JP5444618B2 - Human adrenergic β3 receptor agonist, food and medicine containing the same - Google Patents

Description

The present invention relates to a human adrenergic β ₃ receptor agonist, a food containing the same, and a pharmaceutical product.

  Adrenergic receptors are receptors that bind to catecholamine agonists such as adrenaline and noradrenaline released from sympathetic nerves, and are classified into two types, α receptors and β receptors, depending on the sensitivity to catecholamine agonists. The adrenergic α receptor is sensitive in the order of noradrenaline ≧ adrenaline> dopamine> isoproterenol, and the adrenergic β receptor is sensitive in the order of isoproterenol> adrenaline ≧ noradrenaline> dopamine.

Adrenaline β receptors include β ₁ , β ₂ , and β ₃ receptors, and the presence of β ₄ receptors has recently been suggested. As an agonist (agonist) action for each receptor, an adrenergic β ₁ receptor agonist increases heart rate, an adrenergic β ₂ receptor agonist relaxes bronchial smooth muscle, and an adrenergic β ₃ receptor agonist generates heat. It is known that it has an action of accelerating and promoting lipolysis. Therefore, those that activate sympathetic nerves to promote the secretion of catecholamine agonists, or non-selective adrenergic β receptor agonists are worried about side effects due to β ₁ and β ₂ action, and lifestyle habits such as obesity Not suitable for disease prevention and / or improvement. Therefore, an adrenergic β ₃ receptor agonist is effective in preventing and / or improving lifestyle-related diseases such as obesity.

An adrenergic β ₃ receptor agonist was first discovered in 1984, and in animal experiments, anti-obesity action and anti-diabetic action by heat production and lipolysis were recognized. However, these effects were weak in humans. The cause of this effect difference was 1989, and it became clear that there was a species difference in the chemical structure of rodents such as mice and rats and human adrenergic β ₃ receptors (Non-patent Documents 1 and 2). . From these facts, human adrenergic β ₃ receptor agonists are effective in preventing and / or improving lifestyle-related diseases such as obesity and diabetes, and their development is desired.

Recently, several compounds are known as human adrenergic β ₃ receptor agonists (Non-patent Document 1), and their effects as anti-obesity drugs or anti-diabetic drugs have been confirmed in clinical trials. In addition, a human β ₃ adrenergic receptor agonist agent containing yam extract as an active ingredient has also been reported (Patent Document 1).

  On the other hand, chitosan-containing polysaccharides produced from agaricus, shiitake mushrooms, enokitake mushrooms, shimeji mushrooms, maiko, namoko, etc. have a lowering effect on blood pressure, urine sugar level, blood glucose level, uric acid level, total cholesterol level, neutral fat level, etc. It has been reported that it has a great effect on improving test values of lifestyle-related diseases such as hypertension and diabetes and adult diseases (Patent Document 2).

JP 2006-96666 A WO2004 / 033502 Yasutaka Takakura, Toshihide Yoshida, Japanese Pharmacology Journal, 118, 315-320, 2001 C. Weyer, et al., Diabetes & Metabolism, 25, 11-21, 1999

An object of the present invention is to provide a human adrenergic β ₃ receptor agonist agent.
Another object of the present invention is to provide foods and pharmaceuticals containing the above human adrenergic β ₃ receptor agonist.
Still another object of the present invention is to provide a preventive and / or ameliorating agent for lifestyle-related diseases such as obesity, obesity, diabetes, hyperlipidemia, hypertension and gout, which contains a human adrenergic β ₃ receptor agonist. It is to be.

As a result of various investigations to achieve the above object, the present inventor has found that the hydrophilic solvent extract of persimmon has a high binding activity to human adrenergic β ₃ receptor, and the main component thereof is an incystol compound. As a result, the present invention has been completed.
The present invention provides human adrenergic β ₃ receptor agonists comprising the following specific insystemol compounds as active ingredients, foods and pharmaceuticals containing the same.

式中、Ｒ¹は、水素原子、ＯＲ²又はＮＲ⁴Ｒ⁵を示し、Ｒ²は、水素原子、炭素数１〜１０のアルキル、ＣＯＲ³、又はＮＲ⁴Ｒ⁵を示し、Ｒ³は水素原子、炭素数１〜１０のアルキルを示し、Ｒ⁴及びＲ⁵は同一でも異なっていても良く、炭素数１〜１０のアルキルを示し、ＸはＯ、ＮＨ又はＳを示す。
２．下記の式（１’）又は（２’）で表される化合物、又はその薬学的に許容される塩を有効成分とするヒトアドレナリンβ₃受容体アゴニスト剤。

式中、ＸはＯ、ＮＨ又はＳを示す。
３．下記の式（１”）で表される化合物、又はその薬学的に許容される塩を有効成分とするヒトアドレナリンβ₃受容体アゴニスト剤。

式中、Ｒ⁶は、ＯＲ⁷、ＮＲ⁸Ｒ⁹を示し、Ｒ⁷は水素原子、炭素数１〜１０のアルキルを示し、Ｒ⁸及びＲ⁹は同一でも異なっていても良く、炭素数１〜１０のアルキルを示す。
４．茸の親水性溶媒抽出物を有効成分とするヒトアドレナリンβ₃受容体アゴニスト剤。
５．親水性溶媒が、メチルアルコール、エチルアルコール、アセトン、又は非親水性溶媒が、酢酸エチル、クロロホルム及びこれらの２種以上の混合物からなる群から選ばれる上記４記載のヒトアドレナリンβ₃受容体アゴニスト剤。
６．茸が、アガリクス、椎茸、エノキタケ、しめじ、舞茸、なめこ、ヒラタケ、クリタケからなる群から選ばれる少なくとも１種である上記４又は５記載のヒトアドレナリンβ₃受容体アゴニスト剤。
７．上記１〜６のいずれか1項記載のヒトアドレナリンβ₃受容体アゴニスト剤を含有する食品。
８．上記１〜６のいずれか1項記載のヒトアドレナリンβ₃受容体アゴニスト剤を含有する医薬品。 1. A human adrenergic β ₃ receptor agonist comprising a compound represented by the following formula (1) or (2) or a pharmaceutically acceptable salt thereof as an active ingredient.

In the formula, R ¹ represents a hydrogen atom, OR ² or NR ⁴ R ⁵ , R ² represents a hydrogen atom, alkyl having 1 to 10 carbon atoms, COR ³ or NR ⁴ R ⁵ , and R ³ represents hydrogen An atom, an alkyl having 1 to 10 carbon atoms, R ⁴ and R ⁵ may be the same or different and each represents an alkyl having 1 to 10 carbon atoms, and X represents O, NH or S;
2. A human adrenergic β ₃ receptor agonist comprising a compound represented by the following formula (1 ′) or (2 ′) or a pharmaceutically acceptable salt thereof as an active ingredient.

In the formula, X represents O, NH or S.
3. A human adrenergic β ₃ receptor agonist comprising a compound represented by the following formula (1 ″) or a pharmaceutically acceptable salt thereof as an active ingredient.

In the formula, R ⁶ represents OR ⁷ , NR ⁸ R ⁹ , R ⁷ represents a hydrogen atom or an alkyl having 1 to 10 carbon atoms, R ⁸ and R ⁹ may be the same or different, and have 1 carbon atom. -10 alkyl.
4). A human adrenergic β ₃ receptor agonist containing a hydrophilic solvent extract of salmon as an active ingredient.
5. 5. The human adrenergic β ₃ receptor agonist agent according to 4 above, wherein the hydrophilic solvent is methyl alcohol, ethyl alcohol, acetone, or the non-hydrophilic solvent is selected from the group consisting of ethyl acetate, chloroform and a mixture of two or more thereof. .
6). Mushrooms, Agaricus, Lentinus edodes, Flammulina velutipes, mushrooms, maitake, nameko mushroom, Pleurotus ostreatus, human adrenergic beta ₃ receptor agonist agent of 4 or 5, wherein at least one selected from the group consisting of hypholoma lateritium.
7). A food containing the human adrenergic β ₃ receptor agonist according to any one of 1 to 6 above.
8). 7. A pharmaceutical comprising the human adrenergic β ₃ receptor agonist according to any one of 1 to 6 above.

The human adrenergic β ₃ receptor agonist of the present invention has high binding activity to human adrenergic β ₃ receptor, such as blood pressure, urine sugar level, blood glucose level, uric acid level, total cholesterol level, neutral fat level, visceral fat level, etc. It is effective for the prevention and / or treatment of lifestyle-related diseases such as hypertension, diabetes, obesity, hypercholesterolemia, and hyperlipidemia. Moreover, the active ingredient of the present invention has low cytotoxicity and can be safely used as a food or a pharmaceutical product.

  The compound represented by the formula (1), which is an active ingredient of the present invention, is a cocoon, that is, a fruit body or mycelium of basidiomycetous shiitake mushroom, enoki, mushroom, maitake, agaricus blazei, nameko, eringgi, shimeji, etc. Obtained by extraction with a hydrophilic solvent such as water, alcohols such as methyl alcohol, ethyl alcohol, propanol and butanol, ketones such as acetone and methyl ethyl ketone, or non-hydrophilic solvents such as ethyl acetate and chloroform, and purification. . As the extraction solvent, ethyl alcohol and acetone are particularly preferable. Further, plant chitosan produced according to the method for producing plant chitosan described in JP-A-2005-29770 is treated with a hydrophilic solvent, for example, water, alcohol such as methyl alcohol, ethyl alcohol, propanol, butanol, ketone such as acetone, methyl ethyl ketone, etc. Alternatively, it can be obtained by extraction with a non-hydrophilic solvent such as ethyl acetate or chloroform and purification. As the extraction solvent, ethyl alcohol and acetone are particularly preferable.

Extraction conditions can be selected as appropriate. When ethyl alcohol or acetone is used, 300 to 1000 parts by mass of a solvent is added to 100 parts by mass (dry mass) of basidiomycetes and extracted at 50 to 80 ° C for about 1 to 5 hours. It is appropriate to do. When plant chitosan produced according to the method described in JP-A-2005-29770 is used as a raw material, 300 to 1000 parts by mass of a solvent is added to 100 parts by mass (dry mass) of plant chitosan, and 1 to 50 to 80 ° C. It is appropriate to extract for about 24 hours.
Plant chitosan finally immerses basidiomycetes in 40% to 60% alkaline solution by adding a concentrated alkaline solution to basidiomycetes or adding solid alkali and water, and the liquid temperature is 60 ° C to 120 ° C. Heat for 1 to 24 hours. The heating container is preferably made of stainless steel that can withstand high temperature and high concentration alkali.

  As the basidiomycetes used as raw materials, most edible basidiomycetes such as enoki, shiitake mushrooms, shimeji mushrooms, mushrooms, agaricus brazei, maitake, eringi, and sea cucumber can be used. These basidiomycetes can be used as either dried products or fresh products. After the high-concentration alkali heat treatment is completed, the alkali solution is lightly removed by scooping it into a coarse stainless steel net, and the alkali is removed as much as possible by applying pressure from the top. The weight of the basidiomycete treated with alkali is measured, and the contained alkali concentration is calculated. A 10 to 80% organic acid solution or weak acid solution or solid is added to this so as to be equivalent to the calculated alkali, and neutralized so as to be in the range of pH 9 to pH 6.5. For example, when citric acid is used, 1/3 molar equivalent is added because citric acid is a trivalent acid. Since acetic acid is a monovalent acid, it is added in an equimolar amount with alkali.

  As the acid used for neutralization, an organic acid such as acetic acid, lactic acid, citric acid, malic acid, ascorbic acid, or a weak acid such as carbon dioxide is used. The high-concentration alkaline heat-treated basidiomycetes thus neutralized contain the desired plant chitosan, but possess an appropriate structural strength and have extremely low viscosity. The washing process becomes very easy.

  Basidiomycetes containing plant chitosan are collected by filtration and washed several times with pure water. The obtained plant chitosan is easily dried with warm air to obtain the final product plant chitosan powder. As described above, this production method is characterized in that the plant chitosan can be easily dealkalized and recovered with high reproducibility and high yield. In addition, plant chitosan can be produced at low cost because it does not use a high-speed and large-capacity centrifuge or an expensive organic solvent such as alcohol.

  As the alkali for deacetylation, NaOH (caustic soda), KOH (caustic potash) or the like is used. The alkalis may be solid or solution, but those that enable 50% of the final concentration are preferred. The alkali heating reaction is preferably 80 ° C. or more and 4 hours or more. Under these conditions, deacetylation proceeds smoothly, and thus plant chitosan can be produced with high reproducibility and high yield. The degree of deacetylation of the chitin can be freely adjusted by changing the alkali concentration, the heat treatment time, and the heat treatment temperature.

  As the solvent for washing, a hydrophilic organic solvent such as ethanol, acetone, isopropanol, propanol, butanol or the like can be used in addition to distilled water, ion exchange water, and pure water. It is possible to use tap water or groundwater for the first water washing after neutralization, but use water with a purity of at least ion-exchanged water, considering that chitosan is likely to adsorb metal ions. It is preferable.

  Drying with hot air at 80 ° C. to 105 ° C. is sufficient, but drying at about 50 ° C. under reduced pressure or freeze drying is also possible. In order to obtain fine particles as much as possible by pulverization, lyophilization is preferred. In addition, you may use ethanol, acetone, ether, etc. for a drying process like a normal saccharide polymer compound. Drying at a high temperature makes it difficult to pulverize, so drying at a low temperature is preferable. Or a drying process can be abbreviate | omitted and a water-containing vegetable chitosan can also be grind | pulverized as it is. For example, immediately after washing with water, the mixture may be pulverized with a mixer and, if necessary, a vegetable chitosan solution mixed with a carrier such as dextrin or β-glucan may be spray-dried. As other pulverization methods, a pulverizer such as a jet mill and a polishing apparatus such as a stone mill can be used.

The crude extract obtained by the above extraction is fractionated using a purification means such as column chromatography, and the purification operation is repeated using the adrenaline β ₃ receptor binding activity of the fraction as an index, whereby adrenaline β ₃ receptor is obtained. A fraction with high body binding activity can be obtained. For example, HEK-293 cells expressing human recombinant adrenergic β ₃ receptor are used for adrenaline β ₃ receptor binding activity, and Cell Biology: Feve et al, Proc. Natl. Acad. Sci. USA 91 (1994). , Vol.91, pp.5677-5681. That is, a 1% DMSO solution of a sample and 0.5 nM [ ¹²⁵ I] cyanopindolol were added to Tris buffer (pH 7.4), HEK-293 cells were cultured at 25 ° C. for 90 minutes, filtered, This can be done by washing and measuring the radioactivity of the adrenergic β ₃ receptor binding ligand.
The compound thus finally purified is a compound in which X is O in the formula (1 ′).
In the formula (1), a compound in which X is O and R ¹ is OH has a structural isomer of the following formula (1 ″). The active ingredient of the present invention is such a structural isomer, its pharmaceutical (For example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts, amine salts and ammonium salts), amides and esters (for example, alkyl esters having 1 to 10 carbon atoms) are also included. .

式中、Ｒ⁶は、ＯＲ⁷、ＮＲ⁸Ｒ⁹を示し、Ｒ⁷は水素原子、炭素数１〜１０のアルキルを示し、Ｒ⁸及びＲ⁹は同一でも異なっていても良く、炭素数１〜１０のアルキルを示す。

In the formula, R ⁶ represents OR ⁷ , NR ⁸ R ⁹ , R ⁷ represents a hydrogen atom or an alkyl having 1 to 10 carbon atoms, R ⁸ and R ⁹ may be the same or different, and have 1 carbon atom. -10 alkyl.

The adrenergic β ₃ receptor agonist agent of the present invention comprises a compound represented by the formula (1) or (2) as an active ingredient, and is a fraction having an adrenergic β ₃ receptor binding activity obtained in the purification step. It goes without saying that can be used as an active ingredient of the adrenergic β ₃ receptor agonist of the present invention.

The adrenergic β ₃ receptor agonist of the present invention can be used only with an active ingredient, but can also be used in a form to which an excipient or the like is added.
For example, in order to use the agonist agent of the present invention in the form of a liquid agent, the active ingredient includes a preservative such as sodium benzoate, methyl p-oxybenzoate, sodium dehydroacetate, malic acid, ascorbic acid, citric acid, Add solubilizing agents such as acetic acid, colorants, flavors, flavoring agents, sweeteners such as glucose and mannitol as necessary, and add diluents such as distilled water and physiological saline as necessary. Prepare pharmaceuticals or foods.

Pharmaceuticals containing the above ingredients as active ingredients are usually prepared in the form of solid preparations such as tablets, pills, powders, granules, capsules and suppositories. At that time, these pharmaceutical preparations are prepared using diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used. .
In forming into tablets, conventionally known carriers can be widely used as carriers, such as lactose, mannitol, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients, Distilled water, physiological saline, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, lauryl Disintegrants such as sodium sulfate, stearic acid monoglyceride, starch, lactose, disintegrators such as sucrose, stearin, cocoa butter, hydrogenated oil, dissolution absorption accelerators such as acetic acid, ascorbic acid, malic acid, glycerin, starch, lactose , Kaolin, bentonite, colloid Adsorbent such as Jo silicate, purified talc, stearates, such as lubricants such as polyethylene glycol. Furthermore, the tablet can be a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet as necessary.

In molding into a pill form, conventionally known carriers can be widely used as carriers, such as glucose, lactose, mannitol, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic Powders, disintegrating agents such as gelatin are listed. In molding into a suppository, a conventionally known carrier can be widely used as the carrier, and examples thereof include cocoa butter, higher alcohol esters, and gelatin.
The content of the active ingredient is not particularly limited and is selected within a wide range, but is usually 0.001 to 30% by mass, preferably 0.01 to 10% by mass in the preparation as the compound of the formula (1) or (2) It is good to let them.
The dose is not particularly limited, and may be appropriately selected depending on the usage, patient age, sex, disease degree, and other conditions. For example, the compound of formula (1) or (2) is orally administered in an amount of 0.01 to 20 mg, preferably 0.02 to 10 mg per 1 kg body weight, divided into 1 to 4 times a day.
Although the foodstuff containing the active ingredient of this invention is not specifically limited, For example, soup, miso soup, drink, jelly, gummy, etc. are mentioned. The content of the active ingredient in these foods is preferably 0.001 to 30% by mass, more preferably 0.01 to 10% by mass.

Hereinafter, the present invention will be described in more detail with reference to examples.
Example 1
Separation and purification of adrenaline β ₃ receptor binding active substance (CHG-EW-4-1-4-P) from mushroom chitosan 308.7 g of mushroom chitosan produced by the method described in Example 1 of JP-A-2005-29770 2 L of ethanol was added and the mixture was allowed to stand overnight, and then subjected to ultrasonic waves for 20 minutes and filtered. The filtrate was concentrated under reduced pressure to obtain 8.6 g of ethanol extract. Next, mushroom chitosan as an ethanol extraction residue was immersed in 2 L of 50% acetone for 4 days, and then vortexed by applying ultrasonic waves for 20 minutes. The filtrate was concentrated under reduced pressure to obtain 8.7 g of 50% acetone extract. When these ethanol extracts and 50% acetone extract were subjected to an adrenergic β ₃ receptor binding activity test, 41% and 45% activities were found to be almost the same at a concentration of 10 μg / mL.

Therefore, they were combined and subjected to reverse phase HP-20 column chromatography, and H ₂ O (1.5 L), 40% MeOH (1.5 L), 70% MeOH (2 L), MeOH (5 L) and acetone (3 L ) Were sequentially eluted. Concentrate each eluate under reduced pressure, H ₂ O elution fraction (CHG-EW-1, 2.1 g), 40% MeOH elution fraction (CHG-EW-2, 0.8 g), 70% MeOH elution fraction (CHG-EW-3, 0.6 g), MeOH elution fraction (CHG-EW-4, 8.2 g), and acetone elution fraction (CHG-EW-5, 1.2 g) were obtained. When these fractions were tested for β ₃ receptor binding activity, high activity (52%, 10 μg / mL) was observed in CHG-EW-4.
Therefore, this fraction was subjected to silica gel column chromatography, and n-hexane: ethyl acetate = 4: 1 (3 L), 2: 1 (3.9 L), 1: 1 (3.8 L), ethyl acetate (3 L), eluting sequentially with MeOH (3 L), CHG-EW-4-1 (2.3 g), CHG-EW-4-2 (1.0 g), CHG-EW-4-3 (0.9 g), Five fractions of CHG-EW-4-4 (0.4 g) and CHG-EW-4-5 (3.9 g) were obtained. In the β ₃ receptor binding activity test of these fractions, CHG-EW-4-1 showed the highest activity (71% at 10 μg / mL).
Therefore, CHG-EW-4-1 (500 mg) was separated and purified by reversed-phase HPLC (column: Kaseisorb, ODS PH super, 20 x 250 mm, eluent: 95% MeOH, flow rate 6.0 mL / min). , 11 fractions. [CHG-EW-4-1-1 (5.3 mg), 2 & 3 (20.1 mg), 4 (6.0 mg), 5 (20.1 mg), 6 (191.2 mg), 7 (78.2 mg), 8 (99.5 mg) , 9 (21.2 mg), 10 (12.2 mg), 11 (8.4 mg)]
As a result of conducting an activity test on these fractions, an activity (inhibition rate) of 50% or more was observed in the fractions 2 & 3, 4, 6, 8, and 9. Of these, CHG-EW-4-1-4 was further analyzed by HPLC (column: Kaseisorb, ODS PH super, 10 x 250 mm, eluent: 90% MeOH, flow rate 2.0 mL / min, Rt: 23.7 min). After purification, the active substance (CHG-EW-4-1-4-P) was isolated. The results of the activity test are shown in Table 1.

The physicochemical data of the purified active substance (CHG-EW-4-1-4-P) are as follows.
CHG-EW-4-1-4-P
HR-FAB-MS: m / z 333.2429 (M + 1) ⁺ , 332.2430 (calcd for C ₂₁ H ₃₂ O ₃ ).
¹ H-NMR (500 MHz, CDCl ₃ , δ): 0.61 (3H, s), 0.83 (3H, d, J = 6.9 Hz), 0.84 (3H, d, J = 6.9 Hz), 0.92 (3H, d , J = 6.9 Hz), 1.04 (3H, d, J = 6.6 Hz), 1.45-1.56 (4H, m), 1.62 (1H, ddd, J = 13.4, 13.4, 4.3 Hz), 1.70-1.75 (1H, m), 1.84-1.92 (3H, m), 1.98 (1H, ddd, J = 13.4, 4.6, 2.3Hz), 2.06 (1H, bdt, J = 15.4, 6.6 Hz), 2.28 (1H, ddd, J = 14.3, 4.0, 2.3Hz), 2.63-2.67 (1H, m), 5.17 (1H, dd, J = 15.2, 7.7 Hz), 5.26 (1H, dd, J = 15.2, 8.3 Hz), 5.62 (1H, d , J = 1.8 Hz),
¹³ C-NMR (125 MHz, CDCl ₃ , δ): 11.8 (CH ₃ ), 17.6 (CH ₃ ), 19.7 (CH ₃ ), 20.0 (CH ₃ ), 21.0 (CH ₃ ), 21.4 (CH ₂ ), 28.8 (CH ₂ ), 33.1 (CH ₂ ), 35.1 (CH ₂ ), 35.3 (CH ₂ ), 40.1 (CH), 42.9 (CH), 48.9 (C), 50.4 (CH), 55.4 (CH), 104.8 (C), 112.3 (CH), 132.9 (CH), 134.7 (CH), 170.6 (C), 170.9 (C).
From the above data, the substance is 4-hydroxy-17-methylincystolol (9α-hydroxy-1,2,3,4,5,10,19-heptanol ergostera wherein X is O in formula (1 ′). -7,22-diene-6,9-lactone: 9α-hydroxy-1,2,3,4,5,10,19-heptanol-ergosta-7,22-diene-6,9-lactone) It was confirmed.

Formulation Example 1 (tablet)
10 g of malic acid and 10 g of ascorbic acid are added to 10 g of the active substance (CHG-EW-4-1-4-P) produced in Example 1, dissolved in 1000 ml of water, and lyophilized to produce water-soluble chitosan. did. This has the property of instantly dissolving in pure water. To 10 g of this lyophilized product, 20 g of mannitol, 50 g of lactose and 20 g of polydextrose were added and mixed well, and 2 g of sucrose fatty acid ester was added as a binder to form a tablet.

Formulation Example 2 (granule)
After 1 g of the active substance (CHG-EW-4-1-4-P) produced in Example 1 was sufficiently dispersed in 100 g of dextrin, this was mixed with 900 g of dextrin, and granules were prepared by fluidized bed granulation. .

Formulation Example 3 (Jelly)
10 g of ascorbic acid is added to 1 g of the active substance (CHG-EW-4-1-4-P) produced in Example 1 and dispersed and dissolved in 500 g of liquid sugar. 1 g and 500 ml of water were added, filled into a plastic container, and cooled to make a jelly.

Claims (2)

A human adrenergic β ₃ receptor agonist comprising a compound represented by the following formula (1 ′) or a pharmaceutically acceptable salt thereof as an active ingredient.

In the formula, X represents O. A pharmaceutical product for preventing and / or treating a lifestyle-related disease selected from hypertension, diabetes, obesity, hypercholesterolemia, and hyperlipidemia, comprising the human adrenergic β ₃ receptor agonist according to claim 1 .