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WO2019066010A1 - Agent prophylactique ou thérapeutique contre la stéatohépatite non alcoolique et son utilisation - Google Patents

Agent prophylactique ou thérapeutique contre la stéatohépatite non alcoolique et son utilisation Download PDF

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Publication number
WO2019066010A1
WO2019066010A1 PCT/JP2018/036389 JP2018036389W WO2019066010A1 WO 2019066010 A1 WO2019066010 A1 WO 2019066010A1 JP 2018036389 W JP2018036389 W JP 2018036389W WO 2019066010 A1 WO2019066010 A1 WO 2019066010A1
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nash
group
formula
methyl group
gene
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PCT/JP2018/036389
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English (en)
Japanese (ja)
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礒田　博子
康広 嶋本
富永　健一
浅川　真澄
佐藤　一彦
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国立研究開発法人産業技術総合研究所
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Publication of WO2019066010A1 publication Critical patent/WO2019066010A1/fr

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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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

Definitions

  • the present invention relates to a prophylactic or therapeutic agent for non-alcoholic steatohepatitis (hereinafter sometimes referred to as "NASH") and its use. More specifically, the present invention relates to an agent for the prevention or treatment of NASH, a pharmaceutical composition for the prevention or treatment of NASH, a food composition for the prevention or improvement of NASH, and a method for the prevention or improvement of NASH.
  • NASH non-alcoholic steatohepatitis
  • Patent Document 1 describes an agent for preventing and / or improving NASH, which comprises D-allose and / or isoleucine and / or leucine as an active ingredient.
  • an object of the present invention is to provide a technique for preventing, improving or treating NASH.
  • the present invention includes the following aspects.
  • An agent for the prophylaxis or treatment of NASH which comprises a compound represented by the following formula (1) as an active ingredient.
  • R 1 to R 5 each independently represent a hydrogen atom or a methyl group, and at least one of R 1 to R 5 is a methyl group.
  • a pharmaceutical composition for the prophylaxis or treatment of NASH which comprises the prophylactic or therapeutic agent according to [1] and a pharmaceutically acceptable carrier.
  • a food composition for preventing or improving NASH which comprises a compound represented by the following formula (1) as an active ingredient.
  • R 1 to R 5 each independently represent a hydrogen atom or a methyl group, and at least one of R 1 to R 5 is a methyl group.
  • a method for preventing or ameliorating NASH comprising the step of allowing a subject to take a compound represented by the following formula (1) (excluding medical practice for humans).
  • R 1 to R 5 each independently represent a hydrogen atom or a methyl group, and at least one of R 1 to R 5 is a methyl group.
  • the present invention can provide a technique for preventing, improving or treating NASH.
  • FIG. 1 shows the experimental progress table of the mouse of each group in Experimental example 1.
  • FIG. 1 representative photographs of livers isolated from control group, NASH group, isorhamnetin group and quercetin group mice, photomicrographs of hematoxylin and eosin stained tissue sections, and microscopes of tissue sections stained with a lipophilic structure. It is a figure which shows a photograph.
  • (A)-(c) are the graphs which show the result of having quantified the expression level of SREBP gene, FAS gene, and ACC gene in the liver of each mouse of a control group, NASH group, an isorhamnetin group, and a quercetin group in Experimental example 2, respectively. It is.
  • (A) is a quantitative result of the expression level of the SREBP gene
  • (b) is a quantitative result of the expression level of the FAS gene
  • (c) is a quantitative result of the expression level of the ACC gene.
  • (A) And (b) is a graph which shows the result of having quantified the expression level of the TGF beta gene and COL1 gene in the liver of each mouse of a control group, a NASH group, an isorhamnetin group, and a quercetin group in Experimental example 3, respectively.
  • (A) shows the results of quantification of the expression level of TGF ⁇ gene
  • (b) shows the results of quantification of the expression level of COL1 gene.
  • Experimental example 4 it is a graph which shows the result of having quantified the expression level of ApoB gene in the liver of each mouse of a control group, a NASH group, an isorhamnetin group, and a quercetin group, respectively.
  • (A) and (b) is the result of analyzing the survival rate of HSC in Experimental example 5.
  • (A) is the result of contacting each compound with HSC and analyzing the survival rate of HSC after 12 hours.
  • (B) shows the results of analysis of HSC survival after 24 hours by contacting each compound with HSC.
  • A) to (c) show the results of quantifying the expression levels of ⁇ SMA, Col1 and Timp1 in HSC in Experimental Example 6.
  • (A) shows the result of quantifying the expression level of ⁇ SMA in HSC after contacting TGF ⁇ 1 with each compound
  • (b) shows the result of quantifying the expression level of Col1 in HSC after contacting TGF ⁇ 1 with each compound
  • (C) shows the results of quantifying the expression level of Timp1 in HSC after contacting each compound with TGF ⁇ 1.
  • (A) to (c) show the results of quantifying the expression levels of ⁇ SMA, Col1 and Timp1 in HSC in Experimental Example 7.
  • (A) shows the result of contacting each compound with TGF ⁇ 1 after contacting each compound and quantifying the expression amount of ⁇ SMA
  • (b) shows contacting each compound with TGF ⁇ 1 after contacting each compound to express Col1 It is the result of quantifying the amount
  • (c) is the result of contacting each compound with TGF ⁇ 1 after contacting each compound and quantifying the expression level of Timp1.
  • the present invention provides a preventive agent for NASH or a therapeutic agent for NASH, which comprises a compound represented by the following formula (1) as an active ingredient.
  • R 1 to R 5 each independently represent a hydrogen atom or a methyl group, and at least one of R 1 to R 5 is a methyl group.
  • isorhamnetin a compound in which R 1 is a methyl group, and R 2 , R 3 , R 4 and R 5 are hydrogen atoms is a kind of polyphenol called isorhamnetin.
  • the chemical formula of isorhamnetin is shown in the following formula (2). It is known that isorhamnetin is contained in arid land plants and the like, and in Japan it is known to be present in Ginkgo biloba leaves and Seriaceae plants.
  • Quercetin is a compound represented by the formula (1) in which all of R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen atoms.
  • the chemical formula of quercetin is shown in the following formula (3).
  • azaleatine can be chemically synthesized using quercetin abundantly present in onion skins as a raw material.
  • Azaleatine is a compound represented by the formula (1) in which R 4 is a methyl group, and R 1 , R 2 , R 3 and R 5 are hydrogen atoms.
  • the chemical formula of azaleatine is shown in the following formula (4).
  • 3-methyl quercetin can be chemically synthesized using quercetin abundantly present in onion skins as a raw material.
  • 3-methyl quercetin is a compound in which R 3 is a methyl group, and R 1 , R 2 , R 4 and R 5 are hydrogen atoms.
  • the chemical formula of 3-methyl quercetin is shown in the following formula (5).
  • Tamarixetine can be chemically synthesized using quercetin abundantly present in onion skin of onion as a raw material.
  • tamarixetine is a compound in which R 2 is a methyl group, and R 1 , R 3 , R 4 and R 5 are hydrogen atoms.
  • the chemical formula of tamarixetine is shown in the following formula (6).
  • rhamnetin can be chemically synthesized using quercetin abundantly present in onion skins as a raw material.
  • rhamnetin is a compound in which R 5 is a methyl group, and R 1 , R 2 , R 3 and R 4 are hydrogen atoms.
  • the chemical formula of rhamnetin is shown in the following formula (7).
  • the inventors orally administered an oil by orally administering a compound represented by the above-mentioned formula (1) except that a compound in which all of R 1 to R 5 are hydrogen atoms. It was revealed that the combined effects of droplet size reduction, liver fibrosis suppression, lipid transport suppression, etc. can suppress the progression of NASH and improve symptoms.
  • quercetin has been reported to have anti-obesity activity, improvement of NASH by administration of the compound represented by the above formula (1) (except that compounds wherein all of R 1 to R 5 are hydrogen atoms) The effect was significantly higher than when quercetin was administered.
  • the inventors contact the hepatic stellate cells with the compound represented by the above-mentioned formula (1) (except that a compound in which all of R 1 to R 5 are hydrogen atoms), as described later in the Examples. It was clarified that the expression of genes involved in liver fibrosis can be suppressed by
  • the present invention provides a pharmaceutical composition for the prophylaxis or treatment of NASH, which comprises the agent for the prophylaxis or treatment of NASH described above and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present embodiment can be orally administered, for example, in the form of tablets, capsules, granules, powders, solutions, etc. according to ordinary methods (for example, the method described in the Japanese Pharmacopoeia) or injections It can be administered parenterally in the form of suppositories, external preparations for skin and the like.
  • those generally used for the preparation of pharmaceutical compositions can be used without particular limitation. More specifically, for example, binders such as gelatin, corn starch, tragacanth gum and gum arabic; excipients such as starch and crystalline cellulose; swelling agents such as alginic acid; solvents for injection such as water, ethanol and glycerin;
  • the pressure-sensitive adhesive include rubber-based pressure-sensitive adhesives and silicone-based pressure-sensitive adhesives.
  • the pharmaceutical composition may contain an additive.
  • additives such as calcium stearate and magnesium stearate; sweeteners such as sucrose, lactose, saccharin and maltitol; flavoring agents such as peppermint and red mono oil; stabilizers such as benzyl alcohol and phenol; phosphoric acid Salts, buffers such as sodium acetate; solubilizers such as benzyl benzoate and benzyl alcohol; antioxidants; preservatives and the like.
  • the pharmaceutical composition can be formulated by combining the above-mentioned carriers and additives as appropriate and mixing in the unit dose form required for generally accepted pharmaceutical practice.
  • the pharmaceutical composition may, for example, be formulated to be orally administered once a day.
  • the dose of the pharmaceutical composition varies depending on the patient's condition, body weight, age, sex, etc. and can not be generally determined, but in the case of oral administration, for example, 0.1 to 100 mg / kg body weight per dosage unit form
  • the active ingredient (the compound represented by the above formula (1)) may be administered. In the case of injection, for example, 0.01 to 50 mg of the active ingredient may be administered per dosage unit form.
  • the present invention provides a food composition for preventing or improving NASH, which comprises a compound represented by the following formula (1) as an active ingredient.
  • NASH can be prevented, ameliorated or treated by ingesting the food composition of the present embodiment.
  • R 1 to R 5 each independently represent a hydrogen atom or a methyl group, and at least one of R 1 to R 5 is a methyl group.
  • the food composition of the present embodiment may be, for example, in the form of a supplement, may be in the form of semisolid such as yogurt or gel-like food, or may be in the form of a beverage. It may be in the form of any prepared food or the like.
  • Examples of the form of the supplement include the forms of tablets, capsules and the like.
  • the food composition of the present embodiment may be a functional display food.
  • "Functionally labeled food” means a food notified to the Consumer Agency as displaying functionality on a product package based on scientific evidence.
  • the food composition of the present embodiment may be a food for specific health use.
  • Food for specified health use means food that is recognized based on scientific evidence to help maintain and promote health, and labeling of its effects is permitted. The State reviews the effects and safety displayed and is approved by the Secretary of the Consumer Office for each food item. As described later in the examples, the food composition of the present embodiment is confirmed to have a preventive or ameliorating effect of NASH.
  • the present invention provides a method for preventing or improving NASH (excluding medical practice for humans), which comprises the step of causing a subject to ingest a compound represented by the following formula (1).
  • R 1 to R 5 each independently represent a hydrogen atom or a methyl group, and at least one of R 1 to R 5 is a methyl group.
  • the subject includes NASH patients or affected animals.
  • medical practice means an act of a doctor (including a person who has been instructed by a doctor) performing treatment on a human.
  • NASH can be prevented or improved by allowing a subject to ingest the compound represented by the above-mentioned formula (1).
  • the present invention provides a method for preventing or treating NASH, which comprises administering an effective amount of a compound represented by the following formula (1) to a patient in need of treatment.
  • R 1 to R 5 each independently represent a hydrogen atom or a methyl group, and at least one of R 1 to R 5 is a methyl group.
  • the present invention provides a compound represented by the above formula (1) for the prevention or treatment of NASH.
  • the present invention provides the use of a compound represented by the above formula (1) for producing a preventive or therapeutic agent for NASH.
  • Example 1 administering isorhamnetin to NASH model mice
  • the effect of isorhamnetin was administered to NASH model mice.
  • a mouse is fed a high-fat diet, and carbon tetrachloride which is a liver poison is administered four times at 0.1 mL / kg body weight every 3 days from the 14th day of the high-fat diet intake From the 20th day, mice to which fatty acid synthesis promoter T0901317 (CAS number: 293754-55-9) was administered daily at 2.5 mg / kg body weight were used.
  • Isoramnetin was orally administered at 5 mg / kg body weight for 11 days starting on the 14th day of the high-fat diet. Also, a group to which quercetin was administered instead of isorhamnetin was prepared for comparison. Quercetin was orally administered at 5 mg / kg body weight for 11 days from the 14th day of high fat diet intake. In addition, as a control group, a group was prepared in which a normal diet was taken and a solvent was administered instead of carbon tetrachloride and T0901317.
  • Figure 1 shows a control group (indicated as “control” in the figure), a NASH model mouse group (hereinafter referred to as “NASH group” and indicated as “NASH” in Fig. 1), quercetin in NASH model mice.
  • An administered group hereinafter referred to as “quercetin group”, referred to as “quercetin” in FIG. 1
  • a group administered isorhamnetin to NASH model mice hereinafter referred to as “isorhamnetin group” shown in FIG. Is a chart showing the experimental progress of the group to which “.
  • liver tissue was removed from each group of mice and observed with the naked eye.
  • liver tissue was fixed with paraformaldehyde, embedded in paraffin, tissue sections were prepared, and hematoxylin and eosin staining was performed.
  • tissue section was stained with a dye (type “SRfluor, 680-Phenyl”, Molecular Targeting Technologies, Inc.) to stain a lipid-soluble structure (vesicle, lipid droplet, etc.).
  • FIG. 2 shows representative photographs of livers isolated from mice of control group, NASH group, isorhamnetin group and quercetin group, and photomicrographs of hematoxylin and eosin stained tissue sections (indicated as “HE” in FIG. 2).
  • FIG. 2 is a diagram showing a photomicrograph (denoted as “SR” in FIG. 2) of a tissue section stained with a fat-soluble structure.
  • the scale bar of the liver picture shows 1 cm.
  • the scale bar of the micrograph shows 100 ⁇ m.
  • Example 2 (Examination of gene expression related to lipogenesis) The expression of a gene related to lipogenesis was analyzed by quantitative RT-PCR in liver tissues excised from each group of mice in Experimental Example 1. As a gene for lipogenesis, Sterol regulatory element-binding protein (SREBP), fatty acid synthase (FAS) and acetyl-CoA The expression of the carboxylase (ACC) gene was examined.
  • SREBP Sterol regulatory element-binding protein
  • FAS fatty acid synthase
  • ACC carboxylase
  • FIGS. 3 (a) to 3 (c) are graphs showing the results of quantifying the expression levels of the SREBP gene, FAS gene and ACC gene in the livers of the control group, NASH group, isorhamnetin group and quercetin group mice, respectively.
  • FIG. 3 (a) shows the quantification result of the expression level of SREBP gene
  • FIG. 3 (b) shows the quantification result of the expression level of FAS gene
  • FIG. 3 (c) shows the quantification result of the expression level of ACC gene .
  • Example 3 (Examination of gene expression related to liver fibrosis) The expression of the gene related to liver fibrosis was analyzed by quantitative RT-PCR in liver tissue isolated from each group of mice in Experimental Example 1. The expression of Transforming Growth Factor- ⁇ (TGF ⁇ ) and Collagen Type 1 (COL1) genes was examined as genes for liver fibrosis. TGF ⁇ is a gene involved in liver fibrosis. In addition, COL1 is a gene involved in collagen deposition.
  • TGF ⁇ Transforming Growth Factor- ⁇
  • COL1 Collagen Type 1
  • FIGS. 4 (a) and 4 (b) are graphs showing the results of quantification of the expression levels of the TGF ⁇ gene and COL1 gene in the livers of the control group, NASH group, isorhamnetin group and quercetin group mice, respectively.
  • FIG. 4 (a) shows the results of quantification of the expression level of TGF ⁇ gene
  • FIG. 4 (b) shows the results of quantification of the expression level of COL1 gene.
  • Example 4 (Examination of gene expression related to lipid transport) The expression of genes related to lipid transport in liver tissues isolated from mice of each group in Experimental Example 1 was analyzed by quantitative RT-PCR. The expression of Apolipoprotein B (ApoB) gene was examined as a gene involved in lipid transport.
  • Apolipoprotein B Apolipoprotein B
  • FIG. 5 is a graph showing the results of quantifying the expression level of ApoB gene in the livers of control group, NASH group, isorhamnetin group and quercetin group mice, respectively.
  • “***” indicates that there is a significant difference at p ⁇ 0.001 with respect to the control group
  • “###” indicates a significant difference at p ⁇ 0.001 with respect to the NASH group. Indicates that it exists.
  • FIG. 6 (a) shows the results of analysis of HSC viability after 12 hours by contacting the compounds represented by the above formulas (2) to (7) with HSC.
  • FIG. 6 (b) shows the results of analysis of HSC survival after 24 hours by contacting the compounds represented by the above formulas (2) to (7) with HSC.
  • CN indicates a negative control not contacted with the above compound
  • QCT indicates quercetin
  • ISO indicates isorhamnetin
  • AZA indicates azaleatine
  • 3MQ indicates 3-methyl quercetin
  • TAM indicates tamarixetine.
  • RHA indicates rhamnetin.
  • the HSC was contacted with 1 ng / mL of TGF ⁇ 1 and 40 ⁇ M of the compounds represented by the above formulas (2) to (7) for 1 hour. Thereafter, RNA was separated from HSC by a conventional method, and the obtained RNA was subjected to reverse transcription to obtain cDNA. The expression level of the above-mentioned gene was analyzed by quantitative PCR using the obtained cDNA as a template.
  • FIG. 7 (a) shows the results of quantifying the expression level of ⁇ SMA after contacting TGF ⁇ 1 with the above-mentioned compound
  • FIG. 7 (b) shows the results of quantifying the expression level of Col1 after contacting TGF ⁇ 1 with the above-mentioned compound
  • FIG. 7 (c) shows the result of quantifying the expression level of Timp1 after contacting TGF ⁇ 1 with the above-mentioned compound.
  • CN represents a negative control not contacted with TGF ⁇ 1 and any of the above-mentioned compounds
  • CP represents a positive control contacted with TGF ⁇ 1 and not contacted with the above-mentioned compounds
  • QCT represents quercetin.
  • ISO indicates isorhamnetin
  • AZA indicates azaleatine
  • 3MQ indicates 3-methyl quercetin
  • TAM indicates tamarixetine
  • RHA indicates rhamnetin.
  • Fig. 8 (a) shows the results of contacting TGF ⁇ 1 with the above-mentioned compound after contacting the above-mentioned compound and quantifying the expression amount of ⁇ SMA
  • Fig. 8 (b) shows TGF ⁇ 1 with the above-mentioned compound after contacting
  • the results of quantifying the expression level of Col1 by contacting the compound are shown in FIG. 8 (c), and the results of quantifying the expression level of Timp1 by contacting TGF ⁇ 1 with the above-mentioned compound after contacting the above-mentioned compound.
  • FIG. 8 (c) shows the results of quantifying the expression level of Timp1 by contacting TGF ⁇ 1 with the above-mentioned compound after contacting the above-mentioned compound.
  • CN indicates a negative control which is not in contact with TGF ⁇ 1 and any of the above-mentioned compounds
  • CP indicates a positive control which is in contact with TGF ⁇ 1 and which is not in contact with the above-mentioned compounds
  • QCT indicates quercetin.
  • ISO indicates isorhamnetin
  • AZA indicates azaleatine
  • 3MQ indicates 3-methyl quercetin
  • TAM indicates tamarixetine
  • RHA indicates rhamnetin.
  • the present invention can provide a technique for preventing, improving or treating NASH.

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Abstract

L'invention concerne un agent prophylactique ou thérapeutique contre la stéatohépatite non alcoolique, qui contient un composé représenté par la formule (1) en tant que principe actif. (Dans la formule (1), chacun des R1 à R5 représente indépendamment un atome d'hydrogène ou un groupe méthyle ; et au moins l'un des R1 à R5 est un groupe méthyle.)
PCT/JP2018/036389 2017-09-28 2018-09-28 Agent prophylactique ou thérapeutique contre la stéatohépatite non alcoolique et son utilisation WO2019066010A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011057580A (ja) * 2009-09-08 2011-03-24 Fancl Corp サーチュイン活性促進剤
WO2013100111A1 (fr) * 2011-12-27 2013-07-04 油田 正樹 Activateur de sirtuine
JP2016199545A (ja) * 2015-04-10 2016-12-01 ケイティーティー貿易株式会社 リモネン−１，２−ジオール等のスダチ成分を有効成分とする糖及び脂質の代謝改善剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011057580A (ja) * 2009-09-08 2011-03-24 Fancl Corp サーチュイン活性促進剤
WO2013100111A1 (fr) * 2011-12-27 2013-07-04 油田 正樹 Activateur de sirtuine
JP2016199545A (ja) * 2015-04-10 2016-12-01 ケイティーティー貿易株式会社 リモネン−１，２−ジオール等のスダチ成分を有効成分とする糖及び脂質の代謝改善剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KIM, HWAN, JAE ET AL.: "Salicornia Extract Ameliorates Salt-Induced Aggravation of Nonalcoholic Fatty Liver Disease in Obese Mice Fed a High-Fat Diet", JOURNAL OF FOOD SCIENCE, vol. 82, no. 7, 13 June 2017 (2017-06-13) - July 2017 (2017-07-01), pages 1765 - 1774, XP055585671, ISSN: 0022-1147, DOI: 10.1111/1750-3841.13777 *

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