WO2010110026A1 - Composition pharmaceutique pour le syndrome métabolique, l'obésité, l'hyperglycémie, l'hyperlipémie et/ou la stéatose - Google Patents

Composition pharmaceutique pour le syndrome métabolique, l'obésité, l'hyperglycémie, l'hyperlipémie et/ou la stéatose Download PDF

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WO2010110026A1
WO2010110026A1 PCT/JP2010/053545 JP2010053545W WO2010110026A1 WO 2010110026 A1 WO2010110026 A1 WO 2010110026A1 JP 2010053545 W JP2010053545 W JP 2010053545W WO 2010110026 A1 WO2010110026 A1 WO 2010110026A1
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group
smtp
test
pair
feed
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惠司 蓮見
瑞枝 石川
俊洋 近西
直子 西村
啓子 長谷川
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国立大学法人東京農工大学
株式会社ティムス
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a medicament or food for treating and / or preventing metabolic syndrome, obesity, hyperglycemia, hyperlipidemia and / or fatty liver.
  • 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.
  • compounds named SMTP-7, SMTP-14, 19, 43D and 44D are examples of compounds named SMTP-7, SMTP-14, 19, 43D and 44D.
  • 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.
  • Non-Patent Documents 1 to 4, Patent Documents 3 and 4 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).
  • 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).
  • Junji Hasumi A low-molecular-weight compound derived from microorganisms that promotes fibrinolysis, Journal of the Japan Thrombosis and Hemostasis Journal 12, 314-319 (2001) Shinohara C, Hasumi K, Hatsumi W, Endo A. Staplabin, a novel fungal triprenyl phenol which stimulates the binding of plasminogen to fibrin and U937 cells.
  • 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.
  • 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.
  • SMTP compounds of general formula (I), (II) and / or (III), in particular SMTP-7, 14, 19, 43D and / or 44D, are associated with obesity.
  • SMTP-7, 14, 19, 43D and / or 44D are associated with obesity.
  • SMTP-7, 14, 19, 43D and / or 44D are associated with obesity.
  • 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).
  • 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;
  • 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.
  • 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
  • SMTP indicates an SMTP-7 administration group.
  • the insulin value at the time of OGTT is shown.
  • the upper right graph shows the blood glucose level at this time.
  • 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.
  • the mRNA level value was measured by automatically measuring the fluorescence intensity by real-time PCR, and calculated by correcting the expression level of ⁇ -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.
  • the mRNA level value was measured by automatically measuring the fluorescence intensity by real-time PCR, and calculated by correcting the expression level of ⁇ -actin mRNA.
  • 26 in the free feeding group (n 10)
  • SMTP-7 1 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).
  • 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.
  • t-test Free feeding group vs SMTP-7 10 mg / kg group p ⁇ 0.05.
  • ALP alkaline phosphatase
  • t-test Free feeding group vs SMTP-7 10 mg / kg group p ⁇ 0.05.
  • tBIL total pyrubiline).
  • 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
  • t-test Free feeding group vsSMTP-7 10 mg / kg group p ⁇ 0.05
  • Dunnett test free feeding group vsSMTP-7 10 mg / kg group p ⁇ 0.05. TCho (total cholesterol).
  • 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
  • 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.
  • 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
  • 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
  • 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).
  • 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.
  • t-test Free feeding group vs SMTP-7 10 mg / kg group p ⁇ 0.05. Liver weight / body weight ratio.
  • 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.
  • t-test Free feeding group vsSMTP-7 10 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 8.
  • 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 (%).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • n 10.
  • t-test SMTP-7 for the pair feed group, 10 mg / kg group, p ⁇ 0.01.
  • tBIL total pyrubiline
  • ALB albumin
  • Pair feed group 1.79 ⁇ 0.06 (g / dL)
  • n 10.
  • AcAc acetoacetic acid).
  • 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 (%).
  • 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 (%).
  • 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.
  • 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.
  • 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)
  • SMTP-44D group 27.1 ⁇ 1.7 (g).
  • 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. 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
  • 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
  • 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
  • ALP alkaline phosphatase
  • 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.
  • 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 “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.
  • 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.
  • “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).
  • LDL low density lipoprotein
  • Low HDL cholesterolemia means a type of dyslipidemia with low high-density lipoprotein (HDL) in the blood (less than 40 mg / dL).
  • HDL high-density lipoprotein
  • Hypertriglyceridemia refers to a type of dyslipidemia in which a lot of triglycerides are present in blood (150 mg / dL or more).
  • 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.
  • a visceral fat obesity combined with at least two selected from the group consisting of hyperglycemia, hypertension and hyperlipidemia
  • 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.
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • 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.
  • HDL high density lipoprotein
  • 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.
  • compound (I) It is.
  • SMTP-7 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.
  • compound (III) Compound (IV): Compound (V): It is.
  • 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.
  • compound (III) It is. More preferably, SMTP-19: It is.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • suitable excipients used in soft gelatin capsules include vegetable oils, waxes, fats, semi-solid or liquid polyols and the like.
  • excipients for the preparation of solutions and syrups include water, polyols, saccharose, invert sugar and glucose.
  • excipients for injection include water, alcohol, polyol, glycerin and vegetable oil.
  • 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.
  • 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.
  • SMTP-7 Spores of Stachybotrys microspora IFO30018 strain 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.
  • 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.
  • the main culture 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.
  • 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.
  • 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. .
  • 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.
  • OGTT Oral glucose tolerance test
  • the method is Alberts P., Nilsson C., Goran S., Selen G., et al. Selective Inhibition of 11 ⁇ -Hydroxysteroid dehydrogenase type 1 improves Hepatic Insulin Sensivity in Hyperglycemic Mice Strains. Endcrinol. 144: 4755-4762. (2003)
  • 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).
  • 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
  • TRIzol registered trademark
  • Reagent Invitrogen
  • 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.
  • RNA equivalent to 0.5 ⁇ g was reverse transcribed using Prime® Script® RT® reagent® Kit (Takara Bio Inc.).
  • RNA 500 ng
  • sterilized water RNase and DNase free
  • 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 0.4 ⁇ M (final) Concentration), the reaction solution (25 ⁇ L) was adjusted so that PCR reverse primer 0.4 ⁇ M (final concentration).
  • SYBR PrimeScript RT-PCR Kit II II Perfect Real Time
  • the reaction solution was adjusted to 25 ⁇ L per reaction tube, the reaction tube was capped, and then set in Thermal Cycler Dice Real Time System (Takara Bio, TP800).
  • 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).
  • each mRNA expression level was measured by automatically measuring the fluorescence intensity in real time, and corrected with the ⁇ -actin mRNA expression level.
  • G6Pase glucose-6-phosphatase
  • PEPCK phosphenolpyruvate carboxykinase
  • GCK glucokinase
  • ACC acetyl-CoA carboxylase
  • FAS fatty acid synthase
  • SCD-1 stearoyl-CoA desaturase
  • G6Pase The sequences of G6Pase, PEPCK, GCK, ACC, FAS, SCD-1, and ⁇ -actin primers used for RT-PCR are shown below.
  • F means forward primer
  • R means reverse primer. Primers were obtained by requesting synthesis from Operon Biotechnology Sakai Co., Ltd.
  • 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).
  • Oral glucose tolerance test 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).
  • 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.
  • 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.
  • FIG. 7 shows changes in visceral adipose tissue.
  • various substances that induce insulin resistance TNF ⁇ , fatty acids, resistin
  • leptin that stimulates the obesity center to suppress appetite
  • adiponectin secretion that improves insulin receptor sensitivity, etc. It is known to happen.
  • 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. .
  • 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.
  • PBS pH 9.2-9.3
  • 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”.
  • 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.
  • 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.
  • SMTP-14, SMTP-19, SMTP-43D, or SMTP-44D a corresponding control group (pair feed group) was set. Drinking water was ad libitum.
  • 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".
  • 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.
  • 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.
  • 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.
  • SMTP-43D significantly decreased glucose, total cholesterol, triglycerides and free fatty acids, and lipid lowering and insulin resistance improving effects were observed.
  • SMTP-43D significantly decreased AST, ALT and ALP, and suppressed liver function decline.
  • SMTP-44D Rectal temperature increased significantly with administration of SMTP-44D, and suppression of decrease in basal metabolism was observed.
  • SMTP-44D significantly decreased glucose, total cholesterol, triglycerides, free fatty acids and visceral fat, and reduced lipids and improved insulin resistance.
  • SMTP-44D significantly decreased AST, ALT and ALP, and suppressed liver function decline.
  • 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.

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Abstract

Cette invention concerne une préparation pharmaceutique ou un aliment apte à traiter et/ou à prévenir le syndrome métabolique, l'obésité, l'hyperglycémie, l'hyperlipémie et/ou la stéatose, qui comprend un composé représenté par la formule générale (I), (II) ou (III), en particulier, SMTP-7, -14, -19, -43D ou -44D. (Dans la formule générale (I), n représente un nombre entier de 0 à 10). (Dans la formule générale (II), R1 peut être présent ou absent, et R1 représente au moins un groupe –OH quand R1 est présent; et n2 représente un nombre entier de 0 à 1). (Dans la formule (III), R2 peut être présent ou absent, R2 représente au moins un substituant choisi dans le groupe constitué par un groupe –OH et un groupe –COOH quand R2 est présent).
PCT/JP2010/053545 2009-03-25 2010-03-04 Composition pharmaceutique pour le syndrome métabolique, l'obésité, l'hyperglycémie, l'hyperlipémie et/ou la stéatose WO2010110026A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
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WO2012115209A1 (fr) * 2011-02-24 2012-08-30 国立大学法人東京農工大学 Inhibiteur d'époxyde hydrolase soluble
CN104418868A (zh) * 2013-08-27 2015-03-18 上海医药工业研究院 纤溶活性化合物fgfc1的分离纯化方法
WO2020184691A1 (fr) * 2019-03-12 2020-09-17 学校法人昭和大学 Médicament et procédé de traitement ou de prévention de complications du diabète, à l'aide dudit médicament
US11440920B2 (en) 2018-11-02 2022-09-13 Showa University Chemical method of producing SMTP groups or SMTP-7 and intermediates used in the method

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012115209A1 (fr) * 2011-02-24 2012-08-30 国立大学法人東京農工大学 Inhibiteur d'époxyde hydrolase soluble
JP5952257B2 (ja) * 2011-02-24 2016-07-13 株式会社ティムス 可溶性エポキシドハイドロラーゼ阻害剤
CN104418868A (zh) * 2013-08-27 2015-03-18 上海医药工业研究院 纤溶活性化合物fgfc1的分离纯化方法
US11440920B2 (en) 2018-11-02 2022-09-13 Showa University Chemical method of producing SMTP groups or SMTP-7 and intermediates used in the method
WO2020184691A1 (fr) * 2019-03-12 2020-09-17 学校法人昭和大学 Médicament et procédé de traitement ou de prévention de complications du diabète, à l'aide dudit médicament

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