JP4657778B2 - Arachidonic acid metabolism inhibitor - Google Patents

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 are 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, such as limited administration methods and doses.
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 includes 2-methoxybenzyl methyl ether, 3-methoxybenzyl methyl ether, 4-methoxybenzyl methyl ether, 2-methoxybenzyl ethyl ether, 3-methoxybenzyl ethyl ether, 4-methoxybenzyl ethyl ether, 2-methoxybenzyl. Propyl ether, 3-methoxybenzylpropyl ether, 4-methoxybenzylpropyl ether, 2-methoxyphenethyl methyl ether, 3-methoxyphenethyl methyl ether, 4-methoxyphenethyl methyl ether, 2-methoxyphenethyl ethyl ether, 3-methoxyphenethyl ethyl Ether, 4-methoxyphenethyl ethyl ether, 2-methoxyphenethyl propyl ether, 3-methoxyphenethyl propyl ether, 4-methoxyphene Tylpropyl ether, 2-ethoxybenzyl methyl ether, 3-ethoxybenzyl methyl ether, 4-ethoxybenzyl methyl ether, 2-ethoxybenzyl ethyl ether, 3-ethoxybenzyl ethyl ether, 4-ethoxybenzyl ethyl ether, 2-ethoxybenzyl Propyl ether, 3-ethoxybenzylpropyl ether, 3-ethoxyphenethyl methyl ether, 4-ethoxyphenethyl methyl ether, 3-ethoxyphenethyl ethyl ether, 4-ethoxyphenethyl ethyl ether, 3-ethoxyphenethyl propyl ether, 4-ethoxyphenethyl propyl An arachidonic acid metabolism inhibitor comprising at least one compound selected from ethers as an active ingredient, more preferably 4-methoxybenzylmethyl ester Ter, 4-methoxybenzyl ethyl ether, 4-methoxybenzyl propyl ether, 4-ethoxybenzyl methyl ether, 4-ethoxybenzyl ethyl ether, 4-ethoxybenzylpropyl ether, 4-methoxyphenethyl methyl ether, 4-methoxyphenethyl ethyl ether , An arachidonic acid metabolism inhibitor containing as an active ingredient at least one compound selected from 4-methoxyphenethylpropyl ether, 4-ethoxyphenethylmethyl ether, 4-ethoxyphenethylethyl ether, and 4-ethoxyphenethylpropyl ether. Moreover, this invention is an arachidonic acid metabolism inhibitor which uses Muscari flower essential oil as an active ingredient. Furthermore, the present invention is a blood flow improving agent, an antithrombotic agent or an anti-inflammatory 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 present invention includes 2-methoxybenzyl methyl ether, 3-methoxybenzyl methyl ether, 4-methoxybenzyl methyl ether, 2-methoxybenzyl ethyl ether, 3-methoxybenzyl ethyl ether, 4-methoxybenzyl ethyl ether, 2-methoxybenzyl. Propyl ether, 3-methoxybenzylpropyl ether, 4-methoxybenzylpropyl ether, 2-methoxyphenethyl methyl ether, 3-methoxyphenethyl methyl ether, 4-methoxyphenethyl methyl ether, 2-methoxyphenethyl ethyl ether, 3-methoxyphenethyl ethyl Ether, 4-methoxyphenethyl ethyl ether, 2-methoxyphenethyl propyl ether, 3-methoxyphenethyl propyl ether, 4-methoxyphene Rupropyl ether, 2-ethoxybenzyl methyl ether, 3-ethoxybenzyl methyl ether, 4-ethoxybenzyl methyl ether, 2-ethoxybenzyl ethyl ether, 3-ethoxybenzyl ethyl ether, 4-ethoxybenzyl ethyl ether, 2-ethoxybenzyl Propyl ether, 3-ethoxybenzylpropyl ether, 3-ethoxyphenethyl methyl ether, 4-ethoxyphenethyl methyl ether, 3-ethoxyphenethyl ethyl ether, 4-ethoxyphenethyl ethyl ether, 3-ethoxyphenethyl propyl ether, 4-ethoxyphenethyl propyl Arachidonic acid metabolism inhibitor comprising, as an active ingredient, at least one alkoxybenzyl (or phenethyl) alkyl ether selected from ethers A. These compounds are all known compounds and can be synthesized by known methods.

Further, among these alkoxybenzyl (or phenethyl) alkyl ethers, 4-methoxybenzyl methyl ether, 4-methoxybenzyl ethyl ether, 4-methoxybenzylpropyl, which are compounds in which the side chain bonded to the ring is located in the para position. Ether, 4-ethoxybenzyl methyl ether, 4-ethoxybenzyl ethyl ether, 4-ethoxybenzyl propyl ether, 4-methoxyphenethyl methyl ether, 4-methoxyphenethyl ethyl ether, 4-methoxyphenethyl propyl ether, 4-ethoxyphenethyl methyl ether 4-ethoxyphenethyl ethyl ether and 4-ethoxyphenethyl propyl ether are particularly preferable because of their high effects.

  The above alkoxybenzyl (or phenethyl) alkyl ethers are compounds found in Muscari flower essential oil of the genus Muscari genus (Japanese Patent Laid-Open No. 7-291883). It can also be used.

Muscari flower essential oil in the present invention is obtained by extracting plant parts or whole plants mainly containing essential oil by methods such as steam distillation, solvent extraction, supercritical extraction, etc., and the essential oil produced by these methods , Including those commercially available such as oil. These extraction methods are publicly known, and an extract can be obtained according to a commonly performed extraction method. For example, steam distillation may be performed under normal pressure or reduced pressure. The solvent extraction is preferably performed using a low polarity solvent such as pentane or hexane. Moreover, it is preferable to use carbon dioxide as a solvent for supercritical extraction, which can be combined with liquefied carbon dioxide or subcritical carbon dioxide extraction, and ethanol, water, or the like may be used as an entrainer.

  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 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.

  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, ultraviolet 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%, the 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 portion was centrifuged at 3000 rpm for 15 minutes, and platelet poor plasma (PPP) was collected from the upper layer portion, 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 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.

Next, Table 1 shows the test results of alkoxybenzyl (or phenethyl) alkyl ethers, and the test results of red pepper tincture and pine bark extract as comparative examples.

As shown in Table 1 , in the arachidonic acid metabolism inhibitor of the present invention, alkoxybenzyl (or phenethyl) alkyl ether showed a high effect regardless of the binding position of the side chain or the number of carbons in the side chain. In addition, a compound in which the side chain is bonded to the para position shows a particularly high effect, and even when the addition amount is reduced to 10 μg, a sufficient effect is recognized, and a pine bark that has been conventionally known to improve blood flow. Even when compared with the extract, a much higher effect was observed.

  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.

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
p-methoxyphenethyl methyl ether 0.01
Fragrance 0.2
Water 50.0
─────────────────────────

  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 (6)

2-methoxybenzyl methyl ether, 3-methoxybenzyl methyl ether, 4-methoxybenzyl methyl ether, 2-methoxybenzyl ethyl ether, 3-methoxybenzyl ethyl ether, 4-methoxybenzyl ethyl ether, 2-methoxybenzylpropyl ether, 3 -Methoxybenzylpropyl ether, 4-methoxybenzylpropyl ether, 2-methoxyphenethyl methyl ether, 3-methoxyphenethyl methyl ether, 4-methoxyphenethyl methyl ether, 2-methoxyphenethyl ethyl ether, 3-methoxyphenethyl ethyl ether, 4- Methoxyphenethyl ethyl ether, 2-methoxyphenethylpropyl ether, 3-methoxyphenethylpropyl ether, 4-methoxyphenethylpropyl Ether, 2-ethoxybenzyl methyl ether, 3-ethoxybenzyl methyl ether, 4-ethoxybenzyl methyl ether, 2-ethoxybenzyl ethyl ether, 3-ethoxybenzyl ethyl ether, 4-ethoxybenzyl ethyl ether, 2-ethoxybenzylpropyl ether , 3-ethoxybenzylpropyl ether, 3-ethoxyphenethyl methyl ether, 4-ethoxyphenethyl methyl ether, 3-ethoxyphenethyl ethyl ether, 4-ethoxyphenethyl ethyl ether, 3-ethoxyphenethyl propyl ether, 4-ethoxyphenethyl propyl ether An arachidonic acid metabolism inhibitor comprising at least one selected compound as an active ingredient. 4-methoxybenzyl methyl ether, 4-methoxybenzyl ethyl ether, 4-methoxybenzyl propyl ether, 4-ethoxybenzyl methyl ether, 4-ethoxybenzyl ethyl ether, 4-ethoxybenzyl propyl ether, 4-methoxyphenethyl methyl ether, 4 Inhibition of arachidonic acid metabolism containing at least one compound selected from -methoxyphenethyl ethyl ether, 4-methoxyphenethyl propyl ether, 4-ethoxyphenethyl methyl ether, 4-ethoxyphenethyl ethyl ether, 4-ethoxyphenethyl propyl ether as an active ingredient Agent. The arachidonic acid metabolism inhibitor according to claim 1 or 2, comprising Muscari essential oil as an active ingredient. 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.