WO2010110026A1

WO2010110026A1 - Pharmaceutical composition for metabolic syndrome, obesity, hyperglycemia, hyperlipemia and/or fatty liver

Info

Publication number: WO2010110026A1
Application number: PCT/JP2010/053545
Authority: WO
Inventors: 惠司蓮見; 瑞枝石川; 俊洋近西; 直子西村; 啓子長谷川
Original assignee: 国立大学法人東京農工大学; 株式会社ティムス
Priority date: 2009-03-25
Filing date: 2010-03-04
Publication date: 2010-09-30
Also published as: JPWO2010110026A1

Abstract

Disclosed is a pharmaceutical preparation or a food for treating and/or preventing metabolic syndrome, obesity, hyperglycemia, hyperlipemia and/or fatty liver, which comprises a compound represented by general formula (I), (II) or (III), particularly SMTP-7, -14, -19, -43D or -44D. (In general formula (I), n represents an integer of 0 to 10.) (In general formula (II), R¹ may be present or absent, and R¹ represents at least one –OH group when R¹ is present; and n₂ represents an integer of 0 or 1.) (In formula (III), R² may be present or absent, R² represents at least one substituent selected from the group consisting of a –OH group and a –COOH group when R² is present.)

Description

Pharmaceutical composition for metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and / or fatty liver

The present invention relates to a medicament or food for treating and / or preventing metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and / or fatty liver. Specifically, the present invention relates to general formulas (I), (II) and (III) for treating and / or preventing metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and / or fatty liver. And more specifically to the use of compounds named SMTP-7, SMTP-14, 19, 43D and 44D. That is, an anti-metabolic syndrome agent, an anti-obesity agent, an anti-hyperglycemic agent, an anti-hyperlipidemic agent, an anti-fatty liver agent containing the compounds of the general formulas (I), (II) and (III), more specifically , SMTP-7, 14, 19, 43D and / or 44D, an anti-metabolic syndrome agent, an anti-obesity agent, an anti-hyperglycemic agent, an anti-hyperlipidemic agent, and an anti-fatty liver agent.

A group of new training Puniru phenol compound produced by the filamentous fungus Stachybotrys microspora, S tachybotrys m icrospora t riprenyl p henols (SMTPs) and named compounds, the present inventor aims to develop a localized thrombolytic control agent (Non-Patent Documents 1 to 4, Patent Documents 3 and 4).

It is clear that SMTPs act on plasminogen and lead to a change in its conformation, thereby increasing the sensitivity of activation by activator and the ability of plasminogen to bind fibrin to promote fibrinolytic reactions. Therefore, it is considered that SMTP is used as a thrombolysis promoter (

Non-patent Documents

1 and 5, and Patent Documents 3 and 4). Furthermore, since fibrinolysis is involved in tissue remodeling and tissue regeneration, the effectiveness of SMTP-7 (ornipravine) in healing was verified in chronic hepatitis and nephritis mice, and its usefulness was demonstrated (Patent Literature) 1 and 2).

In the present invention, in order to further explore the pharmacological action of SMTP compounds of the general formulas (I), (II) and (III), particularly SMTP-7, 14, 19, 43D and 44D, experiments were conducted on obese model animals. went.

WO2007 / 040082 A1 WO2007 / 094071 A1 Japanese Patent No. 4257026 WO2007 / 111203

The present invention relates to compounds of general formula (I), (II) and / or (III), in particular metabolic syndrome comprising SMTP-7, 14, 19, 43D and / or 44D, obesity, hyperglycemia, hyperlipidemia A medicament or food for treating and / or preventing symptom and / or fatty liver is provided. The present invention relates to general formulas (I), (II) and / or for producing an anti-metabolic syndrome agent, anti-obesity agent, anti-hyperglycemia agent, anti-hyperlipidemia agent and / or anti-fatty liver agent. There is provided the use of compounds of (III), in particular SMTP-7, 14, 19, 43D and / or 44D. The present invention provides a method for treating and / or preventing metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and / or fatty liver.

The inventors have identified various pathologies in which SMTP compounds of general formula (I), (II) and / or (III), in particular SMTP-7, 14, 19, 43D and / or 44D, are associated with obesity. Here is a big improvement.

The present invention is based on the above findings by the present inventors, and means for solving the above problems are as follows:
(1) General formula (I) for preventing or treating at least one selected from the group consisting of metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and fatty liver:

(Wherein n ₁ represents an integer of 0 to 10),
General formula (II):

(Wherein R ¹ may or may not be present, and when R ¹ is present, R ¹ represents at least one —OH group, and n ₂ represents an integer of 0 or 1). And / or general formula (III):

(Wherein R ² may or may not be present, and when R ² is present, R ² represents at least one substituent selected from the group consisting of —OH group and —COOH group) Or a pharmaceutically acceptable salt, ester or solvate thereof;
(2) General formula (I), (II) and / or (III) for preventing at least one selected from the group consisting of metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and fatty liver Or a food containing a pharmaceutically acceptable salt, ester or solvate thereof;
(3) General for producing a food for preventing at least one selected from the group consisting of metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and fatty liver, or a medicament for prevention or treatment Use of a compound of formula (I), (II) and / or (III) or a pharmaceutically acceptable salt, ester or solvate thereof;
(4) General formulas (I), (II) and / or (1) for preventing or treating at least one selected from the group consisting of metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and fatty liver Use of a compound of III) or a pharmaceutically acceptable salt, ester or solvate thereof.

According to the present invention, a pharmaceutical or food for treating or preventing at least one selected from the group consisting of metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and fatty liver can be provided.

The influence of SMTP-7 on ob / ob mice is shown. (A) Body weight change (g) (Since the fasting was performed from the 4th to the 5th day, the weight of one place is depressed), (B) The ratio of the liver weight to the body weight (%), (C) The body weight Visceral fat weight ratio (%), (D) Plasma total cholesterol level (mg / dL), (E) Plasma triglyceride level (mg / dL), (F) Plasma free fatty acid level (mg / dL), (G) Plasma GPT activity (IU / mL) and (H) Adequate blood glucose (mg / dL). Control indicates a physiological saline (Saline) administration group, and SMTP indicates an SMTP-7 administration group. Data are expressed as mean ± SEM (n = 5). *: P <0.05, **: P <0.01 Liver photographs (A) of control group (control; physiological saline administration group) and SMTP-7 administration group, micrographs of liver tissue sections stained with Oil Red O, and liver cholesterol and triglyceride levels (C) is there. Visual observation shows that fatty liver is suppressed (A). Furthermore, with Oil Red O staining, a large number of adipocytes stained in red were seen in the liver of the control group, but rarely seen in the SMTP-7 administration group (B), and cholesterol and triglycerides in the liver were quantified. Results (C) showed that fatty liver was suppressed. Liver photographs and microscopic photographs of liver tissue sections stained with Oil Red O show representative examples of each group. Quantitative data for liver cholesterol and triglycerides are expressed as mean ± SEM (n = 5). **: P <0.01 The blood glucose level during an oral glucose tolerance test (OGTT) is shown. The control indicates a physiological saline administration group, and SMTP indicates the SMTP-7 administration group. Data are expressed as mean ± SEM (n = 5). **: P <0.01 The insulin value at the time of OGTT is shown. The upper right graph shows the blood glucose level at this time. The control indicates a physiological saline administration group, and SMTP indicates the SMTP-7 administration group. Data are expressed as mean ± SEM (n = 5). *: P <0.05. The comparison of the mRNA level in the liver of ob / ob mice is shown. The control indicates a physiological saline administration group, and SMTP indicates the SMTP-7 administration group. Data are expressed as mean ± SEM (n = 5). *: P <0.05, **: P <0.01. The mRNA level value was measured by automatically measuring the fluorescence intensity by real-time PCR, and calculated by correcting the expression level of β-actin mRNA. The comparison of the visceral fat mRNA level of ob / ob mice is shown. The control indicates a physiological saline administration group, and SMTP indicates the SMTP-7 administration group. Data are expressed as mean ± SEM (n = 5). *: P <0.05, **: P <0.01. The mRNA level value was measured by automatically measuring the fluorescence intensity by real-time PCR, and calculated by correcting the expression level of β-actin mRNA. It is a microscope picture of the visceral adipose tissue section of a control group and an SMTP-7 administration group. Visceral adipose tissues of the control group (control) and the SMTP-7 administration group were observed. As a result, hypertrophy of mast cells was observed in the control group, whereas adipocyte hypertrophy was significantly suppressed in the SMTP-7 administration group. It was. SMTP-7 (1, 3, 10 mg / kg) free dietary high-fat diet normal mice 1 month repeated intraperitoneal free administration group (n = 10), SMTP-7 1 mg / kg group (n = 10), Changes in the average food intake (g / day / mouse) over time from 1 to 26 days in the SMTP-7 3 mg / kg group (n = 10) and the SMTP-7 10 mg / kg group (n = 10). 26 in the free feeding group (n = 10), SMTP-7 1 mg / kg group (n = 10), SMTP-7 3 mg / kg group (n = 10) and SMTP-7 10 mg / kg group (n = 10) Average daily food intake (g / 26 days / mouse). Free feeding group: 66.80 ± 3.47 (g), SMTP-7 1 mg / kg group: 63.79 ± 5.87 (g), SMTP-7 3 mg / kg group: 61.81 ± 5.40 (g) and SMTP-7 10 mg / kg group: 51.58 ± 4.27 (g). Dunnett test: Free feeding group vsSMTP-7 10 mg / kg group p <0.01. Free feeding group (n = 10), SMTP-7 1mg / kg group (n = 10), SMTP-7 3mg / kg group (n = 10) and SMTP-7 10mg / kg group (n = 10) Change in mean body weight (g / mouse) over time on day 26. Average of free feeding group (n = 10), SMTP-7 1 mg / kg group (n = 10), SMTP-7 3 mg / kg group (n = 10) and SMTP-7 10 mg / kg group (n = 10) Change in body weight (g / mouse). Average value of 10 mice of the change in body weight obtained by subtracting the weight of the first day from the weight of the 26th day. Free-feeding group: 1.65 ± 1.13 (g), SMTP-7 1 mg / kg group: 2.02 ± 1.65 (g), SMTP-7 3 mg / kg group: 0.24 ± 1.35 (g) and SMTP-7 10 mg / kg group: -3.20 ± 1.56 (g). Dunnett test: free feeding group vsSMTP-7 3 mg / kg group p <0.05. Free feeding group vsSMTP-7 10 mg / kg group p <0.01. Average of free feeding group (n = 10), SMTP-7 1 mg / kg group (n = 10), SMTP-7 3 mg / kg group (n = 10) and SMTP-7 10 mg / kg group (n = 10) Changes in rectal temperature before and after the test. Before the test in the free-feeding group: 36.56 ± 0.17 (° C); After the test: 36.36 ± 0.27 (° C), before the test in the SMTP-7 1 mg / kg group: 36.65 ± 0.08 (° C); After the test: 36.48 ± 0.22 ( ° C), SMTP-7 3 mg / kg group before test: 36.74 ± 0.14 (° C); After test: 36.54 ± 0.23 (° C), before test of SMTP-7 10 mg / kg group: 36.68 ± 0.09 (° C); Test After: 36.53 ± 0.23 (° C). t-test: SMTP-7 1 mg / kg group before test vs p <0.05, SMTP-7 3 mg / kg group before test vs p <0.05. ALT (GPT). Free-feeding group: 60.1 ± 36.5 (U / dL), SMTP-7 1 mg / kg group: 55.2 ± 20.9 (U / dL), SMTP-7 3 mg / kg group: 44.9 ± 25.5 (U / dL), SMTP- 7 10 mg / kg group: 32.4 ± 14.3 (U / dL), n = 10. t-test: Free feeding group vs SMTP-7 10 mg / kg group p <0.05. ALP (alkaline phosphatase). Free-feeding group: 161.4 ± 22.8 (U / dL), SMTP-7 1 mg / kg group: 150.5 ± 27.8 (U / dL), SMTP-7 3 mg / kg group: 146.5 ± 18.2 (U / dL), SMTP- 7 10 mg / kg group: 138.7 ± 18.3 (U / dL), n = 10. t-test: Free feeding group vs SMTP-7 10 mg / kg group p <0.05. tBIL (total pyrubiline). Free feeding group: 0.092 ± 0.010 (mg / dL), SMTP-7 1 mg / kg group: 0.102 ± 0.019 (mg / dL), SMTP-7 3 mg / kg group: 0.131 ± 0.040 (mg / dL), SMTP- 7 10 mg / kg group: 0.179 ± 0.056 (mg / dL), n = 10. t-test: Free feeding group vsSMTP-7 10 mg / kg group p <0.01, Free feeding group vsSMTP-7 3 mg / kg group p <0.01. Dunnett test: Free feeding group vsSMTP-7 10 mg / kg group p <0.01. Glu (blood sugar). Free feeding group: 286.3 ± 46.5 (mg / dL), SMTP-7 1 mg / kg group: 260.5 ± 32.7 (mg / dL), SMTP-7 3 mg / kg group: 238.6 ± 48.2 (mg / dL), SMTP- 7 10 mg / kg group: 229.0 ± 48.4 (mg / dL), n = 10. t-test: Free feeding group vsSMTP-7 10 mg / kg group p <0.05, Free feeding group vsSMTP-7 3 mg / kg group p <0.05. Dunnett test: free feeding group vsSMTP-7 10 mg / kg group p <0.05. TCho (total cholesterol). Free feeding group: 193.3 ± 20.7 (mg / dL), SMTP-7 1 mg / kg group: 198.0 ± 24.2 (mg / dL), SMTP-7 3 mg / kg group: 193.4 ± 22.9 (mg / dL), SMTP- 7 10 mg / kg group: 158.0 ± 10.3 (mg / dL), n = 10. t-test: free feeding group vsSMTP-7 10 mg / kg group p <0.01. Dunnett test: Free feeding group vsSMTP-7 10 mg / kg group p <0.01. PL (phospholipid). Free feeding group: 359.6 ± 30.3 (mg / dL), SMTP-7 1 mg / kg group: 363.1 ± 50.1 (mg / dL), SMTP-7 3 mg / kg group: 359.5 ± 36.0 (mg / dL), SMTP- 7 10 mg / kg group: 310.7 ± 17.1 (mg / dL), n = 10. t-test: SMTP-7 for the free-feeding group, 10 mg / kg group, p <0.05. Dunnett test: SMTP-7 for the free-feeding group, 10 mg / kg group, p <0.05. TP (total protein). Free feeding group: 5.29 ± 0.20 (g / dL), SMTP-7 1 mg / kg group: 5.21 ± 0.23 (g / dL), SMTP-7 3 mg / kg group: 5.28 ± 0.21 (g / dL), SMTP- 7 10 mg / kg group: 5.00 ± 0.18 (g / dL), n = 10. t-test: free feeding group vsSMTP-7 10 mg / kg group p <0.01. Dunnett test: Free feeding group vsSMTP-7 10 mg / kg group p <0.01. ALB (albumin). Free feeding group: 1.75 ± 0.07 (g / dL), SMTP-7 1 mg / kg group: 1.77 ± 0.07 (g / dL), SMTP-7 3 mg / kg group: 1.75 ± 0.07 (g / dL), SMTP- 7 10 mg / kg group: 1.62 ± 0.08 (g / dL), n = 10. t-test: free feeding group vsSMTP-7 10 mg / kg group p <0.01. Dunnett test: Free feeding group vsSMTP-7 10 mg / kg group p <0.01. HDL-Cho (high density lipoprotein). Free feeding group: 90.5 ± 5.6 (mg / dL), SMTP-7 1 mg / kg group: 88.1 ± 6.5 (mg / dL), SMTP-7 3 mg / kg group: 90.0 ± 5.2 (mg / dL), SMTP- 7 10 mg / kg group: 75.0 ± 2.9 (mg / dL), n = 10. t-test: free feeding group vsSMTP-7 10 mg / kg group p <0.01. Dunnett test: Free feeding group vsSMTP-7 10 mg / kg group p <0.01. AcAc (acetoacetic acid). Free feeding group: 13.3 ± 6.2 (μmol / L), SMTP-7 1 mg / kg group: 11.1 ± 3.7 (μmol / L), SMTP-7 3 mg / kg group: 11.1 ± 2.1 (μmol / L), SMTP- 7 10 mg / kg group: 8.6 ± 3.2 (μmol / L), n = 10. t-test: Free feeding group vs SMTP-7 10 mg / kg group p <0.05. Dunnett test: free feeding group vsSMTP-7 10 mg / kg group p <0.05. Liver weight. Free-feeding group: 1.55906 ± 0.29271 (g), SMTP-7 1 mg / kg group: 1.50821 ± 0.27940 (g), SMTP-7 3 mg / kg group: 1.45685 ± 0.25377 (g), SMTP-7 10 mg / kg group: 1.30947 ± 0.18743 (g), n = 10. t-test: Free feeding group vs SMTP-7 10 mg / kg group p <0.05. Liver weight / body weight ratio. Free-feeding group weight: 42.15 ± 2.96 (g), SMTP-7 1 mg / kg group weight: 42.09 ± 2.98 (g), SMTP-7 3 mg / kg group weight: 40.75 ± 3.88 (g), SMTP-7 10 mg / kg kg group weight: 37.03 ± 2.81 (g), n = 10. Liver weight / body weight ratio in the free feeding group: 3.680 ± 0.520 (%), Liver weight / body weight ratio in the SMTP-7 1 mg / kg group: 3.566 ± 0.470 (%), Liver weight in the SMTP-7 3 mg / kg group / Body weight ratio: 3.556 ± 0.337 (%), SMTP-7 10 mg / kg group liver weight / body weight ratio: 3.525 ± 0.325 (%). Kidney weight. Free-feeding group: 0.37347 ± 0.02628 (g), SMTP-7 1 mg / kg group: 0.35040 ± 0.02661 (g), SMTP-7 3 mg / kg group: 0.34861 ± 0.01910 (g), SMTP-7 10 mg / kg group: 0.34447 ± 0.02646 (g), n = 10. t-test: Free feeding group vsSMTP-7 10 mg / kg group p <0.05, Free feeding group vsSMTP-7 3 mg / kg group p <0.05. Dunnett test: free feeding group vsSMTP-7 10 mg / kg group p <0.05. Kidney weight / body weight ratio. Free-feeding group weight: 42.15 ± 2.96 (g), SMTP-7 1 mg / kg group weight: 42.09 ± 2.98 (g), SMTP-7 3 mg / kg group weight: 40.75 ± 3.88 (g), SMTP-7 10 mg / kg kg group weight: 37.03 ± 2.81 (g), n = 10. Kidney weight / body weight ratio in the free-feeding group: 0.890 ± 0.089 (%), kidney weight / body weight ratio in the SMTP-7 1 mg / kg group: 0.836 ± 0.063 (%), kidney weight in the SMTP-7 3 mg / kg group / Body weight ratio: 0.862 ± 0.098 (%), SMTP-7 10 mg / kg group kidney weight / body weight ratio: 0.933 ± 0.091 (%). Epididymal fat weight. Free-feeding group: 2.32916 ± 0.32371 (g), SMTP-7 1 mg / kg group: 2.59909 ± 0.27933 (g), SMTP-7 3 mg / kg group: 2.27288 ± 0.39170 (g), SMTP-7 10 mg / kg group: 1.96127 ± 0.32576 (g), n = 10. t-test: Free feeding group vs SMTP-7 10 mg / kg group p <0.05. Dunnett test: free feeding group vsSMTP-7 10 mg / kg group p <0.05. Epididymal fat weight / body weight ratio. Free-feeding group weight: 42.15 ± 2.96 (g), SMTP-7 1 mg / kg group weight: 42.09 ± 2.98 (g), SMTP-7 3 mg / kg group weight: 40.75 ± 3.88 (g), SMTP-7 10 mg / kg kg group weight: 37.03 ± 2.81 (g), n = 10. Epididymal fat weight / body weight ratio in the free feeding group: 5.541 ± 0.777 (%), SMTP-7 1 mg / kg group epididymal fat weight / body weight ratio: 6.166 ± 0.382 (%), SMTP-7 3 mg / kg Epididymal fat weight / body weight ratio in kg group: 5.570 ± 0.779 (%), and epididymal fat weight / body weight ratio in SMTP-7 10 mg / kg group: 5.293 ± 0.750 (%). t-test: free feeding group vsSMTP-7 1 mg / kg group p <0.05. Intraperitoneal fat weight. Free feeding group: 1.90895 ± 0.41656 (g), SMTP-7 1 mg / kg group: 2.06955 ± 0.31361 (g), SMTP-7 3 mg / kg group: 1.87496 ± 0.60434 (g), SMTP-7 10 mg / kg group: 1.39595 ± 0.33912 (g), n = 10. t-test: free feeding group vsSMTP-7 10 mg / kg group p <0.01. Dunnett test: free feeding group vsSMTP-7 10 mg / kg group p <0.05. Intraperitoneal fat weight / body weight ratio. Free-feeding group weight: 42.15 ± 2.96 (g), SMTP-7 1 mg / kg group weight: 42.09 ± 2.98 (g), SMTP-7 3 mg / kg group weight: 40.75 ± 3.88 (g), SMTP-7 10 mg / kg kg group weight: 37.03 ± 2.81 (g), n = 10. Peritoneal fat weight / body weight ratio in the free-feeding group: 4.496 ± 0.728 (%), SMTP-7 1 mg / kg group abdominal fat weight / body weight ratio: 4.898 ± 0.462 (%), SMTP-7 3 mg / kg group Intra-abdominal fat weight / body weight ratio: 4.518 ± 1.058 (%), SMTP-7 10 mg / kg group intra-abdominal fat weight / body weight ratio: 3.739 ± 0.693 (%). t-test: SMTP-7 for the free-feeding group, 10 mg / kg group, p <0.05. Total intra-abdominal fat (epididymal fat + intra-abdominal fat) weight. Free-feeding group: 4.23811 ± 0.59867 (g), SMTP-7 1 mg / kg group: 4.68664 ± 0.57736 (g), SMTP-7 3 mg / kg group: 4.14784 ± 0.86968 (g), SMTP-7 10 mg / kg group: 3.35722 ± 0.54727 (g), n = 10. t-test: Free feeding group vs SMTP-7 10 mg / kg group p <0.05. Dunnett test: free feeding group vsSMTP-7 10 mg / kg group p <0.05. Total intraperitoneal fat weight / body weight ratio. Free-feeding group weight: 42.15 ± 2.96 (g), SMTP-7 1 mg / kg group weight: 42.09 ± 2.98 (g), SMTP-7 3 mg / kg group weight: 40.75 ± 3.88 (g), SMTP-7 10 mg / kg kg group weight: 37.03 ± 2.81 (g), n = 10. Total abdominal fat weight / body weight ratio in the free-feeding group: 10.038 ± 1.047 (%), SMTP-7 1 mg / kg group total abdominal fat weight / body weight ratio: 11.063 ± 0.760 (%), SMTP-7 3 mg / kg Total abdominal fat weight / body weight ratio in the kg group: 10.091 ± 1.341 (%), and total abdominal fat weight / body weight ratio in the SMTP-7 10 mg / kg group: 9.032 ± 1.020 (%). t-test: Free feeding group vsSMTP-7 10 mg / kg group p <0.05, Free feeding group vsSMTP-7 1 mg / kg group p <0.05. High-fat diet-loaded normal mouse 1 month repeated intraperitoneal pair feed group (n = 10) and SMTP-7 10 mg / kg group (n = 10) 1-26 under pair feed conditions of SMTP-7 (10 mg / kg) Change in body weight (g) over time. 26-day weight change rate (g / 26 days / mouse) in the pair feed group (n = 10) and SMTP-7 10 mg / kg group (n = 10). Pair feed group: -2.26 ± 1.54 (g) and SMTP-7 10 mg / kg group: -3.31 ± 0.66 (g). Changes in the mean rectal temperature of the pair feed group (n = 10) and SMTP-7 10 mg / kg group (n = 10) before and after the test. Before the test in the pair feed group: 36.74 ± 0.22 (° C.); After the test: 35.64 ± 0.25 (° C.), before the test in the SMTP-7 10 mg / kg group: 36.75 ± 0.16 (° C.); After the test: 36.44 ± 0.14 (° C. ). t-test: before administration in the pair feed group vs after administration p <0.01, after the test in the SMTP-7 10 mg / kg group vs p test 0.01 after the test in the pair feed group vs SMTP-7 10 mg / kg After the group test, p <0.01. CPK (creatinine kinase). Pair feed group: 296.9 ± 142.0 (U / L), SMTP-7 10 mg / kg group: 453.3 ± 162.7 (U / L), n = 10. t-test: Pair feed group vs SMTP-7 10 mg / kg group p <0.05. ALP (alkaline phosphatase). Pair feed group: 145.4 ± 12.8 (U / dL), SMTP-7 10 mg / kg group: 126.2 ± 11.2 (U / dL), n = 10. t-test: SMTP-7 for the pair feed group, 10 mg / kg group, p <0.01. tBIL (total pyrubiline). Pair feed group: 0.101 ± 0.009 (mg / dL), SMTP-7 10 mg / kg group: 0.188 ± 0.031 (mg / dL), n = 10. t-test: Pair feed group vsSMTP-7 10 mg / kg group p <0.01. ALB (albumin). Pair feed group: 1.79 ± 0.06 (g / dL), SMTP-7 10 mg / kg group: 1.66 ± 0.05 (g / dL), n = 10. t-test: Pair feed group vsSMTP-7 10 mg / kg group p <0.01. AcAc (acetoacetic acid). Pair feed group: 12.7 ± 1.1 (μmol / L), SMTP-7 10 mg / kg group: 10.7 ± 1.6 (μmol / L), n = 10. t-test: Pair feed group vs SMTP-7 10 mg / kg group p <0.01. Liver weight. Pair feed group: 1.33906 ± 0.15943 (g), SMTP-7 10 mg / kg group: 1.43198 ± 0.18769 (g), n = 10. Liver weight / body weight ratio. Pair feed group weight: 38.28 ± 2.81 (g), SMTP-7 10 mg / kg group weight: 36.98 ± 2.76 (g), n = 10. Liver weight / body weight ratio in the pair feed group: 3.492 ± 0.237 (%), Liver weight / body weight ratio in the SMTP-7 10 mg / kg group: 3.866 ± 0.350 (%). t-test: Pair feed group vs SMTP-7 10 mg / kg group p <0.05. Epididymal fat weight. Pair feed group: 2.11652 ± 0.30113 (g), SMTP-7 10 mg / kg group: 1.75568 ± 0.28536 (g), n = 10. t-test: Pair feed group vs SMTP-7 10 mg / kg group p <0.05. Epididymal fat weight / body weight ratio. Pair feed group weight: 38.28 ± 2.81 (g), SMTP-7 10 mg / kg group weight: 36.98 ± 2.76 (g), n = 10. Epididymal fat weight / body weight ratio of pair feed group: 5.523 ± 0.622 (%), epididymal fat weight / body weight ratio of SMTP-7 10 mg / kg group: 4.755 ± 0.719 (%). t-test: Pair feed group vsSMTP-7 1 mg / kg group p <0.05. Intestinal fat + perirenal fat. Pair feed group: 1.91696 ± 0.34459 (g), SMTP-7 10 mg / kg group: 1.51826 ± 0.31945 (g), n = 10. t-test: Pair feed group vs SMTP-7 10 mg / kg group p <0.05. Intestinal fat + perirenal fat / weight ratio. Pair feed group weight: 38.28 ± 2.81 (g), SMTP-7 10 mg / kg group weight: 36.98 ± 2.76 (g), n = 10. Intestinal fat + perinephric fat / body weight ratio in the pair feed group: 4.799 ± 0.637 (%), Intestinal fat + perinephric fat / body weight ratio in the SMTP-7 10 mg / kg group: 4.071 ± 0.587 (%). Pair feed group vsSMTP-7 10 mg / kg group p <0.01. Total intraperitoneal fat (epididymal fat + intestinal fat + perirenal fat) weight. Pair feed group: 4.03348 ± 0.59508 (g), SMTP-7 10 mg / kg group: 3.27394 ± 0.47377 (g), n = 10. t-test: Pair feed group vsSMTP-7 10 mg / kg group p <0.01. Total intraperitoneal fat weight / body weight ratio. Pair feed group weight: 38.28 ± 2.81 (g), SMTP-7 10 mg / kg group weight: 36.98 ± 2.76 (g), n = 10. The total intra-abdominal fat weight / body weight ratio of the pair feed group: 10.503 ± 1.082 (%), the total intra-abdominal fat weight / body weight ratio of the SMTP-7 10 mg / kg group: 8.826 ± 0.851 (%). t-test: Pair feed group vsSMTP-7 10 mg / kg group p <0.01. Ob / ob mouse 1 week repeated intraperitoneal free feeding group (n = 10), SMTP-7 group (n = 10) under paired feed conditions of MTP-7,14,19,43D, 44D (10 mg / kg) , SMTP 14g group (n = 10), SMTP-19 group (n = 10), SMTP-43D group (n = 10) and SMTP-44D group (n = 10) average total food intake for 7 days ( g / 7 days / mouse). Free feeding group: 35.8 ± 3.0 (g), SMTP-7 group: 24.7 ± 2.6 (g), SMTP-14 group: 28.0 ± 2.4 (g), SMTP-19 group: 24.2 ± 2.5 (g), SMTP- 43D group: 23.9 ± 2.7 (g) and SMTP-44D group: 27.1 ± 1.7 (g). t-test: free feeding group vsSMTP-7 group p <0.01, free feeding group vsSMTP-14 group p <0.01, free feeding group vsSMTP-19 group p <0.01, free feeding group vsSMTP-43D group p <0.01, free feeding group vsSMTP-44D group p <0.01, SMTP-7 group vsSMTP-14 group p <0.01, SMTP-7 group vsSMTP-44D group p <0. 05. Free Feeding Group (n = 10), Pair Feed Group for SMTP-7 Group (n = 10), SMTP-7 Group (n = 10), Pair Feed Group for SMTP-14 Group (n = 10), SMTP- 14 groups (n = 10), pair feed group for SMTP-19 group (n = 10), SMTP-19 group (n = 10), pair feed group for SMTP-43D group (n = 10), SMTP-43D group (N = 10), change in average body weight (g / mouse) of the pair feed group (n = 10) and SMTP-44D group with respect to the SMTP-44D group. Average value of the change in body weight obtained by subtracting the weight on the first day from the weight on the seventh day for 10 mice. Free Feeding Group: 3.48 ± 1.06 (g), Pair Feed Group for SMTP-7 Group: -0.07 ± 1.79 (g), SMTP-7 Group: 0.92 ± 1.01 (g), Pair Feed Group for SMTP-14 Group: 1.20 ± 1.11 (g), SMTP-14 group: 2.21 ± 0.84 (g), Pair feed group for SMTP-19 group: 0.53 ± 0.89 (g), SMTP-19 group: 0.41 ± 0.89 (g), SMTP-43D Pair feed group for the group: 0.59 ± 0.85 (g), SMTP-43D group: 0.86 ± 0.67 (g), Pair feed group for the SMTP-44D group: 1.33 ± 0.98 (g) and SMTP-44D group: 1.60 ± 0.69 ( g). t-test: Free feeding group vs. each group p <0.01, SMTP-14 group pair feed group vsSMTP-14 group p <0.05, SMTP-7 group vs SMTP-19 group p <0.01. Change in mean rectal temperature between pair feed group (n = 10) and SMTP-7 group (n = 10) versus SMTP-7 group before and after the test. Before the pair feed group test for the SMTP-7 group: 35.4 ± 0.4 (° C); After the test: 32.4 ± 0.6 (° C), before the test for the SMTP-7 group: 35.4 ± 0.6 (° C); After the test: 36.1 ± 0.3 (° C). t-test: Pair-feed group test for SMTP-7 group after test vs pair test after p <0.01, test after test for SMTP-7 group vs. test after p-0.01 for SMTP-7 group After vs. SMTP5 test, p <0.01. Change in mean rectal temperature of pair feed group (n = 10) and SMTP-14 group (n = 10) versus SMTP-14 group before and after the test. Before test in pair feed group for SMTP-14 group: 35.5 ± 0.5 (° C); After test: 32.7 ± 1.0 (° C), before test in SMTP-14 group: 35.3 ± 0.5 (° C); After test: 35.9 ± 0.3 (° C). t-test: Pair-feed group test for SMTP-14 group, p <0.01 after test vs pair-feed group test, p-0.05 after test, test for SMTP-14 group, pair-feed group test for SMTP-14 group After vsSMTP-14 group test p <0.01. Change in mean rectal temperature of pair feed group (n = 10) and SMTP-19 group (n = 10) versus SMTP-19 group before and after the test. Before paired feed test for SMTP-19 group: 35.3 ± 0.5 (° C); After test: 32.3 ± 1.1 (° C), before test for SMTP-19 group: 35.4 ± 0.4 (° C); After test: 35.6 ± 0.4 (° C). t-test: p <0.01 before the paired feed group test for the SMTP-19 group, p <0.01 after the paired feed group test for the SMTP-19 group vs p <0.01 after the test for the SMTP-19 group. Change in mean rectal temperature between pair feed group (n = 10) and SMTP-43D group (n = 10) versus SMTP-43D group before and after the test. Before the pair-feed group test for the SMTP-43D group: 35.6 ± 0.2 (° C); After the test: 33.1 ± 0.5 (° C), before the SMTP-43D group test: 35.5 ± 0.3 (° C); After the test: 35.9 ± 0.3 (° C). t-test: Pair-feed group test for SMTP-43D group after test vs. p test after p <0.01, SMTP-43D group test before test vs. p <0.01, pair-feed group test for SMTP-43D group After test of vsSMTP-43D group, p <0.01. Change in mean rectal temperature between pair feed group (n = 10) and SMTP-44D group (n = 10) versus SMTP-44D group before and after the test. Before the pair-feed group test for the SMTP-44D group: 35.2 ± 0.4 (° C); After the test: 33.2 ± 1.0 (° C), before the test of the SMTP-44D group: 35.5 ± 0.4 (° C); (° C). t-test: p <0.01 after pair-feed group vs test for SMTP-44D group, p <0.01 after pair-feed group test for SMTP-44D group vs. p <0.01 after test for SMTP-44D group. Glu (plasma glucose). Free-feeding group: 512.4 ± 93.8 (mg / dL), pair feed group for SMTP-7 group (n = 10): 379.3 ± 138.9 (mg / dL), SMTP-7 group (n = 10): 385.3 ± 199.3 (Mg / dL), pair feed group for SMTP-14 group (n = 10): 346.6 ± 96.6 (mg / dL), SMTP-14 group (n = 10): 328.7 ± 60.6 (mg / dL), SMTP- Pair feed group for 19 groups (n = 10): 437.7 ± 136.9 (mg / dL), SMTP-19 group (n = 10): 352.3 ± 79.6 (mg / dL), Pair feed group for SMTP-43D group (n = 10): 448.2 ± 77.5 (mg / dL), SMTP-43D group (n = 10): 355.2 ± 60.7 (mg / dL), Pair-feed group for SMTP-44D group (n = 10): 586.0 ± 164.5 ( mg / dL) and SMTP-44D group (n = 10): 423.4 ± 87.7 (mg / dL). t-test: Free Feeding Group vsSMTP-7 Group Pair Feed Group p <0.05, Free Feeding Group vs SMTP-14 Group Pair Feed Group p <0.01, Free Feeding Group vsSMTP-14 Group p <0.05 0.01, free feeding group vsSMTP-19 group, p <0.01, free feeding group vsSMTP-43D group, p <0.01, free feeding group vsSMTP-44D group, p <0.01, SMTP-43D group Pair feed group vsSMTP-43D group p <0.01, SMTP-44D group pair feed group vsSMTP-44D group p <0.01. TCho (total plasma cholesterol). Free Feeding Group: 221.8 ± 37.2 (mg / dL), Pair Feed Group for SMTP-7 Group (n = 10): 203.6 ± 28.4 (mg / dL), SMTP-7 Group (n = 10): 163.1 ± 15.8 (Mg / dL), pair feed group for SMTP-14 group (n = 10): 215.0 ± 32.9 (mg / dL), SMTP-14 group (n = 10): 176.9 ± 20.0 (mg / dL), SMTP- Pair feed group for 19 groups (n = 10): 224.6 ± 26.1 (mg / dL), SMTP-19 group (n = 10): 175.2 ± 22.3 (mg / dL), Pair feed group for SMTP-43D group (n = 10): 213.4 ± 18.9 (mg / dL), SMTP-43D group (n = 10): 166.2 ± 14.5 (mg / dL), Pair-feed group for SMTP-44D group (n = 10): 224.1 ± 18.8 ( mg / dL) and SMTP-44D group (n = 10): 176.1 ± 17.8 (mg / dL). t-test: Free feeding group vs. SMTP-7 group, SMTP-14 group, SMTP-19 group, SMTP-43D group or SMTP-44D group, p <0.01, SMTP-7 group, SMTP-14 group, SMTP- Pair feed group of group 19, SMTP-43D group or SMTP-44D group vs SMTP-7 group, SMTP-14 group, SMTP-19 group, SMTP-43D group or SMTP-44D group p <0.01. TG (triglyceride in plasma). Free feeding group: 51.4 ± 23.9 (mg / dL), pair feed group for SMTP-7 group (n = 10): 122.4 ± 79.7 (mg / dL), SMTP-7 group (n = 10): 82.3 ± 38.9 (Mg / dL), pair feed group for SMTP-14 group (n = 10): 107.3 ± 43.7 (mg / dL), SMTP-14 group (n = 10): 67.7 ± 22.9 (mg / dL), SMTP- Pair feed group for 19 groups (n = 10): 92.6 ± 36.7 (mg / dL), SMTP-19 group (n = 10): 43.3 ± 8.2 (mg / dL), Pair feed group for SMTP-43D group (n = 10): 66.8 ± 16.2 (mg / dL), SMTP-43D group (n = 10): 46.5 ± 15.0 (mg / dL), Pair-feed group for SMTP-44D group (n = 10): 78.9 ± 52.3 ( mg / dL) and SMTP-44D group (n = 10): 34.5 ± 9.4 (mg / dL). t-test: Free Feeding Group vs SMTP-7 Group Pair Feed Group or SMTP-7 Group p <0.05, Free Feeding Group vs SMTP-14 Group or SMTP-19 Group Pair Feed Group p <0.01, SMTP-14 group pair feed group vs. SMTP-14 group p <0.05, SMTP-19 group pair feed group vs. SMTP-19 group p <0.01, SMTP-43D group pair feed group vs. SMTP-43D Group p <0.01, SMTP-44D group pair feed group vs. SMTP-44D group p <0.05, SMTP-7 group vs. SMTP-19 group or SMTP-44D group p <0.01, SMTP-7 group vs. SMTP-43D group p <0.05. NEFA (free fatty acid). Free Feeding Group: 1137.1 ± 223.1 (μEq / mL), Pair Feed Group for SMTP-7 Group (n = 10): 1403.7 ± 289.7 (μEq / mL), SMTP-7 Group (n = 10): 847.4 ± 141.1 (ΜEq / mL), pair feed group for SMTP-14 group (n = 10): 1332.4 ± 195.9 (μEq / mL), SMTP-14 group (n = 10): 830.0 ± 208.2 (μEq / mL), SMTP- Pair feed group for 19 groups (n = 10): 1267.6 ± 161.1 (μEq / mL), SMTP-19 group (n = 10): 806.0 ± 169.0 (μEq / mL), Pair feed group for SMTP-43D group (n = 10): 1159.9 ± 124.1 (μEq / mL), SMTP-43D group (n = 10): 834.4 ± 163.7 (μEq / mL), Pair-feed group for SMTP-44D group (n = 10): 1105.6 ± 288.7 ( μEq / mL) and SMTP-44D group (n = 10): 723.0 ± 142.1 (μEq / mL). t-test: Paired feed group of free feeding group vs. SMTP-7 group, p <0.05, free feeding group vs. SMTP-7 group, SMTP-14 group, SMTP-19 group, SMTP-43D group or SMTP-44D group p <0.01, SMTP-7 group, SMTP-14 group, SMTP-19 group, SMTP-43D group or SMTP-44D group pair feed group vs. SMTP-7 group, SMTP-14 group, SMTP-19 group, SMTP-43D group or SMTP-44D group p <0.01. AST (aspartate aminotransferase). Free Feeding Group: 418.0 ± 126.6 (U / L), Pair Feed Group for SMTP-7 Group (n = 10): 557.6 ± 194.2 (U / L), SMTP-7 Group (n = 10): 392.6 ± 113.4 (U / L), pair feed group for SMTP-14 group (n = 10): 564.4 ± 211.5 (U / L), SMTP-14 group (n = 10): 397.3 ± 171.9 (U / L), SMTP- Pair feed group for 19 groups (n = 10): 502.6 ± 122.4 (U / L), SMTP-19 group (n = 10): 370.7 ± 120.1 (U / L), Pair feed group for SMTP-43D group (n = 10): 440.3 ± 89.2 (U / L), SMTP-43D group (n = 10): 309.8 ± 68.4 (U / L), Pair-feed group (n = 10) for SMTP-44D group: 410.7 ± 100.9 ( U / L L) and SMTP-44D group (n = 10): 293.1 ± 140.0 (U / L L). t-test: Free feeding group vs. SMTP-43D group p <0.05, SMTP-7 group, SMTP-19 group or SMTP-44D group pair feed group vs. SMTP-7 group, SMTP-19 group or SMTP-44D Group p <0.05, SMTP-43D group pair feed group vs SMTP-43D group p <0.01. ALT (alanine aminotransferase). Free Feeding Group: 525.3 ± 178.3 (U / L), Pair Feed Group for SMTP-7 Group (n = 10): 554.0 ± 232.9 (U / L), SMTP-7 Group (n = 10): 438.9 ± 142.0 (U / L), pair feed group for SMTP-14 group (n = 10): 593.9 ± 232.8 (U / L), SMTP-14 group (n = 10): 400.7 ± 171.0 (U / L), SMTP- Pair feed group for 19 groups (n = 10): 610.8 ± 143.9 (U / L), SMTP-19 group (n = 10): 401.8 ± 145.6 (U / L), Pair feed group for SMTP-43D group (n = 10): 564.0 ± 145.5 (U / L), SMTP-43D group (n = 10): 334.5 ± 76.1 (U / L), Pair-feed group (n = 10) for SMTP-44D group: 540.8 ± 125.2 ( U / L L) and SMTP-44D group (n = 10): 363.5 ± 158.4 (U / L L). t-test: Free Feeding Group vs SMTP-43D Group p <0.01, Free Feeding Group vs SMTP-44D Group p <0.05, Pair Feed Group of SMTP-14 Group or SMTP-44D Group vs. SMTP-14 Group Or SMTP-44D group p <0.05, SMTP-19 group or SMTP-43D group pair feed group vs. SMTP-19 group or SMTP-43D group p <0.01. ALP (alkaline phosphatase). Free Feeding Group: 1300.5 ± 293.5 (U / L), Pair Feed Group for SMTP-7 Group (n = 10): 852.9 ± 199.8 (U / L), SMTP-7 Group (n = 10): 621.8 ± 134.5 (U / L), pair feed group for SMTP-14 group (n = 10): 946.2 ± 288.8 (U / L), SMTP-14 group (n = 10): 707.1 ± 223.3 (U / L), SMTP- Pair feed group for 19 groups (n = 10): 968.7 ± 217.5 (U / L), SMTP-19 group (n = 10): 622.9 ± 160.9 (U / L), Pair feed group for SMTP-43D group (n = 10): 925.7 ± 196.7 (U / L), SMTP-43D group (n = 10): 505.7 ± 65.4 (U / L), Pair-feed group (n = 10) for SMTP-44D group: 1012.4 ± 222.3 ( U / L) and SMTP-44D group (n = 10): 734.2 ± 226.7 (U / L). t-test: Free feeding group vs SMTP-7 group or SMTP-43D group feed group p <0.01, free feeding group vsSMTP-14 group, SMTP-19 group or SMTP-44D group pair feed group p <0.05, Free Feeding Group vs SMTP-7 Group, SMTP-14 Group, SMTP-19 Group, SMTP-43D Group or SMTP-44D Group p <0.01, SMTP-7 Group, SMTP-19 Group or SMTP -43D pair feed group vs. SMTP-7 group, SMTP-19 group or SMTP-43D group p <0.01, SMTP-44D group pair feed group vs. SMTP-44D group p <0.05, SMTP-7 Group vs. SMTP-43D group p <0.05. Liver weight. Free feeding group: 8.54 ± 1.42 (g), Pair feed group for SMTP-7 group (n = 10): 7.43 ± 0.66 (g), SMTP-7 group (n = 10): 7.92 ± 1.06 (g), Pair feed group for SMTP-14 group (n = 10): 8.01 ± 0.45 (g), SMTP-14 group (n = 10): 8.02 ± 1.09 (g), pair feed group for SMTP-19 group (n = 10) ): 7.51 ± 0.77 (g), SMTP-19 group (n = 10): 7.92 ± 0.43 (g), pair feed group (n = 10) against SMTP-43D group: 7.13 ± 0.53 (g), SMTP-43D Group (n = 10): 7.85 ± 0.52 (g), Pair-feed group for SMTP-44D group (n = 10): 7.76 ± 0.48 (g) and SMTP-44D group (n = 10): 7.99 ± 0.43 (g ). t-test: paired feed group of free feeding group vsSMTP-7 group, p <0.05, paired feeding group of free feeding group vsSMTP-43D group, p <0.01, pairfeed group of SMTP-43D group vs. SMTP -43D group p <0.01. Kidney weight. Free Feeding Group: 0.69 ± 0.11 (g), Pair Feed Group for SMTP-7 Group (n = 10): 0.70 ± 0.10 (g), SMTP-7 Group (n = 10): 0.67 ± 0.04 (g), Pair feed group for SMTP-14 group (n = 10): 0.69 ± 0.08 (g), SMTP-14 group (n = 10): 0.65 ± 0.03 (g), pair feed group for SMTP-19 group (n = 10) ): 0.69 ± 0.02 (g), SMTP-19 group (n = 10): 0.66 ± 0.03 (g), Pair feed group (n = 10) against SMTP-43D group: 0.66 ± 0.03 (g), SMTP-43D Group (n = 10): 0.66 ± 0.04 (g), Pair-feed group for SMTP-44D group (n = 10): 0.65 ± 0.04 (g) and SMTP-44D group (n = 10): 0.66 ± 0.03 (g ). t-test: Paired feed group vs. SMTP-19 group vs. SMTP-19 group, p <0.01. Visceral fat weight. Free-feeding group: 15.42 ± 1.06 (g), Pair feed group for SMTP-7 group (n = 10): 15.35 ± 0.69 (g), SMTP-7 group (n = 10): 14.77 ± 0.73 (g), Pair feed group for SMTP-14 group (n = 10): 15.08 ± 0.65 (g), SMTP-14 group (n = 10): 15.38 ± 0.81 (g), pair feed group for SMTP-19 group (n = 10) ): 15.39 ± 0.60 (g), SMTP-19 group (n = 10): 15.03 ± 0.87 (g), Pair-feed group (n = 10) against SMTP-43D group: 14.82 ± 0.89 (g), SMTP-43D Group (n = 10): 15.59 ± 0.86 (g), Pair Feed Group for SMTP-44D group (n = 10): 15.86 ± 0.52 (g) and SMTP-44D group (n = 10): 15.06 ± 0.62 (g ). t-test: Pair-feed group of SMTP-44D group vs. SMTP-44D group, p <0.01. SMTP-7 group vs. SMTP-43D group p <0.05. The relationship between total visceral fat, total intraperitoneal fat, visceral fat, intraperitoneal fat, epididymal fat, intestinal fat, and perirenal fat is as follows: viscera = intraperitoneal, visceral (intraperitoneal) fat = intestinal fat + perirenal Fat, total visceral (intraperitoneal) fat = epididymal fat + visceral (intraperitoneal) fat.

The “metabolic syndrome” in the present invention means a metabolic syndrome having symptoms in which visceral fat obesity is combined with at least two selected from the group consisting of hyperglycemia, hypertension and hyperlipidemia. As diagnostic criteria for metabolic syndrome, any of International Diabetes Federation, Japanese Society of Obesity and NCEP-ATPIII can be adopted. Since the standard is revised, the revised standard may be adopted.

In the International Diabetes Federation (IDF) standard (2005),
Abdominal circumference male 90cm, female 80cm or more is required,
And,
Blood pressure 130 / 85mmHg or more,
Neutral fat 150mg / dL or more,
HDLc men less than 40 mg / dL, HDLc women less than 50 mg / dL,
This is the case when 2 or more of the 4 items consisting of blood glucose of 100 mg / dL or more are applicable,
According to the Japan Society of Obesity (JASSO) standards (2005)
Abdominal circumference male 85cm, female 90cm or more is required,
And,
Blood pressure 130 / 85mmHg or more,
Neutral fat 150mg / dL or more or HDLc 40mg / dL,
Blood sugar 110mg / dL or more
When two or more of the three items
According to the revised NCEP-ATPIII standard (2005),
Waist circumference male 90cm, female 80cm or more,
Blood pressure 130 / 85mmHg or more,
Neutral fat 150mg / dL or more,
HDLc men less than 40 mg / dL, HDLc women less than 50 mg / dL,
Blood sugar 100mg / dL or more
This is the case when 3 or more of the 5 items are applicable.

“Obesity” means a state in which the body weight is higher than in a normal state or a state in which body fat is excessively accumulated. For example, in adults, BMI25 or more is considered obese, but the standard is revised, so the revised standard may be adopted. In the world, BMI generally calls 25 or more as an obesity tendency, and 30 or more is called obesity, so the standards of each country may be adopted. In addition, obesity includes visceral fat type obesity in which fat accumulates around an abdominal organ even when BMI is a normal value.

Hyperglycemia means that in a healthy human, the fasting blood glucose level is about 80-100 mg / dl, which means a higher blood sugar level. Since the standard is revised, the revised standard may be adopted. Hyperglycemia is preferably diabetes. More preferred are hyperinsulinemia, insulin resistance syndrome, and type 2 diabetes.

Hyperlipidemia includes hypercholesterolemia, high LDL cholesterolemia, low HDL cholesterolemia, and hypertriglyceridemia (hyperTG).

Hypercholesterolemia means a type of dyslipidemia with a high total cholesterol level (220 mg / dL or more) in the blood.

High LDL cholesterolemia means a type of dyslipidemia in which a large amount of low density lipoprotein (LDL), which is a carrier of cholesterol, is present in blood (140 mg / dL or more).

Low HDL cholesterolemia means a type of dyslipidemia with low high-density lipoprotein (HDL) in the blood (less than 40 mg / dL).

Hypertriglyceridemia (hyperTGemia) refers to a type of dyslipidemia in which a lot of triglycerides are present in blood (150 mg / dL or more).

* Since the standard is revised, the revised standard may be adopted.

Fatty liver refers to a state where fat has accumulated in the liver. More specifically, it refers to a state in which the number of hepatocytes having lipid droplets appears in more than one third of the total number of hepatocytes.

Hypertension means a state in which systolic blood pressure is maintained at 140 or higher or diastolic blood pressure is maintained at 90 or higher. Since the standard is revised, the revised standard may be adopted. In addition, since hypertension is a risk of developing ischemic heart disease, stroke, renal failure, etc., hypertension includes ischemic heart disease, stroke, renal failure, and the like.

Treating metabolic syndrome does not meet the above-mentioned metabolic syndrome diagnostic criteria (a visceral fat obesity combined with at least two selected from the group consisting of hyperglycemia, hypertension and hyperlipidemia) As such, it means improving at least one of the diagnostic criteria of metabolic syndrome.

Treating obesity means reducing body weight and / or fat weight to normal values.

Treating hyperglycemia means reducing the blood glucose level and / or the amount of insulin in the blood so that it becomes a normal value.

Treating hyperlipidemia reduces the amount of total cholesterol, low density lipoprotein (LDL) and / or triglyceride in the blood and / or high density lipoprotein (HDL) so that it is normal. Means increasing the amount of.

Treatment of fatty liver means that the number of hepatocytes having lipid droplets is less than one third of the total number of hepatocytes.

Preventing obesity means not increasing body weight and / or fat weight so as not to exceed normal values.

Preventing hyperglycemia means not increasing the blood glucose level and / or the amount of insulin in the blood so that the normal level is not exceeded.

To prevent hyperlipidemia, do not increase the total cholesterol level, low density lipoprotein level and / or triglyceride level in the blood so that the normal level is not exceeded, and / or do not fall below the normal level. This means that the amount of high density lipoprotein (HDL) is not decreased.

Preventing fatty liver means that the number of hepatocytes having lipid droplets does not exceed one third of the total number of hepatocytes.

General formula (I) of the present invention:

The SMTP compound (wherein n ₁ represents an integer of 0 to 10) can be synthesized by a method described in Japanese Patent No. 4257026 or WO2007 / 111203. Briefly, the filamentous fungus Stachybotrys microspora is represented by the following general formula (IV):

When the compound represented by the formula (I) is cultured in a medium supplemented with an amine as a compound, the compound of general formula (I) accumulates in the culture solution, and can be obtained by purification from the culture solution.

Preferably, compound (I):

It is.

More preferred is SMTP-7 considering the conformation. SMTP-7 (orniplabin) is the following formula:

Means a trepnylphenol compound represented by: SMTP-7 (orniplabin) can be obtained by purifying the filamentous fungus Stachybotrys microspora with the addition of L-ornithine as an amine and purifying it by a known method (Non-Patent Documents 1 to 4).

General formula (II) of the present invention:

(Wherein R ¹ may or may not be present, and when R ¹ is present, R ¹ represents at least one —OH group, and n ₂ represents an integer of 0 or 1). This compound can be synthesized by the method described in Japanese Patent No. 4257026 or WO2007 / 111203. Briefly, the filamentous fungus Stachybotrys microspora is represented by the following general formula (V):

(Wherein R ¹ may or may not be present, and when R ¹ is present, R ¹ represents at least one —OH group, and n ₂ represents an integer of 0 or 1). The compound of general formula (II) accumulates in the culture medium by culturing in the medium to which the compound represented by formula (2) is added as an amine, and can be obtained by purification from the culture liquid.

Preferably, compound (III):

Compound (IV):

Compound (V):

It is.

More preferably, SMTP-14 considering conformation:

SMTP-43D:

SMTP-44D:

It is.

SMTP-14, 43D, and 44D accumulate in the culture medium by culturing in a medium supplemented with L-tyrosine, D-2-phenylglycine, and 4-hydroxy-D-phenylglycine as amines. Each can be obtained by purifying from the liquid.

General formula (III) of the present invention:

(Wherein R ² may or may not be present, and when R ² is present, R ² represents at least one substituent selected from the group consisting of —OH group and —COOH group) ) Can be synthesized by the method described in Japanese Patent No. 4257026 or WO2007 / 111203. Briefly, the following general formula (VI):

(Wherein R ² may or may not be present, and when R ² is present, R ² represents at least one substituent selected from the group consisting of —OH group and —COOH group) The compound of the general formula (III) accumulates in the culture medium by culturing in a medium to which the compound represented by) is added as an amine, and can be obtained by purification from the culture liquid.

Preferably, compound (III):

It is.
More preferably, SMTP-19:

It is.

Since SMTP-19 accumulates in the culture medium by culturing in a medium supplemented with p-aminobenzoic acid as an amine, each can be obtained by purification from the culture medium.

The compound of the present invention may be a pharmaceutically acceptable salt thereof (acid addition salt, base salt). Moreover, you may obtain by methods, such as organic synthesis.
The compound of the present invention may be a pharmaceutically acceptable ester or solvate thereof.

Pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, paratoluenesulfonic acid, etc. And salts with organic acids. In addition, base salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, amine salts, trialkylamine salts and the like are also included. Such salts can be very readily formed by those skilled in the art using standard techniques.

In addition, alcohols having 1 to 10 carbon atoms or carboxylic acids, preferably methyl alcohol, ethyl alcohol, acetic acid, or propionic acid, are suitable for forming a pharmaceutically acceptable ester of the compound of the present invention. .

Also, water or the like is suitable for forming a pharmaceutically acceptable solvate of the compound of the present invention.

The medicament of the present invention may be orally administered, for example, in the form of tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions, emulsions or suspensions. It may also be administered rectally, for example using suppositories. Alternatively, it may be administered topically or transdermally using, for example, an ointment, cream, gel or solution. It may also be administered parenterally, for example intravenously, intramuscularly, subcutaneously, intraspinally or intradermally using injections.

The medicament of the present invention may be mixed with a pharmaceutically inert inorganic or organic excipient. Examples of excipients suitable for tablets, dragees or hard gelatin capsules include lactose, corn starch or derivatives thereof, talc or stearic acid or salts thereof and the like. Examples of suitable excipients used in soft gelatin capsules include vegetable oils, waxes, fats, semi-solid or liquid polyols and the like. Examples of excipients for the preparation of solutions and syrups include water, polyols, saccharose, invert sugar and glucose. Examples of excipients for injection include water, alcohol, polyol, glycerin and vegetable oil. Examples of suppositories and excipients for topical or transdermal application include natural or hardened oils, waxes, fats and semi-solid or liquid polyols. Further, it may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts that change osmotic pressure, buffers, coating agents or antioxidants. In addition, other therapeutically useful agents may be included.

The preferred form of use is intravenous, intramuscular or oral administration, most preferably oral administration. The dosage at which the compounds of the invention are administered as an effective amount depends on the nature of the particular active ingredient, the age and requirements of the patient and the method of administration. For example, in the case of intravenous administration, it is desirable to administer 1 to 25 mg / kg as the amount of active ingredient per day for adults, and in the case of oral administration, it is desirable to administer the amount of 2 to 200 mg / kg as the amount of active ingredient per day for adults.

The patient having at least one selected from the group consisting of metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and fatty liver is a mammal, preferably a pet, such as a dog or a cat, a human, more preferably , Human.

Further, the present invention may be a food for preventing at least one selected from the group consisting of metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and fatty liver. Further, it may be a food additive.

Examples of the present invention will be described below, but the present invention is not limited to these examples.

1. Materials and experimental methods
Purification of SMTP-7 Spores of Stachybotrys microspora IFO30018 strain (Fermentation Laboratories) were inoculated into a 500 ml Erlenmeyer flask containing 100 ml of seed culture medium and seeded at 180 rpm and 25 ° C for 4 days using a rotary shaker. Went. As the seed culture medium, glucose (4%), soybean meal (0.5%), polypeptone (0.3%), and powdered yeast extract (0.3%) are dissolved in water, and the pH is 5.8 using HCl. The antifoaming agent CB442 (0.01%) (0.1 g / ml acetone solution added at 1 ml / L) (Nippon Yushi Chemical, Japan) was added, and 100 ml each was dispensed to the incubator, and then the autoclave (121 What carried out 15 degreeC) was used.

5 ml of this culture solution was inoculated into a 500 ml 1 Erlenmeyer flask containing 100 ml of the main culture medium, and main culture was performed at 180 rpm, 25 ° C. for 6 days using a rotary shaker.

The main culture medium (restriction medium) is sucrose (5%), powdered yeast extract (0.1%), NaNO ₃ (0.3%), K ₂ HPO ₄ (0.1%), MgSO ₄ · 7H ₂ O (0.05%), KC1 (0.05%), CoCl ₂ .6H ₂ O (0.00025%), FeSO ₄ .7H ₂ O (0.0015%), CaCl ₂ .2H ₂ O ( 0.00065%) is dissolved in water, adjusted to pH 5.8 using HCl, and defoamer CB442 (0.01%) (0.1 g / ml acetone solution is added at 1 ml / L) (Nippon Oils Chemicals, Japan) was added, and 100 ml each was dispensed to the incubator, and then autoclaved (121 ° C., 15 min).

The day of inoculation was the 0th day of culture, and on the 4th day (96 hours later), 100 mg of L-ornithine was added to the medium to produce a production medium, and the culture was continued for another 2 days. Two days later, methanol was added at 200 ml / flask, and extraction was performed by shaking at 180 rpm and 25 ° C. for about 2 hours using a rotary shaker.

The methanol in the culture supernatant obtained by filtering the culture under reduced pressure was distilled off, and the remaining aqueous phase was adjusted to pH 2 by adding phosphoric acid. This was allowed to stand at low temperature overnight to 1 week, and the precipitate was collected by centrifugation (12,000 rpm × 30 minutes). An appropriate amount of acetone was added to the precipitate, and the mixture was again separated into a supernatant and a precipitate by centrifugation (12,000 rpm × 30 minutes), and the supernatant was collected. This was dried under reduced pressure, and the resulting oily residue was dissolved in MeOH to about 100 mg / ml, passed through a LiChrolut® RP-18 solid phase extraction column, and passed through an Inertsil® PREP-ODS column (30 × 250 mm). And subjected to preparative HPLC in GL Science (Tokyo, Japan). Gradient elution was performed with a mixed solvent of 0.1% aqueous formic acid and MeOH, changing the MeOH ratio from 80% to 100% over 20 minutes (column temperature 40 ° C., flow rate 25 ml / min), retention time 11-15 minutes From the fraction eluted in step 5, SMTP-7 according to this example was obtained.

Drug preparation SMTP-7: An equal amount of 0.3 N NaOH and physiological saline (0.9% NaCl) were added to the dried product of SMTP-7 purified in this laboratory to prepare a 50 mg / ml solution. Then, using 0.3 N HCl and physiological saline, adjusted to 10 mg / ml, pH from weak alkali to near neutral, sterilized by filtration, subdivided and stored frozen at -30 ° C. .

Experiment schedule [Table 1]

Animal rearing environment and drug administration 5 weeks old male ob / ob mice (Nippon Charles River B6.V-Lep ^ob / J) were acclimatized for 1 week and grouped by weight so that 5 animals per group It was. In addition, pair feeding was performed to unify the food intake with the control group. SMTP-7 was intraperitoneally administered at 10 mg / kg, and body weight and 24-hour food intake were measured. At the same time on the second day, SMTP-7 was administered, and at the same time, physiological saline was administered to the control group. At that time, only the same amount of food eaten by the SMTP-7 administration group one day ago should be added to the control group's food box. Water was ad libitum.

Oral glucose tolerance test (OGTT)
The method is Alberts P., Nilsson C., Goran S., Selen G., et al. Selective Inhibition of 11β-Hydroxysteroid dehydrogenase type 1 improves Hepatic Insulin Sensivity in Hyperglycemic Mice Strains. Endcrinol. 144: 4755-4762. (2003) Followed. OGTT was performed on day 5 of drug administration. D-glucose was orally administered at 2 g / kg 2 hours after the 12-hour fasting and the final administration. Blood was collected using a heparin-coated hematocrit tube from a slightly cut tail before administration of glucose and 15, 30, 60, and 120 minutes after administration, and centrifuged at 3,000 rpm for 10 minutes to obtain plasma. Thereafter, the blood glucose level was measured with Glucose CII-Test Wako (Wako Pure Chemical Industries, Ltd.), and the insulin was measured with an ultrasensitive mouse insulin measurement kit (Morinaga Institute of Science).

Dissection On day 7 of drug administration, dissection was performed 6 hours after the last administration without fasting. Liver, visceral fat and plasma were collected.

Biochemical examination of plasma Using the obtained plasma, blood glucose, total cholesterol, triglyceride, free fatty acid and GPT were measured at any time. The blood glucose level was measured using Glucose CII-Test Wako (Wako Pure Chemical Industries, Ltd.) according to the attached instructions. Total cholesterol was measured using cholesterol E-Test Wako (Wako Pure Chemical Industries, Ltd.) according to the attached instructions. Triglyceride was measured using Triglyceride E-Test Wako (Wako Pure Chemical Industries, Ltd.) according to the attached instructions. Free fatty acids were measured by consigning to BML. GPT was measured using transaminase CII-Test Wako (Wako Pure Chemical Industries, Ltd.) according to the attached instructions.

RT-PCR
Real time-PCR (RT-PCR) was performed to examine gene expression changes due to administration of SMTP-7. All work was performed using RNase-free instruments and reagents.

1 ml of TRIzol (registered trademark) Reagent (Invitrogen) was added to 100 mg of liver or visceral adipose tissue extracted from ob / ob mice and homogenized. After incubating at room temperature for 5 minutes, 0.2 ml of chloroform was added and vortexed for about 15 seconds. After further incubation at room temperature for 3 minutes, the mixture was centrifuged at 12,000 × g for 15 minutes at 4 ° C. The aqueous layer of the supernatant was transferred to a new tube and 0.5 ml of isopropyl alcohol was added. After 10 minutes of incubation at room temperature, the mixture was centrifuged at 12,000 × g × 10 minutes 4 ° C. After removing the supernatant, 1 μml of 75% ethanol was added to the total RNA obtained and vortexed lightly, followed by centrifugation at 7,500 × g for 5 minutes at 4 ° C. After removing the supernatant, the tube was placed on a clean paper towel to dry the total RNA. It was dissolved in RNase and DNase-free sterilized water, and the amount of RNA was quantified. RNA equivalent to 0.5 μg was reverse transcribed using Prime® Script® RT® reagent® Kit (Takara Bio Inc.).

For the reverse transcription reaction, a commercially available kit was used (Takara Bio RP083A). Specifically, according to the instructions of the kit, primeScript Buffer (for real time) 1 × (final concentration), PrimeScript RT Enzyme Mix I 0.5mM (final concentration), Oligo dT Primer 25pmol (final concentration), Randam 6 mer 50pmol (final concentration) Concentration), total RNA (500 ng), sterilized water (RNase and DNase free) was added to prepare 10 μl of the reaction solution. The reverse transcription reaction was carried out at 37 ° C. for 15 minutes, and then the reverse transcriptase was heat-inactivated at 85 ° C. for 5 seconds.

The expression level of each mRNA was measured by the real-time polymerase chain reaction (RealTime PCR) as follows using the reverse transcript obtained by the above-mentioned method (amount corresponding to 20 ng of RNA before reverse transcription) as a template.

RT-PCR is a sample after reverse transcription (amount equivalent to 20 ng RNA), the following primers, a commercially available reagent kit for real-time detection PCR (SYBR PrimeScript RT-PCR Kit II II (Perfect Real Time) (Takara Bio, RR083A Specifically, according to the instructions of the kit, the sample after reverse transcription (amount equivalent to 20 ng RNA), SYBR Premix Ex Taq II 1x (final concentration), PCR forward primer 0.4μM (final) Concentration), the reaction solution (25 μL) was adjusted so that PCR reverse primer 0.4 μM (final concentration).

The reaction solution was adjusted to 25 μL per reaction tube, the reaction tube was capped, and then set in Thermal Cycler Dice Real Time System (Takara Bio, TP800). In the PCR reaction, initial denaturation was carried out at 95 ° C. for 10 seconds, and then PCR reaction was carried out under conditions of a denaturation step of 95 ° C. for 5 seconds and an annealing step of 60 ° C. for 20 seconds (number of cycles: 30 to 45 cycles). After starting the reaction, each mRNA expression level was measured by automatically measuring the fluorescence intensity in real time, and corrected with the β-actin mRNA expression level. The genes examined were G6Pase (glucose-6-phosphatase), PEPCK (phosphenolpyruvate carboxykinase), GCK (glucokinase), ACC (acetyl-CoA carboxylase), FAS (fatty acid synthase), SCD-1 (stearoyl-CoA desaturase) did.

The sequences of G6Pase, PEPCK, GCK, ACC, FAS, SCD-1, and β-actin primers used for RT-PCR are shown below. F means forward primer and R means reverse primer. Primers were obtained by requesting synthesis from Operon Biotechnology Sakai Co., Ltd.

beta Actin-F: 5'-CATCCGTAAAGACCTCTATGCCAAC-3 '(SEQ ID NO: 1)
beta Actin-R: 5'-ATGGAGCCACCGATCCACA-3 '(SEQ ID NO: 2)
ACC-F: 5'-GGATGACAGGCTTGCAGCTATG-3 '(SEQ ID NO: 3)
ACC-R: 5'-GGAACGTAAGTCGCCGGATG-3 '(SEQ ID NO: 4)
FAS-F: 5'-GCAGCAAGTGTCCACCAACAA-3 '(SEQ ID NO: 5)
FAS-R: 5'-CTCATCGGAGCGCAGGATAGA-3 '(SEQ ID NO: 6)
Scd-1-F: 5'-GCCTGTACGGGATCATACTGGTTC-3 '(SEQ ID NO: 7)
Scd-1-R: 5'-CCAGAGCGCTGGTCATGTAGTAGA-3 '(SEQ ID NO: 8)
G6Pase-F: 5'-GGATCCTGGGACAGACACACAA-3 '(SEQ ID NO: 9)
G6Pase-R: 5'-TGTCAACACCTCTGGCCTCAC-3 '(SEQ ID NO: 10)
GCK-F: 5'-TACGACCGGATGGTGGATGA-3 '(SEQ ID NO: 11)
GCK-R: 5'-ACCAGCTCGCCCATGTACTTTC-3 '(SEQ ID NO: 12)
PEPCK-F: 5'-GTGTTTGTAGGAGCAGCCATGAGA-3 '(SEQ ID NO: 13)
PEPCK-R: 5'-GCCAGGTATTTGCCGAAGTTGTAG-3 '(SEQ ID NO: 14)
SHP-1-F: 5'-AGGGCACGATCCTCTTCAACC-3 '(SEQ ID NO: 15)
SHP-1-R: 5'-CAGGGCTCCAAGACTTCACACA-3 '(SEQ ID NO: 16)

2. Results 2.1, Metabolic improvement effect of SMTP-7 on ob / ob mice First, in order to confirm whether SMTP-7 has an anti-obesity effect, SMTP-7 was administered at 10 mg / kg and physiological saline was intraperitoneally administered to the control group (control).

From day 2 of administration, it was found that there was a function of significantly suppressing weight gain compared to the control group (FIG. 1A). Furthermore, not only visceral fat (87%) but also liver weight increased by obesity was significantly suppressed (78%) (FIGS. 1B and C). It was revealed that total cholesterol levels (78%), blood glucose levels (63%), and free fatty acids (78%) were also significantly reduced (FIGS. 1D, F, and H). Regarding triglyceride, it was confirmed that there was a tendency to decrease, although there was no statistically significant difference because it was dissected without fasting (Fig. 1E). Moreover, it was found that the activity of the enzyme pyruvate-glutamateasetransaminase (GPT aka ALT), which is an indicator of liver damage, tends to decrease with the administration of SMTP-7 (78%) (Fig. 1G). (The values in parentheses indicate the percentage of the values obtained in the SMTP-7 administration group compared to the control group.)

Furthermore, when the livers of the SMTP-7 administration group and the control group are compared, it can be clearly seen by visual observation that fatty liver is suppressed in the SMTP-7 administration group (FIG. 2A), and further, neutral lipid is detected. From the microscopic observation of liver tissue sections by O staining and the results of quantification of cholesterol and triglycerides in the liver, the action of SMTP-7 on fatty liver was revealed (FIGS. 2B and C).

2.2, Oral glucose tolerance test (OGTT)
ob / ob mice develop insulin resistance with obesity (Alberts, P., Ronquist-Nii, Y., Larsson, C. Effect of high-fat diet on KKAy and ob / ob mouse liver and adipose tissue corticosterone and 11-dehydrocorticosterone concentrations. Horm Metab Res. 2005 Jul; 37 (7): 402-7) Therefore, OGTT was performed to examine the ability to improve glucose tolerance (Fig. 3).

In individuals treated with SMTP-7, fasting blood glucose decreased significantly compared to the control group, as well as a rapid increase in blood glucose after glucose administration and a significant suppression of blood glucose up to 30 minutes after glucose administration I understood it.

Therefore, OGTT was performed again using a separate body, and blood glucose levels and insulin concentrations were measured up to 30 minutes after glucose administration (FIG. 4). In this experiment, high reproducibility of blood glucose reduction was obtained, and in the SMTP-7 administration group, plasma insulin levels at 15 minutes after glucose administration decreased significantly, and there was a tendency to decrease at other blood sampling points. confirmed.

2.3 Effect of SMTP-7 on gene expression in ob / ob mice The results of 2.1 and 2.2 showed that SMTP-7 has anti-obesity and glucose tolerance improving effects. Moreover, since it is predicted that improvement in glucose tolerance is accompanied by a decrease in the expression level of genes involved in gluconeogenesis and fatty acid-related genes, total RNA was extracted from the extracted liver and RT-PCR of these genes was performed.

It has been clarified that most of the genes measured this time have a significant decrease in expression or a tendency to decrease when SMTP-7 is administered (FIG. 5). The decrease in the expression level of G6Pase and PEPCK, which are the main enzymes of gluconeogenesis, is a result consistent with the improvement of insulin resistance. In addition, the decrease in the expression level of ACC that catalyzes the first step of fatty acid synthesis and FAS that catalyzes the majority of fatty acid synthesis by SMTP-7 indicates that fatty acid synthesis has decreased and is associated with insulin resistance. It is thought that it contributed to the improvement of various symptoms (for example, lipid abnormality). In addition, the decrease in the expression of Scd-1 which is highly expressed in the liver and adipose tissue of obese mice in the SMTP-7 administration group is considered to be a cause of the anti-obesity action. On the other hand, the expression level of GCK was not different from the control group (control) (FIG. 5).

Meanwhile, the expression level of mRNA in adipose tissue was also measured (FIG. 6). In the liver, which plays a central role in gluconeogenesis, SMTP-7 showed a significant tendency to decrease the expression of genes related to glucose metabolism, while in the adipose tissue mainly engaged in fatty acid metabolism, Scd-1 And the decrease in FAS gene expression was noticeable.

2.4, Liver Changes due to Action of SMTP-7 in Obesity Model FIG. 7 shows changes in visceral adipose tissue. When fat cells become enlarged, various substances that induce insulin resistance (TNFα, fatty acids, resistin), leptin that stimulates the obesity center to suppress appetite, decreased adiponectin secretion that improves insulin receptor sensitivity, etc. It is known to happen. In the SMTP-7 administration group, this adipocyte hypertrophy is suppressed, and as described above, the blood glucose level and plasma insulin level are also significantly low.

SMTP-7 (1,3,10mg / kg) high-fat diet-loaded normal mice 1 month repeated intraperitoneal administration 1 under free feeding conditions 1, materials and experimental method 1-1, test substance (drug) preparation and administration:
SMTP-7 / Na salt was dissolved in PBS solution (pH9.2-9.3) (0.25mg / mL, 0.75mg / mL, 2.5mg / mL) and administered intraperitoneally for 1 month with a dose volume of 4mL / kg. .

1-3, Method / Measurement:
C57-BL / 6J (male, 4 weeks old at arrival, purchased from Jackson Laboratories via Japan Charles River), acclimatized for 2 weeks, then high fat diet (D12451 (Research Diet), 45% fat / kcal) For 17 weeks. Thereafter, grouping of 10 animals per group was performed. The test substance was administered intraperitoneally once a day for 25-28 days under free feeding conditions, and the day after the administration was dissected under non-fasting, blood collection and organ collection were performed. Plasma biochemical tests were performed using Hitachi's small-scale biochemical automated analyzer “7070”. The vehicle group was administered 4 mL / kg of PBS solution (pH 9.2-9.3).

1-4, statistics:
A two-sample test (t-test) assuming equal variance was performed between the vehicle group and each test substance-administered group, and a risk rate of 5% or less was considered significant. A Dunnett test was also performed between the vehicle group and the test substance-administered group, and a risk rate of 5% or less was considered significant.

2. The results are shown in FIGS. 8 (1) to (25). Compared to the vehicle group (free intake group), there was a significant decrease in food intake and body weight in the SMTP-7 10 mg / kg group. The changes in rectal temperature before and after the test were significantly different (significant decrease) in the SMTP-7 1 mg / kg group and the SMTP-7 3 mg / kg group. The blood glucose level was significantly decreased in the SMTP-7 3 mg / kg group and the SMTP-7 10 mg / kg group as compared to the vehicle group. Acetoacetic acid (AcAc) was significantly reduced in the SMTP-7 10 mg / kg group compared to the vehicle group. Total intraperitoneal fat mass and its weight ratio were significantly reduced in the SMTP-7 10 mg / kg group compared to the vehicle group.

3. Conclusion These results indicate that the anti-metabolic effect of SMTP-7 is effective in a dietary obesity model (high fat diet load model) of normal mice other than the genetic obesity model (ob / ob mouse). It is suggested, however, that a decrease in food intake was observed in the SMTP-7 10 mg / kg group, suggesting that SMTP-7 resulted in inhibition of feeding, which contributed to the above metabolic improvement, or directly SMTP-7. It is not clear whether or not it showed an effect of improving metabolism. Therefore, as shown in Example 3 below, the action of SMTP-7 was examined under pair-feed conditions.

High-fat diet-loaded normal mouse 1 month repeated intraperitoneal administration 1 for SMTP-7 (10 mg / kg) under pair-feed conditions, materials and experimental method 1-1, test substance (drug) preparation and administration:
SMTP-7 / Na salt was dissolved in a PBS solution (pH 9.2-9.3) to give a final concentration of 2.5 mg / mL and an intraperitoneal dose of 4 mL / kg.

1-3, Method / Measurement:
C57-BL / 6J (male, 4 weeks old at arrival, purchased from Jackson Labs through Japan Charles River), acclimatized for 2 weeks, then high fat diet (D12451 (Research Diet), 45% fat / kcal) For 17 weeks. Thereafter, grouping of 10 animals per group was performed. In addition, pair feeding was performed to unify the food intake with the control group. That is, the food intake given to the corresponding control group (pair feeding group) was matched with the food intake of the compound administration group on the previous day. On the first day, SMTP-7 was intraperitoneally administered at 10 mg / kg, and body weight and food intake for 24 hours were measured. At the same time on the second day, SMTP-7 was administered, and at the same time, a PBS (pH 9.2-9.3) solution was administered to the pair feed group to make the first day of the pair feed group. At that time, only the same amount of feed as that of the SMTP-7 administration group was added to the feed box of the pair feed group one day ago. Drinking water was ad libitum. The test substance was administered intraperitoneally once a day for 25-28 days under pair-feed conditions, dissected under non-fasting the day after the administration was completed, and blood collection and organ collection were performed. The biochemical examination of plasma was performed using Hitachi's small biochemical automatic analyzer “7070”.

1-4, statistics:
A two-sample test (t-test) assuming equal variance was performed between the pair feed group and each test substance administration group, and a risk rate of 5% or less was considered significant.

2. The results are shown in FIGS. 9 (1) to (16). Rectal temperature was significantly increased by SMTP-7, and a decrease in basal metabolic rate was suppressed. Moreover, acetoacetic acid and visceral fat were significantly reduced, and an antidiabetic action was observed. In addition, ALP was significantly reduced and liver function decline was suppressed.

3. Conclusion These results show that the anti-metabolic effect of SMTP-7 is also effective in the dietary obesity model (high fat diet load model) of normal mice other than the genetic obesity model (ob / ob mouse). ing.

Preparation of SMTP-14, 43D, 44D, and 19 Production of L-tyrosine and SMTP-43D in the production of SMTP-14 instead of the addition of L-ornithine in the production of SMTP-7 in Example 1 In the case of D-2-phenylglycine, in the case of production of SMTP-44D, 4-hydroxy-D-phenylglycine or in the case of production of SMTP-19, p-aminobenzoic acid was added and the same as in Example 1. By culturing the cells, SMTP-14, SMTP-43D, SMTP-44D, and SMTP-19 were produced in the culture solution, respectively, and SMTP-14, SMTP-43D, and SMTP-44D were obtained from the culture solution in the same manner as in Example 1. And SMTP-19 were purified (see Patent Document 4).

SMTP / 14,19,43D, 44D (10 mg / kg) pair feed condition under ob / ob mice 1 week repeated intraperitoneal administration 1, material and experimental method 1-1, test substance (drug) preparation, administration:
SMTP-7, 14, 19, 43D and 44D sodium salts were dissolved in physiological saline to give a final concentration of 2.5 mg / mL and a dose volume of 4 mL / kg, which was repeatedly administered intraperitoneally for 1 week.

1-3, Method / Measurement:
9 weeks old male ob / ob mice (Nippon Charles River B6.V-Lep ^ob / J) were acclimated for 1 week and grouped by weight so that 10 mice per group were obtained. In addition, pair feeding was performed to unify the food intake with the control group. That is, the food intake given to the corresponding control group (pair feed group) was matched with the food intake of the compound administration group on the previous day. SMTP-7 was intraperitoneally administered at 10 mg / kg, and body weight and 24-hour food intake were measured. At the same time on the second day, SMTP-7 was administered, and at the same time, physiological saline (pH 9.2-9.3) was administered to the control group, which was designated as the first day of the control group. At that time, only the same amount of feed as that of the SMTP-7 administration group was added to the food box of the control group one day ago. Similarly, in the experiments using SMTP-14, SMTP-19, SMTP-43D, or SMTP-44D, a corresponding control group (pair feed group) was set. Drinking water was ad libitum. On day 7 after drug administration, dissection was performed under non-fasting conditions 6 hours after the final administration. Liver, kidney, visceral fat and plasma were collected. Plasma biochemical tests were performed using Hitachi Small Biochemistry Automatic Analyzer "7070".

2. The results are shown in FIGS. 10 (1) to (13). Rectal temperature decreased by high-fat diet load was significantly increased by administration of SMTP-7, and suppression of decrease in basal metabolic rate was observed. In addition, SMTP-7 significantly reduced total cholesterol and free fatty acids, and reduced lipids and improved insulin resistance. Furthermore, SMTP-7 significantly improved AST and ALP, which are indicators of liver damage.

Similarly, administration of SMTP-14 significantly increased rectal temperature and suppressed the decrease in basal metabolism. SMTP-14 significantly decreased total cholesterol, triglycerides and free fatty acids, and reduced lipids and improved insulin resistance. Furthermore, SMTP-14 significantly improved ALT, which is an indicator of liver damage.

Rectal temperature was significantly increased by administration of SMTP-19, and suppression of decrease in basal metabolic rate was observed. SMTP-19 significantly decreased total cholesterol, triglycerides and free fatty acids, and reduced lipids and improved insulin resistance. Furthermore, SMTP-19 significantly decreased AST, ALT and ALP, and suppressed liver function decline.

Rectal temperature was significantly increased by administration of SMTP-43D, and a decrease in basal metabolic rate was suppressed. In addition, SMTP-43D significantly decreased glucose, total cholesterol, triglycerides and free fatty acids, and lipid lowering and insulin resistance improving effects were observed. Furthermore, SMTP-43D significantly decreased AST, ALT and ALP, and suppressed liver function decline.

Rectal temperature increased significantly with administration of SMTP-44D, and suppression of decrease in basal metabolism was observed. In addition, SMTP-44D significantly decreased glucose, total cholesterol, triglycerides, free fatty acids and visceral fat, and reduced lipids and improved insulin resistance. Furthermore, SMTP-44D significantly decreased AST, ALT and ALP, and suppressed liver function decline.

3. Conclusion These results indicate that all of the examined derivatives (SMTP-7, 14, 19, 43D, 44D) have an anti-metabolic action such as a lipid lowering action. That is, the following general formula (VII)):

(Wherein R represents an optional substituent) In addition to SMTP-7 having two structures (SMTP basic skeleton) excluding the R portion, an SMTP compound group consisting of one SMTP basic skeleton Even so, if there is a basic skeleton of SMTP, it suggests that SMTP compounds have antimetabolic activity.

The present invention is useful for treating and / or preventing at least one selected from the group consisting of metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and fatty liver.

Claims

General formula (I) for preventing or treating at least one selected from the group consisting of metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and fatty liver:

(Wherein n represents an integer of 0 to 10),
General formula (II):

(Wherein R 1 may or may not be present, and when R 1 is present, R 1 represents at least one —OH group, and n 2 represents an integer of 0 or 1). And / or general formula (III):

(Wherein R 2 may or may not be present, and when R 2 is present, R 2 represents at least one substituent selected from the group consisting of —OH group and —COOH group) Or a pharmaceutically acceptable salt, ester or solvate thereof.
General formula (I), (II) and / or (III) or their use for preventing at least one selected from the group consisting of metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and fatty liver A food containing a pharmaceutically acceptable salt, ester or solvate.
General formula (I) for producing a food for preventing at least one selected from the group consisting of metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and fatty liver, or a medicament for prevention or treatment ), (II) and / or a compound of (III) or a pharmaceutically acceptable salt, ester or solvate thereof.
Of the general formulas (I), (II) and / or (III) for preventing or treating at least one selected from the group consisting of metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and fatty liver Use of a compound or a pharmaceutically acceptable salt, ester or solvate thereof.