JP5536912B2 - Platelet aggregation inhibitor - Google Patents

Description

  The present invention relates to a platelet aggregation inhibitor. Furthermore, the present invention relates to a blood flow improving agent, an antithrombotic agent and the like by suppressing platelet aggregation.

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

  The present inventor provides a novel platelet aggregation inhibitor that can reduce or prevent various symptoms of adverse effects on living bodies caused by aggregation of platelets, and is particularly easily available. Another object is to provide a platelet aggregation inhibitor that can be easily mass-produced.

（式中Ｒは、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）で示されるチグリン酸エステル類から選ばれる少なくとも１つをを有効成分として含有する血小板凝集抑制剤である。また、本発明はさらに、該血小板凝集抑制剤を有効成分とする、血流改善剤または抗血栓剤である。 The present invention has the following formula:

(In the formula, R is a phenyl group or a methylphenyl group or an ethylphenyl group to which a hydroxyl group and / or an alkyl group having 1 to 3 carbon atoms may be bonded, or a linear chain having 1 to 10 carbon atoms that may be substituted with a hydroxyl group. Or a platelet aggregation inhibitor containing, as an active ingredient, at least one selected from tiglic acid esters represented by a saturated or unsaturated carbon chain that may form a branched chain or a ring. The present invention is further a blood flow improving agent or antithrombotic agent comprising the platelet aggregation inhibitor as an active ingredient.

  According to the present invention, platelet aggregation can be suppressed, and blood flow promotion, thrombus prevention prevention, and relaxation effects can be obtained.

（式中Ｒは、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）で示されるチグリン酸エステル類は一般に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、いずれも公知の方法によって製造することもできる。 The following formula of the present invention

(In the formula, R is a phenyl group or a methylphenyl group or an ethylphenyl group to which a hydroxyl group and / or an alkyl group having 1 to 3 carbon atoms may be bonded, or a linear chain having 1 to 10 carbon atoms that may be substituted with a hydroxyl group. Or a glycerin ester represented by a saturated or unsaturated carbon chain that may form a branched chain or a ring) is generally commercially available as a perfume compound and can be easily obtained. It can also be produced by this method.

  The platelet aggregation inhibitor of the present invention is a solvent such as ethanol, water, propylene glycol, glycerin, edible oil or fat, or a mixed solution thereof, salts applicable to pharmaceuticals and foods, sugars, sugar alcohols, and excipients, depending on applications. An agent, a solubilizer, an emulsifier, a dispersant, a stabilizer, an antioxidant, a pigment, a fragrance, and the like can be appropriately blended.

  In the platelet aggregation 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 platelet aggregation 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 platelet aggregation inhibitor of the present invention can be used in combination with a nutrient enhancer such as vitamins, minerals, amino acids, antioxidants, antibacterial agents, and other agents.

  When formulating the platelet aggregation inhibitor of the present invention as a pharmaceutical product or quasi-drug, a stabilizer, a coloring agent, a flavoring agent, a fragrance, an excipient, a solvent, a surfactant, an emulsifier, as necessary. , Preservatives, solubilizers, tonicity agents, buffers, moisturizers, binders, coatings, lubricants, disintegrants, transdermal absorption agents, liquids, powders, powders, granules, tablets, Any dosage form such as sugar coating, capsule, suspension, suppository, bath preparation, ointment, cream, gel, patch, injection solution, eye drop can be selected, and the platelet aggregation inhibitor of the present invention Is particularly suitable for the purpose of health support due to its mild action, and thus a dosage form particularly suitable for oral intake is preferred.

  Since the active ingredient used in the platelet aggregation inhibitor of the present invention is a compound that has been used mainly as a fragrance, it 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 By adding to cooked foods such as noodles, retort foods, frozen foods, foods such as seasonings and dietary supplements, health maintenance functions such as promoting blood flow and reducing thrombus prevention can be added.

  The said food / beverage products can be attached | subjected with the display of having the blood-flow improvement 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 platelet aggregation inhibitor of this invention to food-drinks, there is no restriction | limiting in particular in addition amount, However, It is preferable that it is 0.001-5 mass%.

  The method for adding the platelet aggregation 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 platelet aggregation inhibitor of the present invention is added to a food or drink, nutrient enhancers such as vitamins, minerals, amino acids, antioxidants, antibacterial agents, dietary fiber, blood flow promoters other than the platelet aggregation inhibitor of the present invention In addition, other functional components such as an antithrombotic agent can be used in combination as long as the function of the arachidonic acid metabolism inhibitor of the present invention is not inhibited.

  The platelet aggregation inhibitor of the present invention is a body cleansing agent such as perfume, lotion, foundation, lipstick, cream, lotion, emulsion, gel, pack, sunscreen, sun oil, soap, body shampoo, face wash 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, bleach, It can be added to cosmetics such as softeners, bath preparations, hygiene products and contraceptives.

  When adding the platelet aggregation 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 platelet aggregation inhibitor of the present invention to a cosmetic product is not particularly limited, but an emulsifier, a dispersant, a stabilizer, an excipient and the like can be added as necessary.

  When adding the platelet aggregation 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 sensation agents Other functional substances such as warming agents, absorption promoters, blood flow promoters, antithrombotic agents, and antiallergic agents other than those inhibiting the platelet aggregation inhibitor of the present invention do not inhibit the functions of the platelet aggregation inhibitor of the present invention. It can also be used in combination.

(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).

  As a specific measurement method, 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 installation of the measurement container.

  Using a platelet aggregating capacity measuring device (Kowa PA-20) manufactured by Kowa Co., Ltd., the test substance was not added to PRP, but only the aggregation-inducing agent was added and the value when platelets were aggregated was used as a control.

Platelet aggregation inhibition 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 that the amount of the test substance was 2 mM. Table 1 shows the test results of the active ingredients of the present invention. Table 1 also shows, as comparative examples, octanoic acid and undecanoic acid that have a structure similar to that of the active ingredient of the present invention and that did not provide sufficient activity.

  As shown in Table 1, the compound of the present invention was confirmed to have an activity equal to or higher than that of chili tincture.

  An example of a formulation example of the platelet aggregation inhibitor of the present invention is shown below.

Tablet formulation example (mass ratio)
──────────────────────
Platelet aggregation 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
Platelet aggregation 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
Platelet aggregation inhibitor of the present invention 1.3
Fragrance 0.7
Dye 3.0
───────────────────────

  An example of a formulation example of the platelet aggregation 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
Platelet aggregation 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
Platelet aggregation inhibitor of the present invention 0.1
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
Platelet aggregation 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
Fragrance 0.2
Platelet aggregation inhibitor of the present invention 0.01
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
Platelet aggregation inhibitor of the present invention 0.1
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 0.9
Platelet aggregation inhibitor of the present invention 0.1
───────────────────────

  The platelet aggregation 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. Further, since the compound of the present invention can be easily synthesized, it can be mass-produced.

Claims (3)

Following formula

(In the formula, R is a phenyl group or a methylphenyl group or an ethylphenyl group to which a hydroxyl group and / or an alkyl group having 1 to 3 carbon atoms may be bonded, or a linear chain having 1 to 10 carbon atoms that may be substituted with a hydroxyl group. Or a platelet aggregation inhibitor containing, as an active ingredient, at least one selected from tiglic acid esters represented by the following formula: a saturated or unsaturated carbon chain that may form a branched chain or ring. 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.