JP5380170B2 - Composition containing N-acyltryptamine - Google Patents

Description

  The present invention prevents or ameliorates a composition containing N-acyltryptamine, specifically, spots, pimples, wounds, burns, cracks, wrinkles, muscle pain, stiff shoulders, back pain, joint pain, bruise pain, hangover It is related with the composition for.

  As we are shifting to an aging society, raising the quality of life (QOL) of the elderly is an important social welfare issue. As the age increases, the skin fades, and in the aging skin, deep “stains” and hardened pimples are formed and appear on the face, hands, and body. Many kinds of “spots” for young people and cosmetics for breakouts are sold, but the elderly are not. With age, healing of wounds, burns, cracks, muscle pain, stiff shoulders, low back pain, joint pain, bruise pain, hangover, etc. has also slowed down. If the metabolic capacity of this weak body can be increased, the above-mentioned obstacles can be improved, the QOL of the elderly can be increased, and happiness can be felt physically and mentally.

  N-acyltryptamine has been reported for antidepressant / anti-stress action (Patent Document 1), erectile dysfunction treatment and hair growth / hair growth action (Patent Document 2), and melatonin antagonism (Patent Document 3). However, it is not known that N-acyltryptamine has an effect of preventing or improving stains, pimples, wounds, burns, hemorrhoids, muscle pain, stiff shoulders, back pain, joint pain, bruise pain, and hangover.

  N-acyltryptamine is a natural product whose isolated structure has been determined as a seed component of a plant belonging to the genus Annona (Non-Patent Document 1 and Non-Patent Document 2). These plants are cultivated in Central America, Egypt, India, and Southeast Asian countries, and the genus includes Annona reticulata, Annona cherimola, and Ylang-ylang (Cananga odorata). Cocoa (Theobroma cacao) also contains N-acyltryptamine derivatives. In addition to raw food, these fruits are processed into jams, mamalades, and ice cream.

  As compounds structurally similar to N-acyltryptamine, melatonin (N-acetyl-5-methoxytryptamine), a hormone secreted from the pineal gland of the brain, and serotonin (5-hydroxytryptamine), a monoamine neurotransmitter For example, with regard to melatonin, a protective action against skin aging (Patent Document 4) and an anti-wrinkle action (Patent Document 5) have been reported, respectively. For example, in Patent Document 3, N-acyltryptamine is reported. As reported for melatonin antagonism, the physiological activity differs greatly depending on the presence or absence of the methoxy group or hydroxyl group at the 5-position of tryptamine, and the physiological activity of N-acyltryptamine having no methoxy group at the 5-position from the action of melatonin Is difficult to predict.

  In addition, osteoporosis develops when the function of osteoblasts that make bones is weakened and the function of osteoclasts is strengthened, but melatonin has been reported to weaken the function of osteoblasts (Non-patent Document 3). ) If older people take melatonin, there is a risk that osteoporosis is likely to occur.

JP 2003-137780 A Japanese Patent No. 3964417 JP-A-4-173777 Japanese Patent Laid-Open No. 3-145419 JP 2001-348322 A

D. Chavez, L.A. Acevedo, R. Mata, J. Nat. Prod., 62, 1119-1122 (1999) U. Maeda, N. Hara, Y. Fujimoto, A. Srivastava, Y.K. Gupta, M. Sahai, Phytochemistry, 34, 1633-1635 (1993) N. Suzuki, M. Somei, K. Kitamura, R.J.Reiter, A. Hattori, J. Pineal Res., 44, 326-334 (2008)

  An object of the present invention is to provide a composition for preventing or improving highly safe spots, pimples, muscle pain, stiff shoulders, back pain, joint pain, bruise pain, wounds, burns, cracks, wrinkles, and hangovers.

The present inventors have found that N-acyltryptamine has an action of blocking the α ₂ receptor and dilating male organs and skin blood vessels, and has been granted a patent relating to the application to a drug for preventing erectile dysfunction and hair growth of the hair. Owned (Patent Document 2).

  A clinical trial was conducted to develop the patent, and a novel action of N-acyltryptamine was found. That is, these compounds increase the metabolic function of each tissue due to the vasodilatory effect, and the speed at which old skin cells are replaced with new cells is increased, resulting in spots on the face and arms and skin breakouts. , Will fall as dirt. As a result, it was found that it was effective in treating spots and breakouts. Furthermore, it was found that the ability to repair wounds, burns, wrinkles and cracks in the limbs was also promoted. The liver function was also promoted, the metabolism of fatigue substances and alcohol was accelerated, and it was also effective in treating muscle pain, stiff shoulders, low back pain, joint pain, bruise pain and hangover after exercise.

The gist of the present invention is as follows.
(1) The following formula (I):
(In the formula, R represents a saturated aliphatic hydrocarbon group having 2 to 29 carbon atoms.)
A composition for the prevention and / or improvement of stains and / or pimples containing N-acyltryptamine represented by the formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof.

(2) Muscle pain, stiff shoulders, low back pain, joint pain and / or bruise pain containing N-acyltryptamine represented by the above formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof. A composition for preventing and / or improving the above.
(3) Prevention and / or prevention of wounds, burns, cracks and / or wrinkles containing N-acyltryptamine represented by the above formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof. Composition for improvement.
(4) A composition for preventing and / or improving hangover containing the N-acyltryptamine represented by the formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof.
(5) R in said Formula (I) is a C6-C17 saturated aliphatic hydrocarbon group, The composition of any one of Claims 1-4.

  According to the present invention, it is possible to provide a composition for preventing or improving highly safe spots, pimples, muscle pain, stiff shoulders, back pain, joint pain, bruise pain, wounds, burns, cracks, wrinkles, and hangovers. The main object of the present invention is to provide a composition that enhances the quality of life (QOL) of the elderly, but it should be understood that the composition of the present invention can also be applied to young people.

FIG. 1 is a photograph showing the state of a stain on the affected area (outside the right arm) before applying the composition of the present invention. FIG. 2 is a photograph showing the state of the stain on the affected area (outside the right arm) after applying the composition of the present invention. FIG. 3 is a photograph showing the wound state of the affected area (portion close to the right arm wrist) immediately after being injured by the cat. FIG. 4 is a photograph showing the wound state of the affected part (right arm center) immediately after being injured by the cat. FIG. 5 is a photograph showing the state of the wound in the affected area (portion close to the right arm wrist) after applying the composition of the present invention. FIG. 6 is a photograph showing the state of the wound of the affected area (right arm center) after applying the composition of the present invention.

Examples of the saturated aliphatic hydrocarbon group having 2 to 29 carbon atoms represented by R in the formula (I) include an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl And a saturated aliphatic hydrocarbon group having _{2 to 29} carbon atoms such as a linear or branched C2-29-alkyl group such as icosyl group, henicosyl group, and docosyl group.

  The saturated aliphatic hydrocarbon group having 2 to 29 carbon atoms is preferably a saturated aliphatic hydrocarbon group having 6 to 17 carbon atoms. In particular, N-nonanoyltryptamine in which the saturated aliphatic hydrocarbon group having 2 to 29 carbon atoms represented by R in the formula (I) is an octyl group having 8 carbon atoms exhibits the strongest action and can be suitably implemented. .

  Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, pyrosulfuric acid, and metaphosphoric acid. Or a salt with an organic acid such as citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, sulfonic acid (for example, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid).

  The compound represented by the formula (I) is a known compound and can be prepared by synthesis or extraction from plants. For example, tryptamine and halides of various carboxylic acids are reacted, or tryptamine and various compounds It can be synthesized by reacting a carboxylic acid with a carboxylic acid activator (Patent Document 2, K. Yamada, Y. Tanaka, M. Somei, Heterocycles, 79, 635-645 (2009)).

  Further, a plant containing the compound represented by the formula (I), an Annona plant (for example, Annona reticulata, Annona cherimola, Annona squamosa), ylang ylang (Cananga odorata) or The seeds or fruits of cocoa (Theobroma cacao) can be extracted with water-containing ethanol and then purified by column chromatography according to the method described in Non-Patent Document 1, for example, to obtain a mixture of N-acyltryptamines. You may use this mixture as an active ingredient of the composition of this invention as it is.

Since the fruits of plants containing N-acyltryptamine as a natural product are eaten, their safety has been proven. In addition, the present inventors conducted a toxicity test on N-nonanoyltryptamine using male ddy mice, and had an LD ₅₀ of 80 mg / kg or more (K. Yamada, Y. Tanaka, M. Somei, Heterocycles, 79, 635-645 (2008)), and no abnormality was observed in the anatomical findings, and N-acyltryptamine was found to be a safe compound. Furthermore, in an experiment aimed at increasing the yield of goat cashmere hair in Inner Mongolia, N-nonanoyltryptamine was administered at a dose of 1.0 mg / 50 kg / day for two and a half years. It was found that there was no abnormality, a strong reproductive effect, and the cashmere hair was increased by 1.2 to 1.7 times by weight (M. Somei, Heterocycles, 75, 1021-1053 (2008)). From these results, the safety of N-acyltryptamine was confirmed.

  Since the composition of the present invention has high safety as described above, the composition of the present invention can be administered alone or mixed with other pharmaceuticals or any other pharmaceutical carrier, diluent, coating agent, etc., and administered in any dosage form. As an administration method, oral, parenteral, rectal, transdermal or any other administration route can be used. For oral administration, powders, tablets, granules, capsules, oral liquid preparations and the like can be exemplified, and for parenteral administration, injections, liquid preparations, ointments, creams, coatings, patches When suppositories, propellants and the like are administered rectally, suppositories, capsules and the like can be exemplified. Each of these preparation methods can follow a known method.

  Since the composition of the present invention is highly safe as described above, by blending it into various foods and drinks, stains, pimples, wounds, burns, limb cracks, muscle pain, stiff shoulders, back pain, joint pain It is possible to provide a composition having an effect of preventing / ameliorating bruising pain and hangover. For example, the composition includes chewing gum, chocolate, snacks and other sweets, juices, sports drinks, soft drinks, milk, fruit drinks, cocoa drinks, ice cream, yogurt, sprinkles, spices, health foods (for example, Foods for specified health use) and other foods.

  The content of N-acyltryptamine in the composition of the present invention is not limited because the optimal amount varies depending on the dosage form, but generally the content per formulation is 0.001 wt% to 10 wt%. It adjusts so that it may become weight%, Preferably 0.01-1 weight%.

  In the case of an adult, the dose of N-acyltryptamine is 0.001 to 10 mg, preferably 0.01 to 0.1 mg, per kg of body weight and once a day. This amount can be administered once a day or divided into several times.

  In order to illustrate the present invention specifically, preparation examples and examples are given below, but the present invention is not limited thereto.

(Preparation Example 1) Synthesis Method N-nonanoyltryptamine was synthesized according to the method of Somei et al. (K. Yamada, Y. Tanaka, M. Somei, Heterocycles, 79, 635-645 (2009)). And used in the examples.

(Preparation Example 2) Extraction method from plant The fruit of Indonesian Anemona squamosa was dried and crushed. To 50 g of this pulverized powder, 1 L of 80% ethanol aqueous solution was added and extracted by heating under reflux for 1 hour. After cooling, the extract was filtered to remove insolubles, and the solvent was distilled off under reduced pressure and dried to obtain 18.4 g of a crude extract of bancii fruit. The crude extract was purified by column chromatography according to the method of D. Chavez et al. (Non-patent Document 1) to obtain a mixture of N-acyltryptamines.

(Preparation example 3) Preparation of composition Powder: N-nonanoyltryptamine was mixed to 0.5% by weight using galactose or lactose as a diluent.
Solution: 4 g of N-nonanoyltryptamine was dissolved in 4 L of ethanol, and 1 L of purified water was added to prepare a 0.8% aqueous ethanol solution.
N-nonanoyltryptamine was mixed in a 7: 1.5: 1.5 mixture of cream: petrolatum, glycerin and potato starch so as to be 0.5% by weight.

  The composition of the present invention contains N-acyltryptamine as an essential component, but is generally used for foods, cosmetics, quasi-drugs, pharmaceuticals, etc., as long as the effects of the present invention are not impaired. Various ingredients such as glycyrrhetinic acid, hormones, vitamins, nonionic surfactants, cationic surfactants, anionic surfactants, semipolar surfactants, heat retention agents, thickeners, preservatives, antioxidants, A fragrance | flavor, a coloring agent, the extract of various plants, etc. can be mix | blended.

(Example 1) Treatment and treatment of "stain": 65 years old, healthy male.
Treatment location: Patient's home.
Treatment period: September 12 to October 31, 2007 (50 days).
Situation of the affected area: 3 black “stains” on the outside of the right arm that were naturally formed by aging.
Composition used: solution and cream of Preparation Example 3.
Treatment Method: The solution of Preparation Example 3 was applied to “Blots”, dried, and then rubbed with the cream of Preparation Example 3. Application and rubbing were performed twice a day every 12 hours.
Results: In a short period of 50 days, the three “stains” seen in FIG. 1 became thinner as shown in FIG. 2, and the lower one disappeared completely. As a result, the skin became clean.

(Example 2) Treatment and treatment of "stain" and hard "icicle pimple": 59 years old, healthy girl.
Treatment location: Patient's home.
Treatment period: October 1, 2007 to September 30, 2008 (one year).
Situation of affected area: Black large “stains” having a diameter of 3 cm on the right cheek and the left cheek were naturally formed by aging. In addition, a large number of “icicle-shaped breakouts” are generated on the neck and neck of both eyes.
Composition used: solution and cream of Preparation Example 3.
Treatment Method: The solution of Preparation Example 3 was applied to “stain” and “icicle pimple” on the neck. After the liquid dried, the cream of Preparation Example 3 was rubbed. Application and rubbing were performed twice a day every 12 hours.
Results: In one month, the number of “icicle-like breakouts” decreased and the color of “stains” became shallower. In 3 months, all of the breakout disappeared. The “stain” on the right cheek became thinner, but the “stain” on the left cheek was still dark. Half a year later, the “stain” on the right cheek became inconspicuous and the “stain” on the left cheek became thinner. One year later, there was almost no “stain” on the left cheek. The “stain” on the left cheek still remains, but has become very thin. As a result, the skin became clean.

(Example 3) Wound treatment patient: 65 years old, healthy male.
Treatment location: Patient's home.
Treatment period: August 19, 2007 (injured) to August 26.
Injury situation: A playful domestic cat was violently pulled by his right arm and injured numerous wounds.
Therapeutic drug: Cream of Preparation Example 3.
Treatment method: The cream of Preparation Example 3 was applied immediately after injury. Thereafter, it was applied every 12 hours.
Results: Immediately after being injured, bleeding and pain cease (Fig. 3 (portion near the right arm wrist), Fig. 4 (central portion of the right arm)). One day later, the wound did not have the blood clotting “scab” normally seen, but instead a thin film was formed to close the wound. With the scab, when I took a bath and washed it, the wound opened, but the wound did not open and I could wash it. The repair speed was fast and it was completely cured in one week (FIG. 5 (portion close to the right arm wrist), FIG. 6 (center portion of the right arm)).

(Example 4) Treatment patient for cracking of fingers: 60 years old, healthy housewife.
Treatment location: Patient's home.
Treatment period: December 20, 2008 to January 31.
Injury situation: In addition to handling water for cooking and washing in winter, the tip of the thumb, forefinger, and middle finger dried out due to exposure to cold winds, resulting in large cracks. He was unable to sew with bleeding and pain.
Therapeutic drug: Cream of Preparation Example 3.
Treatment method: The cream of Preparation Example 3 was rubbed into the affected area after washing, after cooking, and before going to bed.
Result: The cream was rubbed, and after 30 minutes, the pain stopped and the bulky skin became soft. One day later, the wound started to close. Even after working, it wasn't painful enough. The repair speed was fast, and it was almost completely cured after about 40 days.

(Example 5) Tempura burn treatment patient: 58 years old, healthy housewife.
Treatment location: Patient's home.
Treatment period: May 2, 2008 (injury) to May 10th.
Injury situation: When fried tempura, the oil suddenly splashed and burned the face. Immediately cooled with water, but started to burn.
Therapeutic drug: Solution of Preparation Example 3.
Treatment method: The solution of Preparation Example 3 was applied to the affected area immediately after injury. The pain was tight. Thereafter, it was applied every 12 hours.
Result: After application, the severe pain gradually subsided, and I was able to go to bed normally. One day later, the swelling also ceased and the wound from the blister was closed. The repair speed was fast, and it was almost completely cured in 9 days.

(Example 6) Acupuncture treatment patient: a 64-year-old healthy boy.
Treatment location: Patient's home.
Treatment period: December 9, 2006 to June 8, 2007 (half year).
Situation: Over the years, it became severe. At the time of defecation, with the pain, blood was blown out and the suffering that could not be said to humans was endured.
Therapeutic drug: Cream of Preparation Example 3.
Treatment method: Rubbed into the affected area twice a day every 12 hours.
Result: The pain I felt in my daily life eased after 1 hour. Three days later, the affected skin became soft and the wound was closed. After one month, there was almost no bleeding or pain during defecation. Three months later, the more I forgot that I was addicted, the less I was bothered.

(Example 7) Muscular pain, stiff shoulders, low back pain, joint pain, and bruise pain treatment patient: 63 years old, healthy male.
Treatment location: Patient's home.
Treatment period: November 3 to November 5, 2005 (3 days).
Situation: Throwing about 100 balls as a pitcher in a baseball game in the morning. The ball hit and the left foot was bruised. Muscle pain, stiff shoulders, low back pain, joint pain and bruise started to appear around 12:00 immediately after the game, and the knees laughed with pain and dullness, and freedom of the body was lost.
Therapeutic drugs: powders and solutions as described in the composition preparation column.
Treatment method: The powder of Preparation Example 3 was taken twice a day, equivalent to 1 mg of N-nonanoyltryptamine, every 12 hours. In addition, the liquid preparation of Preparation Example 3 was applied to myalgia, stiff shoulders, low back pain, joint pain and bruised area 3 times a day every 8 hours.
Results: Two hours after taking and application, muscle pain, stiff shoulders, low back pain, joint pain and bruise pain were severe, but the freedom of limbs began to come and I was able to walk. The dullness disappeared in the evening after 5 hours. The next day, at 12 o'clock, my sore muscles, stiff shoulders, low back pain and joint pain were the same as when I was young. Over time, he felt that my sore muscles, stiff shoulders, low back pain, joint pain and bruise disappeared. On the next day, almost all my sore muscles, stiff shoulders, low back pain, joint pain and bruise were resolved and I returned to my normal life.
After that, by taking the above-mentioned powder one hour before starting sports and muscular work, I almost felt no muscle pain, stiff shoulders, low back pain, joint pain, and dullness after work.

(Example 8) Treatment and treatment for hangover: Two healthy boys, 36 and 40 years old.
Treatment location: China Gobi desert tree planting travel destination.
Treatment period: May 15, 2009.
Situation: At the welcome party the night before in Beijing, he went down with a toast of white liquor (alcohol concentration, 55%). The next morning, the complexion was pale, the eyes were gloomy, they felt uncomfortable and had no appetite. I was awakened by force because it would be a hindrance to the group travel plan.
Therapeutic drug: Powder of Preparation Example 3.
Treatment method: The above-mentioned powder equivalent to 1 mg of N-nonanoyltryptamine was taken once.
Result: Both of them followed the same process. One hour after taking it, my feelings of sensation lightened and I was motivated to board the plane. I slept on board for about two hours. The color of the face improved over time, and she seemed to sleep comfortably. When they arrived at the destination airfield 3 hours after taking them, both of them recovered. There was no problem in moving the car for 2 hours, which gradually recovered as time passed and was shaken violently up and down. Five hours after taking it, when the appetite revived and he became hungry, he took a meal and was able to participate in the hard work of planting trees in the desert.

Claims (3)

Formula (I):


(In the formula, R is heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, heicosyl) And a saturated aliphatic hydrocarbon group selected from docosyl groups .)
A composition for the prevention and / or improvement of stains and / or pimples containing N-acyltryptamine represented by the formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof. In the formula (I), R is a saturated aliphatic hydrocarbon group selected from a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, and a heptadecyl group. A composition according to claim 1. The composition according to claim 1, wherein R in the formula (I) is an octyl group.