydrogen or an alkyl group having 1 to 3 carbon atoms) and an ester thereof. The arachidonic acid metabolism inhibitor according to claim 1, wherein the ester of dihydrojasmonate is methyl dihydrojasmonate. A blood flow improving agent comprising the arachidonic acid metabolism inhibitor according to claim 1 as an active ingredient. An antithrombotic agent comprising the arachidonic acid metabolism inhibitor according to claim 1 as an active ingredient. An anti-inflammatory agent comprising the arachidonic acid metabolism inhibitor according to claim 1 as an active ingredient. A food or drink or cosmetic having an arachidonic acid metabolism-suppressing function, comprising the arachidonic acid inhibitor according to claim 1 as an active ingredient.