WO2020035058A1 - Composés pharmaceutiques pour le traitement de maladies du foie et utilisation associée - Google Patents

Composés pharmaceutiques pour le traitement de maladies du foie et utilisation associée Download PDF

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WO2020035058A1
WO2020035058A1 PCT/CN2019/101066 CN2019101066W WO2020035058A1 WO 2020035058 A1 WO2020035058 A1 WO 2020035058A1 CN 2019101066 W CN2019101066 W CN 2019101066W WO 2020035058 A1 WO2020035058 A1 WO 2020035058A1
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methoxy
phenyl
chroman
substituted
alkyl
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PCT/CN2019/101066
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English (en)
Chinese (zh)
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史东方
傅长金
承曦
龚维伟
顾杰
张敏
李鹏飞
杨艳
金文卿
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江苏新元素医药科技有限公司
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    • 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
    • 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
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the field of medicinal chemistry, and particularly relates to a class of pharmaceutical compounds having the effects of treating liver diseases, especially non-alcoholic fatty liver diseases, and applications thereof.
  • Non-Alcoholic Fatty Disease is the most common chronic liver disease, which refers to factors other than alcohol and other well-defined causes of injury, which lead to excessive deposition of fat in the liver cells.
  • NAFLD refers to a series of liver disease processes, from simple steatosis to non-alcoholic steatohepatitis (NASH), to severe liver fibrosis, cirrhosis, and liver cancer (Koplay M, Sivri M, Amsterdam H , Nayman A.Importance of imaging development and innovation development of nonalcoholic fatty diseases. World Journal of Hepatology. 2015, 7: 769-776).
  • NASH is a liver inflammatory lesion caused by NAFLD. Its accumulated fat mass exceeds 5% of the liver's own weight. It is the most serious type of histopathology in NAFLD (Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis , and the metabolic policy. Hepatology. 2003, 37: 917-923.). NASH will greatly increase the probability of liver cirrhosis, which may further make the liver cirrhosis metabolism uncompensated, require patients to undergo liver transplantation, or eventually cause patients to die.
  • liver fat such as NAFLD
  • 2% -5% have substantial liver damage (such as NASH)
  • 1% -2% of people are at risk for developing liver cirrhosis (Goh, G, McCullough, A. Natural, History of Non-Family, Fatty, Liver Disease, Digestive, Diseases, and Science. 2016, 61: 1226-1233).
  • Insulin resistance and metabolic syndrome play an important role in the pathogenesis of NAFLD. 364–377).
  • carbohydrates such as glucose and fructose are metabolized into fatty acids in the liver through the fat synthesis pathway, and then oxidized or converted to triglycerides by mitochondrial ⁇ in liver cells, in the form of very low density lipoproteins. Transported into the blood. If long-term intake of excessive carbohydrates, especially in patients with insulin resistance, fatty acid synthesis in the liver will be significantly increased, which can promote the production of lipotoxic substances (such as diglycerides, ceramides, and lysolecithin, etc.).
  • Obeticholic acid is a farnesyl X receptor agonist that increases insulin sensitivity and reduces liver steatosis, inflammation, and fibrosis.
  • the drug is in the phase III clinical trial phase (Phase, study, evaluation, safety, and safety) of obesityholicacid in subjects with compensated due to non-coalic steatohepatitis (REVERSE) .NCT03439254.2018).
  • Obeticholic acid has a significant itchy allergic reaction (The farnesoid X receptor (FXR) ligand obeticholicacid in NASH treatment (FLINT) .NCT01265498.2015), which can lead to serious liver damage and risk of death at high doses (FDA) safety communication: FDA warns about serious and injury with Ocaliva (obeticholic acid) for rare and chronic disease. September 21, 2017).
  • FXR farnesoid X receptor
  • FLINT ligand obeticholicacid in NASH treatment
  • FDA high doses
  • Elafibranor is a dual receptor agonist of PPAR ⁇ / ⁇ .
  • Vitamin E is also clinically useful abroad to improve liver steatosis and inflammation.
  • a large-scale randomized controlled clinical study showed that after taking vitamin E (800IU / day) for 96 weeks, NASH adult patients can significantly improve serum transaminase levels, liver steatosis and liver lobular inflammation (Sanyal AJ, Chalasani, Kowdley, KV et al. Pioglitanzone, vitamin E, or placebo for nonalcoholic steatohepatitis. The New England Journal of Medicine. 2010, 362: 1675-1685).
  • the Chinese Pharmacopoeia does not include vitamin E for the treatment of chronic hepatitis, and there are risks and hidden dangers of long-term high-dose vitamin E use.
  • Silibinin bicyclic alcohol, polyenephosphorylcholine, glycyrrhizinate, reduced glutathione, S-adenosylmethionine, and ursodeoxycholic acid are widely used in clinical practice in China.
  • Hepatic drugs have been used to treat chronic hepatitis and have achieved relatively accurate results in patients with drug-induced liver injury and cholestatic liver disease.
  • the therapeutic effects of these drugs on NASH and liver fibrosis still need to be designed with rigorous clinical trials to verify.
  • Silybin is an anti-oxidant drug, which can improve the function of mitochondria, scavenge oxygen free radicals, reduce the production of carbon monoxide, thereby reducing the level of lipid peroxidation, and inhibit the fatty degeneration function of liver cells (PFSurai.Silymarin as a natural antioxidant : an overview of the current evidence and perspectives. Antioxidants (Basel) .2015, 4: 204–247); At the same time, silybin can treat NASH in many ways: it can inhibit the production of multiple inflammatory factors, such as NF -kB, IL1, IL6, TNF ⁇ , IFN- ⁇ , and GM-CSF (A. Federico, M. Dallio, C. Loguercio.
  • Silymarin / silybin and chronic liver disease a marriage of many years. Molecules. 2017, 22: 2 ); It can also alleviate or prevent the progress of liver fibrosis by reducing the proliferation of stellate cells induced by platelet-derived factor (PDGF) and down-regulating the levels of type III procollagen, ⁇ -SMA and TGF- ⁇ , D. Olteanu, A. Filip, et al. Beneficial effects of silymarin after the discontinuation of CCl 4 -induced liver fibrosis. Journal of Medicinal Food. 2016, 19: 789–797).
  • PDGF platelet-derived factor
  • NASH Newcastle disease virus
  • the pathogenesis of NASH is very complex, including different stages, from initial steatosis to inflammation, liver cell damage and self-repair, fatty liver, and finally development to cirrhosis.
  • Each stage has different targets, and
  • all kinds of drugs developed clinically are aimed at single targets, which have problems such as unclear curative effect, large toxic and side effects, and inability to use for a long time. Therefore, a class of drugs with good curative effect and low toxicity is urgently needed in the NASH market.
  • the object of the present invention is to provide a class of compounds having potential therapeutic or preventive effects on liver diseases based on the prior art.
  • Another object of the present invention is to provide a use of the above compound in the treatment or prevention of a disease.
  • the object of the present invention can be achieved by the following measures:
  • the present invention provides a class of compounds represented by general formula (I), optical isomers or pharmaceutically acceptable salts thereof,
  • R 1 or R 2 are each independently selected from H, D, -OH, halogen, -CN, -NO 2 , -NH 2 , -NHR, -CONHR, -NHCOR, C 1-5 alkyl, substituted C 1 One or more of -5 alkyl, C 1-5 alkoxy, substituted C 1-5 alkoxy, C 1-5 alkylthio, or substituted C 1-5 alkylthio;
  • the X ring is selected from a benzene ring or a six-membered aromatic ring containing 1-3 N atoms;
  • R is selected from C 1-5 alkyl or substituted C 1-5 alkyl
  • R 'or R are each independently selected from H, D, -OH, halogen, -CN, -COOH, -NO 2 , glycosyl, -NH 2 , -NHR, C 1-5 alkyl, substituted C 1 -5 alkyl, C 1-5 alkoxy or substituted C 1-5 alkoxy;
  • R 3 is selected from H, D, -OH, -NH 2 , -NO 2 , halogen, -CN, glycosyl, -COOH, C 1-5 alkyl, substituted C 1-5 alkyl, C 1-5 alkoxy or substituted C 1-5 alkoxy;
  • R 4 or R 5 are each independently selected from H, D, -OH, halogen, -CN, -NH 2 , -NHR, -CONHR, -NHCOR, C 1-5 alkyl, substituted C 1-5 alkyl , a C 1-3 alkoxy group, a C 1-3 alkoxy-substituted alkoxy, C 1-3 alkylthio or a C 1-3 alkoxy group substituted by one or more;
  • the Y ring or Z ring is independently selected from a benzene ring or a six-membered aromatic ring containing 1-3 N atoms;
  • R 6 or R 7 are each independently selected from H, D, -OH, halogen, -CN, -NO 2 , -NH 2 , -NHR, -CONHR, -NHCOR, C 1-5 alkyl, substituted C 1 -5 alkyl, C 1-3 alkoxy or substituted C 1-3 alkoxy;
  • n, p, q or a are each independently selected from 0, 1 or 2;
  • R 1, R 2, R, R ', R ", R 3, R 4, R 5, R 6, R 7 , or G R 3 of said substituents are independently selected from D, -OH, - One or more of NH 2 , -NO 2 , halogen, -CN, -COOH, C 1-3 alkoxy, or sugar group.
  • R 1 or R 2 are each independently selected from H, D, -OH, -F, -Cl, -CN, -NO 2 , -NH 2 , -NHR, -CONHR, C 1- 5 alkyl, substituted C 1-5 alkyl, C 1-3 alkoxy or substituted C 1-3 alkoxy.
  • R 1 or R 2 are each independently selected from H, -OH, -F, -Cl, -CN, C 1-3 alkyl, substituted C 1-3 alkyl, C 1 -3 alkoxy or substituted C 1-3 alkoxy.
  • the X ring is a benzene ring, a pyridine ring, a pyrimidine ring, or a pyridazine ring.
  • the X ring is a benzene ring or a pyridine ring.
  • the X ring is a benzene ring.
  • A is selected from O, S or -CHOH.
  • R 'or R " is independently selected from H, D, -OH, -CN, -COOH, -NO 2 , -NH 2 , -NHR, C 1-5 alkyl, substituted C 1-5 alkyl, C 1-3 alkoxy or substituted C 1-3 alkoxy.
  • R ′ or R ′′ is independently selected from H, D, —OH, F, —CN, —NO 2 , NH 2 , C 1-5 alkyl, substituted C 1-5 Alkyl, C 1-3 alkoxy or substituted C 1-3 alkoxy.
  • R is selected from C 1-3 alkyl or substituted C 1-3 alkyl.
  • R 3 is selected from H, D, -OH, -NH 2 , -NO 2 , halogen, -CN, -COOH, C 1-5 Alkyl, substituted C 1-5 alkyl, C 1-3 alkoxy or substituted C 1-3 alkoxy.
  • R 3 is selected from H, -OH, -NH 2 , -NO 2 , F, -CN, C 1-5 alkyl, substituted C 1-5 alkyl, C 1-3 alkoxy or substituted C 1-3 alkoxy.
  • R 4 or R 5 are each independently selected from H, D, -OH, halogen, -CN, -NH 2 , C 1-3 alkyl, substituted C 1-3 alkyl, C One or more of a 1-3 alkoxy group or a substituted C 1-3 alkoxy group.
  • R 4 or R 5 are each independently selected from H, -OH, F, Cl, -CN, -NH 2 , C 1-3 alkyl, substituted C 1-3 alkyl, C 1-3 alkoxy or substituted C 1-3 alkoxy.
  • J is selected from O or S.
  • the Y ring or the Z ring is independently selected from a benzene ring, a pyridine ring or a pyrimidine ring.
  • the Y ring or the Z ring is independently selected from a benzene ring or a pyridine ring.
  • R 6 or R 7 are each independently selected from H, D, -OH, F, Cl, -CN, -NO 2 , -NH 2 , C 1-3 alkyl, substituted C 1 -3 alkyl, C 1-3 alkoxy or substituted C 1-3 alkoxy.
  • R 6 or R 7 are each independently selected from H, -OH, F, Cl, -CN, -NO 2 , -NH 2 , C 1-3 alkyl, substituted C 1- 3 alkyl, C 1-3 alkoxy or substituted C 1-3 alkoxy.
  • some specific compounds of the present invention may be selected from:
  • the present invention also provides a pharmaceutical composition which uses each compound, optical isomer or pharmaceutically acceptable salt thereof of the present invention as an active ingredient or a main active ingredient, supplemented with a pharmaceutically acceptable excipient. That is, in the pharmaceutical composition of the present application, in addition to the compound of the present invention, an optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient, other types of active ingredients may be further added to achieve combined use and synergism. Or reduce side effects.
  • the compound, optical isomer or a pharmaceutically acceptable salt thereof according to the present invention can be applied to the preparation of a medicament for treating or preventing liver disease, in particular, it can be applied to the preparation of a medicament for treating or preventing fatty liver, liver fibrosis or cirrhosis. Medication.
  • the compound, optical isomer or a pharmaceutically acceptable salt thereof of the present invention can be used in the treatment or prevention of liver diseases, and particularly in a method for the treatment or prevention of fatty liver, liver fibrosis or cirrhosis.
  • H or hydrogen, refers to thorium (1H), which is the main stable isotope of the element hydrogen.
  • deuterium refers to a stable form of isotope of hydrogen, also known as deuterium, and its element symbol is D.
  • Halogen means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • -CONHR refers to a group in which one hydrogen in the amide group is replaced by R.
  • O means an oxygen atom
  • S refers to a sulfur atom
  • CR'R that is, -C (R ') (R")-, refers to a group in which two hydrogen atoms in a methylene group are substituted with R' and R ", respectively.
  • -CN refers to a cyano group
  • Alkyl refers to saturated aliphatic hydrocarbon groups of 1-10 carbon atoms, including straight-chain and branched-chain groups (the number range mentioned in this application, for example “1-10” refers to the group (At this time, it is an alkyl group, and may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms).
  • An alkyl group having 1-4 carbon atoms is called a lower alkyl group. When a lower alkyl group has no substituent, it is referred to as an unsubstituted lower alkyl group.
  • Alkyl can be selected from C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 2-3 alkyl, C 2-4 Alkyl, etc.
  • Specific alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl.
  • the alkyl group may be substituted or unsubstituted.
  • Alkoxy means -O- (unsubstituted alkyl) and -O- (unsubstituted cycloalkyl) groups, which further represents -O- (unsubstituted alkyl).
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, cyclopropoxy, and the like.
  • Alkylthio means -S- (unsubstituted alkyl) and -S- (unsubstituted cycloalkyl) groups, which further represents -S- (unsubstituted alkyl). Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, cyclopropylthio, and the like.
  • Alkenyl means an unsaturated hydrocarbon group having at least one carbon-carbon double bond, including straight-chain and branched-chain groups (number ranges mentioned in this application, such as "2-5", refer to the group At this time, it is an alkenyl group, and may contain 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, and so on, up to and including 5 carbon atoms).
  • the alkenyl group in the present invention may be a C 2-8 alkenyl group, a C 2-6 alkenyl group, a C 2-5 alkenyl group, a C 2-4 alkenyl group, a C 2-3 alkenyl group, and the like.
  • Specific alkenyl groups include but It is not limited to vinyl, propenyl, and butenyl.
  • a six-membered aromatic ring containing 1-3 N atoms means an aromatic heterocyclic ring containing 6 ring atoms, wherein the ring atoms are composed of C and N, and the ring atoms N are 1-3. It includes, but is not limited to, a pyridine ring, a pyrimidine ring, a pyridazine ring, and the like.
  • E and G are carbon-carbon single bond or carbon-carbon double bond
  • G and R 3 are single bonds; but when E and G are carbon-carbon single bonds, G and R 3 are not necessarily It is a double bond, but when there is a double bond between G and R 3 , there is a carbon-carbon single bond between E and G.
  • glycosyl means a monosaccharide residue or a polysaccharide residue.
  • the monosaccharides used herein are 3-C monosaccharides to 8-C monosaccharides, and preferably 6 -C monosaccharides having the chemical formula C 6 H 12 O 6 (ie, hexose).
  • the hexose may be in the D configuration, the L configuration, or a combination thereof. Hexoses are usually classified according to functional groups.
  • aldohexose has an aldehyde at position 1, for example, allose, altose, glucose, mannose, gulose, idose, galactose, and talose; and ketohexose is in position 2 has ketones such as, for example, ptoseose, fructose, sorbose and tagatose.
  • Hexose also contains 6 hydroxyl groups, and the aldehyde or ketone functional groups in the hexose can react with adjacent hydroxyl functional groups to form hemiacetals or hemiketals in the molecule, respectively. If the obtained cyclic sugar is a 5-membered ring, it is a furanose.
  • cyclic sugar is a 6-membered ring, it is a pyranose.
  • the ring opens and closes spontaneously, allowing the bond between the carbonyl and adjacent carbon atoms to rotate, resulting in two different configurations ( ⁇ and ⁇ ).
  • Hexoses can be in the S or R configuration.
  • “Pharmaceutically acceptable salts” are salts comprising a compound of general formula (I) and an organic or inorganic acid, meaning those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
  • Organic acids such as (but not limited to) acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid , Methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, Mandelic acid, succinic acid or malonic acid.
  • “Pharmaceutical composition” refers to a mixture of one or more of the compounds described herein or their pharmaceutically acceptable salts and prodrugs with other chemical ingredients, such as pharmaceutically acceptable carriers and excipients .
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • the invention further claims a pharmaceutical composition
  • a pharmaceutical composition comprising any one of the compounds described above, a pharmaceutically acceptable salt thereof, or an easily hydrolyzed prodrug amide and other pharmaceutically active ingredients.
  • the present invention also includes any one of the above compounds, pharmaceutically acceptable salts thereof, easily hydrolyzed prodrug amides or isomers thereof, and can be formulated into any clinically or pharmaceutically acceptable in a manner known in the art.
  • Dosage form When used for oral administration, it can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc .; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc.
  • suitable fillers, binders, disintegrating agents, lubricants, and the like can be added.
  • parenteral administration it can be made into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection.
  • When making an injection it can be produced by conventional methods in the existing pharmaceutical field.
  • no additional agent may be added, or a suitable additional agent may be added according to the properties of the drug.
  • the compounds, optical isomers or pharmaceutically acceptable salts thereof provided by the present invention have good curative effect and low toxicity on liver diseases, especially fatty liver.
  • some of the compounds involved in the present invention are non-alcoholic to zebrafish.
  • Fatty liver has a very significant therapeutic effect, and can also significantly improve and treat non-alcoholic steatohepatitis in mice. Therefore, the compounds of the present invention are applied to the treatment or prevention of liver diseases, especially drugs for fatty liver, liver fibrosis or cirrhosis In terms of methods and methods for treating or preventing liver diseases, especially fatty liver, liver fibrosis or cirrhosis, it has good prospects.
  • FIG. 1 is a photomicrograph of zebrafish oil red O staining after administration of each test compound
  • a is the normal control group
  • b is the model control group
  • c is the positive control S-adenosylmethionine group (50 ⁇ M)
  • d is the positive control silybin group (200 ⁇ M)
  • e is compound 20 (200 ⁇ M)
  • f is compound 21 (200 ⁇ M)
  • g is compound 33 (200 ⁇ M)
  • h is compound 34 (200 ⁇ M)
  • i is compound 44 (200 ⁇ M)
  • j Is compound 45 group (200 ⁇ M)
  • k is compound 74 group (200 ⁇ M)
  • l is compound 80 group (200 ⁇ M);
  • a is the normal control group
  • b is the model control group
  • c is the positive control S-adenosylmethionine group (50 ⁇ M)
  • d is the positive control silybin group (100 ⁇ M)
  • e is compound 20 (100 ⁇ M)
  • f is compound 34 (100 ⁇ M)
  • g is compound 45 (100 ⁇ M)
  • h is compound 67 (100 ⁇ M)
  • i is compound 78 (100 ⁇ M)
  • j Is compound 85 group (100 ⁇ M)
  • k is compound 87 group (100 ⁇ M)
  • l is compound 90 group (100 ⁇ M)
  • m is compound 114 group (100 ⁇ M)
  • n is compound 117 group (100 ⁇ M);
  • Figure 3 is a histopathological staining photograph (HE staining).
  • Step A Add 3-hydroxy-4-methoxybenzaldehyde (4.0 g, 26.3 mmol), potassium carbonate (7.26 g, 52.6 mmol), benzyl bromide (4.95 g, 28.9 mmol), and DMF (30 mL) The mixture was stirred at 25 ° C for 3 hours. Water (120 mL) was added, and extraction was performed with ethyl acetate (40 mL ⁇ 2). The combined organic phases were washed with water (40 mL) and saturated brine (30 mL) in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the product was recrystallized from petroleum ether to obtain 3-benzyloxy-4-methoxybenzaldehyde (1) (6.35 g). The yield was 99.6%.
  • Step B Add 2,4,6-trihydroxyacetophenone (5.0 g, 29.7 mmol), chloromethyl methyl ether (9.7 g, 120.5 mmol), potassium carbonate (37.1 g, 269 mmol) and acetone (100 mL) The mixture was stirred under reflux for 2 hours. The solvent was distilled off under reduced pressure, water (50 mL) was added, and extraction was performed with ethyl acetate (40 mL ⁇ 3). The combined organic phases were washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate.
  • Step C In an ice-water bath, chloromethyl methyl ether (2.52 g, 31.3 mmol) was added dropwise to the solution containing compound 2 (4.0 g, 15.6 mmol), sodium hydroxide (1.84 g, 46 mmol), water (4 mL), In a mixture of tetrabutylammonium bromide (252 mg, 0.782 mmol) and dichloromethane (60 mL), after the addition was completed, the resulting mixture was stirred at room temperature for 1 hour. Water (40 mL) was added, and extraction was performed with dichloromethane (60 mL ⁇ 2).
  • Step D Add compound 1 (5.0 g, 20.6 mmol) and compound 3 (6.2 g, 20.6 mmol) to a solution of potassium hydroxide (3.5 g, 62.5 mmol) in ethanol (40 mL) at room temperature. The resulting mixture was stirred at 40 ° C overnight. Most of the solvent was distilled off under reduced pressure, water (70 mL) was added, and extraction was performed with ethyl acetate (70 mL ⁇ 3). The combined organic phases were washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate.
  • Step E Dissolve sodium hydroxide (3.8 g, 95.0 mmol) in water (15 mL) and methanol (50 mL), and then add compound 4 (5.0 g, 9.53 mmol) and 30% hydrogen peroxide (10.8 g, 95.3 mmol) in this order. After the addition was complete, the resulting mixture was stirred at 25 ° C overnight. A 2M sodium sulfite solution (40 mL) was added, most of the solvent was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate (40 mL ⁇ 2). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate.
  • Step F To a solution of compound 5 (4.8 g, 8.88 mmol) in methanol (50 mL) and THF (15 mL) was added concentrated hydrochloric acid (5 mL) dropwise. After the addition was completed, the resulting mixture was stirred at 55 ° C. overnight. Most of the solvent was distilled off under reduced pressure, water (50 mL) was added, and extraction was performed with ethyl acetate (50 mL ⁇ 3). The combined organic phases were washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate.
  • Step A Compound 6 (2.45 g, 6.0 mmol) was dissolved in THF (50 mL), and then diisopropylethylamine (7.8 g, 60.4 mmol) and chloromethyl methyl ether (3.9 g, 48.4 mmol) were added. After completion, the resulting mixture was stirred under reflux for 2 hours. After cooling to room temperature, saturated brine (40 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3). The combined organic phases were washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate.
  • Step B In an ice-water bath, a solution of chloromethyl methyl ether (190 mg, 2.36 mmol) in dichloromethane (2 mL) was added dropwise to a solution containing sodium hydroxide (130 mg, 3.25 mmol), dichloromethane (15 mL), and water. (1.5 mL), compound 7 (710 mg, 1.57 mmol) and tetrabutylammonium bromide (25 mg, 0.0752 mmol). After the addition was complete, the resulting mixture was stirred at room temperature for 30 minutes. Water (40 mL) was added, and extraction was performed with dichloromethane (50 mL ⁇ 3).
  • Step C To a solution of compound 8 (780 mg, 1.57 mmol) in DMF (10 mL) was added 5% palladium on carbon (80 mg), and the resulting mixture was stirred under hydrogen at 40 ° C. under normal pressure overnight. After filtration through celite, water (40 mL) was added, and extraction was performed with ethyl acetate (40 mL ⁇ 3). The combined organic phases were washed with water (20 mL ⁇ 3) and saturated brine (20 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step D The mixture containing Compound 9 (150 mg, 0.369 mmol), potassium carbonate (153 mg, 1.11 mmol), 3-bromomethylpyridine hydrobromide (112 mg, 0.443 mmol), and DMF (5 mL) was stirred at room temperature. After 2 hours, 3-bromomethylpyridine hydrobromide (93 mg, 0.368 mmol) was added, and the resulting mixture was stirred at room temperature overnight. Water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with water (15 mL) and saturated brine (15 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step E A mixture containing Compound 10 (77 mg, 0.155 mmol), concentrated hydrochloric acid (1.5 mL), and methanol (5 mL) was stirred under reflux for 4 hours. Water (20 mL) was added, the pH was adjusted to 7-8 with a saturated sodium bicarbonate solution, and extracted with ethyl acetate / tetrahydrofuran (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (15 mL), and anhydrous sodium sulfate dry.
  • Step A Add compound 1 (7.7 g, 31.8 mmol) and compound 2 (8.1 g, 31.6 mmol) to a solution of potassium hydroxide (5.3 g, 94.6 mol) in ethanol (100 mL) at room temperature. The resulting mixture was stirred at 40 ° C overnight. Water (70 mL) was added, and the filter cake was dissolved in dichloromethane (200 mL), and then the pH was adjusted to 4-5 with a 2M citric acid solution. The layers were separated and the organic layer was washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate.
  • Step C To a solution of potassium hydroxide (700 mg, 12.5 mmol) in methanol (30 mL) was added compound 14 (2.0 g, 4.16 mmol), and then iodophenyl ethyl ester (1.5 g) was added in portions at 5-10 ° C. , 4.66 mmol). After the addition was complete, the resulting mixture was stirred at room temperature overnight. Water (90 mL) was added, and extraction was performed with dichloromethane (50 mL ⁇ 3). The combined organic phases were washed with water (30 mL) and saturated brine (30 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step D To a solution of compound 15 (1.0 g, 2.09 mmol) in DMF (15 mL) was added 5% palladium on carbon (100 mg), and the resulting mixture was stirred under hydrogen at 40 ° C. under normal pressure overnight. After filtering through celite, water (45 mL) was added, and extraction was performed with ethyl acetate (30 mL ⁇ 4). The combined organic phases were washed with water (20 mL ⁇ 2) and saturated brine (20 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step E The mixture containing compound 16 (150 mg, 0.386 mmol), potassium carbonate (138 mg, 1.0 mmol), 4-bromomethylpyridine hydrobromide (102 mg, 0.403 mmol), and DMF (5 mL) was stirred at room temperature. overnight. Water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with water (15 mL) and saturated brine (15 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step F A mixture containing Compound 17 (140 mg, 0.292 mmol), concentrated hydrochloric acid (1.5 mL), and methanol (5 mL) was stirred under reflux for 4 hours. Cool to room temperature, filter and collect solids. The solid was then suspended in water (10 mL), and the pH was adjusted to 7-8 with a saturated sodium bicarbonate solution. After filtration, the obtained solid was washed with acetonitrile and dried to obtain 5,7-dihydroxy-2- [4-methoxy-3- (pyridin-4-ylmethoxy) -phenyl] -4H-benzopyran 4-one (18) (92 mg). The yield was 80.1%.
  • sodium borohydride (278 mg, 7.35 mmol) was added to a solution of compound 6 (300 mg, 0.735 mmol) in ethanol (10 mL). After the addition was completed, the resulting mixture was stirred at room temperature for 0.5 hours. Water (30 mL) was added and the pH was adjusted to 3 to 4 with a 2M citric acid solution. It was extracted with ethyl acetate (20 mL ⁇ 3), and the combined organic phases were washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate.
  • Step A Chloromethyl methyl ether (10.2 g, 126 mmol) was added dropwise to 3-hydroxy-6-methylpyridine (10.5 g, 96.2 mmol) and diisopropylethylamine (18.6 g) in an ice-water bath. (144 mmol) in dichloromethane (200 mL). After the addition was complete, the resulting mixture was stirred at room temperature overnight. Water (100 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (100 mL). The combined dichloromethane layers were washed with saturated brine (60 mL) and dried over anhydrous sodium sulfate.
  • Step B In an ice-water bath, 85% m-chloroperoxybenzoic acid (23.1 g, 114 mmol) was added in portions to a solution containing sodium bicarbonate (19.1 g, 228 mmol), compound 22 (11.6 g, 75.7 mmol), and dichloride. In a mixture of methane (220 mL), after the addition was completed, the resulting mixture was stirred at room temperature for 2 hours. Water (200 mL) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane (100 mL ⁇ 3).
  • Step C Place a mixture containing acetic anhydride (7.82 g, 76.6 mmol), diisopropylethylamine (10.73 g, 83.0 mmol), compound 23 (10.8 g, 63.8 mmol) and dioxane (50 mL) in Stir overnight at reflux. Most of the solvent was distilled off under reduced pressure, water (100 mL) was added, and extraction was performed with ethyl acetate (70 mL ⁇ 3). The combined organic phases were washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate.
  • Step E In an ice water bath, diisopropyl azodicarboxylate (2.42 g, 12.0 mmol) was added dropwise to 3-hydroxy-4-methoxybenzaldehyde (1.35 g, 8.87 mmol) and triphenylphosphine. (3.14 g, 12.0 mmol) and compound 25 (1.50 g, 8.87 mmol) in a THF (30 mL) solution. After the addition was complete, the resulting mixture was stirred at room temperature overnight.
  • Step F Add compound 3 (2.47 g, 8.23 mmol) and compound 26 (2.50 g, 8.24 mmol) to a solution of potassium hydroxide (1.40 g, 25.0 mmol) in ethanol (70 mL) at room temperature. The resulting mixture was stirred at 45 ° C overnight. Most of the solvent was distilled off under reduced pressure, water (60 mL) was added, and extraction was performed with ethyl acetate (60 mL ⁇ 3). The combined organic phases were washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate.
  • Step G Dissolve sodium hydroxide (1.0 g, 25.0 mmol) in water (5 mL) and methanol (40 mL), then add compound 27 (3.0 g, 5.12 mmol) and 30% hydrogen peroxide (5.80 g, 51.2 mmol) in this order. After the addition was completed, the resulting mixture was stirred at 25 ° C overnight. Water (120 mL) was added and extraction was performed with ethyl acetate (60 mL ⁇ 3). The combined organic phases were washed with water (40 mL), 2M sodium sulfite solution (40 mL), and saturated brine (30 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step H A solution of concentrated hydrochloric acid (4 mL) in methanol (16 mL) was added dropwise to a solution of compound 28 (2.40 g, 3.99 mmol) in methanol (16 mL) and THF (4 mL). After the addition was completed, the resulting mixture was stirred at 50 ° C. 1.5 hours. Most of the solvent was distilled off under reduced pressure, water (50 mL) was added, and the pH was adjusted to 7-8 with a saturated sodium bicarbonate solution. It was extracted with ethyl acetate (50 mL ⁇ 3), and the combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate.
  • Step A In an ice water bath, 60% sodium hydride (3.80 g, 95.0 mmol) was added portionwise to a solution of ethyl mercaptan (16.3 g, 262 mmol) in THF (50 mL). After the addition, the resulting mixture was at this temperature Continue stirring for about 5 minutes and filter. The obtained solid was added to a DMF (80 mL) solution of Compound 1 (12.7 g, 52.5 mmol), and the resulting mixture was stirred at 70 ° C for 1.5 hours. After cooling to room temperature, water (320 mL) was added, and insoluble matter was removed by filtration through celite.
  • the filtrate was extracted with methyl tert-butyl ether (50 mL x 2) and the product was in the aqueous phase.
  • the aqueous phase was adjusted to pH 3 to 4 with 2M hydrochloric acid. It was then extracted with methyl tert-butyl ether (100 mL ⁇ 3), and the combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure, and the product was recrystallized from methyl tert-butyl ether / petroleum ether to obtain 3-benzyloxy-4-hydroxybenzaldehyde (35) (10.1 g). The yield was 84.3%.
  • Step B In an ice water bath, chloromethyl methyl ether (4.60 g, 57.1 mmol) was added dropwise to two compounds of compound 35 (10.0 g, 43.8 mmol) and diisopropylethylamine (8.50 g, 65.8 mmol). In a solution of methyl chloride (70 mL), after the addition was complete, the resulting mixture was stirred at room temperature overnight. Water (40 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (70 mL). The combined dichloromethane layers were washed with water (30 mL) and saturated brine (30 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step A Place a mixture containing methyl gallate (34.0 g, 185 mmol), triethyl orthoformate (50.0 g, 337 mmol), Armberlyst (2.2 g) and toluene (350 mL) in a reaction flask equipped with a water separator Stir slowly at reflux overnight. During the reaction, approximately 200 mL of solvent was separated. After cooling to room temperature, insoluble matter was removed by filtration through celite. The solvent was distilled off under reduced pressure to obtain crude 2-ethoxy-7-hydroxy-benzo [1,3] dioxolene-5-carboxylic acid methyl ester (46) (60 g). This compound was used in the next reaction without purification.
  • Step B Add benzyl bromide (15.0 g, 87.7 mmol) to a mixture containing crude compound 46 (29.0 g), potassium carbonate (17.3 g, 125 mmol) and DMF (100 mL). After the addition is complete, the resulting mixture is at 40 Stir overnight at ° C. Water (400 mL) was added and extracted with methyl tert-butyl ether (300 mL ⁇ 3). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step C A mixture containing Compound 47 (28.0 g, 84.8 mmol), 2M hydrochloric acid (120 mL), and THF (120 mL) was stirred at room temperature for 2 hours. The layers were separated and the aqueous layer was extracted with ethyl acetate (120 mL ⁇ 2). The combined organic layers were washed with saturated brine (60 mL ⁇ 2) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain methyl 3-benzyloxy-4,5-dihydroxybenzoate (48) (23.2 g). The yield was 100%.
  • Step D Methyl iodide (14.5 g, 102 mmol) was added dropwise to a mixture containing compound 48 (18.7 g, 68.2 mmol), sodium carbonate (10.9 g, 103 mmol), and DMF (35 mL). After the addition, the resulting mixture was Stir at 45 ° C for 1.5 hours. Water (130 mL) was added, and extraction was performed with ethyl acetate (100 mL ⁇ 3). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step E Chloromethyl methyl ether (3.79 g, 47.1 mmol) was added dropwise to the compound 49 (9.78 g, 33.9 mmol) and diisopropylethylamine (6.32 g, 48.9 mmol) in an ice-water bath.
  • methyl chloride 100 mL
  • Dichloromethane 100 mL was added to the reaction solution, and the mixture was washed with water (60 mL) and saturated brine (50 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step F Add a solution of compound 50 (8.45 g, 25.4 mmol) in THF (20 mL) dropwise to a mixture containing lithium aluminum hydride (2.41 g, 63.5 mmol) and THF (40 mL) at 0 to 2 ° C, add After completion, the resulting mixture was further stirred at this temperature for 30 minutes. To the reaction solution, water (2.4 mL), a 10% sodium hydroxide solution (4.8 mL), and water (7.2 mL) were slowly and sequentially added. To the reaction mixture was added THF (50 mL), followed by filtration through Celite, and the filter cake was rinsed with ethyl acetate (50 mL).
  • Step H To a solution of compound 52 (7.1 g, 23.5 mmol) in DMF (50 mL) was added 5% palladium on carbon (700 mg), and the resulting mixture was stirred under normal pressure in hydrogen for 4 hours. Water (150 mL) and ethyl acetate (150 mL) were added, and then insoluble matter was removed by filtration through Celite. The filtrate was separated into layers, and the aqueous layer was extracted with ethyl acetate (50 mL ⁇ 2). The combined organic layers were washed with water (40 mL) and saturated brine (40 mL ⁇ 2) in this order, and dried over anhydrous sodium sulfate.
  • steps I, J, K and L were performed according to the methods of steps E, F, G and H in Example 8, wherein the compound 25 and 3-hydroxy-4-methoxybenzaldehyde in step E of Example 8 Substituted with (5-methoxypyridin-2-yl) -methanol and compound 53 to obtain 3,5,7-trihydroxy-2- [3-hydroxy-4-methoxy-5- (5-methyl Oxypyridin-2-ylmethoxy) phenyl] chroman-4-one (57).
  • Step A A solution of chloromethyl methyl ether (2.77 g, 34.4 mmol) in dichloromethane (10 mL) was added dropwise to 4-hydroxy-3-methoxybenzaldehyde (3.5 g, 23.0 mmol) in an ice-water bath. And diisopropylethylamine (5.95 g, 46.0 mmol) in dichloromethane (45 mL). After the addition was complete, the resulting mixture was stirred at room temperature for 30 minutes. Water (30 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (40 mL).
  • Step B Sodium borohydride (1.74 g, 46.0 mmol) was added portionwise to a solution of compound 61 (5.1 g) in ethanol (40 mL). After the addition was complete, the resulting mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, water (40 mL) was added, and extraction was performed with ethyl acetate (40 mL ⁇ 3). The combined organic phases were washed with water (30 mL) and saturated brine (30 mL) in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain [3-methoxy-4- (methoxymethoxy) phenyl] methanol (62) (4.36 g). The total yield of the two-step reaction in steps A and B was 95.6%.
  • Step C In an ice water bath, diisopropyl azodicarboxylate (1.93 g, 9.54 mmol) was added dropwise to 3-hydroxy-4-methoxybenzaldehyde (1.08 g, 7.10 mmol) and triphenylphosphine. (2.50 g, 9.53 mmol) and compound 62 (1.40 g, 7.06 mmol) in a THF (25 mL) solution. After the addition was complete, the resulting mixture was stirred at room temperature for 1.5 hours.
  • Step D Add compound 3 (1.72 g, 5.73 mmol) and compound 63 (1.90 g, 5.72 mmol) to a solution of potassium hydroxide (962 mg, 17.1 mmol) in ethanol (20 mL) at room temperature. After the addition, The resulting mixture was stirred at 40 ° C overnight. Most of the solvent was distilled off under reduced pressure, water (60 mL) was added, and extraction was performed with ethyl acetate (60 mL ⁇ 3). The combined organic phases were washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate.
  • Step E Dissolve sodium hydroxide (814mg, 20.4mmol) in water (4mL) and methanol (30mL), then add compound 64 (2.50g, 4.07mmol) and 30% hydrogen peroxide (4.61g, 40.7mmol) in this order. After the addition was complete, the resulting mixture was stirred at 25 ° C overnight. Water (90 mL) was added and extracted with ethyl acetate (40 mL ⁇ 3). The combined organic phases were washed with water (30 mL), 2M sodium sulfite solution (20 mL), and saturated brine (20 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step F A solution of compound 65 (2.2 g, 3.49 mmol) in methanol (12 mL) and THF (3 mL) was added dropwise to a mixture containing concentrated hydrochloric acid (3 mL) and methanol (12 mL). After the addition was completed, the resulting mixture was at 50 Stir at 0.5 ° C for 0.5 hours. Most of the solvent was distilled off under reduced pressure, water (50 mL) was added, and extraction was performed with ethyl acetate (50 mL ⁇ 3). The combined organic phases were washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate.
  • steps A, B, C, and D were performed according to the methods of steps A, I, F, and G in Example 19, wherein triethyl orthoformate in step A of Example 19 was replaced with trimethyl orthoformate to obtain 2-methoxy-7-[(5-methoxypyridin-2-yl) methoxy] benzo [1,3] dioxol-5-carbaldehyde (71).
  • Step A A mixture containing compound 35 (5.0 g, 22.0 mmol), bromoethanol (3.60 g, 28.8 mmol), potassium carbonate (6.0 g, 43.5 mmol), potassium iodide (364 mg, 2.19 mmol), and acetonitrile (50 mL) was mixed Stir overnight at 85 ° C. Cool to room temperature and remove insolubles by filtration. Most of the solvent was distilled off under reduced pressure, water (50 mL) was added, and the pH was adjusted to 10 to 11 with a 2M sodium oxide solution.
  • Example 8 The synthesis of compound 90 was sequentially prepared according to steps B, C, D, E, F, G, and H in Example 8 and the methods of Examples 7 and 13, wherein compound 22 in step B of Example 8 was prepared using 2-formaldehyde The substituted 5-hydroxyethoxypyridine was used, and the 3-hydroxy-4-methoxybenzaldehyde in step E of Example 8 was substituted with 3-hydroxy-4-ethoxybenzaldehyde.
  • Step A Add 1,4-dioxane (8 mL), benzyl mercaptan (866 mg, 6.97 mmol), and diisopropylethylamine (1.20 mg, 9.29 mmol) to the three-necked flask A. The resulting mixture was under nitrogen Stir at room temperature for 40 minutes.
  • Step A In an ice water bath, add phosphorus oxychloride (6.4 mL) dropwise to a solution of 1-bromo-3,5-dimethoxybenzene (5.0 g, 23.0 mmol) in DMF (10.5 mL), add After completion, the resulting mixture was further stirred at this temperature for 0.5 hours, and then heated to 100 ° C and stirred overnight. After cooling to room temperature, it was slowly poured into ice water (50 mL), and the pH was adjusted to 6-7 with a 2.0M sodium hydroxide solution.
  • Step B Add a 3.0M solution of methyl magnesium bromide in THF (6.4mL) to a solution of compound 99 (4.25g, 17.3mmol) in THF (30mL) at -10 ⁇ -5 ° C. After the addition is complete, The resulting mixture was further stirred at this temperature for 1 hour. Saturated brine (40 mL) was added and extracted with ethyl acetate (40 mL ⁇ 3). The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1- (2-bromo-4,6-dimethoxyphenyl) ethanol (100) (4.31 g). The yield was 95.4%.
  • Step C The mixture containing Compound 100 (4.30 g, 16.5 mmol), 2-iodoacylbenzoic acid (6.0 g, 21.4 mmol) and DMSO (50 mL) was stirred at room temperature overnight. Water (200 mL) was added, and extraction was performed with ethyl acetate (40 mL ⁇ 3). The combined organic phases were washed with water (30 mL ⁇ 2) and saturated brine (30 mL) in this order, and dried over anhydrous sodium sulfate.
  • Step D In an ice water bath, add a 1.0 M solution of boron tribromide in toluene (10 mL) to a solution of compound 101 (1.0 g, 3.86 mmol) in dichloromethane (20 mL) dropwise. After the addition, the resulting mixture is at room temperature. Stir overnight. The reaction mixture was slowly poured into ice water (50 mL), and the pH was adjusted to 6-7 with a saturated sodium bicarbonate solution. It was extracted with ethyl acetate (30 mL ⁇ 3), and the combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate.
  • Step E In an ice water bath, chloromethyl methyl ether (966 mg, 12.0 mmol) was added dropwise to compound 102 (920 mg, 3.98 mmol) and diisopropylethylamine (2.57 g, 19.9 mmol) in dichloromethane. (30 mL) of the solution, after the addition was complete, the resulting mixture was stirred at this temperature for 1.5 hours. Dichloromethane (30 mL) was added to the reaction mixture, washed with water (15 mL ⁇ 2), and dried over anhydrous sodium sulfate.
  • Step F A mixture containing Compound 95 (257 mg, 0.940 mmol), Compound 103 (300 mg, 0.940 mmol), potassium hydroxide (158 mg, 2.82 mmol), and ethanol (10 mL) was stirred at 40 ° C overnight. Most of the solvent was distilled off under reduced pressure, water (30 mL) was added, and extraction was performed with ethyl acetate (30 mL ⁇ 3). The combined organic phases were washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate.
  • Step G A mixture containing Compound 104 (450 mg, 0.783 mmol), potassium ethylxanthate (251 mg, 1.57 mmol), copper acetate (14 mg, 0.0771 mmol), and DMSO (6 mL) was stirred at 90 ° C for 36 hours under nitrogen . Water (25 mL) was added, and extraction was performed with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate.
  • Step H The mixture containing Compound 105 (25 mg, 0.0474 mmol), concentrated hydrochloric acid (0.1 mL), and methanol (3 mL) was stirred at room temperature for 1 hour. Water (20 mL) was added, the pH was adjusted to 7-8 with a saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (10 mL ⁇ 3) and dried over anhydrous sodium sulfate.
  • Step A Diisopropyl azodicarboxylate (2.70 g, 13.4 mmol) was added dropwise to compound 37 (1.80 g, 9.89 mmol), triphenylphosphorus (3.50 g, 13.3 mmol) and ( After 5-ethylpyridin-2-yl) methanol (1.50 g, 10.9 mmol) in THF (20 mL) was added, the resulting mixture was stirred at room temperature for 1.5 hours.
  • Step B The mixture containing Compound 107 (2.80 g, 9.29 mmol), methanol (33 mL), and concentrated hydrochloric acid (11 mL) was stirred at room temperature for 1.5 hours. Adjust the pH to 7-8 with a saturated sodium bicarbonate solution. It was extracted with ethyl acetate (30 mL ⁇ 4), and the combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3-[(5-ethylpyridin-2-yl) methoxy] -4-hydroxybenzaldehyde (108) (1.91 g). The yield was 79.9%.
  • Step C Mix a mixture containing Compound 108 (1.90 g, 7.38 mmol), bromoethanol (1.21 g, 9.68 mmol), potassium carbonate (2.05 g, 14.9 mmol), potassium iodide (123 mg, 0.741 mmol), and acetonitrile (20 mL) in Stir overnight at reflux. Most of the solvent was distilled off under reduced pressure, water (40 mL) was added, and the pH was adjusted to 10 to 11 with a 2M sodium oxide solution. It was extracted with ethyl acetate (30 mL ⁇ 3), and the combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate.
  • Step A Add tert-butyldimethylchlorosilane (4.05g, 26.9mmol) to the solution containing 3,4-dihydroxybenzaldehyde (3.71g, 26.9mmol), imidazole (1.87g , 27.5 mmol), 4-dimethylaminopyridine (336 mg, 2.75 mmol) and dichloromethane (40 mL). After the addition was completed, the resulting mixture was stirred at this temperature for 1 hour. Water (40 mL) was added and extraction was performed with dichloromethane (60 mL ⁇ 3). The combined organic phases were washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate.
  • Step B In an ice water bath, diisopropyl azodicarboxylate (4.32 g, 21.4 mmol) was added dropwise to compound 117 (4.0 g, 15.8 mmol), triphenylphosphorus (5.62 g, 21.4 mmol) and the compound In a solution of 62 (3.14 g, 15.8 mmol) in THF (40 mL), after the addition was completed, the resulting mixture was stirred at room temperature for 1.5 hours.
  • Step C To a solution of compound 118 (1.60 g, 3.70 mmol) in THF (16 mL) was added a 1.0 M solution of tetrabutylammonium fluoride in THF (4.1 mL). After the addition, the resulting mixture was stirred at room temperature for 1.5 hours. Saturated brine (20 mL) was added and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate.
  • Step D The mixture containing Compound 119 (1.12 g, 3.52 mmol), iodoethane (755 mg, 4.84 mol), potassium carbonate (816 mg, 5.91 mmol), and DMF (10 mL) was stirred at room temperature for 5 hours. Water (40 mL) was added and extraction was performed with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate.
  • steps H and I were performed according to the preparation methods of Example 7 and Example 13, respectively, to obtain 2- ⁇ 4-ethoxy-3-[(4-hydroxy-3-methoxybenzyl) oxy] phenyl ⁇ Saman-3,5,7-triol (125).
  • Step A A mixture containing Compound 35 (5.0 g, 21.9 mmol), sodium difluorochloroacetate (5.0 g, 32.8 mmol), potassium carbonate (6.0 g, 43.5 mmol), water (10 mL), and DMF (50 mL) was placed in Stir overnight at 120 ° C. Cool to room temperature, add water (200 mL), and extract with ethyl acetate (50 mL ⁇ 3). The combined organic phases were washed with water (30 mL ⁇ 2) and saturated brine (30 mL) in this order, and dried over anhydrous sodium sulfate.
  • steps C, D, E and F were carried out according to the preparation method of steps E, F, G and H in Example 8, wherein the compound 25 in Example 8 Step E used (5-methoxypyridin-2-yl ) Methanol replacement, 2- ⁇ 4- (difluoromethoxy) -3-[(5-methoxypyridin-2-yl) methoxy] phenyl ⁇ -3,5,7-trihydroxy color Pan-4-one (134).
  • Step B To a solution of compound 135 (2.10 g, 7.04 mmol) in toluene (25 mL) at -50 ° C was added dropwise a 1.5 M solution of diisobutylaluminum hydride in toluene (23.2 mL, 23.2 mmol). After the addition was completed, the temperature was kept stirring for 0.5 hours. The reaction solution was slowly poured into ice water (40 mL), and the pH was adjusted to 5-6 with a 2M citric acid solution. It was extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate.
  • Step C A mixture containing the compound 136 (500 mg, 1.95 mmol), methyl gallate (359 mg, 1.95 mmol), acetone (10 mL) and benzene (20 mL) was stirred at 50 ° C for 10 minutes, and then silver carbonate (536 mg) was added , 1.94 mmol). After the addition was complete, the resulting mixture was stirred at 50 ° C. overnight under the protection of N 2 . Cool to room temperature and remove insolubles by filtration.
  • Step D To a mixture containing lithium aluminum hydride (20 mg, 456 ⁇ mol) and THF (5 mL) was added dropwise a solution of compound 137 (100 mg, 228 ⁇ mol) in THF (5 mL) under an ice-water bath. After the addition was complete, stirring was continued for 10 minutes, and then warmed to room temperature and continued stirring for 30 minutes. The reaction system was quenched by adding water, extracted with ethyl acetate (10 mL ⁇ 2), washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 53 Test of Compounds on Fat Reduction or Clearance in Zebrafish Nonalcoholic Fatty Liver
  • test compounds 20, 21, 33, 34, 44, 45, 67, 74, 78, 80, 85, 87, 90, 114, and 117 were respectively prepared into a 40 mM stock solution with DMSO for future use and stored in a refrigerator at -20 ° C.
  • the positive control compound S-adenosylmethionine (hereinafter referred to as SAM) was purchased from Aladdin Reagent (Shanghai) Co., Ltd., batch number F1523051, and was prepared into a 50 mM stock solution with DMSO for later use.
  • the control compound silibinin was purchased from Shanghai Dibo Biotechnology Co., Ltd., with batch number EE09, and was prepared into a 40 mM stock solution with DMSO for later use.
  • Thioacetamide purchased from Sigma-Aldrich, lot number BCBV3031, was made into 1M mother liquor with DMSO for future use.
  • Oil Red O was purchased from Sigma-Aldrich, lot number SLBP5248V.
  • 4% paraformaldehyde was purchased from Dingguo Biotechnology Co., Ltd., batch number 773001800.
  • Propylene glycol was purchased from Sinopharm Chemical Reagent Co., Ltd., lot number 20170615.
  • Zebrafish of the melanin allelic mutant translucent Albino strain were reproduced in natural pairs. The age of the fish was 3 days after fertilization, and 30 fish per test group.
  • the above zebrafish are all raised in 28 ° C aquaculture water (water quality: 200 mg of instant sea salt is added per 1 L of reverse osmosis water, the conductivity is 480-510 ⁇ S / cm; the pH is 6.9-7.2; the hardness is 53.7-71.6 mg / L CaCO 3 )
  • the experimental animal use license number is: SYXK (Zhejiang) 2012-0171. Feeding management meets the requirements of international AAALAC certification.
  • Zebrafish were transferred to a six-well plate with 30 tails per well (ie, each experimental group) randomly.
  • Non-alcoholic fatty liver model was induced by thioacetamide in zebrafish.
  • 40 mM test compounds 20, 21, 33, 34, 44, 45, 67, 74, 78, 80, 85, 87, 90, 114, and 117 were quantitatively transferred to a six-well plate and diluted with water to the corresponding concentration.
  • test compounds 20, 34, and 45 were formulated into two concentration dose groups with a final concentration of 100 ⁇ M and 200 ⁇ M, respectively; the test compounds 21, 33, 44, 74, and 80 were formulated into a dose group with a final concentration of 200 ⁇ M; Compounds 67, 78, 85, 87, 90, 114, and 117 were formulated into a dose group with a final concentration of 100 ⁇ M; 50 mM positive control SAM was formulated into a dose group with a final concentration of 50 ⁇ M, and 40 mM positive control silybin was formulated with water Two concentration and dose groups with a final concentration of 100 ⁇ M and 200 ⁇ M were set up, while a normal control group (zebrafish treated with water for fish farming) and a model control group were set up, and the total volume of liquid in each well was 3 mL.
  • test compounds 21, 33, 44, 74, and 80 were formulated into a dose group with a final concentration of 200 ⁇ M
  • Inhibition rate of liver steatosis [S (model control group) -S (test compound group)] / [S (model control group) -S (normal control group)] ⁇ 100%
  • Inhibition rate of liver steatosis indicates the degree of reduction of liver fat in the zebrafish after model formation by the test compound. The larger the value, the more obvious the effect of the test compound on reducing or eliminating liver fat.
  • the average value of the total optical density of zebrafish liver fat in the model control group was 24826, which was significantly larger than the average value of the normal control group (16562).
  • Statistical analysis between the model control group and the normal control group showed that , P value ⁇ 0.001, indicating that the model was successfully established.
  • the positive control SAM 50 ⁇ M
  • the concentrations of silibinin at 100 ⁇ M and 200 ⁇ M Inhibition rates of zebrafish liver steatosis were 50% and 70%, respectively, with p-values ⁇ 0.05 and ⁇ 0.01.
  • the positive control SAM and silibinin have protective effects on non-alcoholic fatty liver in zebrafish.
  • the test compounds 20, 21, 33, 34, 44, 45, 74, and 80 have significant therapeutic effects on non-alcoholic fatty liver disease in zebrafish.
  • the inhibition rates of zebrafish liver steatosis were> 100%, 99%, 87%,> 100%, 87%,> 100%, 93%, and 79%, respectively. Oil Red O staining) was significantly reduced, while the inhibition rate of silibinin, the positive control, was only 70% at the same concentration, indicating that these compounds had far better fat reduction or clearance effects on non-alcoholic fatty liver in zebrafish. Silybin.
  • the test compounds 20, 34, 45, 67, 78, 85, 87, 90, 114, and 117 all have significant therapeutic effects on non-alcoholic fatty liver in zebrafish.
  • the inhibition rates of zebrafish liver steatosis after modeling were 90%, 87%, 90%, 89%, 96%, 80%, 78%,> 100%, 86%, and 86%.
  • the test compounds in each group Lipid droplets (oil red O staining) in the liver of zebrafish were significantly reduced, while the inhibition rate of silibinin, the positive control, was only 50% at the same concentration, suggesting that these compounds have reduced fat in non-alcoholic fatty liver The reduction or elimination effect is far superior to silibinin.
  • test results show that some of the compounds of this patent have very significant therapeutic effects on non-alcoholic fatty liver in zebrafish, and the inhibition rate of liver steatosis is significantly greater than that of silybin.
  • Example 54 Evaluation of the efficacy of compounds on non-alcoholic steatohepatitis (NASH) mice
  • test compounds were 34 and 45, respectively; the positive control was silibinin, which was purchased from Shanghai Dibo Biotechnology Co., Ltd. and the batch number was HH06.
  • Low-dose group (35mg / kg) solution preparation precisely weighed a quantitative amount of the test compound, added a certain amount of physiological saline, and formulated it into an oral suspension solution with a concentration of 3.5mg / mL.
  • the administration volume was 10 mL / kg body weight.
  • Preparation of high-dose group (70mg / kg) solution Weigh accurately the quantitative test compound, add a certain amount of physiological saline, and formulate them into oral suspension solutions with a concentration of 7.0mg / mL. The administration volume was 10 mL / kg body weight.
  • High-fat feed The basic feed ingredients are corn, flour, imported fish meal, soybean meal, secondary meal, yeast meal, soybean oil, etc. High-fat feed is added 73% basal feed with 10% lard, 10% egg yolk powder, 5% sucrose, 1.2% cholesterol and 0.2% pig bile salt.
  • Source, germ line, and strain C57BL / 6 mice, provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. Nanjing Branch (Laboratory Animal Production License: SCXK (Su) 2016-0003); Laboratory Animal Use Permit: SYXK (Military) 2012-0049; Weeks of age: 6-8 weeks at the beginning of administration; Weight: 18-22g; Gender: Male and female.
  • mice were adaptively fed with normal feed they were randomly assigned according to body weight: 8 mice were fed with normal feed and set as normal control group (NC); other mice were fed with high-fat feed until the end of the experiment. Mice were weighed every 3 days and recorded. After 56 days (8 weeks) of feeding the mice with high-fat diet to make a model, the mice received blood from the orbital vein, and the blood biochemical indicators were tested to determine whether the model was successfully created.
  • NC normal control group
  • mice in the high-fat diet group were randomly divided into 6 groups of 8 animals each, which were model group, compound 34 low-dose group, compound 34 high-dose group, compound 45 low-dose group, and compound 45 high-dose.
  • Group and the positive control silibinin high-dose group were administered orally and intragastrically for 28 days (4 weeks) according to the weight of the animals.
  • the animals in each administration group and model group continued to be fed with high-fat diet until the end of the experiment.
  • the normal control group was given the corresponding volume of normal saline.
  • mice in each group were fasted for 8 hours, blood was collected from the orbits, and the serum was separated. The serum was separated and stored at -20 ° C. Mice were sacrificed after blood collection was completed, the liver was quickly separated, weighed, and stored in a -80 ° C refrigerator.
  • Serum samples and liver tissue samples were subjected to serum triglyceride (TG), serum total cholesterol (TC), serum low density lipoprotein (LDL-C), serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and serum Detection of tumor necrosis factor alpha (TNF ⁇ ), liver triglyceride (TG), liver total cholesterol (TC), liver malondialdehyde (MDA) and other biochemical indicators; blank control group, model group, compound 34 low-dose group The livers of some mice in the high-dose silibinin group were fixed in a neutral formaldehyde fixative solution, HE stained, and the liver tissues were analyzed pathologically.
  • TG serum total cholesterol
  • LDL-C serum low density lipoprotein
  • ALT serum alanine aminotransferase
  • AST serum aspartate aminotransferase
  • TNF ⁇ tumor necrosis factor alpha
  • TG liver triglyceride
  • TC
  • liver coefficient of the model group was significantly higher than that of the blank control group after 3 months (p ⁇ 0.01).
  • Serum indicators (TC, TG, LDL-C, ALT, AST, and TNF ⁇ ) and liver tissue indicators (TC, TG, and MDA) in the model group were significantly different from those in the blank control group.
  • silibinin a positive control, was administered by continuous intragastric administration at 70 mg / kg for 1 month, which significantly reduced the levels of ALT, AST, LDL-C and TNF ⁇ in the blood, and significantly reduced TC in liver tissues.
  • TG and MDA levels all p ⁇ 0.01)
  • the liver coefficient decreased significantly (p ⁇ 0.05), indicating that the positive control silibinin has a certain therapeutic effect on NASH mice.
  • Compounds 34 and 45 were administered orally for one month at 35 or 70 mg / kg, respectively. Compared with the model group, the liver coefficient was reduced (p ⁇ 0.05); and TG, ALT, AST, and LDL- C level also significantly improved TC and TG in liver tissue (p ⁇ 0.01); meanwhile, compound 34 and 45 high and low dose groups can reduce serum TNF ⁇ and liver MDA levels (p ⁇ 0.01 or p ⁇ 0.05). ).
  • liver coefficient (%) liver weight / body weight * 100%
  • the histopathological results of the NASH mouse model group showed (Fig. 3) that the liver cells of the model group had significant steatosis and necrosis, and there were inflammatory cell foci, so the NASH model was successfully established.
  • hepatocytes of individual mice in Compound 34 low-dose group had lipid droplet vacuoles caused by steatosis and a small amount of inflammatory cell invasion. Therefore, it was shown that compound 34 can effectively improve the degree of lipidation of liver tissue of NASH mice and reduce the inflammatory response.
  • test results show that some of the compounds involved in this patent have significant therapeutic effects on non-alcoholic steatohepatitis in mice.

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Abstract

L'invention concerne une classe de composés pharmaceutiques pour le traitement de maladies du foie et une utilisation associée. En particulier, lesdits composés pharmaceutiques sont des composés représentés par la formule générale (I), des isomères optiques ou des sels pharmaceutiquement acceptables de ceux-ci. Ces composés, isomères optiques ou sels pharmaceutiquement acceptables de ceux-ci présentent une faible toxicité et un bon effet curatif sur des maladies du foie, en particulier le foie gras. Des expériences ont montré que les composés ont un effet protecteur significatif sur le foie gras non alcoolique chez des poissons zèbres, et ont donc une bonne perspective d'application dans des médicaments pour le traitement ou la prévention de maladies hépatiques, en particulier du foie gras, de la fibrose hépatique ou de la cirrhose.
PCT/CN2019/101066 2018-08-17 2019-08-16 Composés pharmaceutiques pour le traitement de maladies du foie et utilisation associée WO2020035058A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102327260A (zh) * 2010-10-26 2012-01-25 李秀丽 槲皮素在制备治疗非酒精性脂肪肝药物中的应用
CN102993148A (zh) * 2011-09-13 2013-03-27 复旦大学 槲皮素衍生物或其类似物及其应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
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CN101914084B (zh) * 2010-07-30 2012-10-17 中国人民解放军第二军医大学 双苯吡喃酮氮杂环衍生物及其制备方法与应用
WO2012171488A1 (fr) * 2011-06-17 2012-12-20 Beijing Hanmi Pharmaceutical Co., Ltd. Dérivé de coumarine, composition pharmaceutique et utilisation associées
KR101325058B1 (ko) * 2011-10-04 2013-11-06 건국대학교 산학협력단 신규한 케르세틴 유도체, 3',4'-디플루오로케르세틴, 그 제조방법 및 그 용도
CN103933027B (zh) * 2014-04-09 2016-08-17 中国中医科学院中药研究所 瑞香狼毒提取物在抗肿瘤中的应用
WO2016026139A1 (fr) * 2014-08-22 2016-02-25 财团法人国防教育研究基金会 Médicament pour le traitement de la stéatose hépatique non alcoolique et son utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102327260A (zh) * 2010-10-26 2012-01-25 李秀丽 槲皮素在制备治疗非酒精性脂肪肝药物中的应用
CN102993148A (zh) * 2011-09-13 2013-03-27 复旦大学 槲皮素衍生物或其类似物及其应用

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry CAS; 10 December 2006 (2006-12-10), retrieved from STN Database accession no. RN915096-80-9 *
DATABASE Registry CAS; 11 January 2010 (2010-01-11), retrieved from STN Database accession no. RN1201808-12-9 *
DATABASE Registry CAS; 21 March 2017 (2017-03-21), retrieved from STN Database accession no. RN2088005-91-6 *
DATABASE Registry CAS; 25 March 2010 (2010-03-25), retrieved from STN Database accession no. RN1214721-94-4 *
DATABASE Registry CAS; 29 October 2014 (2014-10-29), retrieved from STN Database accession no. RN1630829-81-0 *
DATABASE Registry CAS; 8 May 2006 (2006-05-08), retrieved from STN Database accession no. RN883242-80-6 *

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