WO2017114413A1 - 三乙酰基-3-羟基苯基腺苷在制备预防或者治疗非酒精性脂肪肝药物中的应用 - Google Patents

三乙酰基-3-羟基苯基腺苷在制备预防或者治疗非酒精性脂肪肝药物中的应用 Download PDF

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WO2017114413A1
WO2017114413A1 PCT/CN2016/112623 CN2016112623W WO2017114413A1 WO 2017114413 A1 WO2017114413 A1 WO 2017114413A1 CN 2016112623 W CN2016112623 W CN 2016112623W WO 2017114413 A1 WO2017114413 A1 WO 2017114413A1
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Prior art keywords
liver
fatty liver
triacetyl
preventing
hydroxyphenyladenosine
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PCT/CN2016/112623
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English (en)
French (fr)
Chinese (zh)
Inventor
朱海波
史会杰
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Institute of Materia Medica of CAMS and PUMC
Jiangsu Tasly Diyi Pharmaceutical Co Ltd
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Institute of Materia Medica of CAMS and PUMC
Jiangsu Tasly Diyi Pharmaceutical Co Ltd
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Priority to RU2018126158A priority Critical patent/RU2759916C2/ru
Priority to CA3010097A priority patent/CA3010097C/en
Priority to US16/067,228 priority patent/US11058703B2/en
Priority to AU2016383376A priority patent/AU2016383376B2/en
Priority to KR1020187021547A priority patent/KR102676056B1/ko
Priority to EP16881202.2A priority patent/EP3398604A4/en
Application filed by Institute of Materia Medica of CAMS and PUMC, Jiangsu Tasly Diyi Pharmaceutical Co Ltd filed Critical Institute of Materia Medica of CAMS and PUMC
Priority to HK18114837.8A priority patent/HK1255689A1/en
Priority to JP2018533743A priority patent/JP7382716B2/ja
Publication of WO2017114413A1 publication Critical patent/WO2017114413A1/zh
Anticipated expiration legal-status Critical
Priority to ZA201805080A priority patent/ZA201805080B/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the invention relates to the application of triacetyl-3-hydroxyphenyladenosine and a pharmaceutical composition containing the same for preparing a medicament for preventing or treating non-alcoholic fatty liver, and belongs to the technical field of medicine.
  • Non-alcoholic fatty liver disease refers to a group of clinical pathological syndromes characterized by hepatic parenchymal cell damage and fat accumulation, excluding excessive drinking and other well-defined causes of liver damage.
  • a metabolic stress liver injury closely related to insulin resistance (IR) and genetic susceptibility.
  • the pathological changes are similar to alcoholic liver disease, but the patient has no history of excessive drinking.
  • the composition includes nonalcoholic simple fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver fibrosis, nonalcoholic fatty liver cirrhosis and related liver cancer (HCC).
  • the exact pathogenesis of NAFLD is still unclear. It is generally recognized as the "second strike” doctrine.
  • the first strike in the two stages of the theory is due to the excessive intake of high-fat diet and the decrease in the amount of decomposition, resulting in lipid deposition. Form a simple fatty liver.
  • IR can weaken and destroy the regulation of insulin metabolism, increase lipid dissolution, increase the concentration of nonesterified free fatty acid (FFA), and promote the uptake of FFA in the liver by the liver.
  • Oxidative stress and lipid peroxidation damage play an important role in the formation and development of fatty liver, which is an important factor for the further development of fatty liver.
  • Mitochondria are the respiratory organs of cells, and the production of reactive oxygen species (ROS) increases damage to mitochondria, further aggravating lipid accumulation in the liver.
  • ROS reactive oxygen species
  • LPO lipid peroxidation
  • MDA malondialdehyde
  • colleagues destroy the structure of biofilm Function, so that cell membrane permeability increases, cytochrome C efflux, initiate apoptosis program, and finally lead to liver fibrosis, cirrhosis, and even progress to liver cancer.
  • LPO lipid peroxidation
  • MDA malondialdehyde
  • Triacetyl-3-hydroxyphenyladenosine (Patent No. ZL200980101131.6, Bulletin No. CN101874036B, Announcement Day 2012.01.25) is a new screening of cordycepin derivatives with significant lipid-lowering activity in the Institute of Materia Medica, Chinese Academy of Medical Sciences. It is a pre-clinical research stage characterized by structural type compounds with small toxic and side effects and good pharmacokinetics. There are no reports of the use of this compound in the prevention or treatment of nonalcoholic fatty liver disease.
  • the technical problem to be solved by the present invention is to provide a compound triacetyl-3-hydroxyphenyl adenosine and a pharmaceutical composition thereof for use in the preparation of a medicament for preventing or treating nonalcoholic fatty liver.
  • a first aspect of the present invention provides a triacetyl-3-hydroxyphenyl adenosine represented by the formula (I) and a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating nonalcoholic fatty liver disease Applications
  • the non-alcoholic fatty liver is a fatty liver caused by a high-energy diet.
  • the triacetyl-3-hydroxyphenyladenosine of the present invention is capable of significantly reducing serum AST, ALT and TG levels, and significantly improving the liver function of the fatty liver golden hamster and reducing the degree of fatty liver. Thereby preventing or treating non-alcoholic fatty liver.
  • a second aspect of the present invention provides a pharmaceutical composition for the preparation of a medicament for preventing or treating non-alcoholic fatty liver, characterized in that the pharmaceutical composition comprises triacetyl of the formula (I) 3-hydroxy-phenyl adenosine and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
  • the pharmaceutical composition includes tablets, capsules, pills and injections, sustained release preparations, controlled release preparations or various microparticle delivery systems.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 95% by weight.
  • the compound of the present invention or a pharmaceutical composition containing the same can be administered in a unit dosage form, and the administration route can be intestinal or non-intestinal.
  • the administration route can be intestinal or non-intestinal.
  • the dosage form can be in a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
  • a preferred pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a pill, and an injection
  • the compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • diluents may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agent may be water, ethanol, or different Propyl alcohol, etc.
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group
  • disintegrant can be dry starch, microcrystalline cellulose, low substitute
  • Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • the active ingredient of the present compound may be first mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • a variety of diluents, binders, wetting agents, disintegrants, glidants useful in the preparation of tablets of the compounds of the invention are also useful in the preparation of capsules of the compounds of the invention.
  • a suitable amount of a solubilizing agent, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added as a solvent with water, ethanol, isopropanol, propylene glycol or a mixture thereof.
  • the solubilizing agent or the glidant may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure adjusting agent It may be sodium chloride, mannitol, glucose, phosphate, acetate or the like. For preparing a lyophilized powder injection, mannitol, glucose or the like may also be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of the compound of the invention will range from 0.001 to 150 mg/kg body weight, preferably from 0.1 to 100 mg/kg body weight, more preferably from 1 to 60 mg/kg body weight, and most preferably from 2 to 30 mg/kg body weight.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • the invention uses the pharmacodynamic research method to confirm the significant effect of triacetyl-3-hydroxyphenyladenosine in preventing or treating non-alcoholic fatty liver disease, and provides a chronic disease with complicated pathogenesis and poor therapeutic effect.
  • a new preventive or therapeutic drug, triacetyl-3-hydroxyphenyladenosine has remarkable curative effect, small toxic and side effects, and is safe to use. It provides scientific research for its clinical application in preventing or treating nonalcoholic fatty liver disease. in accordance with.
  • Figure 1 is a comparison of body weight and liver coefficient of each group of golden hamsters in the experimental example of the present invention
  • Figure 4 is a comparison of the results of determination of lipid content in liver tissues of golden hamsters in the experimental examples of the present invention.
  • Figure 5 is a diagram showing the nuclear magnetic imaging of the liver of golden hamster in the experimental example of the present invention.
  • Figure 6 is a comparison of HE pathological staining results of liver hamsters in each group of the experimental examples of the present invention.
  • Fig. 7 is a comparison of the results of oil red O staining of liver hamsters of each group of golden hamsters in the experimental example of the present invention.
  • Example 1 Application of triacetyl-3-hydroxyphenyladenosine (IMM-H007) in the treatment of nonalcoholic fatty liver disease
  • OCT frozen slice embedding agent American cherry; sodium pentobarbital, sigma company; PEG6000, sigma company; glycine, sigma company; paraformaldehyde, Sinopharm reagents; oil red O, sigma company; HE staining solution, Taiwan Besso Company; Total Cholesterol (TC) Test Kit, Japan Sekisui Medical Technology (China) Co., Ltd.; Total Triglyceride Test Kit, Zhongsheng Beikong Biotechnology Co., Ltd.; Free Fatty Acid Test Kit, Japan Product Water Medical Technology (China) Co., Ltd. Alanine aminotransferase (AST/ALT) test kit, Nanjing Institute of Bioengineering; Aspartate Transaminase (AST/GOT) test kit, Nanjing Institute of Bioengineering;
  • Multi-purpose low temperature high speed centrifuge Eppendorff, Germany; paraffin slicer, Lycra, Germany; frozen slicer, Lycra, Germany; En Vision multi-function microplate reader, PerkinElmer, USA; small animal anesthesia machine, American Matrx product; small animal magnetic Resonance Imager, Bruker PharmaScan 70T/16US, Germany.
  • the animals were raised in the Animal Experimental Center of the Institute of Materia Medica, Chinese Academy of Medical Sciences.
  • the feeding conditions were SPF, temperature 21 ⁇ 2°C, relative humidity 50 ⁇ 5%, photoperiod 12/112, and 5 per cage.
  • the normal group was given normal basal diet, and the high fat diet group was given high fat diet (79.8% basal diet plus 20% lard and 0.2% cholesterol).
  • the animals were free to eat and drink.
  • the feed was commissioned by Beijing Huakang Biotechnology Co., Ltd. Body weight was recorded every 2 weeks in the experiment.
  • liver tissue 100 mg was accurately weighed, triglyceride was added to detect the lysate, and the homogenizer was used to homogenize the tissue in an ice bath to no obvious tissue block. Place on ice for 5 min, transfer to a 1.5 ml centrifuge tube, centrifuge at 14000 g for 10 min at 4 ° C, transfer the supernatant, take a portion of the supernatant for protein quantification, and measure the lipid content according to the instructions of the TC and TG test kits.
  • the liver fixed with paraformaldehyde fixative was rinsed with tap water, dehydrated according to the following steps, 70% ethanol overnight, 80% ethanol overnight, 90% ethanol I30min, 90% ethanol II 30 min, 95% ethanol I60 min, 95% ethanol II 60 min, 100% ethanol I60min, 100% ethanol II 60min, normal tissue can prolong the dehydration time. After the tissue was dehydrated, it was super-transparent, ultra-safe I60min, super-anal II60min, and super-analthic III60min. The normal control group liver can prolong the transparent time. Immersion wax at 65 °C, paraffin wax I50min, paraffin wax 5050min, paraffin wax for 5050min, embedded, slice thickness 7um, 45 °C exhibit, 50 °C baked overnight.
  • the temperature of the slicer freezer was set to -19 ° C, and the sample head was set to -21 ° C.
  • the liver stored in liquid nitrogen or -80 °C is equilibrated with the temperature at -20 ° C, and the tissue is placed on the sampler of the microtome for temperature equilibration. After the tissue block was repaired, it was serially sliced, and the slice thickness was 7 ⁇ m, which was attached to a clean poly-lysine coated glass slide.
  • Frozen sections were fixed in 4% paraformaldehyde physiological solution for 10 min, rinsed with tap water for 2 min, washed with 60% isopropanol for several seconds, and stained with 0.5% oil red O in a dark-proof staining box for 10-15 min, 60% isopropyl The alcohol is separated by a few seconds, and the tap water is gently rinsed. Hematoxylin counterstaining for 3-5min, tap water gently rinse, 1% hydrochloric acid water, rinse with tap water for 2min, return to blue, glycerin gelatin seal, observed under the microscope.
  • paraffin section was dehydrated by the following steps: super-A5 min, super-ampere II 5 min, super-ampere III 5 min, 100% ethanol I3 min, 100% ethanol II 3 min, 95% ethanol I3 min, 95% ethanol II 3 min, 80% ethanol 3 min, tap water rinse for 1 min.
  • the serum TC, TG, LDL-C, HDL-C and FFA of the model group were significantly increased; compared with the model group, after IMM-H007, TC, TG, LDL- C, HDL-C and FFA were significantly reduced (Table 2 and Figure 2).
  • the HE staining results shown in Fig. 6 showed that the normal animal liver cells were arranged radially around the central vein, and the collagen fibers were regularly distributed in the central vein and other vessel walls.
  • the hepatocytes in the model group were vacuolated, and between the hepatocytes. Collagen fibers appeared, and the distribution was irregular. There were vacuoles in the liver cells of the simvastatin group, collagen fibers appeared between the liver cells, and showed irregular distribution.
  • Hepatocytes in each dose group of IMM-H007 were arranged radially around the central vein, and collagen fibers were regularly distributed in the central vein and hepatic lobule border areas.
  • IMM-H007 triacetyl-3-hydroxyphenyladenosine
  • IMM-H007 can significantly reduce the blood lipid levels of non-alcoholic fatty liver golden hamsters, significantly reduce AST, ALT levels, and significantly improve liver function. It is suggested that IMM-H007 can be used to prepare drugs for preventing or treating non-alcoholic fatty liver.

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PCT/CN2016/112623 2015-12-31 2016-12-28 三乙酰基-3-羟基苯基腺苷在制备预防或者治疗非酒精性脂肪肝药物中的应用 Ceased WO2017114413A1 (zh)

Priority Applications (9)

Application Number Priority Date Filing Date Title
CA3010097A CA3010097C (en) 2015-12-31 2016-12-28 Application of triacetyl-3-hydroxyphenyladenosine in preparation of pharmaceutical drug for preventing or treating non-alcoholic fatty liver disease
US16/067,228 US11058703B2 (en) 2015-12-31 2016-12-28 Application of triacetyl-3-hydroxyphenyladenosine in preparation of pharmaceutical drug for preventing or treating non-alcoholic fatty liver disease
AU2016383376A AU2016383376B2 (en) 2015-12-31 2016-12-28 Triacetyl-3-hydroxyphenyladenosine and application in preparing pharmaceutical drug for preventing or treating non-alcoholic fatty liver disease
KR1020187021547A KR102676056B1 (ko) 2015-12-31 2016-12-28 비알코올성 지방간 질환의 치료 또는 예방용 의약의 제조에서의 트리아세틸-3-하이드록시페닐아데노신의 용도
EP16881202.2A EP3398604A4 (en) 2015-12-31 2016-12-28 TRACETYL-3-HYDROXYPHENYLADENOSINE AND APPLICATION IN THE PREPARATION OF A PHARMACEUTICAL MEDICAMENT FOR PREVENTING OR TREATING NON-ALCOHOLIC FATERS
RU2018126158A RU2759916C2 (ru) 2015-12-31 2016-12-28 Применение триацетил-3-гидроксифениладенозина для получения фармацевтического лекарственного средства для предупреждения или лечения неалкогольной жировой болезни печени
HK18114837.8A HK1255689A1 (en) 2015-12-31 2016-12-28 Triacetyl-3-hydroxyphenyladenosine and application in preparing pharmaceutical drug for preventing or treating non-alcoholic fatty liver disease
JP2018533743A JP7382716B2 (ja) 2015-12-31 2016-12-28 非アルコール性脂肪性肝疾患（ｎａｆｌｄ）の予防または治療用医薬の調製におけるトリアセチル－３－ヒドロキシフェニルアデノシンの使用
ZA201805080A ZA201805080B (en) 2015-12-31 2018-07-27 Application of triacetyl-3-hydroxyphenyladenosine in preparation of pharmaceutical drug for preventing or treating non-alcoholic fatty liver disease

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US (1) US11058703B2 (enExample)
EP (1) EP3398604A4 (enExample)
JP (1) JP7382716B2 (enExample)
KR (1) KR102676056B1 (enExample)
CN (2) CN106943420A (enExample)
AU (1) AU2016383376B2 (enExample)
CA (1) CA3010097C (enExample)
HK (1) HK1255689A1 (enExample)
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EP3801496A4 (en) * 2018-06-05 2022-07-06 Flagship Pioneering Innovations V, Inc. ACTIVE AGENTS AND METHODS OF USE THEREOF FOR TREATING METABOLIC DISORDERS AND NAFLD
CN114869901A (zh) * 2022-05-06 2022-08-09 安徽医科大学 马鞭草苷在治疗酒精性肝损伤药物中的应用

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CN107334775A (zh) * 2016-03-14 2017-11-10 中国医学科学院药物研究所 三乙酰基-3-羟基苯基腺苷在制备治疗动脉粥样硬化药物中的应用
CN111821313A (zh) * 2019-04-17 2020-10-27 江苏天士力帝益药业有限公司 三乙酰基-3-羟基苯基腺苷在制备抑制心脏纤维化的药物中的应用
CN117599076A (zh) * 2023-11-15 2024-02-27 中国医学科学院药物研究所 三乙酰基-3-羟基苯基腺苷在制备运动模拟药物中的应用

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CN105663152A (zh) * 2014-11-19 2016-06-15 中国医学科学院药物研究所 三乙酰基-3-羟基苯基腺苷在制备改善胰岛素抵抗及相关疾病中的应用

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EP3801496A4 (en) * 2018-06-05 2022-07-06 Flagship Pioneering Innovations V, Inc. ACTIVE AGENTS AND METHODS OF USE THEREOF FOR TREATING METABOLIC DISORDERS AND NAFLD
US11813272B2 (en) 2018-06-05 2023-11-14 Flagship Pioneering Innovations V, Inc. Active agents and methods of their use for the treatment of metabolic disorders and nonalcoholic fatty liver disease
CN114869901A (zh) * 2022-05-06 2022-08-09 安徽医科大学 马鞭草苷在治疗酒精性肝损伤药物中的应用
CN114869901B (zh) * 2022-05-06 2023-10-27 安徽医科大学 马鞭草苷在治疗酒精性肝损伤药物中的应用

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