WO2005123711A1 - Glycosides de bicyclol, leurs procedes de preparation et leurs utilisations - Google Patents

Glycosides de bicyclol, leurs procedes de preparation et leurs utilisations Download PDF

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Publication number
WO2005123711A1
WO2005123711A1 PCT/CN2005/000871 CN2005000871W WO2005123711A1 WO 2005123711 A1 WO2005123711 A1 WO 2005123711A1 CN 2005000871 W CN2005000871 W CN 2005000871W WO 2005123711 A1 WO2005123711 A1 WO 2005123711A1
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WIPO (PCT)
Prior art keywords
preparation
compound
reaction
iii
lactose
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PCT/CN2005/000871
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English (en)
Chinese (zh)
Inventor
Piaoyang Sun
Yongjiang Chen
Jiabao Ou
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Jiangsu Hengrui Medicine Co., Ltd.
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Publication of WO2005123711A1 publication Critical patent/WO2005123711A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • 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
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms

Definitions

  • the present invention relates to pharmacy and organic chemistry, in particular, the present invention relates to a bicyclic alcohol glycoside compound, a preparation method thereof, and its clinical application. Background technique
  • Bicyclol is a known compound. It is a synthetic anti-chronic viral hepatitis drug with significant liver-protective effect and certain anti-hepatitis virus activity. The results of various studies on the mechanism of the drug's action indicate that bicyclol is not a transaminase inhibitor Instead, it has the effect of scavenging free radicals to protect the cell membrane, and can protect nuclear DNA from damage and reduce the occurrence of apoptosis. Its structure can be expressed by the formula (II):
  • European patent EP0353358 discloses a preparation method thereof, and the reaction scheme is shown in Scheme 1.
  • a known compound biphenyl diester ( ⁇ -1) (the preparation method is disclosed in Japanese Patent JP60209582) is used as a raw material, and a dicarboxylic acid (11-2) is obtained by alkaline hydrolysis according to a general method of ester hydrolysis, and then The dicarboxylic acid is heated with acetic anhydride to obtain the acid anhydride ( ⁇ -3).
  • the acid anhydride is reduced with sodium borohydride and heated with p-toluenesulfonic acid to obtain the lactone ( ⁇ -4).
  • the lactone is then reacted with methanol in the carboxylic acid. It is reacted in the presence of a salt (sodium acetate), and then conventionally separated and purified to obtain bicyclic alcohol ( ⁇ ).
  • the present invention relates to a novel bicyclic alcohol glycoside compound which can be applied to the treatment of liver diseases, a production method and clinical application thereof.
  • the present invention relates to a bicyclic alcohol glycoside compound, which is characterized by having the following structural formula:
  • R and respectively represent H, 0H or galactosyl.
  • galactosyl is represented by the following formula, and R2 represents! "!.
  • the present invention also relates to a method for preparing a bicyclic alcohol glycoside compound (I), which is characterized by:
  • the invention also relates to a pharmaceutical composition containing a pharmaceutically effective dose of the compound (I) and a pharmaceutically acceptable carrier, and the use of the compound in the preparation of a pharmaceutical preparation for treating liver diseases.
  • the bicyclic alcohol glycoside compound of the present invention is a novel compound, and it can be represented by the formula (I)
  • R, and R2 represent groups of the following structure:
  • the preparation route of the target compound of the present invention is shown in the following reaction scheme 2.
  • benzoyl chloride is used to obtain the fully benzoylated lactose (III-2), and then the fully acylated sugar 1-position protecting group is selectively removed in the presence of hydrazine acetate Compound ⁇ 1-2 is obtained, and then reacted with trichloroacetonitrile to obtain trichloroimide (III-3) of acylated sugar; trichloroimide ( ⁇ -3) and bicyclic alcohol glycosylation coupling reaction to obtain bicyclic alcohol benzyl Acylated glycoside (IV), acylated glycoside (IV) was treated with sodium alkoxide to deprotect it to give bicyclic alcohol glycoside (1).
  • the total acylation of sugar, the reaction to prepare the active imide, and the glycosylation reaction need to be performed in an inactive solvent.
  • the inactive solvents are tetrahydrofuran, dioxane, ether, acetone, ethyl acetate, toluene, chloroform, Ethers, ketones, esters, halogenated hydrocarbons, and hydrocarbon solvents such as dichloromethane; These solvents can be used alone or in combination. Halogenated hydrocarbons such as chloroform and dichloromethane are preferred.
  • the deprotection reaction is usually performed in a conventional solvent.
  • solvent used examples include ethanol, methanol, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, and the like.
  • a suitable catalyst in some reaction steps.
  • a suitable amount of organic base such as pyridine, triethylamine, etc. can be added to the sugar acylation reaction, and a suitable amount of alkali catalyst such as DBU can be added to prepare the trichloroimide ester.
  • Lewis acids such as trisilyl triflate and the like.
  • the reaction is usually carried out at normal temperature, and the temperature range is about -20 to 60 ° C, preferably -10 to 40 ° C, and most preferably, the reaction is performed in the range of 0 ° C to 35 ° C.
  • the reaction time is determined by the type of reaction, the type of solvent, the reaction temperature, and other factors.
  • the reaction time ranges from 0.5 to 72 hours; specifically, the acylation reaction is about 6 to 12 hours, and the 1-position deprotection is about 36- In 72 hours, the preparation of the active imide and the glycosylation reaction takes about 0.5 to 2 hours, and the acylated glycoside is deprotected for about 2-6 hours.
  • Post-treatment of the reaction can be carried out in a conventional manner. Generally, products are obtained by extraction, concentration, decantation, macroporous resin chromatography, silica gel chromatography, crystallization or freeze drying.
  • the present invention also provides a pharmaceutical composition containing the bicyclic alcohol glycoside compound as an active ingredient and a pharmaceutically acceptable carrier, such as a pharmaceutical auxiliary such as an excipient or a diluent.
  • a pharmaceutically acceptable carrier such as a pharmaceutical auxiliary such as an excipient or a diluent.
  • the pharmaceutical composition is obtained by mixing the bicyclic alcohol glycoside compound prepared by the above method with a pharmaceutically acceptable pharmaceutical adjuvant, and then preparing the desired preparation form according to the conventional preparation method of the preparation.
  • the composition can be in the form of tablets, capsules, granules, or liquid preparations such as oral solutions or sterile parenteral solutions; the route of administration, dose, and number of administrations can be adjusted appropriately according to the age, weight and disease of the patient.
  • composition may also be in the form of a large or small volume injection, a lyophilized powder injection, a sterile powder packaging and the like.
  • Single-dose representations for oral administration may be tablets and capsules, and may contain conventional excipients such as binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, For example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; Or a pharmaceutically acceptable wetting agent, such as sodium lauryl sulfate.
  • binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone
  • fillers For example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants such as magnesium stearate
  • disintegrants such as starch,
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. Repeated mixing operations can be used to distribute the active agent sufficiently into a composition using a large amount of filler. Such operations are of course routine in the art.
  • the tablets can be made into coated or plain tablets according to a conventional method.
  • Oral liquid preparations can be in the form of, for example, emulsions, dragees, or can be used as a dry The product exists and is reconstituted with water or other suitable carrier before use.
  • This liquid formulation may contain conventional additives such as suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated food fat; emulsification; Agents, such as lecithin, sorbitan monooleate, or gum arabic; anhydrous carriers (which may include edible oils), such as almond oil, distilled coconut oil, or oily esters, such oily esters include glycerides, propylene glycol Or ethanol; preservatives, such as methyl or propyl parabens, or sorbic acid; if desired, conventional flavoring or coloring agents can also be added.
  • suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxye
  • the active ingredient can be dissolved in a sterile carrier to prepare a unit liquid dosage form.
  • a sterile carrier When preparing a solution, the active ingredient can be dissolved in water for injection and filtered for sterilization, and then poured into a vial or ampoule and sealed.
  • adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the carrier.
  • the composition can be frozen and filled into vials, and the water can be removed under vacuum. Or a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • Another object of the present invention is to provide application of a bicyclic alcohol glycoside compound (I) and a composition thereof for preparing a medicament for treating liver diseases.
  • the present invention has found through research that a new bicyclic alcohol glycoside compound prepared by glycosylation of a bicyclic alcohol and a saccharide compound has a strong liver injury protection effect, and thus constitutes the present invention.
  • the purpose of the present invention is to prepare medicines with better curative effect for the treatment of liver diseases, and overcome the shortcomings of the clinical curative effect and treatment scope of the existing preparations. detailed description
  • Galactobicyclic alcohol (lb) Preparation According to the preparation process of Example 11, 3.5 g (3.61 mmol) of bicycloalcohol acylated galactoside (IVb) was used instead of bicycloalcohol acylated lactoside (IVa) to obtain 1.87 g of galactobicyclic alcohol (lb), yield 94.6 %.
  • the bicyclic alcohol acylated glucoside (IVc) 3.5 g (3.61 mmol) was used in place of the bicyclic alcohol acylated glucoside (IVa) to obtain the glucose bicyclic alcohol (Ic).
  • Lactose bicyclic alcohol, microcrystalline cellulose, lactose, and magnesium stearate are sieved and mixed well, and divided into hard capsules to obtain.
  • Example 19 Preparation of glucose bicyclic alcohol granules
  • test efficacy data of the compound (I) of the present invention for the treatment of liver injury are given below.
  • test drug name Lactose bicyclic alcohol: molecular weight 714.61, white powder; galactose bicyclic alcohol: molecular weight 552.47, white powder; : Molecular weight 552.47, white powder; positive control D: bicyclic alcohol, molecular weight 390.33, white particles.
  • Dose design Based on the results of the pharmacodynamic study of the positive control drug bicyclol on the CC1 4 injury model (effective dose is 100mg g ' 1 ), it is proposed to set the test drugs VIII, B, and C to the mouse CC1 4 injury model.
  • the doses were 183.1, 141.5, and 145.5 mg'kg ' 1 , respectively, that is, the test drug and bicyclo alcohol were administered at a dose of 0.256 mg-kg ⁇
  • mice grouping Mice were randomly divided into 6 groups, 10 in each group, half male and half male, weighing 25 to 2 g. They were set as normal control group, CC1 4 injury model control group, positive control drug bicyclol group, test drug lactobicyclol group, test drug galactose bicyclol group, and test drug glucobicyclol group.
  • mice were ip 0.1% CC1 4 (10 ml-kg 1 ) 24 hours before, except the normal control group and the model control group, the other groups were ig bicyclol, test lactose bicyclol group, test drug
  • the galactose bicyclic alcohol group and the test drug glucobicyclic alcohol group were twice, spaced 6 hours before and after, and the doses were 100, 183.1, 141.5, and 141.5 mg.kg, respectively.
  • the normal control group and the model control group were ig saline (NS).
  • the volume of the drug is SO ml'kg '.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • the other group is ALT AST normal control group 1342.96 + 277.92 2906.84 ⁇ 1450.80
  • the biochemical index test results showed that the ALT and AST of the model control group were significantly higher than those of the normal control group. Combined with the pathological changes of the hepatocytes seen by pathological morphology examination, this experiment was successful. According to biochemical indicators, the ALT values of the test drug and the positive control group were significantly lower than those of the model control group, and there was no significant difference between the four groups; meanwhile, pathological morphological examination results showed that the liver The degree of cell damage was generally milder than that of the model control group.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Saccharide Compounds (AREA)

Abstract

La présente invention relève de la pharmaceutique et de la chimie organique, et se rapporte en particulier à un nouveau type de glycosides de bicyclol, ainsi qu'à leur procédé de préparation. Le procédé selon l'invention consiste à faire réagir du bicyclol avec un ester de trichloroimide d'un sucre d'acylation en présence d'un solvant classique, afin d'effectuer la glycosidation, puis à traiter les glycosides acylés avec un alcoxyde de sodium, afin de former lesdits glycosides de bicyclol. Les glycosides de bicyclol selon l'invention sont utiles pour le traitement des hépatopathies.
PCT/CN2005/000871 2004-06-21 2005-06-17 Glycosides de bicyclol, leurs procedes de preparation et leurs utilisations WO2005123711A1 (fr)

Applications Claiming Priority (2)

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CN200410048198 2004-06-21
CN200410048198.7 2004-06-21

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WO2005123711A1 true WO2005123711A1 (fr) 2005-12-29

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100404527C (zh) * 2006-03-07 2008-07-23 河南省科学院质量检验与分析测试研究中心 手性4,4＇-二甲氧基-5,6,5＇,6＇-二次甲二氧基联苯-2,2＇-二甲酸衍生物及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4868207A (en) * 1988-07-28 1989-09-19 Taisho Pharmaceutical Co., Ltd. Bis (methylenedioxy) biphenyl compounds useful for the treatment of liver diseases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4868207A (en) * 1988-07-28 1989-09-19 Taisho Pharmaceutical Co., Ltd. Bis (methylenedioxy) biphenyl compounds useful for the treatment of liver diseases

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100404527C (zh) * 2006-03-07 2008-07-23 河南省科学院质量检验与分析测试研究中心 手性4,4＇-二甲氧基-5,6,5＇,6＇-二次甲二氧基联苯-2,2＇-二甲酸衍生物及其制备方法

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