JP2017222616A - Autonomic nerve regulating agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an autonomic nerve regulating agent that activates the sympathetic nervous system.SOLUTION: As the autonomic nerve regulating agent of the present invention is able to activate the sympathetic nervous system which is part of the autonomic nervous system, the use thereof in cases of autonomic nerve disorders, particularly when the parasympathetic nervous system is relatively dominant, can effectively improve the disorders. Furthermore it is possible to make use of this agent for the purpose of: preventing or improving a feeling of fatigue after waking; dizziness; preventing or improving allergic symptoms such as sneezing and a runny nose; preventing or improving depression; and preventing or improving jet lag.SELECTED DRAWING: Figure 1

Description

  The present invention relates to an autonomic nerve modulating agent.

  The autonomic nervous system is composed of the sympathetic nervous system and the parasympathetic nervous system. The balance of these two nervous systems controls the functions of blood vessels and internal organs, regulates the internal environment, and further breathes, circulates blood, digestive and absorption. It plays a role in regulating the systemic system such as excretion, endocrine secretion, heat production, etc., and adjusting the body circulation necessary for life support. If the balance between the sympathetic and parasympathetic nervous systems is lost due to aging, poor physical condition, illness, stress, fatigue, etc., headache, nausea, tinnitus, slight fever, trembling, tinnitus, dizziness, vasoconstriction, fatigue and sweat may be abnormal Symptoms such as scratches appear. It also causes mental distrust, emotional instability, anxiety, irritation, and depression.

  Among the autonomic nerves, those that regulate sympathetic nerves include odor stimulation by methyl 2-methoxybenzoate (Patent Document 1), and intake of oral sympathetic nerve activators including Viburnum dilatatum. Activation of sympathetic nerve activity and increase of blood flow (Patent Document 2), improvement of sleepiness by sympathetic nerve activation action of orotic acid or a salt thereof, increase in body temperature, promotion of lipolysis, or maintenance of concentration (Patent Document 3), Etc. are known.

JP, 2015-221808, A JP 2013-194019 A JP 2012-126683 A

  However, the autonomic nerve regulating action by 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one is not known. In addition, autonomic nerve regulation has different effects depending on whether the nervous system of the sympathetic nervous system or parasympathetic nervous system is activated or suppressed, so that more detailed treatment is performed according to various symptoms and purposes. In addition, development of new autonomic nerve regulators is required.

  It is an object of the present invention to provide an autonomic nervous regulator that activates the function of the sympathetic nervous system.

  The present inventors have found that 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one activates the sympathetic nervous system and completes the present invention. It came to. That is, the present invention includes the following.

  (1) An autonomic nervous regulator comprising 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one as an active ingredient.

  (2) A sympathetic nerve activator comprising 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one.

  (3) A composition for regulating autonomic nerve, comprising 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one as an active ingredient.

  (4) A composition for sympathetic nerve activation, comprising 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one.

  (5) A food for autonomic nervous regulation characterized by containing 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one as an active ingredient.

  (6) A food for sympathetic nerve activation characterized by containing 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one.

  By using the autonomic nerve modulating agent of the present invention, this can be improved when there is an autonomic disturbance, particularly when the parasympathetic nervous system is relatively dominant. In addition, by adjusting the autonomic nerve, it is possible to prevent and / or improve sleep sensation, particularly dizziness, prevention and / or improvement of allergic symptoms such as sneezing and runny nose, prevention and / or improvement of depression, prevention of jet lag and / or It can be used for the purpose of improvement.

2 shows the time course of brown adipose tissue sympathetic nerve activity (BAT-SNA) in mice.

  Hereinafter, embodiments of the present invention will be described.

  2- (3,4-Dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one (hereinafter also referred to as “Compound 1”) used in the present invention is a derivative of benzopyran. Compound 1 may be a pulverized or squeezed plant body containing the compound 1 or a dried product thereof, or an extract or purified product from the plant body. Moreover, you may use the compound obtained by the synthesis | combination, a commercially available reagent, etc. In the present invention, an extract is preferable because the concentration of the active ingredient is high and it is easily available.

  The extraction operation in the case of extracting a compound from a plant body is not limited to once, and the extraction operation may be repeated by adding a solvent to the extraction residue. At this time, a different solvent may be used. Further, the plant extract containing Compound 1 may be the extract itself obtained by the extraction operation from the plant, and the concentrate (concentrated extract) or the dried product (dried extract) obtained by removing the solvent from the extract. But it may be. Further, the extract may be an extract obtained by purifying the extract obtained by the extraction operation (purified product). The purification method is not particularly limited, and may be, for example, liquid-liquid distribution using two or more solvents, or purification using chromatography (for example, column chromatography or high performance liquid chromatography) using an adsorbent.

  The extraction solvent is not particularly limited and can be appropriately selected by those skilled in the art. The extraction solvent may be water or an organic solvent, or may be a mixture of water and an organic solvent. The organic solvent may be either a hydrophilic solvent or a lipophilic solvent. Examples of the organic solvent include hydrophilic alcohols having 4 or less carbon atoms such as methanol, ethanol, propyl alcohol, isopropyl alcohol, and butyl alcohol, and lipophilic alcohols having more carbon atoms such as methyl ether and ethyl. Ethers such as ethers, hydrocarbons such as hexane and heptane, and polyhydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol, and glycerin may be used. Among these extraction solvents, one kind of solvent or two or more kinds of mixed solvents are used for extraction. In the present invention, a solvent from which flavones are easily extracted is preferably selected. From this viewpoint, the extraction solvent is preferably one or a mixed solvent of two or more hydrophilic solvents such as water, ethanol, and methanol.

Since the autonomic nervous modulator of the present invention activates the sympathetic nervous system, sympathetic nerve activation, in particular, prevention and / or improvement of sleepiness fatigue, prevention and / or improvement of allergic symptoms such as dizziness, sneezing and runny nose, It can be given to animals or humans for the purpose of preventing and / or improving depression symptoms, preventing and / or improving jet lag.
Moreover, it becomes possible to adjust a life rhythm through adjustment of an autonomic nerve, and may be accompanied by a body temperature rise effect, a hypothermia improvement effect, or a diet effect.
In contrast to the present invention, as a substance that activates the parasympathetic nerve, pilocarpine hydrochloride, for example, is effective in treating presbyopia as a parasympathomimetic stimulant (Japanese Patent Publication No. 2010-513454), and phenyllactic acid, It is known that it is effective in the treatment or improvement of hypertension (WO2008 / 120713), and that γ-aminobutyric acid and glycine are effective in improving sleep (WO2007 / 125883), etc., and activates parasympathetic nerves. Is known to exhibit an action different from sympathetic activation.

  The autonomic nerve modulating agent of the present invention can be used as it is or as a mixture with other components as a parenteral agent, an oral agent and the like according to the above-mentioned purpose. As parenteral administration agents, intravenous administration agents, intramuscular administration agents, subcutaneous administration agents, transdermal administration agents, and the like are used. It is good also as an intraperitoneal administration agent which is one of the subcutaneous administration agents. Moreover, it is also preferable to administer directly to the internal organs by injection etc. as an enteral agent.

  Moreover, the autonomic nerve regulator of this invention can also be used as a form suitable for cosmetics. For example, it can be processed into various forms such as lotions, emulsions, gels, creams, ointments and the like. Specifically, it can be used as a lotion, cosmetic cream, milky lotion, cream, pack, hair tonic, hair cream, shampoo, hair rinse, treatment, facial cleanser, foundation, hair restorer, aqueous ointment, spray and the like.

  In addition, the autonomic nerve modulating agent of the present invention may be a parenteral administration agent from the viewpoint of preventing degeneration, but since it is difficult to denature upon exposure to gastric juice etc., sufficient effects as an oral administration agent are obtained. be able to. Examples of the orally administered agent include tablets, granules, powders, and capsules. As tablets and capsules, it is preferable to increase the amount that can reach the internal organs as they are.

  As an orally-administered agent, for example, it may be formed into a tablet, granule or the like using an additive (for example, excipient) usually used by those skilled in the art, or dissolved in water, beverages or the like. Or a liquid agent. Preferred are capsules, granules, tablets and the like.

  As a method for producing capsules, a conventionally known method for producing soft capsules may be used except that the autonomic nervous regulator of the present invention is used as the contents. Examples of such a production method include a method of encapsulating contents with a rotary filling machine using a capsule film sheet and molding a capsule preparation, or a method of producing seamless capsules by a dropping method.

  In addition, for tablets, an appropriate binder, excipient, disintegrant and, if necessary, a lubricant are added to the granule or extract itself containing the autonomic nervous regulator of the present invention. It can be prepared by the method. As for the granule, known various wet and dry granulation methods can be applied, and it can be molded together with an appropriate binder and excipient.

When the autonomic nervous regulator of the present invention is used by adding to foods, for example, beverages, granules, fine granules, capsules, tablets, powders, dairy products, gums, gummi, puddings, bars, other solid foods, etc. Blended. A food containing the compound can be used as a food for specified health use, a dietary supplement, a functional labeling food, a food for the sick, etc. in addition to a general food.

  Although there is no restriction | limiting in particular as a compounding quantity of the autonomic-nerve regulator of this invention, If it is an oral administration agent, Preferably it is 0.00001% or more in a composition, More preferably, 0.0001% or more may be mix | blended. Desirably, in the case of a parenteral administration agent such as cosmetics, it is desirable that 0.000001% or more, more preferably 0.00001% or more is added to the composition.

  The daily dose of Compound 1 used in the present invention is preferably 10 mg to 500 mg, more preferably 20 mg to 300 mg, and particularly preferably 30 to 150 mg as long as it is an oral administration agent.

Next, the present invention will be described in more detail based on examples, but the present invention is not limited thereto.

(Test substance)
As an example, 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one, which is compound 1, and 2- (3,4-dimethoxyphenyl)-as a comparative example. A 3,5,7-trimethoxy-4H-1-benzopyran-4-one (hereinafter also referred to as “compound 2”) was subjected to a sympathetic nerve activity evaluation test using commercially available reagents. Compound 2 is a compound that differs from Compound 1 in the number of methoxy groups (—OCH ₃ ).

(Sympathetic nerve activity evaluation test)
Wistar male rats (about 9 weeks old) having a body weight of about 300 g and kept in a constant temperature animal room at 24 ° C. for 1 week or more under a light / dark cycle every 12 hours (lighted from 8:00 to 20:00) were used. On the day of the experiment, the rats were fasted for 3 hours and then anesthetized with urethane, a cannula for duodenal administration was inserted, and then the centrifugal branch of the interscapular brown adipose tissue sympathetic nerve was lifted with a silver electrode, and the electrical activity of the nerve was measured. When these measured values settled, 1 ml of an aqueous suspension containing Compound 1 at a concentration of 30 mg / ml was administered to the duodenum as Example 1, and changes in autonomic nerve activity were measured electrophysiologically. As a control experiment, 1 ml of water as a control or 1 ml of an aqueous suspension containing Compound 2 at a concentration of 30 mg / ml as Comparative Example 1 was administered to the duodenum. Was measured electrophysiologically. In each test group, a tube was inserted into the trachea from the start of surgery to the end of measurement to secure the airway, and the body temperature (rat rectal temperature) was maintained at 35.0 ± 0.5 ° C. with a heat retention device. Data on autonomic nerve activity in each test section is analyzed by the average value of the firing frequency (pulse / 5s) per 5 seconds every 10 minutes, and the value before the start of stimulation (0 minute value) is set to 0 and the change value is expressed.

  FIG. 1 shows the time course of interscapular brown adipose tissue sympathetic nerve activity (BAT-SNA) in mice diluted 100-fold, 1000-fold and 10000-fold with 60% ethanol. FIG. 1 shows the brown adipose tissue sympathetic activity (BAT-SNA) data of Example 1, Control and Comparative Example 1 as 0 before duodenal administration (0 minutes), and the change value is defined as 0. It is a representation.

  In FIG. 1, in Example 1, BAT-SNA gradually increased, and the change value of BAT-SNA reached the maximum value + 15.37 60 minutes after administration. On the other hand, in the control, BAT-SNA hardly changed during the measurement period, and in Comparative Example 1, the change value of BAT-SNA became negative throughout the measurement period after administration, and BAT-SNA 60 minutes after administration. The change value of was the lowest value of -15.74.

  From the above experiments, it was revealed that 1 ml of an aqueous suspension containing Compound 1 at a concentration of 30 mg / ml was administered to the duodenum to increase BAT-SNA. On the other hand, it was revealed that when 1 ml of an aqueous suspension containing Compound 2 at a concentration of 30 mg / ml was administered to the duodenum, there was an action of suppressing sympathetic nerve activity. From the above, Compound 1 can regulate autonomic nerves, and by sympathetic nerve activation action, it prevents and / or ameliorates fatigue, especially waking up, and prevents and / or improves allergic symptoms such as dizziness, sneezing and runny nose. It was suggested that it has the effect of preventing and / or improving depressive symptoms and preventing and / or improving jet lag.

Hereinafter, formulation examples according to specific embodiments of the composition of the present invention are shown. However, the present invention is not limited to these formulation examples, and the present invention has various modes as long as the problems of the present invention can be solved. Can take.

(Formulation example 1: lotion)
Based on 100 parts by weight as a whole, 0.01 part by weight of 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one, 10 parts by weight of glycerol, 3 parts by weight of diglycerol, 1,3-butylene glycol 12 parts by mass, pentylene glycol 3 parts by mass, sodium hyaluronate 0.1 part by mass, citric acid 0.01 part by mass, sodium citrate 0.02 part by mass, xanthan gum 0.1 part by mass, Methylparaben 0.15 parts by mass, carbomer 0.2 parts by mass, sodium hydroxide 0.03 parts by mass and water balance were mixed to prepare the composition of the present invention in the form of a lotion.

(Formulation example 2: shampoo)
Based on 100 parts by mass as a whole, 0.01 part by mass of 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one, 7.5 parts by mass of sodium laureth sulfate, cocamide Propyl betaine 4.2 parts by mass, cocamide DEA 3 parts by mass, 1,3-butylene glycol 0.1 part by mass, polyquaternium-10 0.225 parts by mass, citric acid 0.15 parts by mass, sodium citrate 0.05 parts by mass The composition of the present invention was prepared in the form of a shampoo by mixing 0.9 parts by weight of phenoxyethanol and the remainder of water.

(Formulation example 3: soap)
Based on 100 parts by mass as a whole, 0.5 part by mass of 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one, 0.1 part by mass of elastin, 2 parts by mass of glycerin 1 part by weight of olive oil, 0.1 part by weight of EDTA-4 sodium, 0.2 part by weight of etidronate sodium and 0.2 part of soap base were mixed and solidified to prepare the composition of the present invention in the form of soap. .

(Formulation example 4: emulsion)
Based on 100 parts by mass as a whole, 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one 0.1 parts by mass, alanine 0.1 parts by mass, arginine 0.1 Parts by weight, sucrose fatty acid ester 3 parts by weight, glycerin 12 parts by weight, squalane 6 parts by weight, dimethyl silicone oil 24 parts by weight, polypropylene glycol 1 part by weight, thickener 0.06 parts by weight, phenoxyethanol 0.2 parts by weight, Ethanol 5 parts by mass, sodium hydroxide 0.01 part by mass and purified water remainder were mixed to prepare the composition of the present invention in the form of an emulsion.

(Formulation example 5: cosmetic cream)
Based on 100 parts by mass as a whole, 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one 0.005 parts by mass, squalane 15.0 parts by mass, octyldodecyl myristate 4.0 parts by mass, hydrogenated soybean phospholipid 0.2 parts by mass, butyl alcohol 2.4 parts by mass, hydrogenated oil 1.5 parts by mass, stearic acid 1.5 parts by mass, lipophilic glyceryl monostearate 5 parts by mass, polyglyceryl monostearate 0.5 parts by mass, behenyl alcohol 0.8 parts by mass, polyglyceryl monomyristicate 0.7 parts by mass, beeswax 0.3 parts by mass, d-δ-tocopherol 0.1 parts by mass, Methylparaben 0.3 part by mass, C10-30 alkyl-modified carboxyvinyl polymer 0.2 part by mass, carboxyvinyl polymer 0 1 part by weight, 18.0 parts by weight 1,3-butanediol, 0.1 parts by mass of sodium hydroxide and a mixture of purified water balance, the composition of the present invention was prepared in the manner of a cosmetic cream.

(Formulation Example 6: Packing agent)
100 parts by mass as a whole, 0.1 part by mass of 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one, 0.01 part by mass of gallic acid, polyvinyl alcohol 20 0.0 parts by weight, 5.0 parts by weight of glycerin, 20.0 parts by weight of ethanol, 6.0 parts by weight of kaolin, 0.2 parts by weight of preservatives, 0.1 part by weight of fragrance and the balance of purified water The composition of the present invention was prepared in the form of an agent.

(Formulation Example 7: Tablet 1)
100 parts by mass as a whole, 0.1 part by mass of 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one, 8 parts by mass of ginger extract, 5 parts of caffeine The composition of the present invention was prepared in the form of a tablet by mixing and tableting 20 parts by weight of crystalline cellulose, 50 parts by weight of lactose, 4 parts by weight of magnesium stearate and the remainder of corn starch.

(Formulation Example 8: Granules)
100 parts by mass as a whole, 0.5 part by mass of 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one, 10 parts by mass of lactose, 1 part by mass of calcium stearate and The composition of the present invention was prepared in the form of granules by mixing and granulating the crystalline cellulose remainder.

(Formulation example 9: capsule)
Based on 100 parts by weight as a whole, 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one 5 parts by weight, ginger extract 20 parts by weight, elastin 5 parts by weight, lecithin A composition prepared by mixing 8 parts by mass and the remainder of olive oil was used as a content liquid and encapsulated in a capsule shell to prepare a composition of the present invention in the form of a capsule.

(Formulation example 10: liquid agent)
Based on 100 parts by mass as a whole, 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one 0.005 parts by mass, arginine 1 part by mass, alanine 1 part by mass, fructose Glucose liquid sugar 10 parts, citric acid 1 part, sodium benzoate 0.02 part, flavor preparation 2 parts, sucralose 0.05 part, acesulfame potassium 0.03 part, and purified water remaining Thus, the composition of the present invention was prepared in the form of a solution.

  INDUSTRIAL APPLICABILITY The present invention can be used in the field of manufacturing foods and beverages such as functional display foods and supplements for the purpose of regulating autonomic nerves and pharmaceuticals.

Claims (2)

  An autonomic neuromodulator comprising 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one.   A sympathetic nerve activator comprising 2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran-4-one.