JP2007262050A - Adiponectin production promotor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new pharmaceutical with high safety and a high adiponectin production promoting effect. <P>SOLUTION: The pharmaceutical reinforcing or promoting adiponectin production in animal fat cell is obtained by formulating a phenolic compound represented by general formula (1) and an 8-22C unsaturated fatty acid or its glyceride or lower alkyl ester as active ingredients. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a drug that enhances or promotes adiponectin production, which is useful in pharmaceuticals and health foods.

  Recently, lifestyle-related diseases such as type 2 diabetes have rapidly increased in Japan and have become social problems. By the way, many of these lifestyle-related diseases are closely related to a deficiency of a hormone called adiponectin, and it has been medically shown that it can be improved by increasing this (Non-patent Document 1). Adiponectin is mainly produced by adipocytes in adipose tissue, and adipocytes are generated by differentiation from mesoderm-derived preadipocytes under the influence of various hormones. Accordingly, a preadipocyte differentiation inducer and a mature adipocyte adiponectin production promoter are effective in maintaining and improving blood adiponectin levels in the living body. Such drugs include synthetic thiazolidinediones such as pioglitazone (Patent Document 1, Non-Patent Document 2). However, since this drug has strong side effects, it cannot be easily used for prevention or mild treatment. In addition, sarpogrelate (Patent Document 2), pravastatin derivatives (Patent Documents 3 and 4), kinase inhibitor IMD-0354 (Non-Patent Document 3) and the like have an adiponectin production promoting action, but have the same problems. On the other hand, fermented tea (Patent Document 5), ergosterol, oryzanol ester (Patent Document 6), soybean protein (Non-Patent Document 4), anthocyanin (Non-Patent Document 5), pyrimidine nucleoside derivatives (Non-Patent Document) Document 6), conjugated linoleic acid (Non-patent Document 7) and the like are known to have an adiponectin production enhancing action, but are not sufficiently strong compared to pioglitazone and the like.

Recently, the present inventors have confirmed that curcumin and gingerol contained in ginger plant rhizomes, ferulic acid derivatives such as N-feruloyltryptamine and β-phenethylferrate having similar partial structures, and homovanillic acid and vanillic acid amides. And esters, capsaicin and vanillylamine 3-phenyl-2-propenamide promoted and enhanced adiponectin production in cultured adipocytes, and were found to be effective in hypoglycemia in experiments using type 2 diabetes model mice (Patent Documents 7 and 8, Japanese Patent Application No. 2004-201827, Japanese Patent Application No. 2004-345134, Japanese Patent Application No. 2005-61659, Japanese Patent Application No. 2005-194160, Japanese Patent Application No. 2005-218519). This activity is most prominent in a compound having a structure in which a 4-hydroxy-3-methoxyphenyl nucleus and another aromatic nucleus are linked by a linear amide or ester having 4 to 6 atoms. However, not only that, but with a single aromatic nucleus such as 4-hydroxy-3-methoxybenzoic acid n-butyl ester, or with a phenolic hydroxyl group such as N- (3-phenylpropyl) -4-hydroxybenzamide. Even when it lacks an adjacent methoxy group, the activity is weak. Therefore, the compound having the activity is summarized as general formula 1. It has not been known so far that the compounds encompassed by Formula 1 have an adiponectin production enhancing action other than the aforementioned patent application of the present inventors. Of these compounds, curcumin is contained in curry powder, and N-feruloyltryptamine, β-phenethylferrate and the like are corn (Non-patent Document 8), propolis (Non-patent Document 9), and herbal medicine plants (Non-patent). In literature 10), capsaicin is chili, and lower alkyl esters of vanillic acid and p-coumaric acid are wine (non-patent document 11), olive oil (non-patent document 12), blueberry (non-patent document 13), propolis (non-patent document 10). (Patent Document 14) and the like, and higher alkyl esters are also included in herbal medicinal plants (Non-Patent Documents 15 and 16). Further, amines having an aromatic nucleus such as tyramine amide and benzyl ester of p-coumaric acid and alcohol derivatives are also included. It is included in traditional Chinese medicine (Non-patent document 17) and propolis (Non-patent document 9) and has been orally ingested by humans. Therefore, it is considered that the compound of the present invention is highly safe and can be used on a daily basis. Adiponectin production enhancing activity is also strong enough to show effectiveness in animal tests as described above. However, it was desired that this activity be stronger when practical application is taken into consideration.

U.S. Pat.No. 6,153,432; JP 2005-53890 A International publication WO2004096278 pamphlet Japanese Unexamined Patent Publication No. 2005-232150 JP 2004-315379 A JP 2005-68132 A JP 2005-60308 A JP 2005-225872 A Maeda Hoichi et al., Molecular Medicine, Vol. 42, No. 1, 11-21 (2005) N. Maeda etal., Diabetes, 50, 2094-2099 (2001) Kamon et al., Biochem. Biophys. Res. Commun., 323,242-248 (2004) Nagasawa etal., Horm. Metab. Res., 34, 635-639 (2002) Tsuda et al., Biochem. Biophys. Res. Commun., 316, 149-157 (2004) Lihn et al., Biochem. Biophys. Res. Commun., 316, 853-858 (2004) Nagao et al., Biochem. Biophys. Res. Commun., 310, 562-566 (2003) A. Ehmann, Phytochem., 13, 1979-1983 (1974) P. Georgieva etal., Z. Naturforsch., 52c, 60-64 (1997) S. Zschocke etal., Planta Med., 63, 203-206 (1997) R. Schneider etal., J. Agric. Food Chem., 46 (8), 3230-3237 (1998) M. Esti et al., Riv. Ital. Sostanze Grasse, 73 (4), 147-150 (1996) F. Kader etal., Food Chem., Volume Date 1996, 55 (1), 35-40 (1995) W. Greenaway etal., Proc. R. Soc. London, B, 232 (1268), 249-272 (1987) U. Koetter etal., Planta Med., 59 (3), 279-280 (1993); M. Li et al., Zhongcaoyao, 23 (5), 227-228 (1992) T. Okuyama etal., Planta Med., (3), 171-175 (1986)

  Therefore, an object of the present invention is to develop and put to practical use a new drug that is contained in edible and medicinal plants and natural products, has high safety, and has a strong adiponectin production enhancing action.

  In such a situation, as a result of intensive studies, the present inventors obtained knowledge that suggests that a part of the phenolic compound activates the transcription factor RXRα, and further functioned to bind to RXRα and initiate transcription of adiponectin. In order to activate other transcription factors PPARγ, unsaturated fatty acids such as docosahexaenoic acid were administered simultaneously with the phenolic compound. As a result, it was found that the production of adiponectin in the preadipocytes is remarkably enhanced as compared with administration alone, and the present invention has been completed.

  Polyunsaturated fatty acids such as docosahexaenoic acid are known to have health-related physiological activities such as anti-obesity and antithrombotic effects, and some of their functions are thought to be related to increased production of adiponectin. ing. However, there are no reports that prove this. Among the long-chain unsaturated fatty acids, conjugated linoleic acid has been reported to increase plasma adiponectin levels when administered to rats as described above [Nagao K. et al., Biochem. Biophys. Res. Commun., 310, 562-566 (2003)], and there is a conflicting report that adiponectin gene expression is reduced in mouse muscle [Warren JM et al., Lipids, 38, 497-504 (2003)].

  On the other hand, the gene expression of adiponectin requires that the nuclear transcription factor PPARγ be activated. Therefore, when the present inventors added 10 μM docosahexaenoic acid or eicosapentaenoic acid to the mouse 3T3-L1 preadipocyte cell line, the concentration of adiponectin secreted into the medium was 1.5 to 2 times that of the control. I found. However, in addition to 10 μM docosahexaenoic acid, β-phenethylferramide, which is a representative of this phenolic compound, was added at a concentration of 10 μM. Surprisingly, β-phenethylferrulea was about 8 times that of docosahexaenoic acid alone. It was found that a large amount of adiponectin was produced in the medium about twice as much as that of imide alone and nearly 15 times that of the control. That is, the action of both compounds appears synergistically rather than additively. Such a phenomenon has never been known for unsaturated fatty acids and phenolic compounds. In terms of mechanism, as described above, PPARγ is activated by docosahexaenoic acid and RXRα is activated by β-phenethylferramide at the same time, and activation of both transcription factors synergizes the actual functional PPARγ-RXRα heterodimer. This is considered to be due to the stronger activation.

  As described above, it has been clarified that the mixed composition of the phenolic compound and the unsaturated fatty acid has a strong adiponectin production enhancing action. It has been found that the activity is further increased by using a xanthine derivative usually contained in tea or coffee, such as theophylline, caffeine, or theobromine. This is thought to be because xanthine derivatives inhibit the phosphodiesterase in the living body and increase the level of cAMP, which is the second messenger, but caffeine is also widely consumed and highly safe, so it can be mixed with the mixed composition of the present invention. The combination is practically significant in terms of further enhancement of drug efficacy and dose reduction.

  Furthermore, as such unsaturated fatty acids, not only linear unsaturated fatty acids contained in so-called fats and oils, but also relatively short chains such as unsaturated fatty acids having a branched skeleton such as gellanic acid and farnesic acid, and decenoic acid. These unsaturated fatty acids are also effective. Although branched and short-chain unsaturated fatty acids themselves are weak, they have an adiponectin production-enhancing effect, and this was also found for the first time in the present invention. In addition to the above ferulic acid derivatives, curcumin, gingerol, etc., the phenolic compounds related to the present invention include hydroxychalcone derivatives that are close in structure, either by themselves or in combination with unsaturated fatty acids to enhance adiponectin production. It was found to have an action.

（ただし、式１中においてR₁、R₂、R₃、R_４は水素原子(H)、水酸基、アルコキシ基、又は炭素数1〜20のアルキル基もしくはアルケニル基を表し、Xは単結合又は炭素数１〜６の２価脂肪族炭化水素基を表し、Yはアミド基（-CO-NH‐もしくは‐NH-CO-）、エステル基(−CO-O-もしくは-O-CO-)、又はカルボニル基（-CO-）を表し、Zは、水酸基、アルコキシ基、オキソ基、カルボキシル基又はアミノ基により置換されているかあるいは非置換の炭素数１〜２０の２価脂肪族炭化水素基を表し、Qは水素原子（H）、若しくは水酸基、オキソ基、アルコキシ基、アミノ基、又は炭素数1〜10のアルキル基もしくはアルケニル基により置換されているかあるいは非置換の芳香族炭化水素基又は複素環基を表す。）

２）グリセリドが、炭素数８〜２２の不飽和脂肪酸の少なくとも1つがグリセロールと結合してなるエステルであることを特徴とする、上記１）に記載の薬剤。

３）低級アルキルエステルが、炭素数８〜２２の不飽和脂肪酸のエチル、メチル、プロピル、もしくはブチルエステルであることを特徴とする、上記１）に記載の薬剤。

４）炭素数８〜２２の不飽和脂肪酸が4Z,7Z,10Z,13Z,16Z,19Z-ドコサヘキサエン酸、4Z,7Z,10Z,13Z,16Z-ドコサペンタエン酸、7Z,10Z,13Z,16Z,19Z-ドコサペンタエン酸、5Z,8Z,11Z,14Z,17Z-エイコサペンタエン酸、アラキドン酸、6Z,9Z,12Z,15Z-オクタデカテトラエン酸、α-リノレン酸、リノール酸、オレイン酸、ミリストオレイン酸（シス-9-テトラデセン酸）、2-ドデセン酸、2-デセン酸、3-デセン酸、2-オクテン酸、ゲラン酸（トランス-3,7-ジメチル-2,6-オクタジエン酸）、シトロネル酸（トランス-3,7-ジメチル-6-オクテン酸）又はファルネソイック酸[ (2E,6E,10E)-3,7,11-トリメチル-2,6,10-ドデカトリエン酸]のいずれか1つ又は2つ以上であることを特徴とする、上記１）〜３）のいずれかに記載の薬剤。

５）さらに、カフェイン、テオフィリン、又はテオブロミンの中から選ばれる1又は２以上のキサンチン誘導体を含有することを特徴とする、上記１）〜４）のいずれかに記載の薬剤。

６）一般式（１）で示されるフェノール性化合物が下記一般式（２）で示されるフェルラ酸又はカフェイン酸の誘導体であることを特徴とする、上記１）〜５）のいずれかに記載の薬剤。

（ただし、式２においてR₁は水酸基またはメトキシ基であり、Y₁はイミノ基（NH）または酸素原子(O)であり、Zは炭素数１〜１０の２価脂肪族炭化水素基であり、Qは水素原子（H）、若しくは水酸基又はアミノ基により置換されていてもよい、芳香族炭化水素基又は複素環基を表す。）
That is, the present invention is as shown in the following (1) to (36).

1) Production of adiponectin in animal adipocytes, comprising as an active ingredient a phenolic compound represented by the following general formula (1) and an unsaturated fatty acid having 8 to 22 carbon atoms or a glyceride or lower alkyl ester thereof: A drug that enhances or promotes.

(In the formula 1, R ₁ , R ₂ , R ₃ and R ₄ represent a hydrogen atom (H), a hydroxyl group, an alkoxy group, or an alkyl or alkenyl group having 1 to 20 carbon atoms, and X is a single bond or Represents a divalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, and Y represents an amide group (—CO—NH— or —NH—CO—), an ester group (—CO—O— or —O—CO—), Or a carbonyl group (—CO—), wherein Z is a hydroxyl group, an alkoxy group, an oxo group, a carboxyl group, an amino group or an unsubstituted divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms. Q represents a hydrogen atom (H), a hydroxyl group, an oxo group, an alkoxy group, an amino group, an alkyl group or an alkenyl group having 1 to 10 carbon atoms, or an unsubstituted aromatic hydrocarbon group or a heterocyclic group. Represents a cyclic group.)

2) The drug according to 1) above, wherein the glyceride is an ester formed by binding at least one of unsaturated fatty acids having 8 to 22 carbon atoms with glycerol.

3) The agent according to 1) above, wherein the lower alkyl ester is an ethyl, methyl, propyl, or butyl ester of an unsaturated fatty acid having 8 to 22 carbon atoms.

4) Unsaturated fatty acids having 8 to 22 carbon atoms are 4Z, 7Z, 10Z, 13Z, 16Z, 19Z-docosahexaenoic acid, 4Z, 7Z, 10Z, 13Z, 16Z-docosapentaenoic acid, 7Z, 10Z, 13Z, 16Z, 19Z-docosapentaenoic acid, 5Z, 8Z, 11Z, 14Z, 17Z-eicosapentaenoic acid, arachidonic acid, 6Z, 9Z, 12Z, 15Z-octadecatetraenoic acid, α-linolenic acid, linoleic acid, oleic acid, mi List oleic acid (cis-9-tetradecenoic acid), 2-dodecenoic acid, 2-decenoic acid, 3-decenoic acid, 2-octenoic acid, geranic acid (trans-3,7-dimethyl-2,6-octadienoic acid) , Either citronellic acid (trans-3,7-dimethyl-6-octenoic acid) or farnesic acid [(2E, 6E, 10E) -3,7,11-trimethyl-2,6,10-dodecatrienoic acid] The drug according to any one of 1) to 3) above, wherein the drug is one or two or more.

5) The drug according to any one of 1) to 4) above, further comprising one or more xanthine derivatives selected from caffeine, theophylline, or theobromine.

6) The phenolic compound represented by the general formula (1) is a derivative of ferulic acid or caffeic acid represented by the following general formula (2), according to any one of 1) to 5) above Drugs.

(In the formula 2, R ₁ is a hydroxyl group or a methoxy group, Y ₁ is an imino group (NH) or an oxygen atom (O), and Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms. Q represents a hydrogen atom (H), an aromatic hydrocarbon group or a heterocyclic group which may be substituted with a hydroxyl group or an amino group.

（ただし、式３においてR₁は水酸基またはメトキシ基であり、Y₁はイミノ基（NH）または酸素原子(O)であり、Zは炭素数１〜10の２価脂肪族炭化水素基であり、Qは水素原子（H）、若しくは水酸基又はアミノ基で置換されていてもよい、芳香族炭化水素基又は複素環基を表す。）

８） 一般式（１）で示されるフェノール性化合物が下記一般式（４）で示されるホモバニリン酸の誘導体であることを特徴とする、上記１）〜５）のいずれかに記載の薬剤。

（ただし、式４においてY₁はイミノ基（NH）または酸素原子(O)であり、Zは炭素数１〜10の２価脂肪族炭化水素基であり、Qは水素原子（H）、若しくは水酸基又はアミノ基により置換されていてもよい、芳香族炭化水素基または複素環基を表す。）

９） 一般式（１）で示されるフェノール性化合物が下記一般式（５）で示されるｐ−クマル酸の誘導体であることを特徴とする、上記１）〜５）のいずれかに記載の薬剤。

（ただし、式５においてY₁はイミノ基（NH）または酸素原子(O)であり、Zは炭素数１〜10の２価脂肪族炭化水素基であり、Qは水素原子（H）、若しくは水酸基又はアミノ基により置換されていてもよい、芳香族炭化水素基又は複素環基を表す。）

１０） 一般式（１）で示されるフェノール性化合物が下記一般式（６）で示されるｐ−ヒドロキシ安息香酸の誘導体であることを特徴とする、上記１）〜５）のいずれかに記載の薬剤。

（ただし、式６においてY₁はイミノ基（NH）または酸素原子(O)であり、Zは炭素数１〜10の２価脂肪族炭化水素基であり、Qは水素原子（H）、若しくは水酸基又はアミノ基により置換されていてもよい、芳香族炭化水素基又は複素環基を表す。）

１１） 一般式（１）で示されるフェノール性化合物が下記一般式（７）で示されるバニリルアミン誘導体であることを特徴とする、上記１）〜５）のいずれかに記載の薬剤。

（ただし、式７においてR₁は水酸基又はメトキシ基であり、Y₁は炭素数１〜６の２価脂肪族炭化水素基であり、Zは炭素数１〜20の２価脂肪族炭化水素基であり、Qは水素原子（H）、若しくは水酸基又はアミノ基により置換されていてもよい、芳香族炭化水素基又は複素環基を表す。）

１２） 一般式（１）で示されるフェノール性化合物が下記一般式（８）で示されるジンゲロールもしくはその類縁体であることを特徴とする、上記１）〜５）のいずれかに記載の薬剤。

（ただし、式８において、Ｚ_１は炭素数１〜１１の２価脂肪族炭化水素基であり、Qは水素原子（Ｈ）、若しくは水酸基又はアミノ基により置換されていてもよい、芳香族炭化水素基又は複素環基を表す。）
7) The phenolic compound represented by the general formula (1) is a derivative of vanillic acid or protocatechuic acid represented by the following general formula (3), according to any one of the above 1) to 5) Drugs.

(In the formula 3, R ₁ is a hydroxyl group or a methoxy group, Y ₁ is an imino group (NH) or an oxygen atom (O), and Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms. , Q represents a hydrogen atom (H), an aromatic hydrocarbon group or a heterocyclic group which may be substituted with a hydroxyl group or an amino group.

8) The drug according to any one of 1) to 5) above, wherein the phenolic compound represented by the general formula (1) is a derivative of homovanillic acid represented by the following general formula (4).

(In the formula 4, Y ₁ is an imino group (NH) or an oxygen atom (O), Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and Q is a hydrogen atom (H), or (Represents an aromatic hydrocarbon group or a heterocyclic group which may be substituted with a hydroxyl group or an amino group.)

9) The drug according to any one of 1) to 5) above, wherein the phenolic compound represented by the general formula (1) is a derivative of p-coumaric acid represented by the following general formula (5). .

(However, in Formula 5, Y ₁ is an imino group (NH) or an oxygen atom (O), Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and Q is a hydrogen atom (H), or (Represents an aromatic hydrocarbon group or a heterocyclic group optionally substituted with a hydroxyl group or an amino group.)

10) The phenolic compound represented by the general formula (1) is a derivative of p-hydroxybenzoic acid represented by the following general formula (6), according to any one of the above 1) to 5) Drugs.

(In formula 6, Y ₁ is an imino group (NH) or an oxygen atom (O), Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and Q is a hydrogen atom (H), or (Represents an aromatic hydrocarbon group or a heterocyclic group optionally substituted with a hydroxyl group or an amino group.)

11) The drug according to any one of 1) to 5) above, wherein the phenolic compound represented by the general formula (1) is a vanillylamine derivative represented by the following general formula (7).

(Wherein, R ₁ in Formula 7 is a hydroxyl group or a methoxy group, Y ₁ is a divalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, Z is a divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms Q represents a hydrogen atom (H), an aromatic hydrocarbon group or a heterocyclic group which may be substituted with a hydroxyl group or an amino group.

12) The drug according to any one of 1) to 5) above, wherein the phenolic compound represented by the general formula (1) is gingerol represented by the following general formula (8) or an analog thereof.

(In Expression 8, Z ₁ is a divalent aliphatic hydrocarbon group having 1 to 11 carbon atoms, Q is a hydrogen atom (H), a or may be substituted by a hydroxyl group or an amino group, an aromatic hydrocarbon Represents a hydrogen group or a heterocyclic group.)

（ただし、式９においてR₁とR₂は水素原子又はメトキシ基を表す。）

１４）一般式（２）で表される化合物が、N-(β-フェネチル)フェルラミド、フェルロイルトリプタミン、フェルロイルチラミン、β-フェネチルフェルレート、フェルラ酸3-フェニル-2-プロペニル、N-(β-フェネチル)カフェイン酸アミド、カフェイン酸フェネチルエステル、フェルラ酸2-(3-インドリル)エチル、N-ベンジルフェルラミド、及びN-(3-フェニルプロピル)フェルラミドから選ばれたものであることを特徴とする、上記６）に記載の薬剤。

１５）一般式（３）で表される化合物が、N-(3-フェニルプロピル)-4-ヒドロキシ-3-メトキシベンズアミド、4-ヒドロキシ-3-メトキシ安息香酸3-フェニル-2-プロペニル、N-(3-フェニルプロピル)-3,4-ジヒドロキシベンズアミド、N-(4-フェニルブチル)-4-ヒドロキシ-3-メトキシベンズアミドから選ばれたものであることを特徴とする、上記７）に記載の薬剤

１６）一般式（４）で表される化合物がN-(3-フェニルプロピル)-(4-ヒドロキシ-3-メトキシフェニル)アセトアミドであることを特徴とする、上記８）に記載の薬剤

１７）一般式（５）で表される化合物が、N-(β-フェネチル)-3-(4-ヒドロキシフェニル)-2-プロペンアミド又は3-(4-ヒドロキシフェニル)-2-プロペン酸3-フェニル-2-プロペニルであることを特徴とする、上記９）に記載の薬剤

１８）一般式（６）で表される化合物がN-(3-フェニルプロピル)-4-ヒドロキシベンズアミドであることを特徴とする、上記１０）に記載の薬剤
13) The drug according to any one of 1) to 5) above, wherein the phenolic compound represented by the general formula (1) is further curcumin represented by the following general formula (9) or a derivative thereof.

(However, in Formula 9, R ₁ and R ₂ represent a hydrogen atom or a methoxy group.)

14) The compound represented by the general formula (2) is N- (β-phenethyl) ferramide, feruloyltryptamine, feruloyltyramine, β-phenethylferrate, 3-phenyl-2-propenyl ferulate, N- ( β-phenethyl) caffeic acid amide, caffeic acid phenethyl ester, 2- (3-indolyl) ethyl ferulate, N-benzyl ferramide, and N- (3-phenylpropyl) ferramide The drug according to 6) above, which is characterized by

15) The compound represented by the general formula (3) is N- (3-phenylpropyl) -4-hydroxy-3-methoxybenzamide, 3-phenyl-2-propenyl 4-hydroxy-3-methoxybenzoate, N The above 7), characterized in that it is selected from-(3-phenylpropyl) -3,4-dihydroxybenzamide and N- (4-phenylbutyl) -4-hydroxy-3-methoxybenzamide Drug

16) The drug according to 8) above, wherein the compound represented by the general formula (4) is N- (3-phenylpropyl)-(4-hydroxy-3-methoxyphenyl) acetamide.

17) The compound represented by the general formula (5) is N- (β-phenethyl) -3- (4-hydroxyphenyl) -2-propenamide or 3- (4-hydroxyphenyl) -2-propenoic acid 3 The drug according to 9) above, which is 2-phenyl-2-propenyl

18) The drug according to 10) above, wherein the compound represented by the general formula (6) is N- (3-phenylpropyl) -4-hydroxybenzamide.

19) The compound represented by the general formula (7) is capsaicin, N- (4-hydroxy-3-methoxyphenyl) methyl-3-phenyl-2-propenamide, N- (3,4-dihydroxyphenyl) methyl. -3-phenyl-2-propenamide, a compound selected from N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] -3-phenyl-2-propenamide, 11) Drugs

20) The drug according to 12) above, wherein the compound represented by the general formula (8) is [6] -gingerol.

21) The drug according to 13) above, wherein the compound represented by the general formula (9) is curcumin.

22) A drug that enhances or promotes adiponectin production in animal adipocytes, comprising an unsaturated fatty acid having 8 to 22 carbon atoms or a glyceride or lower alkyl ester thereof as an active ingredient.

23) The drug according to 22) above, wherein the glyceride is an ester formed by binding at least one of unsaturated fatty acids having 8 to 22 carbon atoms with glycerol.

24) The agent according to 22) above, wherein the lower alkyl ester is an ethyl, methyl, propyl, or butyl ester of an unsaturated fatty acid having 8 to 22 carbon atoms.

（ただし、式1ｂ中においてR₁、R₂、R₃、R₄、R_５、R₆、R₇、R₈、R₉ は水素原子(H)、水酸基、アルコキシ基又は炭素数１〜20のアルキル基を表し、このアルキル基は分岐と不飽和結合を含んでいてもよい。）

２7) 上記２６）の一般式（1b）で表される化合物が、４’−ヒドロキシカルコン、イソリキリチゲニン、リコカルコンA、キサントフモール、及びキサントアンゲロールから選ばれたものであることを特徴とする、上記１) 〜５）のいずれかに記載の薬剤。

２8）一般式（1b）で示されるカルコン誘導体を活性成分として含むことを特徴とする、動物脂肪細胞におけるアディポネクチン産生を増強もしくは促進する薬剤。

２９）さらに、カフェイン、テオフィリン、又はテオブロミンの中から選ばれる1又は２以上のキサンチン誘導体を含有することを特徴とする、上記２8）に記載の薬剤。

３０）一般式（1ｂ）で表される化合物が、４’−ヒドロキシカルコン、イソリキリチゲニン、リコカルコンA、キサントフモール、及びキサントアンゲロールから選ばれたものであることを特徴とする、上記２9）に記載の薬剤。
25) Unsaturated fatty acids having 8 to 22 carbon atoms are 4Z, 7Z, 10Z, 13Z, 16Z, 19Z-docosahexaenoic acid, 4Z, 7Z, 10Z, 13Z, 16Z-docosapentaenoic acid, 7Z, 10Z, 13Z, 16Z, 19Z-docosapentaenoic acid, 5Z, 8Z, 11Z, 14Z, 17Z-eicosapentaenoic acid, arachidonic acid, 6Z, 9Z, 12Z, 15Z-octadecatetraenoic acid, α-linolenic acid, linoleic acid, oleic acid, mi List oleic acid (cis-9-tetradecenoic acid), 2-dodecenoic acid, 2-decenoic acid, 3-decenoic acid, 2-octenoic acid, geranic acid (trans-3,7-dimethyl-2,6-octadienoic acid) , Either citronellic acid (trans-3,7-dimethyl-6-octenoic acid) or farnesic acid [(2E, 6E, 10E) -3,7,11-trimethyl-2,6,10-dodecatrienoic acid] The drug according to any one of the above 22) to 24), wherein the drug is one or two or more.

26) The phenolic compound represented by the general formula (1) is a 4′-hydroxychalcone derivative represented by the following general formula (1b), according to any one of the above 1) to 5) Drugs.

(In the formula 1b, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are a hydrogen atom (H), a hydroxyl group, an alkoxy group, or 1 to 20 carbon atoms) And this alkyl group may contain a branch and an unsaturated bond.)

27) The compound represented by the general formula (1b) of the above 26) is selected from 4′-hydroxychalcone, isolithicigenin, lycochalcone A, xanthohumol, and xanthoangelol. The drug according to any one of 1) to 5), which is characterized in that

2.8) A drug that enhances or promotes adiponectin production in animal adipocytes, comprising a chalcone derivative represented by the general formula (1b) as an active ingredient.

29) The drug according to 28), further comprising one or more xanthine derivatives selected from caffeine, theophylline, or theobromine.

30) The compound represented by the general formula (1b) is selected from 4′-hydroxychalcone, isoliquiritigenin, lycochalcone A, xanthohumol, and xanthoangelol, The drug according to the above 29).

31) A phenolic compound represented by the general formula (1) described in 1) above and an unsaturated fatty acid having 8 to 22 carbon atoms or a glyceride or a lower alkyl ester thereof as active ingredients. Type diabetes hypoglycemic agent

32) A phenolic compound represented by the general formula (1) described in 1) above, and an unsaturated fatty acid having 8 to 22 carbon atoms or a glyceride or lower alkyl ester thereof as active ingredients. Antilipidemic agent

33) The compound represented by the general formula (1) is a derivative of ferulic acid or caffeic acid represented by the general formula (2), or [6] -gingerol represented by the general formula (8) or an analog thereof. The drug according to 31) above, which is characterized by

34) The compound represented by the general formula (1) is a ferulic acid or caffeic acid derivative represented by the general formula (2), or [6] -gingerol represented by the general formula (8) or an analog thereof. 32. The drug according to 32) above, wherein

35) Unsaturated fatty acids having 8 to 22 carbon atoms are 4Z, 7Z, 10Z, 13Z, 16Z, 19Z-docosahexaenoic acid, 4Z, 7Z, 10Z, 13Z, 16Z-docosapentaenoic acid, 7Z, 10Z, 13Z, 16Z, 19Z-docosapentaenoic acid, 5Z, 8Z, 11Z, 14Z, 17Z-eicosapentaenoic acid, arachidonic acid, 6Z, 9Z, 12Z, 15Z-octadecatetraenoic acid, α-linolenic acid, linoleic acid, oleic acid, mi List oleic acid (cis-9-tetradecenoic acid), 2-dodecenoic acid, 2-decenoic acid, 3-decenoic acid, 2-octenoic acid, geranic acid (trans-3,7-dimethyl-2,6-octadienoic acid) , Either citronellic acid (trans-3,7-dimethyl-6-octenoic acid) or farnesic acid [(2E, 6E, 10E) -3,7,11-trimethyl-2,6,10-dodecatrienoic acid] The drug according to any one of 31) to 34) above, wherein the drug is one or two or more.

36) The drug according to any one of 31) to 35) above, further comprising one or more xanthine derivatives selected from caffeine, theophylline, or theobromine.

  The phenolic compound of the present invention (compound represented by the general formula (1)) works in cooperation with highly unsaturated fatty acids, branched unsaturated fatty acids or xanthine derivatives such as caffeine to produce adiponectin in animal adipocytes. Strengthen or promote. As a result, at the individual level, it has the effect of lowering the high blood sugar level in type 2 diabetes and reducing the blood neutral fat concentration. That is, the drug according to the present invention is also useful as a type 2 diabetes hypoglycemic agent or hyperlipidemia therapeutic agent.

  On the other hand, substances such as the above-mentioned thiazolidinedione known as adiponectin production enhancing substances have problems of safety and side effects, whereas derivatives such as ferulic acid and chalcone of the present invention have conventionally been Many ingredients that have been eaten or taken as health promotion ingredients such as horticultural crops, traditional Chinese medicine, and propolis, and highly unsaturated fatty acids such as docosahexaenoic acid are also ingested as fish oil ingredients, and terpenes such as gellanic acid and citronellic acid. Branched unsaturated fatty acids have been used in contact with the human body as components of perfume oils and fragrances, and xanthine derivatives such as caffeine have also been ingested from tea, coffee, etc. It can be said that the drug of the present invention has high safety.

  Furthermore, as described above, adiponectin has the effect of preventing and treating type 2 diabetes, a so-called lifestyle-related disease, in which blood glucose levels do not decrease despite the production of insulin. It has many important physiological actions such as suppression of connected vascular lesions, improvement of obesity, anti-inflammation, suppression of monocyte cell proliferation, suppression of liver fibrosis, etc. It is a safe and extremely useful drug as a drug for the prevention or treatment of cancer.

（ただし、式１中においてR₁、R₂、R₃、R_４は水素原子(H)、水酸基、アルコキシ基、又は炭素数1〜20のアルキル基もしくはアルケニル基を表し、Xは単結合又は炭素数１〜６の２価脂肪族炭化水素基を表し、Yはアミド基（-CO-NH‐もしくは‐NH-CO-）、エステル基(−CO-O-もしくは-O-CO-)、又はカルボニル基（-CO-)を表し、Zは、水酸基、アルコキシ基、オキソ基、カルボキシル基又はアミノ基により置換されているかあるいは非置換の炭素数１〜２０の２価脂肪族炭化水素基を表し、Qは水素原子（H）、若しくは水酸基、オキソ基、アルコキシ基、アミノ基、又は炭素数1〜10のアルキル基もしくはアルケニル基により置換されているかあるいは非置換の芳香族炭化水素基又は複素環基を表す。）
The pharmaceutical composition used in the present invention is obtained by blending a compound represented by the following general formula (1) and an unsaturated fatty acid having 8 to 22 carbon atoms or a glyceride or lower alkyl ester thereof. Further, if necessary, a xanthine derivative such as caffeine is further added thereto.

(In the formula 1, R ₁ , R ₂ , R ₃ and R ₄ represent a hydrogen atom (H), a hydroxyl group, an alkoxy group, or an alkyl or alkenyl group having 1 to 20 carbon atoms, and X is a single bond or Represents a divalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, and Y represents an amide group (—CO—NH— or —NH—CO—), an ester group (—CO—O— or —O—CO—), Or a carbonyl group (—CO—), wherein Z is a hydroxyl group, an alkoxy group, an oxo group, a carboxyl group, an amino group, or an unsubstituted divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms. Q represents a hydrogen atom (H), a hydroxyl group, an oxo group, an alkoxy group, an amino group, an alkyl group or an alkenyl group having 1 to 10 carbon atoms, or an unsubstituted aromatic hydrocarbon group or a heterocyclic group. Represents a cyclic group.)

（ただし、式２においてR₁は水酸基またはアルコキシ基であり、Y₁はイミノ基（NH）または酸素原子(O)であり、Zは炭素数１〜１０の２価脂肪族炭化水素基であり、Qは水素原子（H）、若しくは水酸基又はアミノ基により置換されていてもよい、芳香族炭化水素基又は複素環基を表す。）
上記置換基の定義中、アルコキシ基としては、メトキシ基、エトキシ基、イソペンテニルオキシ基等、炭素数１〜１０の２価脂肪族炭化水素基としては、メチレン基、エチレン基、トリメチレン基、ビニレン基等のアルキレン基またはアルケニレン基、芳香族炭化水素基としては、フェニル基、トリル基、ナフチル基等、複素環基としては、３−インドリル基、２−インドリル基、５−イミダゾリル基等がそれぞれ例示される。

ｂ）下記一般式（３）で示されるバニリン酸又はプロトカテク酸の誘導体

（ただし、式３においてR₁は水酸基またはアルコキシ基であり、Y₁はイミノ基（NH）または酸素原子(O)であり、Zは炭素数１〜10の２価脂肪族炭化水素基であり、Qは水素原子（H）、若しくは水酸基又はアミノ基で置換されていてもよい、芳香族炭化水素基又は複素環基を表す。）
これら置換基の定義中、アルコキシ基、炭素数１〜１０の２価脂肪族炭化水素基、芳香族炭化水素基及び複素環基の具体例は上記ａ）と同様である。
ｃ） 下記一般式（４）で示されるホモバニリン酸の誘導体

（ただし、式４においてY₁はイミノ基（NH）または酸素原子(O)であり、Zは炭素数１〜10の２価脂肪族炭化水素基であり、Qは水素原子（H）、若しくは水酸基又はアミノ基により置換されていてもよい、芳香族炭化水素基または複素環基を表す。）
これら置換基の定義中、炭素数１〜１０の２価脂肪族炭化水素基、芳香族炭化水素基及び複素環基の具体例は上記ａ）と同様である。

ｄ） 下記一般式（５）で示されるｐ−クマル酸の誘導体

（ただし、式５においてY₁はイミノ基（NH）または酸素原子(O)であり、Zは炭素数１〜10の２価脂肪族炭化水素基であり、Qは水素原子（H）、若しくは水酸基又はアミノ基により置換されていてもよい、芳香族炭化水素基又は複素環基を表す。）
これら置換基の定義中、炭素数１〜１０の２価脂肪族炭化水素基、芳香族炭化水素基及び複素環基の具体例は上記ａ）と同様である。
Specific examples of the phenolic compound of the present invention are as follows.

a) Ferulic acid or caffeic acid derivative represented by the following general formula (2)

(In the formula 2, R ₁ is a hydroxyl group or an alkoxy group, Y ₁ is an imino group (NH) or an oxygen atom (O), and Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms. Q represents a hydrogen atom (H), an aromatic hydrocarbon group or a heterocyclic group which may be substituted with a hydroxyl group or an amino group.
In the definition of the above substituents, the alkoxy group includes a methoxy group, an ethoxy group, an isopentenyloxy group, and the like, and the divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms includes a methylene group, an ethylene group, a trimethylene group, and a vinylene. As an alkylene group such as a group or alkenylene group, and an aromatic hydrocarbon group, a phenyl group, a tolyl group, a naphthyl group, and the like, and as a heterocyclic group, a 3-indolyl group, a 2-indolyl group, a 5-imidazolyl group, and the like, respectively Illustrated.

b) Derivatives of vanillic acid or protocatechuic acid represented by the following general formula (3)

(However, in Formula 3, R ₁ is a hydroxyl group or an alkoxy group, Y ₁ is an imino group (NH) or an oxygen atom (O), and Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms. , Q represents a hydrogen atom (H), an aromatic hydrocarbon group or a heterocyclic group which may be substituted with a hydroxyl group or an amino group.
In the definition of these substituents, specific examples of the alkoxy group, the divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, the aromatic hydrocarbon group and the heterocyclic group are the same as those in the above a).
c) Derivatives of homovanillic acid represented by the following general formula (4)

(In the formula 4, Y ₁ is an imino group (NH) or an oxygen atom (O), Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and Q is a hydrogen atom (H), or (Represents an aromatic hydrocarbon group or a heterocyclic group which may be substituted with a hydroxyl group or an amino group.)
In the definition of these substituents, specific examples of the divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, the aromatic hydrocarbon group and the heterocyclic group are the same as those in the above a).

d) Derivative of p-coumaric acid represented by the following general formula (5)

(However, in Formula 5, Y ₁ is an imino group (NH) or an oxygen atom (O), Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and Q is a hydrogen atom (H), or (Represents an aromatic hydrocarbon group or a heterocyclic group optionally substituted with a hydroxyl group or an amino group.)
In the definition of these substituents, specific examples of the divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, the aromatic hydrocarbon group and the heterocyclic group are the same as those in the above a).

（ただし、式６においてY₁はイミノ基（NH）または酸素原子(O)であり、Zは炭素数１〜10の２価脂肪族炭化水素基であり、Qは水素原子（H）、若しくは水酸基又はアミノ基により置換されていてもよい、芳香族炭化水素基又は複素環基を表す。）
これら置換基の定義中、炭素数１〜１０の２価脂肪族炭化水素基、芳香族炭化水素基及び複素環基の具体例は上記ａ）と同様である。

ｆ） 下記一般式（７）で示されるバニリルアミン誘導体

（ただし、式７においてR₁は水酸基又はアルコキシ基であり、Y₁は炭素数１〜６の２価脂肪族炭化水素基であり、Zは炭素数１〜20の２価脂肪族炭化水素基であり、Qは水素原子（H）、若しくは水酸基又はアミノ基により置換されていてもよい、芳香族炭化水素基又は複素環基を表す。）
これら置換基の定義中、炭素数１〜６の２価脂肪族炭化水素基としては、メチレン基、エチレン基等が挙げられ、アルコキシ基、芳香族炭化水素基及び複素環基の具体例は上記ａ）と同様である。

ｇ） ジンゲロールもしくはその類縁体。

（ただし、式８において、Ｚ_１は炭素数１〜１１の２価脂肪族炭化水素基であり、Qは水素原子（Ｈ）、若しくは水酸基又はアミノ基により置換されていてもよい、芳香族炭化水素基又は複素環基を表す。）
これら置換基の定義中、炭素数１〜１１の２価脂肪族炭化水素基としては、例えばメチレン基、エチレン基、テトラメチレン基、ヘキサメチレン基等が挙げられ、芳香族炭化水素基及び複素環基の具体例は上記ａ）と同様である。

ｈ） 下記一般式（９）で示されるクルクミンもしくはその誘導体

（ただし、式９においてR₁とR₂は水素原子又はメトキシ基を表す。）

i) 下記一般式（１ｂ）で示される４’-ヒドロキシカルコン誘導体

（ただし、式1ｂ中においてR₁、R₂、R₃、R₄、R_５、R₆、R₇、R₈、R₉ は水素原子(H)、水酸基、アルコキシ基又は炭素数１〜20のアルキル基を表し、このアルキル基は分岐と不飽和結合を含んでいてもよい。）
e) Derivatives of p-hydroxybenzoic acid represented by the following general formula (6)

(In formula 6, Y ₁ is an imino group (NH) or an oxygen atom (O), Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and Q is a hydrogen atom (H), or (Represents an aromatic hydrocarbon group or a heterocyclic group optionally substituted with a hydroxyl group or an amino group.)
In the definition of these substituents, specific examples of the divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, the aromatic hydrocarbon group and the heterocyclic group are the same as those in the above a).

f) Vanillylamine derivative represented by the following general formula (7)

(Wherein, R ₁ in Formula 7 is a hydroxyl group or an alkoxy group, Y ₁ is a divalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, Z is a divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms Q represents a hydrogen atom (H), an aromatic hydrocarbon group or a heterocyclic group which may be substituted with a hydroxyl group or an amino group.
In the definition of these substituents, examples of the divalent aliphatic hydrocarbon group having 1 to 6 carbon atoms include a methylene group and an ethylene group. Specific examples of the alkoxy group, the aromatic hydrocarbon group and the heterocyclic group are the above. Same as a).

g) Zingerol or its analogs.

(In Expression 8, Z ₁ is a divalent aliphatic hydrocarbon group having 1 to 11 carbon atoms, Q is a hydrogen atom (H), a or may be substituted by a hydroxyl group or an amino group, an aromatic hydrocarbon Represents a hydrogen group or a heterocyclic group.)
In the definition of these substituents, the divalent aliphatic hydrocarbon group having 1 to 11 carbon atoms includes, for example, a methylene group, an ethylene group, a tetramethylene group, a hexamethylene group, an aromatic hydrocarbon group and a heterocyclic ring. Specific examples of the group are the same as those in the above a).

h) Curcumin represented by the following general formula (9) or a derivative thereof

(However, in Formula 9, R ₁ and R ₂ represent a hydrogen atom or a methoxy group.)

i) 4′-hydroxychalcone derivative represented by the following general formula (1b)

(In the formula 1b, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are a hydrogen atom (H), a hydroxyl group, an alkoxy group, or 1 to 20 carbon atoms) And this alkyl group may contain a branch and an unsaturated bond.)

  When the phenolic compound represented by the above general formula 1 is administered simultaneously with a highly unsaturated fatty acid such as docosahexaenoic acid or a xanthine derivative such as these highly unsaturated fatty acid and caffeine, the phenolic compound is more potent than when administered alone. It promotes the differentiation of human and mouse preadipocytes into adipocytes and, accordingly, promotes and enhances the production of adiponectin in these cells. This activity is comparable to that of pioglitazone, an antidiabetic drug that has been put into practical use, depending on the structure and concentration of the phenolic compound and the type and concentration of the unsaturated fatty acid to be combined.

As an unsaturated fatty acid having 8 to 22 carbon atoms used in the present invention,
Docosahexaenoic acid (4Z, 7Z, 10Z, 13Z, 16Z, 19Z-docosahexaenoic acid),
(n-6) docosapentaenoic acid (4Z, 7Z, 10Z, 13Z, 16Z-docosapentaenoic acid),
(n-3) docosapentaenoic acid (7Z, 10Z, 13Z, 16Z, 19Z-docosapentaenoic acid),
Eicosapentaenoic acid (5Z, 8Z, 11Z, 14Z, 17Z-eicosapentaenoic acid),
Arachidonic acid (5Z, 8Z, 11Z, 14Z-eicosatetraenoic acid),
Stearidonic acid (6Z, 9Z, 12Z, 15Z-octadecatetraenoic acid),
Homo-γ-linolenic acid (8Z, 11Z, 14Z-eicosatrienoic acid),
α-linolenic acid (9Z, 12Z, 15Z-octadecatrienoic acid),
γ-linolenic acid (6Z, 9Z, 12Z-octadecatrienoic acid),
Linoleic acid (9Z, 12Z-octadecadienoic acid),
Oleic acid (9Z-octadecenoic acid),
Conjugated linolenic acid (10E, 12Z-octadecadienoic acid
Or 9Z, 11E-octadecadienoic acid),
Myristooleic acid (9Z-tetradecenoic acid),
2-dodecenoic acid,
2-decenoic acid,
3-decenoic acid,
2-octenoic acid,
Gellanic acid (3,7-dimethyl-2E, 6E-octadienoic acid),
Citronellic acid (3,7-dimethyl-6E-octenoic acid),
Farnesic acid (3,7,11-trimethyl-2E, 6E, 10E-dodecatrienoic acid)
Etc. Of these, docosahexaenoic acid and eicosapentaenoic acid are most preferably used, but are not limited thereto. In addition, when these unsaturated fatty acids are used as glycerides, they may be monoglycerides, diglycerides, or triglycerides as long as they are esters to which at least one of these fatty acids is bonded, and the bonding of unsaturated fatty acids in glycerol. The position may be any of positions 1, 2, and 3. In the case of diglyceride and triglyceride, fatty acids other than the unsaturated fatty acid, such as palmitic acid or stearic acid, may be bound.

Further, among the phenolic compounds used in the present invention, specific examples of preferred chemical structures include the following 10 to 39 compounds.

The substituents of these compounds will be described below in correspondence with the substituents in the general formula (1). The values in parentheses correspond to the substituents of the corresponding formulas in the more specific general formulas (2) to (9) and (1b).
10 compounds (N- (β-phenethyl) ferramide); in general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =-OMe, X =-CH = CH, Y = -CO- Compounds in which NH-group, Z = -CH ₂ CH _2- , Q = -C ₆ H ₅ (in general formula (2), R ₁ = -OMe, Y ₁ = -NH, Z = -CH ₂ CH ₂ -, Q = -C ₆ H ₅ ).
11 compounds (feruloyltryptamine); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =-OMe, X = -CH = CH-, Y = -CO-NH- group, A compound in which Z = -CH ₂ CH _2- , Q = 3-indolyl group (in general formula (2), R ₁ = -OMe, Y ₁ = -NH-, Z = -CH ₂ CH _2- , Q = Compounds that are 3-indolyl groups).
12 compounds (feruloyl tyramine); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =-OMe, X = -CH = CH-, Y = -CO-NH- group, A compound in which Z = -CH ₂ CH _2- , Q = p-hydroxyphenyl group (in formula (2), R ₁ = -OMe, Y ₁ = -NH-, Z = -CH ₂ CH _2- , Q = p-hydroxyphenyl group).
13 compounds (β-phenethyl ferrate); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =-OMe, X = -CH = CH-, Y = -CO-O- Group, Z = -CH ₂ CH _2- , Q = phenyl group (in general formula (2), R ₁ = -OMe, Y ₁ = -O-, Z = -CH ₂ CH _2- , Q = A compound which is a phenyl group).
14 compounds (ferulic acid 3-phenyl-2-propenyl); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =-OMe, X = -CH = CH-, Y =- Compounds in which CO-O- group, Z = -CH ₂ CH = CH-, Q = phenyl group (in general formula (2), R ₁ = -OMe, Y ₁ = -O-, Z = -CH ₂ CH = CH-, Q = phenyl group).

15 compounds (N- (β-phenethyl) caffeic acid amide); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ = -OMe, X = -CH = CH-, Y = -CO-NH-group, Z = -CH ₂ CH _2- , Q = -C ₆ H ₅ (in general formula (2), R ₁ = -OH, Y ₁ = -NH-, Z = _{-CH 2 CH 2 -, Q =} -C 6 H 5 , compound).
16 compounds (caffeic acid phenethyl ester); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ = -OH, X = -CH = CH-, Y = -CO-O- Group, Z = -CH ₂ CH _2- , Q = -C ₆ H ₅ (in general formula (2), R ₁ = -OH, Y ₁ = -O-, Z = -CH ₂ CH _2- , Q = -C ₆ H ₅ ).
17 compounds (N- (3-phenylpropyl) -4-hydroxy-3-methoxybenzamide); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =-OMe, X = simple Bond, Y = —CO—NH— group, Z = —CH ₂ CH ₂ CH ₂ —, Q = —C ₆ H ₅ (in general formula (3), R ₁ = −OMe, Y ₁ = − NH-, Z = -CH ₂ CH ₂ CH _2- , Q = -C ₆ H ₅ compound).
18 compounds (3-phenyl-2-propenyl 4-hydroxy-3-methoxybenzoate); in general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =-OMe, X = single bond , Y = -CO-O-, Z = -CH 2 CH = CH-, Q = in -C ₆ H _5, compound (general formula _{(3), R 1 = -OMe} , Y 1 = -O-, _{Z = -CH 2 CH = CH-,} Q = -C 6 H 5 , compound).
19 compounds (N- (3-phenylpropyl)-(4-hydroxy-3-methoxyphenyl) acetamide); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ = -OMe, X = -CH _2- , Y = -CO-NH- group, Z = -CH ₂ CH ₂ CH _2- , Q = -C ₆ H ₅ (in general formula (4), Y ₁ = -NH _{-, Z = -CH 2 CH 2} CH 2 -, Q = -C 6 H 5 , compound).

20 compounds (N- (β-phenethyl) -3- (4-hydroxyphenyl) -2-propenamide); in the general formula (1), R ₁ = R ₂ = R ₃ = R ₄ = H, X =- CH = CH-, Y = -CO- NH- _{group, Z = -CH 2 CH 2 -} , in Q = -C ₆ H _5, compound (general formula _{(5), Y 1 = -NH-} , Z = _{-CH 2 CH 2 -, Q =} -C 6 H 5 , compound).
21 compounds (3- (4-hydroxyphenyl) -2-propenoic acid 3-phenyl-2-propenyl); in the general formula (1), R ₁ = R ₂ = R ₃ = R ₄ = H, X =- CH = CH—, Y = —CO—O— group, Z = —CH ₂ CH═CH—, Q = —C ₆ H ₅ (in general formula (5), Y ₁ = —O—, Z = —CH ₂ CH═CH—, Q = —C ₆ H ₅ ).
22 compounds (N- (3-phenyl) -4-hydroxybenzamide); in the general formula (1), R ₁ = R ₂ = R ₃ = R ₄ = H, X = single bond, Y = -CO- NH-group, Z = -CH ₂ CH ₂ CH _2- , Q = -C ₆ H ₅ (in formula (6), Y ₁ = -NH-, Z = -CH ₂ CH ₂ CH _2- , Q = -C ₆ H ₅ ).
23 compounds (capsaicin); in general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =-OMe, X = -CH _2- , Y = -NH-CO- group, Z =- (CH ₂ ) ₄ CH═C (CH ₃ ) CH ₂ —, Q = H (in formula (7), R ₁ = −OMe, Z = — (CH ₂ ) ₄ CH═C (CH ₃ ) Compounds where CH _2- , Q = H).
24 compounds (N- (4-hydroxy-3-methoxyphenyl) methyl-3-phenyl-2-propenamide); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =- OMe, X = —CH ₂ —, Y = —NH—CO— group, Z = —CH═CH—, Q = —C ₆ H ₅ (in formula (7), R ₁ = −OMe, Y ₁ = —CH ₂ —, Z = —CH═CH—, Q = —C ₆ H ₅ ).

25 compounds ([6] -gingerol); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =-OMe, X = -CH ₂ CH _2- , Y = -CO- group , Z = -CH ₂ CH (OH) (CH ₂ ) ₄ CH _2- , Q = H (in formula (8), Z ₁ =-(CH ₂ ) ₃ CH _2- , Q = H Some compounds).
26 compounds (curcumin); in general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ = -OMe, X = -CH = CH-, Y = -CO- group, Z = -CH _{2 A} compound wherein COCH = CH-, Q = 3-methoxy-4-hydroxyphenyl group (a compound wherein R ₁ = R ₂ = -OMe in the general formula (9)).
27 compounds (2- (3-indolyl) ethyl ferulate); in general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =-OMe, X = -CH = CH-, Y = -CO-O- group, Z = -CH ₂ CH _2- , Q = 3-Indolyl group (in general formula (2), R ₁ = -OMe, Y ₁ = -O-, Z = -CH ₂ CH _2- , Q = 3-indolyl group).
28 compounds (N- (3,4-dihydroxyphenyl) methyl-3-phenyl-2-propenamide); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ = -OH, X = —CH ₂ —, Y = —NH—CO— group, Z = —CH═CH—, Q = —C ₆ H ₅ (in formula (7), R ₁ = —OH, Y _{1 = -CH 2 -, Z = -CH} = CH-, Q = -C 6 H 5 , compound).
29 compounds (N- (3-phenylpropyl) -3,4-dihydroxybenzamide); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ = -OH, X = single bond, Y = —CO—NH— group, Z = —CH ₂ CH ₂ CH ₂ —, Q = —C ₆ H ₅ (in formula (3), R ₁ = —OH, Y ₁ = —NH— _{, Z = -CH 2 CH 2 CH} 2 -, Q = -C 6 H 5 , compound).

30 compounds (N-benzyl ferramide); in general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =-OMe, X = -CH = CH-, Y = -CO-NH- Group, Z = —CH ₂ —, Q = —C ₆ H ₅ (in general formula (2), R ₁ = −OMe, Y ₁ = −NH—, Z = —CH ₂ −, Q = − Compound that is C ₆ H ₅ ).
31 compounds (N- (3-phenylpropyl) ferramide); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ = -OMe, X = -CH = CH-, Y =- A compound in which CO—NH— group, Z = —CH ₂ CH ₂ CH ₂ —, Q = —C ₆ H ₅ (in the general formula (2), R ₁ = −OMe, Y ₁ = −NH—, Z = _{-CH 2 CH 2 CH 2 -,} Q = -C 6 H 5 , compound).
32 compounds (N- (4-phenylbutyl) -4-hydroxy-3-methoxybenzamide); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ =-OMe, X = simple A bond, Y = —CO—NH— group, Z = —CH ₂ CH ₂ CH ₂ CH ₂ —, Q = —C ₆ H ₅ (in general formula (3), R ₁ = −OMe, Y ₁ = —NH—, Z = —CH ₂ CH ₂ CH ₂ CH ₂ —, a compound in which Q = —C ₆ H ₅ ).
33 compounds (N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] -3-phenyl-2-propenamide); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ = —OMe, X = —CH ₂ CH ₂ —, Y = —NH—CO— group, Z = —CH═CH—, Q = —C ₆ H ₅ (in general formula (7) R ₁ = —OMe, Y ₁ = —CH ₂ CH—, Z = —CH═CH—, Q = —C ₆ H ₅ ).
34 compounds (N- [2- (3-indolyl) ethyl] caffeic acid amide); in the general formula (1), R ₁ = R ₃ = R ₄ = H, R ₂ = -OH, X = -CH = CH-, Y = -CO-NH- group, Z = -CH ₂ CH _2- , Q = 3-indolyl group (in general formula (2), R ₁ = -OH, Y ₁ = -NH -, Z = -CH ₂ CH _2- , Q = 3-indolyl group).

35 compounds (4'-hydroxychalcone); in the general formula (1), R ₁ = R ₂ = R ₃ = R ₄ = H, X = single bond, Y = -CO- group, Z = -CH = CH -, Q = -C ₆ H ₅ (in general formula (1b), R ₁ = R ₂ = R ₃ = R ₄ = R ₅ = R ₆ = R ₇ = R ₈ = R ₉ = H Compound).
36 compounds (isolithicigenin); in general formula (1), R ₁ = R ₂ = R ₃ = H, R ₄ = -OH, X = single bond, Y = -CO- group, Z = -CH = CH-, Q = -p-OH-C ₆ H ₅ (in general formula (1b), R ₁ = R ₂ = R ₃ = R ₅ = R ₆ = R ₈ = R ₉ = H, R ₄ = R ₇ = -OH compound).
37 compounds (xanthohumol); in the general formula (1), R ₁ = -OMe, R ₂ = H, R ₄ = -OH, R ₃ = -CH ₂ CH = C (CH ₃ ) _2, X = Single bond, Y = -CO- group, Z = -CH = CH-, Q = -p-OH-C ₆ H ₅ (in formula (1b), R ₁ = -OMe, R ₂ = R _{5 = R 6 = R 8 =} R 9 = H, R 4 = R 7 = -OH, R 3 = -CH 2 CH = C (CH 3) 2).
38 compounds (xanthoangelol); in the general formula (1), R ₁ = R ₂ = H, R ₄ = -OH, R ₃ = -CH ₂ CH = C (CH ₃ ) CH ₂ CH ₂ CH = C (CH ₃ ) ₂ , X = single bond, Y = —CO— group, Z = —CH═CH—, Q = —p—OH—C ₆ H ₅ (in general formula (1b), R ₁ = R ₂ = R ₅ = R ₆ = R ₈ = R ₉ = H, R ₄ = R ₇ = -OH, R ₃ = -CH ₂ CH = C (CH ₃ ) CH ₂ CH ₂ CH = C (CH ₃ ) A compound that is ₂ ,).
Compound 39 (lycochalcone A); in general formula (1), R ₁ = R ₂ = R ₃ = R ₄ = H, X = single bond, Y = -CO-group, Z = -CH = CH-, Q = -2-OCH ₃ -4-OH-5- (C (CH ₃ ) ₂ CH═CH ₂ ) C ₆ H ₅ (in formula (1b), R ₁ = R ₂ = R ₃ = R _{4 = R 6 = R 9 =} H, R 5 = OCH 3, R 7 = -OH, R 8 = - C (CH 3) 2 CH = CH 2, a compound).

  The unsaturated fatty acid used in the present invention is a naturally distributed fatty acid having 8 to 22 carbon atoms and having 1 to 6 double bonds, and docosahexaenoic acid and eicosapentaenoic acid contained in fish oil are particularly preferable. Used. Further, α-linolenic acid and oleic acid are also used, and gellanic acid and citronellic acid derived from terpenes contained in plants are also used. Furthermore, when applied to a living body, it is also used in the form of glycerides or ethyl esters which can be decomposed by lipase or esterase in the body. These unsaturated fatty acids and glycerides containing them are easily produced from fish oils, vegetable oils, microbial oils and the like by known methods. On the other hand, the phenolic compound according to the present invention condenses an appropriate derivative of ferulic acid or vanillic acid easily extracted from nature and the corresponding amine or alcohol by a known method such as an acid chloride method or a carbodiimide method. Can be easily manufactured. The synthesis method of phenolic compounds such as N- (β-phenethyl) ferramide (FAPA) used in the following examples is the same as described in JP-A-2005-225872, Japanese Patent Application No. 2005-61659, and Japanese Patent Application No. 2005-218519. It is. As a representative example, the synthesis method of FAPA is shown in Example 1. Further, compounds abundantly contained in plants such as curcumin, [6] -gingerol, and hydroxychalcone are easily extracted and produced from these plants by a known method. In this case, as long as there are no inconvenient impurities, it can be used as a crude extract or a partially purified product. Extraction can be easily performed with water or ethanol. On the other hand, the xanthine derivative used for further enhancing the production of adiponectin in combination with the compound represented by Formula 1 and unsaturated fatty acid is one or a mixture of theophylline, caffeine, or theobromine. is there. These can be extracted from tea leaves, coffee beans, cacao beans, etc., and can be easily synthesized by known methods. When used in the present invention, these may be mixed with the compound of formula 1 and an unsaturated fatty acid as a pure product or in the form of a crude extract such as tea or coffee. When used in the present invention, the amount of the compound of Formula 1 is adjusted within a physiologically safe range depending on the type of compound, the method and degree of purification, and the degree of effect required. For example, the amount of the compound of formula 2 is set to several mg or less per 1 ml of drinking water or 1 g of food, but it is appropriately increased or decreased within a physiologically safe range depending on the total intake amount and the intake form. The amount of unsaturated fatty acid such as DHA is appropriately determined within the physiologically safe range with reference to the amount actually used as a health food, etc., but as detailed above, the phenolic compound of the present invention It is possible to reduce the weight because it is used as a mixture. Moreover, about the addition amount of a xanthine derivative, it shall apply to the density | concentration contained in coffee and green tea used regularly. That is, caffeine is 0.1 mg to 0.5 mg (about 3 mM) per gram of drinking water or 1 g of food, theophylline is 0.01 mg to 0.05 mg (about 0.3 mM) per liter of drinking water or 1 g of food, and theobromine is drinking. The standard is 0.1 mg to 2 mg (about 10 mM) per gram of water or 1 g of food, but the dosage should be adjusted appropriately within a physiologically safe range depending on the total intake and form. Next, the present invention will be described in more detail based on examples.

Preparation of N- (β-phenethyl) ferramide (FAPA) 30 g of O-acetylferulic acid chloride synthesized by a known method was dissolved in 350 ml of toluene. This solution was placed in a dropping funnel and added to a solution obtained by mixing 25 ml of β-phenethylamine and 50 ml of pyridine in 100 ml of toluene with ice cooling and stirring. After addition of the entire amount, the ice bath was removed and the mixture was stirred overnight at room temperature. The reaction was divided into 2 portions, put into a separatory funnel, 500 ml of ethyl acetate was added, 150 and 100 ml of water, 150 and 100 ml of 10% aqueous citric acid solution, 150 and 100 ml of 10% aqueous NaHCO ₃ solution, 100 and 50 ml of saturation Washed sequentially with aqueous NaCl solution. The organic layers were combined, dried over Na ₂ SO ₄ and concentrated on a rotary evaporator. The resulting candy-like substance was recrystallized from ethyl acetate to obtain 32.6 g of O-acetyl-N- (β-phenethyl) ferramide. . This whole amount was dissolved in 500 ml of ethanol, and 12 ml of hydrazine monohydrate was added and left at room temperature for 1 hour. Next, 12 ml of acetic acid was added, and 500 ml of ethyl acetate and 100 ml of water were added to the residue concentrated by a rotary evaporator, and shaken vigorously in a separatory funnel. The organic layer was washed with 200 ml of saturated aqueous sodium chloride twice, dried over sodium sulfate, and the oil concentrated on a rotary evaporator was crystallized from benzene to give 28.3 g of N- (β-phenethyl) ferramide (FAPA) Among them, 12.7 g was recrystallized from ethanol to obtain 10.6 g of needle-like crystals (melting point: 153 to 154 ° C.). MS m / z: 297.1355 (M +) (. Calcd C 18 H 19 NO 3 = 297.1364). Further, the NMR spectrum showed the following signal, which confirmed the expected structure. ¹ H-NMR (CDCl ₃ ) δ: 2.889 (2H, t, J = 7 Hz, CH ₂ ), 3.664 (2H, dt, J = 7 and 6 Hz, CH ₂ ), 3.903 (3H, s, OMe) , 5.597 (1H, t, J = 6 Hz, NH), 5.896 (1H, s., OH), 6.173 (1H, d, J = 15.5 Hz, C H = CH), 6.894 (1H, d, J = 8 Hz, H-5), 6.968 (1H, d, J = 2 Hz, H-2), 7.041 (1H, dd, J = 8 and 2 Hz, H-6), 7.2-7.4 (5H, m, phenyl), 7.539 (1H, d, J = 15.5 Hz, CH = C H ).

After 3 days pre-culture in DMEM medium containing mouse 3T3-L1 preadipocyte cell line (Dainippon Pharmaceutical purchased from Ltd.) with 10% fetus bovine serum (FBS), were collected in EDTA- trypsin solution, 6 x 10 ⁴ As a cell / ml suspension, 0.2 ml per well was inoculated into a 96-well multiwell plate previously coated with collagen. After culturing for 3 days, the medium (DMEM medium containing 10% fetal bovine serum) is replaced with 0.2 ml of fresh medium with or without 10 μM or 100 μM docosahexaenoic acid (Cayman, abbreviated as DHA), and then β -Ethanol solution of phenethyl ferramide (FAPA) (0.01, 0.1, 1 mM) was added in 2 μl increments. The same amount of pure ethanol was added to the control. After culturing for 9 days, accumulation of intracellular fat globules in the sample addition well was confirmed with a phase contrast microscope, and the medium was collected. The concentration of adiponectin in the medium was quantified by ELISA (Otsuka Pharmaceutical Mouse / Rat Adiponectin ELISA Kit). The results are shown in FIG. 1, and it can be seen that when a mixture of FAPA and DHA is added at the same time, a large amount of adiponectin is produced in excess of the sum of adiponectin production alone.

The same experiment as in Example 2 was performed using feruloyl tyramine (Fer-Tyr) instead of FAPA, and changing the DHA concentration to three steps of 10, 30, and 100 μM. The results are shown in FIG. 2, and the amount of adiponectin produced, which was about 5 ng / ml with Fer-Tyr alone, increased nearly 15-fold to 73.3 ng / ml with the addition of 30 μM DHA. From the DHA side, the production of 4.4 ng / ml with 30 μM alone increased 17-fold with the addition of 10 μM Fer-Tyr.
FIG. 3 shows the results of experiments similar to those described above in which 30 μM DHA was combined with other various phenolic compounds.
In addition, FIG. 4 and FIG. 5 show the results of similar experiments using various phenolic compounds, 10 μM eicosapentaenoic acid (manufactured by Cayman, abbreviated as EPA) as a highly unsaturated fatty acid, and DHA, respectively. .
Furthermore, in addition to DHA and EPA as unsaturated fatty acids, various unsaturated fatty acids such as α-linolenic acid and conjugated linolenic acid (CL1) are added in the form of free acid or in the form of triglycerides or ethyl esters. It is shown in FIG. In any case including the case of triglyceride and ethyl ester, it was confirmed that a large amount of adiponectin was produced by simultaneous addition of unsaturated fatty acid and phenolic compound than when each was used alone.

Normal human preadipocytes (manufactured by Sanko Junyaku) are pre-cultured for 4 days in PBM medium (PBM growth medium, PBM is Sanko Junyaku) supplemented with 10% FBS and 2 mM glutamine, and then the cells are EDTA-trypsin solution And suspended in PBM growth medium at a rate of 7.5 × 10 ⁴ cells / ml, and each 0.2 ml was planted in a 96-well plate previously coated with collagen. After culturing at 37 ° C. for 3 days in the presence of 5% CO ₂ , the medium is further added to the PBM basic differentiation medium [PBM growth medium supplemented with insulin (10 μg / ml) and dexamethasone (0.1 μM)] The medium was replaced with a medium supplemented with or without added unsaturated fatty acid or pioglitazone (Alexis Biochemicals, abbreviated as PGZ) (0.2 ml / well). 2 μl of ethanol solutions of various phenolic compounds were added to each well. Only 2 μl of ethanol was added to the control. After incubation for 12 days, the medium was collected, and adiponectin was quantified by ELISA (Otsuka Pharmaceutical, ELISA kit for human adiponectin). The results are shown in FIG. From this result, even in the case of human preadipocytes, the simultaneous addition of polyunsaturated fatty acids such as DHA and EPA and phenolic compounds such as FAPA and Fer-Tyr induces adiponectin production in a larger amount than in the case of each alone. It was confirmed that Adiponectin production by PGZ is also synergistically enhanced by phenolic compounds such as FAPA, but depending on the type and concentration, the combination of unsaturated fatty acid and phenolic compound may be stronger than the combination containing PGZ. This is also shown in FIG.

  Normal human preadipocytes are cultured in a 96-well plate for 3 days in the same manner as in Example 4, and the medium contains either the fresh PBM basal differentiation medium, 30 μM DHA or 500 μM caffeine, or both. The medium was replaced with PBM basic differentiation medium (0.2 ml / well). Subsequently, 2 μl of an ethanol solution of FAPA or Fer-Tyr (compound 12) was added to each of these wells, incubated for 13 days, the medium was collected, and adiponectin was quantified by ELISA. The results are shown in FIG. From this result, the adiponectin production enhancing action of FAPA is enhanced when either caffeine or DHA is present, but can be further enhanced when both are present (ie, in the coexistence of FAPA, DHA, and caffeine). Recognize. A similar effect of three-party coexistence was also observed for Fer-Tyr.

  As in Example 2, FAPA (10 μM), feruloyl tyramine (Fer-Tyr, 100 μM), feruloyl tryptamine (Fer-Trp, 30 μM), β-phenethyl ferrate (FAPE, 30 μM) or [6] -Gingerol (manufactured by Wako Pure Chemicals, 30 μM), gellanic acid (Sigma, 50 μM), farnesic acid (Echelon Biosciences, 10 μM), citronellic acid (Tokyo Kasei, 100 μM), 2 -Experiments were conducted to enhance adiponectin production in 3T3-L1 cells in combination with either octenoic acid [Tokyo Kasei, 100 μM] or 2-dodecenoic acid [Tokyo Kasei, 100 μM]. The results are shown in FIG. 9 and FIG. It is confirmed that when these unsaturated fatty acids having 8 to 15 carbon atoms are added at the same time as a phenolic compound such as FAPA, the production of adiponectin more than the sum of the production amounts when used alone is confirmed. It was done. For reference, the experimental results using pioglitazone are also shown in FIG.

  In the same manner as in Example 4, FAPA (30 μM) was combined with gellanic acid (100 μM) or farnesic acid (100 μM), and experiments were conducted on enhancement of adiponectin production in human preadipocytes. The results are shown in FIG. These unsaturated fatty acids were confirmed to enhance the adiponectin producing action of FAPA.

  In the same manner as in Example 2, [6] -gingerol (10 μM) or curcumin (BIOMOL, 10 μM) was combined with DHA (10 μM), and experiments were conducted to enhance adiponectin production in 3T3-L1 cells. The results are shown in FIG. 12A. In the same manner as in Example 4, [6] -gingerol (10 μM) or curcumin (10 μM) was combined with DHA or EPA (both 100 μM), and experiments were conducted on the enhancement of adiponectin production in normal human preadipocytes. The results are shown in FIG. 12B. From these results, it was confirmed that DHA and EPA enhance adiponectin production by gingerol and curcumin.

  As in Example 2, xanthohumol (abbreviated as Xhum, manufactured by Alexis), 4′-hydroxychalcone (4′-OH-C., Manufactured by Wako Pure Chemical Industries), xanthoangelol (Xang, stem of tomorrow) , Extracted from the root (Mitsubishi Ozawa et al., Pharmaceutical Journal, 98, 210-214, 1978), purified and crystallized], Licochalcone A (LicoA, manufactured by CALBIOCHEM), or isoliquiritigenin (Isoliq , Extrasynthese, Inc.) were combined with either docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA), and experiments were conducted to enhance adiponectin production in 3T3-L1 cells. The results are shown in FIG. 13 and FIG. 14, and it was confirmed that these chalcones alone enhance the production of adiponetin and further enhance them when unsaturated fatty acids such as docosahexaenoic acid are added simultaneously. In addition, although the experimental result using pioglitazone is also shown for reference, it is understood that chalcones enhance the adiponectin production enhancing action of pioglitazone.

  In the same manner as in Example 4, 4'-hydroxychalcone was combined with docosahexaenoic acid or pioglitazone, and an experiment for enhancing adiponectin production in human preadipocytes was performed. The results are shown in FIG. It was confirmed that 4'-hydroxychalcone enhances the adiponectin producing action of docosahexaenoic acid and pioglitazone.

KK-Ay / Ta Jc1 mice genetically developing type 2 diabetes (male, 5 weeks old, 16 animals, manufactured by Claire Japan), N- (β-phenethyl) ferramide (abbreviated as FAPA) and / or docosahexaene Body weight, food intake, fed for 4 weeks with or without acid-enriched fat (DHA-70G, Nippon Chemical Feed Co., Ltd., 70% DHA in all fatty acids) And blood glucose level etc. were measured regularly. In addition, the feed was based on A-13251 low fat diet powder feed manufactured by Claire Japan, and each component was mixed in the proportions shown in Table 1, but the total fat content was 5% (w / w) in each group. In the DHA group and the FAPA + DHA group, the DHA fat content is 4% (w / w) and the FAPA content is 0.3% (w / w). FAPA was dissolved in the amount of ethanol shown in Table 1 and added. The mixed feed was placed in a plastic container with a capacity of 50 cc in units of 32 g, repeatedly degassed under reduced pressure and replaced with nitrogen gas, then sealed and stored in a refrigerator. The mice were individually raised in groups of 4 and were usually fed with 8g of fresh feed per mouse in a powder feeder every day. The leftovers were collected and sieved to feces, flooring, etc., weighed, and the amount of food consumed was calculated from the difference from the amount of food fed. As water, tap water sterilized by an autoclave was freely ingested. The measurement results of body weight and food intake are summarized in Table 2. When DHA oil was added, the amount of food consumed was reduced by about 20% compared to the control, but the body weight was only about several to 10% smaller than that of the control group. During the breeding period, body weight continued to increase almost constantly in all groups.

  Plasma (plasma) for measuring blood glucose and adiponectin is collected approximately 9 μl of blood from the tip of the mouse tail once a week, and immediately mixed with 3 μl of heparin solution (50 mg / ml) and centrifuged. It was prepared by removing blood cells at (12000 rpm, 12 minutes). The glucose and triglyceride concentrations in the plasma were measured with glucose CII-Test Wako and triglyceride E-Test Wako (both manufactured by Wako Pure Chemical Industries, Ltd.), respectively. On the other hand, 2 μl of plasma was mixed with 8 μl of water and 10 μl of 2 × SDS buffer, and then heat-treated at 95 ° C. for 5 minutes to prepare an electrophoresis sample. Detection of adiponectin by electrophoresis using polyacrylamide gel (applying 2 μl of each lane) and Western blotting was performed by a conventional method. The primary antibody used was mouse anti-adiponectin, mouse monoclonal antibody (Catalog No. MAB3608) manufactured by Chemicon, and the secondary antibody was rabbit anti-mouse Ig G1-HRP conjugate (Catalog No. 61- 0120). For detection of the band, an ECL Plus measurement kit manufactured by Pharmacia was used. Moreover, about the gel after electrophoresis, the part with a molecular weight of about 80,000 was dye | stained with the CBB reagent, and serum albumin was detected. These bands were loaded into a personal computer as an image with a scanner, and the density of the bands was digitized with a gel pro analyzer (software, BioRad). From these values, the relative level of adiponectin in blood based on serum albumin was determined. The results are shown in FIG. FIG. 16A shows that the plasma glucose concentration of the mice in the FAPA + DHA group is significantly lower than that in the control group for 2 to 5 weeks after the start of feeding. On the other hand, the mice in the DHA single group also showed a lower average value than the control group, but only the values at the 4th week (31st day) were significantly lower. Therefore, the increase in blood glucose due to the onset of diabetes was suppressed by DHA, but it was confirmed that the effect became more remarkable by the simultaneous addition of FAPA. Fig. 16B shows the results of plasma triglyceride measurement. In this case, the FAPA + DHA group showed significantly lower values than the control group and the FAPA alone group, as well as the DHA alone group. A synergistic effect of DHA was confirmed. Further, FIG. 16C shows the measurement result of blood adiponectin, and the FAPA + DHA group showed the highest value, and the value on the 24th day was significantly higher than the value of the DHA single group. Therefore, the synergistic effect of FAPA and DHA was also confirmed regarding the increase in blood adiponectin level.

1 kg of ginger rhizome dry chips (made by Uchida Wakahan Yakuhin Co., Ltd.) was mixed with 0.6 g of ethanol every 250 g, and pulverized and extracted with a mixer at room temperature. Insoluble matter was collected by filtration and extracted again with 0.6 liter of ethanol. The ethanol solutions were combined and concentrated with a rotary evaporator to obtain 60 g of a crude extract as an oil. The total amount of this extract was re-extracted with 1 liter of hexane-ethyl acetate (4: 1), and insoluble matter was removed by filtration. The solvent of the extract was removed, the residue was dissolved in 0.65 liters of methanol, 1.5 liters of hexane was added, and after partitioning, the upper layer solvent was distilled off to obtain 39 g of gingerol-containing extract (SG). As shown in Table 3, KK-Ay / Ta Jc1 mice (male, 5 weeks old, 12 mice, 4 groups in 3 groups) using feed prepared by mixing with A-13251 powder and fat as shown in Table 3 And the same experiment as in Example 11 was conducted. The total fat content in each group feed is 5% (w / w), the DHA fat content in the DHA group and SG + DHA group feed is 3% (w / w), and the SG content is 0.5% (w / w).

Changes in body weight and food intake are summarized in Table 4. In the case of a feed containing only SG or only DHA oil and fat, both food intake and body weight were usually suppressed by about 10% from the control group. On the other hand, when both SG and DHA fat were added, food intake was suppressed by 20% and body weight was suppressed by 15-20%. However, even in that case, weight continued to increase slowly. The results of measurement of plasma glucose, triglyceride concentration and adiponectin level are shown in FIG. 17, but the glucose and triglyceride concentrations were significantly lower in the SG and DHA simultaneous administration groups than in the single administration group and the control group. The adiponectin level was also significantly higher in the co-administered group than in the control group and the SG alone group, and also tended to be higher than in the DHA alone group, but in particular the value on the 30th day was significantly higher than that in the DHA group It was. These results indicate that SG and DHA work synergistically in enhancing adiponectin production and decreasing blood glucose and blood lipid levels.

Instead of DHA, Eicosapentaenoic acid (EPA) concentrated fat (EPA-45G, manufactured by Nippon Chemical Feed Co., Ltd., 45% of EPA in the total fatty acids contained) is used together with FAPA or the above ginger extract (SG The same experiment as in Example 11 was performed using the feed mixed with). Table 5 shows the composition of the feed, Table 6 shows the body weight and food intake data of the mice (3 mice in each group), and Table 7 shows the measurement results of plasma glucose, triglyceride concentration and adiponectin level 30 days after the start of feeding. It is summarized.

  Although there was no statistically significant difference from the control group in this experimental result, the blood glucose level was lowest in the SG and EPA group, and the plasma triglyceride level was the lowest in the FAPA and EPA group. It was. In addition, the SG + EPA group showed significantly higher (p <0.05) adiponectin levels than the SG alone group, and also showed higher adiponectin levels than the EPA alone group, although not statistically significant. These results indicate that EPA enhances adiponectin production and its effect on improving blood glucose and plasma triglyceride levels tends to be enhanced in the presence of SG or FAPA.

この結果から、生姜抽出物とDHAに更にカフェインを配合すると、前2者のみの場合よりも血糖、血中トリグリセリド濃度ともに一層低下することがわかる。 The same experiment as in Example 11 was performed using the feed obtained by mixing the above-described ginger extract (SG), DHA concentrated oil and fat, and caffeine. Table 8 shows the composition of the feed, Table 9 shows the weight and food intake data of the mice (3 mice in each group), and Table 10 shows the measurement results of plasma glucose, triglyceride concentration and adiponectin level on the 36th day after the start of feeding. It is summarized. In this table, among the asterisks attached to the SG + DHA + caffeine group data, ** 1 is significantly lower than the control group (p <0.01), and * 2 is significant for the SG + DHA group Is low (p <0.05), and ** 3 is significantly lower (p <0.01) than the caffeine alone group. In addition, † 1 indicates that the adiponectin level is significantly higher (p <0.01) than the control group.

From this result, it can be seen that when caffeine is further added to the ginger extract and DHA, both the blood glucose level and the blood triglyceride concentration are further reduced as compared with the former two cases alone.

[Reference Example 1]
Tables 11 to 13 show the results of animal experiments using combinations of ginger extract (SG) and caffeine alone as reference examples. The type of mouse and the experimental method are the same as described above except for the concentrations of SG and caffeine. In Table 13, the asterisks ** 1, ** 2, and ** 3 attached to the SG + caffeine group data are significantly lower (p <0.01) than the values of the control group, SG alone group, and caffeine alone group, respectively. † 1, † 2, and † 3 indicate that the adiponectin level is significantly higher (p <0.01) than the control group, the SG single group, and the caffeine single group, respectively. From these results, it can be seen that the combined use of SG and caffeine lowers the blood triglyceride concentration and raises the adiponectin level more than each use alone.

Concentration of adiponectin secreted into the medium when docosahexaenoic acid (DHA) and β-phenethylferramide (FAPA, compound 10) were added to mouse 3T3-L1 preadipocytes alone or simultaneously (average of two wells) And standard deviation). DHA and FAPA concentrations (μM) are shown in the figure. Concentration of adiponectin secreted into the medium when DHA and feruloyltyramine (Fer-Tyr, compound 12) were added to mouse 3T3-L1 preadipocytes alone or simultaneously (average of three wells and standard deviation) It is a graph which shows. DHA and Fer-Tyr concentrations (μM) are shown in the figure. Concentration of adiponectin secreted into the culture medium when 30 μM DHA and various phenolic compounds (30 μM, 10 μM for compound 18, 100 μM for capsaicin) were added to mouse 3T3-L1 preadipocytes alone or simultaneously. It is a graph which shows (average and standard deviation of 3 wells). Compounds 17, 20, 22, 24, 18, 27, 21, 15 are respectively N- (3-phenylpropyl) -4-hydroxy-3-methoxybenzamide, N- (β-phenethyl) -3- (4-hydroxy Phenyl) -2-propenamide, N- (3-phenyl) -4-hydroxybenzamide, N- (4-hydroxy-3-methoxyphenyl) methyl-3-phenyl-2-propenamide, 4-hydroxy-3- 3-phenyl-2-propenyl methoxybenzoate, 2- (3-indolyl) ethyl ferulate, 3-phenyl-2-propenyl 3- (4-hydroxyphenyl) -2-propenoate, N- (β-phenethyl) Caffeic acid amide. In addition, uM displayed in the figure is a unit of concentration and is synonymous with μM. Concentration of adiponectin secreted into the medium when 10 μM eicosapentaenoic acid (EPA) and various phenolic compounds (concentrations are shown in the figure) were added to mouse 3T3-L1 preadipocytes alone or simultaneously. It is a graph which shows (average and standard deviation of 3 wells). Compounds 11, 12, 13, and 16 are feruloyltryptamine, feruloyl tyramine, β-phenethyl ferrate, and caffeic acid phenethyl ester, respectively. Mouse 3T3-L1 preadipocytes were cultured with 10 μM DHA or eicosapentaenoic acid (EPA) and various phenolic compounds (concentrations shown in the figure, unit uM is synonymous with μM), either alone or simultaneously. FIG. 4 is a graph showing the concentration of adiponectin (average and standard deviation of two wells) sometimes secreted into the medium. Compounds 12, 28, 29, 34, 19, 30, 31, 32 and 33 are respectively feruloyl tyramine, N- (3,4-dihydroxyphenyl) methyl-3-phenyl-2-propenamide, N- (3- Phenylpropyl) -3,4-dihydroxybenzamide, N- [2- (3-indolyl) ethyl] caffeic acid amide, N- (3-phenylpropyl)-(4-hydroxy-3-methoxyphenyl) acetamide, N -Benzylferramide, N- (3-phenylpropyl) ferramide, N- (4-phenylbutyl) -4-hydroxy-3-methoxybenzamide, N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] -3-Phenyl-2-propenamide. In mouse 3T3-L1 preadipocytes, 30 μM compound 10 (FAPA) and 0.1 μM pioglitazone or unsaturated fatty acid or triglyceride or ethyl ester thereof (concentration is shown in the figure, unit uM is the same as μM), either alone or It is a graph which shows the density | concentration (average and standard deviation of two wells) of the adiponectin secreted in the culture medium when adding and culture | cultivating simultaneously. The meanings of the abbreviations for unsaturated fatty acids are as follows. n3DPA, (n-3) docosapentaenoic acid (7Z, 10Z, 13Z, 16Z, 19Z-docosapentaenoic acid); 18: 1, oleic acid; 18: 2, linoleic acid; 18: 3, α-linolenic acid; CLA1 Conjugated linolenic acid (9Z, 11E-octadecadienoic acid); DHAee, DHA ethyl ester; n3DPAee, (n-3) docosapentaenoic acid ethyl ester. Adiponectin concentration (2 wells) secreted into the medium when DHA, EPA, or arachidonic acid and various phenolic compounds (concentrations are shown in the figure) were added to human preadipocytes alone or simultaneously. It is a graph which shows (average and standard deviation). For comparison, the results of experiments using pioglitazone (PGZ) are also displayed. The description of the compounds 10 to 13 is the same as described above. (a) shows the concentration of adiponectin secreted into the medium when two or three of compound 10 (FAPA), DHA, and caffeine are added to human preadipocytes and cultured. It is a graph which shows the average and standard deviation of a well. The concentration of each compound is described in the figure, but the unit uM is synonymous with μM. (B) is a graph showing the results of measuring the adiponectin concentration by conducting the same experiment as (a) using Compound 12 (Fer-Tyr). Mouse 3T3-L1 preadipocytes with 10 μM FAPA or 100 μM Fer-Tyr separately or simultaneously with unsaturated fatty acids with 8 to 15 carbon atoms (name and concentration shown in the figure, unit uM is synonymous with μM) It is a graph which shows the density | concentration (average and standard deviation of two wells) of the adiponectin secreted in the culture medium when adding and culture | cultivating. For comparison, results of experiments using pioglitazone (PGZ, 0.1 μM) are also shown. Mouse 3T3-L1 preadipocytes were treated with 30 μM feruloyltryptamine (Fer-Trp), β-phenethylferrate (FAPE), or [6] -gingerol as an unsaturated fatty acid (name and concentration shown in the figure). uM is the same as μM) and is a graph showing the concentration (average and standard deviation of two wells) of adiponectin secreted into the medium when cultured separately or simultaneously. A graph showing the concentration of adiponectin secreted into the medium (average and standard deviation of two wells) when 30 μM FAPA was added to human preadipocytes separately or simultaneously with 100 μM gellan acid or farnesic acid. is there. A: Concentration of adiponectin secreted into the medium when cultured in mouse 3T3-L1 preadipocytes with 10 μM gingerol or 10 μM curcumin alone or simultaneously with 10 μM docosahexaenoic acid (DHA) (2 wells) It is a graph which shows (average and standard deviation). B: Concentration of adiponectin secreted into the medium when cultured in human preadipocytes with 10 μM gingerol or 10 μM curcumin alone, or with 100 μM docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) It is a graph which shows (the average and standard deviation of two wells). “No PUFA” means that neither DHA nor EPA is added. Mouse 3T3-L1 preadipocytes can be treated with 10 μM xanthoangelol (Xang), 10 μM xanthohumol (Xhum), or 30 μM 4′-hydroxychalcone (4′-OH-C.) Alone or 10 Or graph showing the concentration of adiponectin secreted into the medium (average and standard deviation of two wells) when incubated with 30 μM docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) or 0.1 μM pioglitazone. It is. The number on the horizontal axis in the figure is the concentration (μM). When cultured in mouse 3T3-L1 preadipocytes with 10 μM lycochalcone A (LicoA), 10 or 30 μM isoliquiritigenin (Isoliq) alone or simultaneously with 10 μM docosahexaenoic acid (DHA) FIG. 2 is a graph showing the concentration of secreted adiponectin (average and standard deviation of two wells). The number on the horizontal axis in the figure is the concentration (μM). Concentration of adiponectin secreted into the medium when 30 μM 4′-hydroxychalcone (4′-OH-Chal.) Was added to human preadipocytes separately or simultaneously with 10 μM docosahexaenoic acid or 0.1 μM pioglitazone It is a graph which shows (the average and standard deviation of two wells). Relative value of plasma glucose concentration (A), triglyceride concentration (B), and blood adiponectin level (C) in KK-Ay / TaJc1 mice fed with diet supplemented with 0.3% FAPA and / or 4% DHA-enriched oil ). The blood collection days are the 17th, 24th, 31st, and 37th days of feeding, and the average values are indicated by white, diagonal lines, double diagonal lines, and black bars, respectively. Error bars are standard deviations (n = 12 for A and B, n = 8-12 for C). In C, the average value indicated by the control group was 1. The * mark in the table indicates that it is significantly lower (A, B) or significantly higher (C) than the corresponding value in the control group (p <0.05). In addition, the † marks on the bars of the FAPA + DHA group are significantly lower (B) or significantly higher (C) than the corresponding values of the DHA single group (p <0.05). Plasma glucose concentration (A), triglyceride concentration (B), and blood adiponectin level in KK-Ay / TaJc1 mice fed with diets supplemented with 0.5% ginger extract (SG) and / or 3% DHA concentrate Relative value of (C). The blood collection days are the 16th, 23rd, 30th, and 35th days from the start of feeding, and the average values are indicated by white, diagonal lines, double diagonal lines, and black bars, respectively. Error bars are standard deviations (n = 9 for A and B, n = 8-12 for C). In C, the average value indicated by the control group was 1. The * mark in the table indicates that it is significantly lower (A, B) or significantly higher (C) than the control (p <0.05). An asterisk added to the value of the SG + DHA group indicates that it is significantly smaller than any of the corresponding values of the SG single group and the DHA single group (p <0.05). (C) indicates that the † mark given to the value on the 30th day in the SG + DHA group is significantly larger than the corresponding value in the DHA single group (p <0.05).

Claims (36)

It enhances adiponectin production in animal adipocytes, comprising a phenolic compound represented by the following general formula (1) and an unsaturated fatty acid having 8 to 22 carbon atoms or a glyceride or lower alkyl ester thereof as active ingredients: Promoting drugs.

(In the formula 1, R ₁ , R ₂ , R ₃ and R ₄ represent a hydrogen atom (H), a hydroxyl group, an alkoxy group, or an alkyl or alkenyl group having 1 to 20 carbon atoms, and X is a single bond or Represents a divalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, and Y represents an amide group (—CO—NH— or —NH—CO—), an ester group (—CO—O— or —O—CO—), Or a carbonyl group (—CO—), wherein Z is a hydroxyl group, an alkoxy group, an oxo group, a carboxyl group, an amino group or an unsubstituted divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms. Q represents a hydrogen atom (H), a hydroxyl group, an oxo group, an alkoxy group, an amino group, an alkyl group or an alkenyl group having 1 to 10 carbon atoms, or an unsubstituted aromatic hydrocarbon group or a heterocyclic group. Represents a cyclic group.)   The drug according to claim 1, wherein the glyceride is an ester formed by binding at least one of unsaturated fatty acids having 8 to 22 carbon atoms with glycerol.   The agent according to claim 1, wherein the lower alkyl ester is an ethyl, methyl, propyl, or butyl ester of an unsaturated fatty acid having 8 to 22 carbon atoms.   The unsaturated fatty acid having 8 to 22 carbon atoms is 4Z, 7Z, 10Z, 13Z, 16Z, 19Z-docosahexaenoic acid, 4Z, 7Z, 10Z, 13Z, 16Z-docosapentaenoic acid, 7Z, 10Z, 13Z, 16Z, 19Z- Docosapentaenoic acid, 5Z, 8Z, 11Z, 14Z, 17Z-eicosapentaenoic acid, arachidonic acid, 6Z, 9Z, 12Z, 15Z-octadecatetraenoic acid, α-linolenic acid, linoleic acid, oleic acid, myristolein Acid (cis-9-tetradecenoic acid), 2-dodecenoic acid, 2-decenoic acid, 3-decenoic acid, 2-octenoic acid, geranic acid (trans-3,7-dimethyl-2,6-octadienoic acid), citronel Acid (trans-3,7-dimethyl-6-octenoic acid) or farnesic acid [(2E, 6E, 10E) -3,7,11-trimethyl-2,6,10-dodecatrienoic acid] Or the medicine in any one of Claims 1-3 characterized by the above-mentioned.   Furthermore, the chemical | medical agent in any one of Claims 1-4 containing the 1 or 2 or more xanthine derivative chosen from caffeine, theophylline, or theobromine. The drug according to any one of claims 1 to 5, wherein the phenolic compound represented by the general formula (1) is a derivative of ferulic acid or caffeic acid represented by the following general formula (2).

(In the formula 2, R ₁ is a hydroxyl group or a methoxy group, Y ₁ is an imino group (NH) or an oxygen atom (O), and Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms. Q represents a hydrogen atom (H), an aromatic hydrocarbon group or a heterocyclic group which may be substituted with a hydroxyl group or an amino group. The drug according to any one of claims 1 to 5, wherein the phenolic compound represented by the general formula (1) is a derivative of vanillic acid or protocatechuic acid represented by the following general formula (3).

(In the formula 3, R ₁ is a hydroxyl group or a methoxy group, Y ₁ is an imino group (NH) or an oxygen atom (O), and Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms. , Q represents a hydrogen atom (H), an aromatic hydrocarbon group or a heterocyclic group which may be substituted with a hydroxyl group or an amino group. The drug according to any one of claims 1 to 5, wherein the phenolic compound represented by the general formula (1) is a homovanillic acid derivative represented by the following general formula (4).

(In the formula 4, Y ₁ is an imino group (NH) or an oxygen atom (O), Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and Q is a hydrogen atom (H), or (Represents an aromatic hydrocarbon group or a heterocyclic group which may be substituted with a hydroxyl group or an amino group.) The drug according to any one of claims 1 to 5, wherein the phenolic compound represented by the general formula (1) is a derivative of p-coumaric acid represented by the following general formula (5).

(However, in Formula 5, Y ₁ is an imino group (NH) or an oxygen atom (O), Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and Q is a hydrogen atom (H), or (Represents an aromatic hydrocarbon group or a heterocyclic group optionally substituted with a hydroxyl group or an amino group.) The drug according to any one of claims 1 to 5, wherein the phenolic compound represented by the general formula (1) is a derivative of p-hydroxybenzoic acid represented by the following general formula (6).

(In formula 6, Y ₁ is an imino group (NH) or an oxygen atom (O), Z is a divalent aliphatic hydrocarbon group having 1 to 10 carbon atoms, and Q is a hydrogen atom (H), or (Represents an aromatic hydrocarbon group or a heterocyclic group optionally substituted with a hydroxyl group or an amino group.) The drug according to any one of claims 1 to 5, wherein the phenolic compound represented by the general formula (1) is a vanillylamine derivative represented by the following general formula (7).

(Wherein, R ₁ in Formula 7 is a hydroxyl group or a methoxy group, Y ₁ is a divalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, Z is a divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms Q represents a hydrogen atom (H), an aromatic hydrocarbon group or a heterocyclic group which may be substituted with a hydroxyl group or an amino group. The drug according to any one of claims 1 to 5, wherein the phenolic compound represented by the general formula (1) is gingerol represented by the following general formula (8) or an analog thereof.

(In Expression 8, Z ₁ is a divalent aliphatic hydrocarbon group having 1 to 11 carbon atoms, Q is a hydrogen atom (H), a or may be substituted by a hydroxyl group or an amino group, an aromatic hydrocarbon Represents a hydrogen group or a heterocyclic group.) The drug according to any one of claims 1 to 5, wherein the phenolic compound represented by the general formula (1) is curcumin represented by the following general formula (9) or a derivative thereof.

(However, in Formula 9, R ₁ and R ₂ represent a hydrogen atom or a methoxy group.)   The compound represented by the general formula (2) is N- (β-phenethyl) ferramide, feruloyltryptamine, feruloyltyramine, β-phenethylferrate, 3-phenyl-2-propenyl ferulate, N- (β- It is selected from phenethyl) caffeic acid amide, caffeic acid phenethyl ester, 2- (3-indolyl) ethyl ferulate, N-benzyl ferramide, and N- (3-phenylpropyl) ferramide The drug according to claim 6.   The compound represented by the general formula (3) is N- (3-phenylpropyl) -4-hydroxy-3-methoxybenzamide, 4-phenyl-3-methoxybenzoate 3-phenyl-2-propenyl, N- ( The drug according to claim 7, wherein the drug is selected from 3-phenylpropyl) -3,4-dihydroxybenzamide and N- (4-phenylbutyl) -4-hydroxy-3-methoxybenzamide.   9. The drug according to claim 8, wherein the compound represented by the general formula (4) is N- (3-phenylpropyl)-(4-hydroxy-3-methoxyphenyl) acetamide.   The compound represented by the general formula (5) is N- (β-phenethyl) -3- (4-hydroxyphenyl) -2-propenamide or 3-phenyl (3-hydroxyphenyl) -2-propenoate. The drug according to claim 9, which is -2-propenyl   11. The drug according to claim 10, wherein the compound represented by the general formula (6) is N- (3-phenylpropyl) -4-hydroxybenzamide.   Compounds represented by general formula (7) are capsaicin, N- (4-hydroxy-3-methoxyphenyl) methyl-3-phenyl-2-propenamide, N- (3,4-dihydroxyphenyl) methyl-3 12. A compound selected from -phenyl-2-propenamide and N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] -3-phenyl-2-propenamide. Drugs described in   13. The drug according to claim 12, wherein the compound represented by the general formula (8) is [6] -gingerol.   14. The drug according to claim 13, wherein the compound represented by the general formula (9) is curcumin.   An agent for enhancing or promoting adiponectin production in animal adipocytes, comprising an unsaturated fatty acid having 8 to 22 carbon atoms or a glyceride or lower alkyl ester thereof as an active ingredient.   The drug according to claim 22, wherein the glyceride is an ester formed by binding at least one of unsaturated fatty acids having 8 to 22 carbon atoms with glycerol.   The drug according to claim 22, wherein the lower alkyl ester is an ethyl, methyl, propyl, or butyl ester of an unsaturated fatty acid having 8 to 22 carbon atoms.   The unsaturated fatty acid having 8 to 22 carbon atoms is 4Z, 7Z, 10Z, 13Z, 16Z, 19Z-docosahexaenoic acid, 4Z, 7Z, 10Z, 13Z, 16Z-docosapentaenoic acid, 7Z, 10Z, 13Z, 16Z, 19Z- Docosapentaenoic acid, 5Z, 8Z, 11Z, 14Z, 17Z-eicosapentaenoic acid, arachidonic acid, 6Z, 9Z, 12Z, 15Z-octadecatetraenoic acid, α-linolenic acid, linoleic acid, oleic acid, myristolein Acid (cis-9-tetradecenoic acid), 2-dodecenoic acid, 2-decenoic acid, 3-decenoic acid, 2-octenoic acid, geranic acid (trans-3,7-dimethyl-2,6-octadienoic acid), citronel Acid (trans-3,7-dimethyl-6-octenoic acid) or farnesic acid [(2E, 6E, 10E) -3,7,11-trimethyl-2,6,10-dodecatrienoic acid] Or the medicine in any one of Claims 22-24 characterized by being two or more. The drug according to any one of claims 1 to 5, wherein the phenolic compound represented by the general formula (1) is a 4'-hydroxychalcone derivative represented by the following general formula (1b).

(In the formula 1b, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are a hydrogen atom (H), a hydroxyl group, an alkoxy group, or 1 to 20 carbon atoms) And this alkyl group may contain a branch and an unsaturated bond.)   The compound represented by the general formula (1b) is selected from 4'-hydroxychalcone, isoliquiritigenin, lycochalcone A, xanthohumol, and xanthoangelol, The medicine in any one of 1-5.   A drug that enhances or promotes adiponectin production in animal adipocytes, comprising a chalcone derivative represented by the general formula (1b) as an active ingredient.   29. The drug according to claim 28, further comprising one or more xanthine derivatives selected from caffeine, theophylline, or theobromine.   The compound represented by the general formula (1b) is selected from 4'-hydroxychalcone, isoliquiritigenin, lycochalcone A, xanthohumol, and xanthoangelol, 28. The drug according to 28 or 29.   A type 2 diabetes comprising the phenolic compound represented by the general formula (1) according to claim 1 and an unsaturated fatty acid having 8 to 22 carbon atoms or a glyceride or a lower alkyl ester thereof as active ingredients. Hypoglycemic agent   A hyperlipidemia comprising the phenolic compound represented by the general formula (1) according to claim 1 and an unsaturated fatty acid having 8 to 22 carbon atoms or a glyceride or a lower alkyl ester thereof as active ingredients. Treatment   The compound represented by the general formula (1) is a ferulic acid or caffeic acid derivative represented by the general formula (2), or [6] -gingerol represented by the general formula (8) or an analog thereof. The drug according to claim 31.   The compound represented by the general formula (1) is a ferulic acid or caffeic acid derivative represented by the general formula (2), or [6] -gingerol represented by the general formula (8) or an analog thereof. The drug according to claim 32.   The unsaturated fatty acid having 8 to 22 carbon atoms is 4Z, 7Z, 10Z, 13Z, 16Z, 19Z-docosahexaenoic acid, 4Z, 7Z, 10Z, 13Z, 16Z-docosapentaenoic acid, 7Z, 10Z, 13Z, 16Z, 19Z- Docosapentaenoic acid, 5Z, 8Z, 11Z, 14Z, 17Z-eicosapentaenoic acid, arachidonic acid, 6Z, 9Z, 12Z, 15Z-octadecatetraenoic acid, α-linolenic acid, linoleic acid, oleic acid, myristolein Acid (cis-9-tetradecenoic acid), 2-dodecenoic acid, 2-decenoic acid, 3-decenoic acid, 2-octenoic acid, geranic acid (trans-3,7-dimethyl-2,6-octadienoic acid), citronel Acid (trans-3,7-dimethyl-6-octenoic acid) or farnesic acid [(2E, 6E, 10E) -3,7,11-trimethyl-2,6,10-dodecatrienoic acid] Or the medicine in any one of Claims 31-34 characterized by being two or more. Furthermore, the chemical | medical agent in any one of Claims 31-35 characterized by including the 1 or 2 or more xanthine derivative chosen from caffeine, theophylline, or theobromine.

Images