[go: up one dir, main page]

WO2021160139A1 - Composés de 9,10-dihydrophénanthrène et leur utilisation dans le traitement d'une lésion hépatique - Google Patents

Composés de 9,10-dihydrophénanthrène et leur utilisation dans le traitement d'une lésion hépatique Download PDF

Info

Publication number
WO2021160139A1
WO2021160139A1 PCT/CN2021/076395 CN2021076395W WO2021160139A1 WO 2021160139 A1 WO2021160139 A1 WO 2021160139A1 CN 2021076395 W CN2021076395 W CN 2021076395W WO 2021160139 A1 WO2021160139 A1 WO 2021160139A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
liver
compound
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2021/076395
Other languages
English (en)
Chinese (zh)
Inventor
叶阳
潘国宇
姚胜
薛亚茹
邓强强
唐春萍
彭兆亮
柯昌强
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Publication of WO2021160139A1 publication Critical patent/WO2021160139A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • 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
    • A61K31/11—Aldehydes
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
    • C07C205/20—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings
    • C07C205/25—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups bound to carbon atoms of six-membered aromatic rings being part of a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/18—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring
    • C07C39/19—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring containing carbon-to-carbon double bonds but no carbon-to-carbon triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/225—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/24—Halogenated derivatives
    • C07C39/40—Halogenated derivatives with at least one hydroxy group on a condensed ring system containing more than two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/257—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings
    • C07C43/295—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/38—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
    • C07C47/46—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings containing hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

  • the invention belongs to the field of medicinal chemistry, and more specifically, relates to a new class of 9,10-dihydrophenanthrene compounds, a preparation method thereof, and use in medicines for the treatment of liver injury.
  • the liver is not only involved in energy storage and the synthesis and catabolism of various substances, including sugar metabolism, protein metabolism, fat metabolism, etc., but also in the detoxification process of toxins and drug catabolites produced by human metabolism.
  • the liver is also an organ frequently invaded by various pathogenic factors or diseases. For example, drugs, viruses, alcohol, abnormal metabolism, ischemia reperfusion, etc. can cause damage to the liver and cause inflammation.
  • Acute and chronic hepatitis eventually transforms into liver fibrosis, cirrhosis and hepatocellular carcinoma.
  • the global incidence of primary liver cancer remains high, which is mainly related to the high incidence of acute and chronic hepatitis.
  • 9,10-Dihydrophenanthrene compounds are a class of compounds that are ubiquitous in plants such as Orchidaceae and Juncus family. There are more than two benzene rings in their structure, and they contain multiple phenolic hydroxyl groups. They are aromatic and have a certain degree of hydrophobicity. .
  • Existing studies have shown that these compounds generally have anti-tumor, antispasmodic, anti-platelet aggregation, anti-allergic and other biological activities, but the protective effects of such compounds on liver injury have not been reported in the literature.
  • the purpose of the present invention is to provide a class of 9,10-dihydrophenanthrene compounds or derivatives thereof that can be used for liver injury protection.
  • the first aspect of the present invention provides a use of a compound represented by the following formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • R a , R b and R c are each independently selected from the following group: H, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, -CHO, -NO 2 ;
  • n and p are each independently selected from the following group: 0, 1, 2, 3 or 4;
  • n is selected from the following group: 0, 1 or 2;
  • R d is a C2-C4 alkenyl group, or -(O) x -R; wherein, the x is 0 or 1, and the R is a structural fragment formed by a structural unit selected from the following group losing one hydrogen atom : Substituted or unsubstituted Substituted or unsubstituted substituted or unsubstituted Substituted or unsubstituted
  • R d and any one of R a , R b and R c and their respective connected carbon atoms together form a group selected from the following group: substituted or unsubstituted 3-7 membered heterocyclic group, substituted or unsubstituted 3-7 membered cycloalkyl;
  • the said substitution is substituted by one or more substituents selected from the following group: H, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, -CHO, -NO 2 , or phenyl substituted by one or more groups selected from the group consisting of hydroxyl, C1-C4 alkyl, C1-C4 alkoxy;
  • It is characterized in that it is used for preparing a pharmaceutical composition for treating or preventing liver injury.
  • the R is a group selected from the group consisting of substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted
  • the R d is substituted by one or more substituents selected from the group consisting of H, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, and C2-C4 alkenyl.
  • the compound has the structure shown in the following formula I-a or I-b:
  • the compound is selected from the following group:
  • the second aspect of the present invention provides a use of a compound represented by the following formula II, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • the dashed line indicates chemical bond or absence
  • R d and R e are each independently selected from the group: H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl group, -CHO, -NO 2, a substituted or unsubstituted benzyl, or base;
  • q and r are each independently selected from the following group: 0, 1, 2, 3 or 4;
  • the said substitution is substituted by one or more substituents selected from the following group: H, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, -CHO, -NO 2 , or phenyl substituted by one or more groups selected from the group consisting of hydroxyl, C1-C4 alkyl, C1-C4 alkoxy;
  • It is characterized in that it is used for preparing a pharmaceutical composition for treating or preventing liver injury.
  • the compound is selected from the following group:
  • the third aspect of the present invention provides a use of the compound according to the first or second aspect of the present invention, wherein the liver damage is selected from the group consisting of liver damage due to cholestasis symptoms, or hepatitis.
  • the hepatitis is selected from the group consisting of toxic hepatitis (drugs, chemical substances and biological toxins), alcoholic hepatitis, and ischemic hepatitis.
  • the liver damage is liver damage caused by drugs, preferably, the liver damage is liver damage caused by Chinese herbal medicine.
  • the fourth aspect of the present invention provides a compound selected from the following group:
  • Figure 1 The protective effect of YS30 on acute liver injury in mice with CCl4.
  • A ALT
  • B AST and C
  • C LDH levels in mouse serum
  • D pathological analysis of liver tissue after H&E staining.
  • the boxes, arrows, and solid triangles indicate liver tissue swelling, central lobular necrosis, and inflammatory infiltration, respectively.
  • E H&E staining Suzuki's score. ### P ⁇ 0.001, ## P ⁇ 0.01 CCl4 group vs. Vehicle group; *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001 vs. CCl4 group.
  • Figure 2 The effect of YS30 on serum inflammatory factors and liver lipid peroxidation levels.
  • C lipid peroxidation level in liver tissue. ### P ⁇ 0.001, ## P ⁇ 0.01 vs Vehicle group, ***P ⁇ 0.001, **P ⁇ 0.01, *P ⁇ 0.01 vs CCl4 group.
  • Figure 3 The protective effect of YS30 on ischemia-reperfusion liver injury in mice.
  • A ALT, (B) AST, (C) LDH levels in mouse serum, (D) pathological analysis of liver tissue after H&E staining. The boxes, arrows, and solid triangles indicate liver tissue swelling, central lobular necrosis, and inflammatory infiltration, respectively.
  • E H&E staining Suzuki's score. ### P ⁇ 0.001, ## P ⁇ 0.01 I/R group vs. Sham group; *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001 vs. I/R group.
  • a class of 9,10 dihydrophenanthrene compounds as described in the present invention has good anti-inflammatory and antioxidant properties, and is particularly suitable for the treatment of inflammation and lipids.
  • Peroxidation is the pathological basis of diseases such as liver disease, including toxic hepatitis (drugs, chemical substances and biological toxins), alcoholic hepatitis, ischemic hepatitis and so on. Based on the above findings, the inventor completed the present invention.
  • C 1 -C 6 alkyl or “C 1 -C 10 alkyl” refers to a straight or branched chain alkyl group having 1 to 6 or 1 to 10 carbon atoms, such as methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
  • C 3 -C 6 cycloalkyl refers to a cycloalkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, or the like.
  • halogen refers to F, Cl, Br, and I.
  • the term “comprising”, “comprising” or “including” means that various ingredients can be used together in the mixture or composition of the present invention. Therefore, the terms “mainly consisting of” and “consisting of” are included in the term “containing”.
  • the term "pharmaceutically acceptable” ingredients refers to substances that are suitable for use in humans and/or animals without excessive side effects (such as toxicity, irritation, and allergic reactions), that is, substances that have a reasonable benefit/risk ratio.
  • the term "effective amount" refers to the amount of a therapeutic agent that treats, alleviates, or prevents the target disease or condition, or shows a detectable therapeutic or preventive effect.
  • the precise effective amount for a subject depends on the size and health of the subject, the nature and extent of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given situation, routine experiments can be used to determine the effective amount, and the clinician can judge it.
  • substituted means that one or more hydrogen atoms on the group are substituted by a substituent selected from the following group: halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted A substituted or halogenated C 2 -C 6 acyl group, an unsubstituted or halogenated C1-C6 alkyl-hydroxy group.
  • each chiral carbon atom may optionally be R configuration or S configuration, or a mixture of R configuration and S configuration.
  • the term "compound of the invention” refers to a compound represented by formula I.
  • the term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of formula I.
  • the term "pharmaceutically acceptable salt” refers to a salt formed by a compound of the present invention and an acid or base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of this invention with acids.
  • Acids suitable for salt formation include but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • the term "dimer” refers to dibenzyl or stilbene, 9,10-dihydrophenanthrene or phenanthrene itself or with other dibenzyl or stilbene, 9,10-dihydrophenanthrene or phenanthrene through COC, or CC , Or a dimer formed by connecting COC and CC at the same time.
  • Cholestasis is a common complication of drug-induced liver injury, accompanied by the accumulation of hydrophobic cholic acid (such as Deoxycholic acid (DCA) and Lithocholic acid (LCA) in liver cells.
  • Hydrophobic cholic acid It can destroy the cell basement outer membrane, organelle membrane and specifically destroy the outer layer of microtubule membrane. It is one of the main endogenous substances that cause liver cell damage.
  • DCA Deoxycholic acid
  • LCA Lithocholic acid
  • this class of compounds can significantly resist the hepatocyte damage caused by hydrophobic cholic acid DCA and LCA in the concentration range of 0.1-25uM. This suggests that this class of compounds may be useful for a class of liver damage accompanied by cholestasis symptoms.
  • Such as medicines, especially Chinese herbal medicines have a significant improvement effect on liver damage.
  • the 9,10 dihydrophenanthrene compound or its analog obtained by separation in the present invention specifically includes:
  • the first category Compound YS1 ⁇ 37 isolated from Shixiantao
  • the second category compounds XYW1 ⁇ 10 isolated from wild rushes:
  • the compound of the present invention Since the compound of the present invention has excellent liver injury reversal activity, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and containing the compound of the present invention as the main active ingredient
  • the pharmaceutical composition can be used to treat, prevent and alleviate various liver injury-related diseases, such as a type of hepatitis based on inflammation and lipid peroxidation.
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-3000 (active dose range 1-100 mg/kg) mg of the compound of the present invention/agent, more preferably, 10-2000 mg of the compound of the present invention/agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • antioxidants
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, propellant and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the administered dose is usually 1 to 2000 mg, preferably 6 to 600 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • the main advantages of the present invention include:
  • the active compounds of the present invention also have antioxidant and anti-inflammatory activities.
  • hepatitis with oxidative stress and inflammation as the main pathological characteristics, such as toxic hepatitis (drugs, chemical Substances and biological toxins), alcoholic hepatitis, and ischemic hepatitis also have potential protective effects, which have been confirmed by animal experiments.
  • UV spectrum Shimadzu UV-2550 UV spectrometer
  • Circular dichroism JASCO J-810 spectropolarimeter
  • Mass spectrometry Waters 3100 SQDMS (low resolution ESI), Waters Xevo QTof MS (high resolution ESI);
  • MCI resin CHP20P (75-150 ⁇ m), Mitsubishi Chemical Corporation;
  • TLC prefabricated thin-layer board HSGF254 is produced by Yantai Chemical Plant;
  • Sephadex Sephadex LH-20: Pharmacia Biotech AB, Uppsala, Sweden;
  • High performance liquid chromatography and mass spectrometer Waters 2695 LC coupled to Waters 2998 DAD, Waters Acquity ELSD, Waters 3100 SQDMS, analytical column model: Waters RP C-18, 3.5 ⁇ m, 4.6mm ⁇ 100mm;
  • Color detection method 10% vanilla aldehyde sulfate solution, UV254 and UV365 ultraviolet lamps;
  • Experimental solvents analytical grade solvents (Sinopharm Group), chromatographic grade solvents (Merck KGaA, Germany); experimental animals: male ICR mice, weighing 22-25g, male SD rats, weighing 200-250g. The animals were purchased from Shanghai Slack Laboratory Animal Co., Ltd.;
  • L929 cells were from the cell bank of Shanghai Academy of Biological Sciences, Chinese Academy of Sciences.
  • Hihep cells are transdifferentiated human hepatocytes, gifted by teacher Hui Lijian, Institute of Biochemical Cells, Chinese Academy of Sciences.
  • BMDM cells were isolated from ICR mouse bone marrow, and rat primary hepatocytes were isolated from SD rats;
  • DPPH radical was purchased from Shanghai Macleans Biochemical Technology Co., Ltd.; olive oil, formaldehyde solution, 75% alcohol, and absolute ethanol were purchased from Sinopharm Chemical Reagent Co., Ltd.; DMSO, vitamin C, silymarin, resveratrol, Dexamethasone, lipopolysaccharide (LPS) was purchased from Sigma-Aldrich; bicyclol was purchased from the National Institute for the Control of Pharmaceutical and Biological Products; 1 ⁇ EBSS buffer, William'E medium, penicillin, and fetal bovine serum (FBS) , Insulin-transferrin-selenium additive (ITS), 10 ⁇ PBS was purchased from Gibco; high-sugar DMEM medium was purchased from Hyclone; RIPA lysate and NO detection kit were purchased from Shanghai Biyuntian Biotechnology Co., Ltd.; Mouse TNF ⁇ and IL-6 ELISA kits were purchased from Hangzhou Lianke Biotechnology Co., Ltd.; ALT,
  • Surgical instruments ophthalmic scissors, ophthalmic tweezers, 200 mesh/300 mesh screen, 1ml syringe, among which scissors, tweezers and screen need to be sterilized and dried in advance;
  • Fraction 6 was separated and purified by repeated silica gel column chromatography to obtain compounds YS25 (coelonin, 11mg), YS26 (dihydropinosylvin, dihydropinosylvin, 140mg), YS27 (4-hydroxy-3-methoxydibenzyl, 43mg), YS30 (gigantol, YS30, 60mg), YS33 (thunalbene, 45mg), YS34 (3'-hydroxy-3,5-dimethoxystilbene, 35mg).
  • Fraction 7 is a small fraction obtained by silica gel column chromatography and then purified by Sephadex LH-20 to obtain compound YS23 (2-hydroxy-4,7-dimethoxy-9,10-dihydrophenanthrene, 23mg) and YS31 ( 3-hydroxy-5-methoxystilbene, 11 mg).
  • Fraction 8 is the small fraction obtained by silica gel column chromatography and then is purified by Sephadex LH-20 and preparative high performance liquid phase to obtain compound YS1 (phochinenin A, 18mg), YS3 ⁇ 5 (phochinenins CE, 4,72 and 59mg) , YS8 (phochinenin H, 27mg), YS11-12 (phochinenins K and L, 7 and 4mg), YS21 (blestrin A, 16mg), YS29 (batatasin III, 14mg), YS35 (shancidin, 48mg), YS36 (1- (4-Hydroxybenzyl)-4-methoxy-2,7-dihydroxy-9,10 dihydrophenanthrene, 8mg], YS37 (isoarundinin I, 114mg).
  • YS1 phochinenin A, 18mg
  • YS3 ⁇ 5 phochinenins CE, 4,
  • Brown amorphous powder [ ⁇ ] 20 D +0.003(c 0.315,MeOH).UV(MeOH) ⁇ max nm(log ⁇ ):216(5.14),280(4.95),296(4.85).CD data recorded on- line in hexane/ethanol 7:3 for(aS)-18: ⁇ max ( ⁇ ):307(8.7),287sh(5.5),271(-9.1),246(8.5),219(-9.7).(aR )-18: 311(-8.8), 286sh(-5.5), 269(10.0), 243(-8.3), 222(9.8).
  • YS23 7-hydroxy-2,4-dimethoxy-9,10-dihydrophenanthrene,7-hydroxy-2,4-dimethoxy-9,10-dihydrophenanthrene
  • YS34 3'-hydroxy-3,5-dimethoxy-stilbene,3'-hydroxy-3,5-dimethoxy-stilbene
  • YS36 9,10-dihydro-1-(4-hydroxybenzyl)-4-methoxy-2,7-phenanthrenediol, 1-(4-hydroxybenzyl)-4-methoxy-2,7-dihydroxy-9 ,10 Dihydrophenanthrene
  • Rush officinalis dried 9.5 kg of the whole plant, extracted with 95% industrial ethanol (35L) cold soaking for 3 times for 3 days each time, the extracts were combined, and the solvent was recovered under reduced pressure to obtain 445 g of total extract.
  • the total extract was dissolved in water, partitioned and extracted with ethyl acetate and n-butanol to obtain 217 g of ethyl acetate, 62 g of n-butanol layer and 153 g of water layer.
  • the ethyl acetate fraction (217g) was passed through the silica gel column layer (petroleum ether-acetone 6:1-0:1) to obtain 8 fractions.
  • Fraction 3 (16.7g) was separated by silica gel column chromatography (PE-isopropyl ether 10:1 ⁇ 1:1) and the secondary fraction F3-1 obtained was recrystallized with isopropyl ether to obtain compound XYW-1 (juncuenin A, 51 mg), the secondary fraction F3-4 was subjected to Sephadex LH-20 (chloroform-methanol 1:1) to obtain compound XYW-5 (dehydrojuncuenin A, 333 mg).
  • Fraction 4 70.53g was recrystallized from chloroform to obtain compound XYW-3 (juncuenin C, 22g).
  • the secondary fraction F5-5 (314mg) was recrystallized with chloroform to obtain compound XYW-4 (juncuenin D, 66mg); F5-10 (1.492g) was purified by silica gel column chromatography (PE: Actone 7:2) and the obtained fraction was recrystallized (MeOH-PE) to obtain compound XYW-7 (dehydrojuncuenins C, 28mg).
  • XYW-1 juncuenin A (2-hydroxy-1,7-dimethyl-6-vinyl-9,10-dihydrophenanthrene)
  • XYW-2 juncuenin B (2,6-Dihydroxy-1-methyl-7carboxy-8-vinyl-9,10-dihydrophenanthrene)
  • XYW-3 juncuenin C (2,6-dihydroxy-1,7-dimethyl-8 vinyl-9,10-dihydrophenanthrene)
  • XYW-4 juncuenin D (2,8a-dihydroxy-1,7-dimethyl-6-carbonyl-8-vinyl-9,10-dihydrophenanthrene)
  • XYW-5 dehydrojuncuenin A (2-hydroxy-1,7-dimethyl 6-vinylphenanthrene)
  • XYW-6 dehydrojuncuenin B (2,6-dihydroxy-1,7-dimethyl-8-vinylphenanthrene)
  • XYW-7 dehydrojuncuenin C (2,6-dihydroxy-1-methyl-12-lactone-phenanthrene)
  • XYW-8 2,8-dihydroxy-1,6-dimethyl-5-vinyl-9,10-dihydrophenanthrene
  • the dichloromethane parts were treated with MCI column chromatography, and then eluted with 50, 60, 70, 80, and 95% ethanol-water to obtain seven parts.
  • Compounds, wherein compounds XF-1-11, 24, 29 are 9,10-dihydrophenanthrene/phenanthrene monomers, and XF-14-20, 33 are 9,10-dihydrophenanthrene/phenanthrene dimers.
  • XF-33 8-[4-(2,7-dihydroxy-1,6-dimethyl-5-vinyl-9,10-dihydrophenanthrene)yl]-2,7-dihydroxy-1, 6-Dimethyl-5-vinyl-phenanthrene
  • Cholestasis is a common complication of drug-induced liver injury. It is accompanied by the accumulation of hydrophobic cholic acid, such as deoxycholic acid (DCA) and lithocholic acid (LCA) in liver cells. Hydrophobic cholic acid can destroy cell basement outer membrane and organelles. The membrane specifically destroys the outer layer of the microtubule membrane and is one of the main endogenous substances that cause liver cell damage. Hydrophobic bile acid-induced liver cell injury model can be used to evaluate the effect of compounds against cholic acid toxicity, so as to infer the protective effect of compounds on a type of liver injury accompanied by cholestasis symptoms, such as drugs, especially Chinese herbal medicines.
  • hydrophobic cholic acid such as deoxycholic acid (DCA) and lithocholic acid (LCA) in liver cells.
  • Hydrophobic cholic acid can destroy cell basement outer membrane and organelles. The membrane specifically destroys the outer layer of the microtubule membrane and is one of the main endogenous substances that cause liver
  • the primary rat hepatocytes were separated by two-step perfusion method, seeded in 96-well plates at a density of 3 ⁇ 10 5 cells/ml, and administered after 4 hours of adherence. After co-incubating rat primary hepatocytes with 200 ⁇ M DCA and corresponding compounds for 24 hours, the cell viability was measured by the CCK8 method. Measure the absorbance at 450nm with a multifunctional microplate reader. The absorbance is directly proportional to cell viability. The protective effect of the compound is judged according to the cell viability.
  • Hihep cells were cultured in HMM (Hepatocytes Maintaining Medium) medium, and when the cells grew to 90% confluency, the cells were seeded in a 96-well plate at a density of 1 ⁇ 10 5 cells/ml, and the drug was administered after 3 days of culture.
  • the hihep cells were incubated with 250 ⁇ M DCA and corresponding compounds for 24h.
  • the CCK8 method was then used to determine the cell viability, and the operation method was the same as above.
  • Hihep is cultured according to the above method.
  • the hihep cells were incubated with 30 ⁇ M LCA and corresponding compounds for 24h.
  • the CCK8 method was then used to determine the cell viability, and the operation was the same as above.
  • the experimental results show that the tested 9,10 dihydrophenanthrene compounds have a significant effect against the hepatotoxicity of hydrophobic cholic acid in the concentration range of 0.1-25uM, and have a potential hepatoprotective effect, especially for associated cholestasis Symptomatic liver damage, such as liver damage caused by drugs, especially Chinese herbal medicine, has a potential protective effect.
  • Table 1 The specific experimental results are shown in Table 1.
  • Example 3 The protective effect of compound YS30 on CCl4 liver injury in mice
  • the CCl 4 induced acute liver injury model in mice is one of the commonly used models for preclinical evaluation of drugs against acute liver injury.
  • the damage mechanism is that CCl 4 is metabolized by CYP2E1, CYP2B and other metabolic enzymes into free radicals in the liver. Free radicals combine with nucleic acids, proteins and lipids in the liver, leading to nucleic acid denaturation, protein synthesis hindered and steatosis.
  • the above-mentioned pathological changes can cause cell death, release damage pattern factors (DAMPs), activate immune cells, induce inflammation, and cause downstream fulminant liver injury. Oxidative stress and inflammation are two important pathological processes of liver injury.
  • This model can be used to evaluate the protective effects of compounds on a type of hepatitis based on inflammation and oxidative stress. These include toxic hepatitis (drugs, chemicals and biological toxins), alcoholic hepatitis, liver damage caused by ischemic hepatitis.
  • mice 60 ICR mice were randomly divided into 7 groups, 8 in each group: vehicle group, YS30 high-dose (40mg/kg ⁇ day) single administration group, CCl4 acute model, CCl4 model plus positive drug bicyclol group (200mg/kg ⁇ day), CCl4 modeling plus YS30 low-dose (10mg/kg ⁇ day), middle-dose (20mg/kg ⁇ day), and high-dose (40mg/kg ⁇ day) groups.
  • YS30 was given by intragastric administration at the corresponding dose for 7 days, once a day.
  • Bicyclic alcohol was given by intragastric administration for 3 consecutive days at the corresponding dose.
  • the vehicle group and the CCl4 acute model group were given a 0.5% Tween 80 solvent for continuous intragastric gavage for 7 days.
  • 0.5% CCl4 olive oil solution (10ml/kg) was injected subcutaneously.
  • the vehicle group and YS30 single administration group were injected with corresponding volume of olive oil subcutaneously. All mice were fasted and freely drinking water, and samples were collected 16 hours after modeling. The mice were anesthetized with sodium pentobarbital, then the eyeballs were removed for blood collection, the mice were dissected, and the liver was taken, a part of the mice was washed with saline and then quickly frozen in liquid nitrogen and stored at -80°C for subsequent biochemical index detection. The remaining part is soaked in formalin for hematoxylin-eosin staining.
  • the same large liver leaf of the mouse was soaked in formalin for histopathological analysis. Take the same part of the liver tissue for paraffin embedding, obtain a 3um section, perform H&E staining, observe the pathological changes of the liver under a microscope, and comprehensively evaluate the congestion, vacuole, necrosis, and inflammation of the liver tissue using Suzuki’s scoring method.
  • Use Biyuntian MDA kit to detect MDA level in tissue samples Take 20-30mg liver tissue samples, add the pre-cooled PBS homogenate according to 1:9, centrifuge at 12000rpm/min 4°C for 10min to take the supernatant, use the BCA kit to detect the corresponding protein concentration, and then detect the MDA in the tissue according to the MDA kit instructions content.
  • YS30 has an effect on the inflammatory factors TNF- ⁇ , IL-6 and liver lipid peroxidation in acute liver injury.
  • Oxidation (MDA) levels have a significant improvement effect, which suggests that YS30 has an effect on a type of liver injury based on inflammation and oxidative stress, such as toxic hepatitis (drugs, chemicals, and biological toxins), alcoholic hepatitis, and deficiency. Blood hepatitis has potential protective effects.
  • Example 4 The protective effect of compound YS30 on ischemia-reperfusion liver injury in mice
  • liver ischemia-reperfusion injury can occur in cases of liver transplantation, liver resection, trauma, hemorrhagic shock, and other systemic low blood flow diseases such as sepsis, respiratory failure, and congestive heart failure.
  • the mechanism of this injury is related to the oxidative stress response during the ischemic period and the explosive inflammatory response during the reperfusion period.
  • Using a 70% warm ischemia reperfusion model in mice can simulate clinical perioperative liver injury and evaluate the protective effect of the compound on this type of liver injury.
  • the compounds of the present invention all have anti-oxidant or/and anti-inflammatory activities similar to YS30 in vitro,
  • C57/BL mice were divided into 3 groups: sham operation group (Sham group), ischemia-reperfusion group (I/R), and YS30 administration group (I/R+YS30).
  • YS30 40mg/kg was dissolved in physiological saline and administered via the tail vein 24h, 12h and 1h before surgery.
  • a 70% warm ischemia reperfusion model was constructed according to literature reports, and mice were anesthetized with 4% chloral hydrate (intraperitoneal injection) Afterwards, the hepatic artery, portal vein, and bile duct were separated along the midline of the abdomen, and the left and middle lobe hepatic artery, portal vein, and bile duct were clamped using non-invasive microscopy hemostatic clips to cause 70% liver ischemia. After 60 minutes of ischemia, The non-invasive hemostatic clip was removed, the blood supply was restored, the abdominal cavity was sutured, and the blood samples and tissue samples of each group were collected after 6 hours of reperfusion.
  • the results are shown in Figure 3.
  • the experimental results show that YS30 can significantly improve the liver damage caused by ischemia-reperfusion in mice, significantly inhibit the levels of ALT, AST and LDH in the serum of mice, and can significantly improve the pathological changes of liver tissue. , which shows that YS30 has the application prospect of preventing clinical perioperative liver injury.
  • Example 5 The effect of 9,10-dihydrophenanthrene active compounds on oxidative stress and inflammation in the pathological process of liver injury
  • DPPH radical scavenging experiment Weigh a certain amount of DPPH reagent, dissolve it with absolute ethanol, prepare a 0.2mM DPPH absolute ethanol solution, and place it in a refrigerator at 4°C for later use.
  • the compound to be tested was dissolved in DMSO to form a 100 mM mother liquor, and then diluted 1:1000 in anhydrous ethanol solution to form a 100 uM solution to be tested.
  • Both the positive drug and the test compound are provided with corresponding negative control wells without DPPH free radicals (100ul of absolute ethanol is used instead of DPPH free radicals) to deduct the influence of the color of the test product on the readings. After mixing, let it stand at room temperature for 30 minutes, and then measure the absorbance at 517 nm.
  • DPPH free radical scavenging rate [OD DPPH-control -(OD DPPH-sample -OD sample-control )]/OD DPPH- control *100%
  • OD DPPH-control means the average OD value of no compound plus DPPH group
  • OD DPPH-sample represents the OD value of the compound + DPPH group
  • OD sample-control means the OD value of the compound group without DPPH
  • the scavenging rate of DPPH free radical of silymarin is about 35%.
  • the scavenging rate of DPPH free radical is better than that of silymarin, and compounds with statistical differences (p ⁇ 0.05) are strong antioxidants.
  • the results showed that among the 46 compounds tested, 39 compounds (100 ⁇ M) had a DPPH free radical scavenging rate greater than 35%, which was defined as a strong antioxidant effect.
  • the results are shown in Table 2.
  • BMDM Mouse bone marrow macrophages
  • monocyte colonies were induced with high glucose DMEM medium containing 15% L929 cell supernatant for one week.
  • the cells were seeded into a 96-well plate at a seeding density of 5 ⁇ 10 5 cells/ml. After culturing for 24 hours, the corresponding drugs were added for incubation.
  • a 10 mM solution of the positive drug or test compound was dissolved in a high-sugar DMEM medium containing 10% FBS at a ratio of 1:1000.
  • the drug to be tested (10 ⁇ M) and 1ug/ml LPS were incubated with BMDM at the same time, and the supernatant was collected 24h later for NO detection.
  • the level of NO reflects the strength of the inflammatory response in the system. To determine the anti-inflammatory effect of the compound.
  • the positive drug dexamethasone (10 ⁇ M) can significantly inhibit the release of NO from BMDM. Comparing the administration group with the LPS induction group, the level of NO after administration is lower than that of the LPS induction group, and there is a statistical difference between the two (p ⁇ 0.05) The compound is defined as having an anti-inflammatory effect. The results showed that among the 46 compounds tested, 21 compounds had significant anti-inflammatory effects. The results are shown in Table 2.
  • 9,10-dihydrophenanthrene compounds with hepatoprotective activity have similar anti-oxidant or/and anti-inflammatory properties to YS30, and are effective against a type of liver injury whose main pathological basis is inflammation and oxidative stress.
  • Such as toxic hepatitis (drugs, chemicals and biological toxins), alcoholic hepatitis, ischemic hepatitis also have potential protective effects.
  • the CCl4-induced acute liver injury model in mice is one of the commonly used models for pre-clinical evaluation of drugs against heterologous substances (such as alcohol, drugs, chemical poisons) liver toxicity.
  • the damage mechanism is that CCl4 is metabolized into free radicals in the liver by metabolic enzymes such as CYP2E1 and CYP2B. Free radicals bind to nucleic acids, proteins and lipids in the liver, resulting in nucleic acid denaturation, hindered protein synthesis and steatosis.
  • the above-mentioned pathological changes can cause cell death, release damage pattern factors (DAMPs), activate immune cells, induce inflammation, and cause downstream fulminant liver injury.
  • DAMPs release damage pattern factors
  • YS30 (gigantol) has a good protective effect on CCl4-induced acute liver injury at animal level, and can significantly reduce the elevation of ALT, AST and LDH caused by liver injury (Figure 1A). Histopathological examination found that YS30 can improve the pathological changes such as vacuoles, necrosis and inflammation in liver tissues (Figure 1B).
  • liver ischemia-reperfusion injury can occur in cases of liver transplantation, liver resection, trauma, hemorrhagic shock, and other systemic low blood flow diseases such as sepsis, respiratory failure, and congestive heart failure.
  • the mechanism of this injury is related to the oxidative stress response during the ischemic period and the explosive inflammatory response during the reperfusion period.
  • the experimental results showed that YS30 significantly improved the increase in serum ALT, AST, LDH and liver pathological changes caused by ischemia-reperfusion in mice. It can be seen that YS30 has a potential therapeutic effect in clinical liver perioperative liver injury.
  • the 9,10-dihydrophenanthrene compound of the present invention has a good hepatoprotective effect, and is effective in drug-induced liver injury accompanied by cholestasis symptoms, toxic hepatitis, alcoholic hepatitis, and liver perioperative liver injury. All have potential application value in treatment.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de 9,10-dihydrophénanthrène et son utilisation dans le traitement d'une lésion hépatique. En particulier, l'Invention concerne un composé représenté par la formule (I) ou un composé représenté par la formule (II), qui présente des activités anti-inflammatoires et antioxydantes dans les tissus hépatiques, et peut par conséquent être utilisé dans le traitement ou la prévention de maladies avec lésions hépatiques, en particulier des maladies avec lésions hépatiques liées, au plan pathologique, à une inflammation et une peroxydation des lipides.
PCT/CN2021/076395 2020-02-11 2021-02-09 Composés de 9,10-dihydrophénanthrène et leur utilisation dans le traitement d'une lésion hépatique Ceased WO2021160139A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010087201.5 2020-02-11
CN202010087201.5A CN113244203A (zh) 2020-02-11 2020-02-11 9,10-二氢菲类化合物及其用于肝损伤治疗的用途

Publications (1)

Publication Number Publication Date
WO2021160139A1 true WO2021160139A1 (fr) 2021-08-19

Family

ID=77219549

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/076395 Ceased WO2021160139A1 (fr) 2020-02-11 2021-02-09 Composés de 9,10-dihydrophénanthrène et leur utilisation dans le traitement d'une lésion hépatique

Country Status (2)

Country Link
CN (2) CN120247669A (fr)
WO (1) WO2021160139A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114438016A (zh) * 2022-02-18 2022-05-06 军事科学院军事医学研究院环境医学与作业医学研究所 石斛酚对肝细胞的毒性作用及其在肝细胞毒性研究中的用途
CN114557985A (zh) * 2022-03-15 2022-05-31 浙江中医药大学 一种用于治疗骨性关节炎的贝母兰宁组合物及其应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116768833B (zh) * 2023-06-09 2025-04-29 海南医学院 一个从盘龙参中分离获得的二氢菲类化合物及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104069365A (zh) * 2013-03-28 2014-10-01 东海大学 石斛多酚于保肝、治疗/预防糖尿病的用途
TW201828968A (zh) * 2017-02-06 2018-08-16 吳天賞 經單離成分、具抗炎性活性的提取物及其用途
CN109516903A (zh) * 2017-09-19 2019-03-26 北京理工大学 一类用于治疗肝损伤的茋类化合物、其制备方法及其应用
CN110075094A (zh) * 2019-02-27 2019-08-02 延边大学 紫檀芪在制备药物或保健品中的应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021525268A (ja) * 2018-05-31 2021-09-24 ソシエテ・デ・プロデュイ・ネスレ・エス・アー Ａｍｐｋ直接活性化剤化合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104069365A (zh) * 2013-03-28 2014-10-01 东海大学 石斛多酚于保肝、治疗/预防糖尿病的用途
TW201828968A (zh) * 2017-02-06 2018-08-16 吳天賞 經單離成分、具抗炎性活性的提取物及其用途
CN109516903A (zh) * 2017-09-19 2019-03-26 北京理工大学 一类用于治疗肝损伤的茋类化合物、其制备方法及其应用
CN110075094A (zh) * 2019-02-27 2019-08-02 延边大学 紫檀芪在制备药物或保健品中的应用

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
ABDEL-RAZIK AYMAN F, ELSHAMY ABDEL-SAMID I, NASSAR MAHMOUD I, EL-KOUSY SALAH M, HAMDY HANAA: "CHEMICAL CONSTITUENTS AND HEPATOPROTECTIVE ACTIVITY OF Juncus subulatus", REV. LATINOAMER. QUÍM., vol. 37, no. 1, 1 May 2015 (2015-05-01), pages 70 - 84, XP055835833, DOI: 10.13140/RG.2.1.2939.7926 *
LIN CHE-WEI, HWANG TSONG-LONG, CHEN FU-AN, HUANG CHIA-HSIN, HUNG HSIN-YI, WU TIAN-SHUNG: "Chemical Constituents of the Rhizomes of Bletilla formosana and Their Potential Anti-inflammatory Activity", JOURNAL OF NATURAL PRODUCTS, AMERICAN CHEMICAL SOCIETY, US, vol. 79, no. 8, 26 August 2016 (2016-08-26), US, pages 1911 - 1921, XP055835835, ISSN: 0163-3864, DOI: 10.1021/acs.jnatprod.6b00118 *
MA WEI, LIU FENG, DING YUN-YUN, ZHANG YUE, LI NING: "Four new phenanthrenoid dimers from Juncus effusus L. with cytotoxic and anti-inflammatory activities", FITOTERAPIA, IDB HOLDING, MILAN., IT, vol. 105, 10 June 2015 (2015-06-10), IT, pages 83 - 88, XP055835839, ISSN: 0367-326X, DOI: 10.1016/j.fitote.2015.06.006 *
MA WEI; ZHANG YUE; DING YUN-YUN; LIU FENG; LI NING: "Cytotoxic and anti-inflammatory activities of phenanthrenes from the medullae ofJuncus effususL.", ARCHIVES OF PHARMACAL RESEARCH, NATL. FISHERIES UNIVERSITY , PUSAN, KR, vol. 39, no. 2, 19 November 2015 (2015-11-19), KR, pages 154 - 160, XP035958522, ISSN: 0253-6269, DOI: 10.1007/s12272-015-0680-x *
XUE YARU, DENG QIANGQIANG, ZHANG QINGLI, MA ZHENGHUA, CHEN BINFAN, YU XIAOLU, PENG HUIGE, YAO SHENG, LIU JIA, YE YANG, PAN GUOYU: "Gigantol Ameliorates CCl4-induced Liver Injury via Preventing Activation of JNK/cPLA2/12-LOX Inflammatory Pathway.", SCIENTIFIC REPORTS, vol. 10, no. 1, 1 December 2020 (2020-12-01), XP055835830, DOI: 10.1038/s41598-020-79400-0 *
XUE YA-RU; YAO SHENG; LIU QIAN; PENG ZHAO-LIANG; DENG QIANG-QIANG; LIU BO; MA ZHENG-HUA; WANG LE; ZHOU HU; YE YANG; PAN GUO-YU: "Dihydro-stilbene gigantol relieves CCl-induced hepatic oxidative stress and inflammation in mice via inhibiting C5b-9 formation in the liver", ACTA PHARMACOLOGICA SINICA, NATURE PUBLISHING GROUP, GB, vol. 41, no. 11, 13 May 2020 (2020-05-13), GB, pages 1433 - 1445, XP037286159, ISSN: 1671-4083, DOI: 10.1038/s41401-020-0406-6 *
YAO, CHUNSUO ET AL.: "Synthesis of the Active Stilbenoids by Photooxidation Reaction of Trans-ε-Viniferin.", CHINESE JOURNAL OF CHEMISTRY, vol. 22, no. 11, 31 December 2004 (2004-12-31) *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114438016A (zh) * 2022-02-18 2022-05-06 军事科学院军事医学研究院环境医学与作业医学研究所 石斛酚对肝细胞的毒性作用及其在肝细胞毒性研究中的用途
CN114557985A (zh) * 2022-03-15 2022-05-31 浙江中医药大学 一种用于治疗骨性关节炎的贝母兰宁组合物及其应用
CN114557985B (zh) * 2022-03-15 2023-06-27 浙江中医药大学 一种用于治疗骨性关节炎的贝母兰宁组合物及其应用

Also Published As

Publication number Publication date
CN113244203A (zh) 2021-08-13
CN120247669A (zh) 2025-07-04

Similar Documents

Publication Publication Date Title
AU2022200876B2 (en) Enhancing autophagy or increasing longevity by administration of urolithins or precursors thereof
US9687469B2 (en) Agent containing flavonoid derivatives for treating cancer and inflammation
WO2021160139A1 (fr) Composés de 9,10-dihydrophénanthrène et leur utilisation dans le traitement d'une lésion hépatique
JP2010525053A (ja) 新規なフェナントレンキノン系化合物およびそれを含むメタボリックシンドローム関連疾患を治療または予防するための医薬組成物
CN104768542B (zh) 含有马鞭草烯酮衍生物的神经退行性疾病治疗或者预防用药物组合物
CA2599352A1 (fr) Nouveaux inhibiteurs de la lipoxygenase
Zhang et al. A novel, highly-water-soluble apigenin derivative provides neuroprotection following ischemia in male rats by regulating the ERK/Nrf2/HO-1 pathway
JP2002520260A (ja) ヒペリシンおよびヒペリスム抽出物：特定のｔ型カルシウムチャネル遮断剤、およびそれらのｔ型カルシウムチャネルを標的にした治療法としての使用
US20100297760A1 (en) Pharmaceutical composition and a method for treatment of prostate cancer
AU2013208308B2 (en) Methods of treating or preventing insulin resistance and associated diseases and conditions
CN109485691B (zh) 丹参酮类化合物及其用于治疗血管瘤的用途
KR101800346B1 (ko) 망막 내 혈관 누수 억제용 조성물
AU756948B2 (en) Decursinol or derivative thereof as analgesic agent
KR101674622B1 (ko) 세스퀴테르펜 유도체의 신규한 용도
CN115160251B (zh) 一种n-n-双-恶唑烷酮生物碱类化合物、制备方法及在医药领域的应用
KR101629558B1 (ko) 나프탈렌계 칼콘 및 그의 항암제로서의 용도
KR101692378B1 (ko) 세스퀴테르펜 유도체의 신규한 용도
CN105712982B (zh) 二氢-β-沉香呋喃型倍半萜类化合物、其制法和用途
CN110256468B (zh) 双吲哚生物碱化合物或其药学上可接受的盐及其制备方法和应用
CN113754622B (zh) 二苯并呋喃类化合物的降脂应用
CN115073463B (zh) 一类苦参碱型二聚体生物碱类化合物、其药物组合物及其应用
EP3750904A1 (fr) Médicament thérapeutique pour maladie neurodégénérative et son application
CN110090216A (zh) 吲哚生物碱类化合物及其衍生物或盐在防治糖尿病肾病制品中的应用
RU2799454C2 (ru) Терапевтический препарат для лечения нейродегенеративных заболеваний и его применение
WO2025108157A1 (fr) Utilisation pharmaceutique d'un dérivé de sesquiterpène de guaiane

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21753468

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21753468

Country of ref document: EP

Kind code of ref document: A1