WO2012022101A1 - 二吲哚甲烷及前体和衍生物在制备治疗肝病药物中的应用 - Google Patents

二吲哚甲烷及前体和衍生物在制备治疗肝病药物中的应用 Download PDF

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WO2012022101A1
WO2012022101A1 PCT/CN2010/080348 CN2010080348W WO2012022101A1 WO 2012022101 A1 WO2012022101 A1 WO 2012022101A1 CN 2010080348 W CN2010080348 W CN 2010080348W WO 2012022101 A1 WO2012022101 A1 WO 2012022101A1
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methanol
indole
dimethane
derivatives
hydrazine
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PCT/CN2010/080348
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English (en)
French (fr)
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张峻峰
董磊
黄振
张正平
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南京大学
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Priority to EP10856099.6A priority Critical patent/EP2606887B1/en
Priority to JP2013524335A priority patent/JP5759000B2/ja
Publication of WO2012022101A1 publication Critical patent/WO2012022101A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals

Definitions

  • the invention belongs to the field of biomedical technology, and particularly relates to 3,3'-dioxane and indole-3-methanol and derivatives thereof for preparing for treating viral hepatitis, or alcoholic hepatitis, or drug-induced hepatitis, or fatty liver , or the application of drugs for liver fibrosis, or cirrhosis.
  • Hepatic fibrosis refers to the excessive deposition of diffuse extracellular matrix (especially collagen) in the liver. It is not an independent disease, many chronic liver diseases can cause liver fibrosis, and its etiology can be roughly divided into infectious (chronic hepatitis B, C and D viral hepatitis, schistosomiasis, etc.), congenital metabolic defects ( Hepatolenticular degeneration, hemochromatosis, ⁇ -antitrypsin deficiency, etc., chemical metabolic defects (chronic alcoholic liver disease, chronic drug-induced liver disease) and autoimmune hepatitis, primary biliary cirrhosis and primary Sclerosing cholangitis and the like.
  • infectious chronic hepatitis B, C and D viral hepatitis, schistosomiasis, etc.
  • congenital metabolic defects Hepatolenticular degeneration, hemochromatosis, ⁇ -antitrypsin deficiency, etc.
  • the clinical symptoms mainly include fatigue, loss of appetite, indigestion, bleeding, etc., and the course of the disease is unhealed, and even cancer may be possible.
  • the treatment of liver fibrosis mainly focused on glucocorticosteroids, colchicine, interferon, etc.
  • the traditional treatment has the disadvantages of unclear target, large side effects, easy recurrence after stopping the drug, and high cost.
  • liver fibrosis occurs mainly because hepatic stellate cells (HSC) are activated, and activated HSC can be transformed into myofibroblasts.
  • HSC hepatic stellate cells
  • ⁇ -SMA Actin
  • ECM extracellular matrix
  • Free radicals mainly include superoxide anion radicals (0 2 _), hydroxyl radicals (OH'_), hydrogen peroxide (H 2 0 2 ), etc.
  • liver fibrosis a large number of macrophages in the liver Secretion of free radicals, the danger of free radicals is that they can directly act on various signal molecules, promote the proliferation and activation of HSC, induce the occurrence of liver fibrosis, and on the other hand, attack the various membrane phase structures of hepatocytes, causing lipids.
  • the peroxidative chain reaction forms a series of lipid peroxides, which can cause the formation of liver fibrosis by affecting collagen metabolism.
  • 3,3'-Dimercaptomethane (DIM) and its parent compound ⁇ -3-methanol (I3C) were first reported to have anticancer effects.
  • Indole-3-carbinol (I3C) is very unstable in the gastric acid environment in the body, and a condensation reaction can be formed to form an oligomer 3,3'-dioxane.
  • 3,3'-dioxane has been reported in the literature to protect the body from free radical damage, it has not been reported to be used in the treatment of liver fibrosis.
  • the invention content has been reported in the literature to protect the body from free radical damage, it has not been reported to be used in the treatment of liver fibrosis.
  • the problem to be solved by the present invention is to disclose a small molecule drug which can effectively protect the body from free radical damage and thereby block the onset of liver fibrosis, and specifically relates to indole-3-methanol and diterpene methane and derivative compounds. And the treatment of its aqueous solution preparation in liver fibrosis.
  • the present invention provides a compound having the following structure:
  • the R1, R2, R4, R5, R6, and R7 positions of the compound may be a hydrogen atom, respectively, or a substituent selected from the group consisting of halogen, nitro, and main chain.
  • the linear or branched alkane or alkoxy group having from one to five carbon atoms is preferably one to ten carbon atoms, and the above compound has at least one substituent.
  • R1, R2, R4, R6, and R7 are hydrogen atoms
  • R5 is a halogen selected from the group consisting of chlorine, bromine, and fluorine.
  • preferred I3C derivatives include 5-chloro-indole-3-methanol, 5-bromo-indol-3-methanol, 5-fluoro-indole-3-methanol.
  • Other preferred I3C derivatives include those wherein R1, R2, R4, R6, R7 are hydrogen atoms, and R5 is an alkane or alkoxy group of one to five carbon atoms, preferably one to ten carbon atoms.
  • These compounds include, but are not limited to, 5-methyl-indole-3-methanol, 5-ethyl-indole-3-methanol, 5-propyl ⁇ ⁇ - 3 -methanol, 5 -butyl ⁇ - 3 - Methanol, 5-pentyl-indole-3-methanol.
  • These compounds also include, but are not limited to: 5-methoxy-indole-3-methanol, 5-ethoxy-indole-3-methanol, 5-propoxy-indole-3-methanol, 5-butyl Oxy-indole-3-methanol, 5-pentyloxy-indole-3-methanol.
  • I3C derivatives include compounds wherein R2, R4, R5, R6, and R7 are hydrogen atoms, and R1 is an alkane or alkoxy group of one to five carbon atoms, preferably one to ten carbon atoms.
  • R2 R4, R5, R6, and R7 are hydrogen atoms
  • R1 is an alkane or alkoxy group of one to five carbon atoms, preferably one to ten carbon atoms.
  • These compounds include, but are not limited to: N-methyl-indole-3-methanol, N-ethyl-indole-3-methanol, N-propyl-indole-3-methanol, N-butyl-hydrazine 3-Methanol, N-pentyl-indole-3-methanol.
  • Still another class of derivatives of I3C includes R1, R4, R5, R6, a compound wherein R7 is a hydrogen atom and R2 is an alkane or alkoxy group of one to five carbon atoms, preferably one to ten carbon atoms.
  • R1, R2, R4, R6, R7 are hydrogen atoms and R5 is a nitro group.
  • the invention also provides a compound having the structure:
  • the R1, R2, R4, R5, R6, R7, Rl', R2', R4', R5', R6' and R7' positions of this compound may each be a hydrogen atom or a group selected from the group below.
  • a substituent group which includes a halogen, a nitro group, and a linear or branched alkane or alkoxy group having a main chain length of about one to ten carbon atoms and preferably one to five carbons, and the above compound has at least one substituent.
  • Halogen is selected from the group consisting of chlorine, bromine and fluorine. Such compounds are referred to as DIM derivatives or DIM analogs.
  • Rl, R2, R4, R6, R7, Rl', R2', R4', R6' and R7' are hydrogen atoms, and R5 and R5' are one from chlorine, bromine, and fluorine.
  • preferred DIM derivatives include 5,5'-dichloro-diindenyl methane; 5,5'-dibromo-dioxane;5,5'-difluoro-diindo methane.
  • Rl, R2, R4, R6, R7, Rl', R2', R4', R6' and R7' are hydrogen atoms, and R5 and R5' are preferred for one to ten carbon atoms.
  • DIM derivatives include R2, R4, R5, R6, R7, R2', R4', R5', R6' and R7' are hydrogen atoms, and Rl and Rl' are preferred for one to ten carbon atoms.
  • Rl, R4, R5, R6, R7, Rl', R4', R5', R6' and R7' are hydrogen atoms, and R2 and R2' are preferred for one to ten carbon atoms.
  • R1, R2, R4, R6, R7, Rl', R2', R4', R6' and R7' are hydrogen atoms
  • R5 and P R5' are nitro groups.
  • anthracene derivatives include, but are not limited to: 5-methoxy, 5-chloro, 5-bromo, 5-fluoro, 5'-methyl, 5-nitro, N-methyl and 2-methylindole .
  • the substituted indole-3-acetaldehyde product is reduced by treatment with a suitable alcohol such as methanol and sodium borohydride to give a substituted derivative of I3C.
  • the substituted derivative of DIM is synthesized by condensing a substituted product of indole-3-methanol, which can be achieved by, for example, a phosphate buffer solution having a pH of about 5.5.
  • the present invention also provides a pharmaceutical preparation comprising a biologically active dose of a compound having the following structure:
  • the R1, R2, R4, R5, R6, and R7 positions of the compound may be a hydrogen atom, respectively, or a substituent selected from the group consisting of halogen, nitro, and main chain.
  • the linear or branched alkane or alkoxy group having from one to five carbon atoms is preferably one to ten carbon atoms, and the above compound has at least one substituent.
  • Halogen is selected from the group consisting of chlorine, bromine and fluorine.
  • Another object of the present invention is to provide a method of treating liver fibrosis by administering a biologically active dose of the following compounds:
  • the R1, R2, R4, R5, R6, and R7 positions of the compound may be a hydrogen atom, respectively, or a substituent selected from the group consisting of halogen, nitro, and main chain.
  • Halogen is selected from the group consisting of chlorine, bromine and fluorine.
  • the present invention also provides a pharmaceutical preparation comprising a biologically active dose of a compound having the following structure:
  • the R1, R2, R4, R5, R6, R7, Rl', R2', R4', R5', R6' and R7' positions of this compound may each be a hydrogen atom or a group selected from the group below.
  • a substituent group which includes a halogen, a nitro group, and a linear or branched alkane or alkoxy group having a main chain length of about one to ten carbon atoms and preferably one to five carbons, and the above compound has at least one substituent.
  • Halogen is selected from the group consisting of chlorine, bromine and fluorine.
  • a still further object of the present invention is to provide a method of treating liver fibrosis by administering a biologically active dose of the following compounds:
  • the R1, R2, R4, R5, R6, R7, Rl', R2', R4', R5', R6' and R7' positions of this compound may each be a hydrogen atom or a group selected from the group below.
  • a substituent group which includes a halogen, a nitro group, and a linear or branched alkane or alkoxy group having a main chain length of about one to ten carbon atoms and preferably one to five carbons, and the above compound has at least one substituent.
  • Halogen is selected from the group consisting of chlorine, bromine and fluorine.
  • the agent of the present invention can be administered by buccal, intravenous, nasal, rectal or any other means which can deliver an effective amount of the active substance. Suitable dosages are those which provide the desired final amount. Different doses may also be required to treat different diseases. An effective amount of the agent is an amount which results in a significant decrease in the degree of liver fibrosis.
  • the active agent can be administered by a pharmaceutical carrier or diluent.
  • Reagents provided by this invention can also be administered in combination with other agents such as chemotherapy or immunostimulating drugs or therapeutic agents.
  • Examples of pharmaceutical carriers or diluents suitable for use in this invention include any physiological buffer in which a water-soluble organic vehicle is dissolved, such as a cyclodextrin phosphate buffer and other buffers containing a suitable water-soluble organic carrier at pH 7.0 to 7.4. liquid.
  • Suitable water soluble organic vehicles include, but are not limited to, cyclodextrins, corn oil, DMSO, capsules and the like.
  • This invention is exemplified by a model of liver fibrosis in vivo.
  • Animals herein include, but are not limited to: mice, rats, domesticated animals including, but not limited to, cats, dogs, and other animals such as, but not limited to, cows, sheep, pigs, horses, primates such as, but not limited to, monkeys and people.
  • In vivo detection of a mouse liver fibrosis model is a widely accepted and accepted model for detecting in vivo drug activity, and can also be used as a reference for other organisms such as humans, but not limited to humans.
  • a TAA-type liver fibrosis model was established by intraperitoneal injection of a phosphate buffer solution of thioacetamide (TAA) in ICR mice.
  • TAA thioacetamide
  • TAA and ⁇ -3-methanol and di-methane and its derivative compounds were administered twice a week. After 4 weeks of administration, the mice were sacrificed, and the liver was taken out for hydroxyproline determination and alanine aminotransferase assay.
  • a TAA-type liver fibrosis model was established by intraperitoneal injection of a phosphate buffer solution of thioacetamide (TAA) in ICR mice.
  • TAA thioacetamide
  • the prepared aqueous injection preparation of ⁇ -3-methanol and di-methane and its derivative compounds was injected simultaneously with the establishment of a TAA-type fibrosis model to treat liver fibrosis.
  • TAA and ⁇ -3-methanol and di-methane and its derivative compounds were administered twice a week. After 4 weeks of administration, the mice were sacrificed, and the liver was taken out for hydroxyproline determination and alanine aminotransferase assay.
  • the effective result of the present invention is to provide a new method for treating liver fibrosis by administering ⁇ -3- ⁇ Alcohols and diterpene methane and derivatives thereof and related aqueous injection formulations protect the body from free radical damage, thereby inhibiting and blocking the onset of liver fibrosis.
  • the small molecule drugs used in the present invention are easy to obtain, inexpensive, stable in nature, and easy to store and transport.
  • Anthraquinone derivatives eg, 5-methoxy, 5-chloro, 5-bromo, 5-fluoro, 5'-methyl, 5-nitro, N-methyl and 2-methylindole
  • a suitable alcohol such as methanol and sodium borohydride
  • the substituted indole-3-acetaldehyde product is reduced by using a suitable alcohol such as methanol and sodium borohydride to obtain a substituted derivative of I3C.
  • 2.9 ml of dimethylformamide was cooled to 0 ° C through an ice salt bath, and then 0.86 ml of phosphorus oxychloride (time greater than 30 min) was slowly added.
  • the Og ⁇ -3-acetaldehyde derivative was dissolved in 5.0 ml of methanol, and solid sodium borohydride was continuously added until all of the aldehyde groups were reduced. Then 50 ml of H 2 O was added to the reaction, which was cooled to 0 ° C, filtered to give the I3C derivative, which was dried in vacuo in vacuo.
  • the lg I3C derivative was added to pH 5.5 phosphate buffer, stirred at room temperature for 6 h, and the whole reaction was detected by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the DIM derivative was filtered, dried in vacuo, and placed in the dark (yield: 80% to 90%). The yield was confirmed by gas chromatography, liquid chromatography and thin layer chromatography.
  • mice I3C, DIM, and methoxy DIM were dissolved in corn oil and formulated into a 2.0 mg/ml stock solution for use.
  • the mouse model of TAA-type liver fibrosis was established according to the literature report method. 40 male ICR mice, weighing 16-18 g, were randomly divided into four groups: TAA model group, I3C treatment group, DIM treatment group, 5- In the methoxy DIM treatment group, each group of mice was intraperitoneally injected with TAA phosphate buffer (200 mg/kg) twice a week. The model was established at the beginning of the week.
  • the I3C treatment group, the DIM treatment group, and the 5-methoxy DIM treatment group were intragastrically administered at 20 mg/kg, and the TAA model group was given the corresponding amount of corn oil twice a week. After the model was established for four weeks, the liver tissue was taken and the hydroxyproline assay and alanine aminotransferase assay were performed. (1) Liver hydroxyproline assay
  • the supernatant of the diseased liver tissue was taken and the supernatant was taken, and the hydroxyproline content was determined by alkaline hydrolysis.
  • Mouse serum was taken and the alanine aminotransferase content was determined.
  • liver fibrosis the main component of the liver is collagen fiber, and hydroxyproline is unique to collagen fiber.
  • hydroxyproline is unique to collagen fiber.
  • the content of hepatic hydroxyproline reflects the degree of liver fibrosis to some extent. It can be seen from Table 1 that oral administration of I3C and DIM and its derivative compounds can effectively alleviate the onset of liver fibrosis in mice.
  • the hydroxyproline value of the treatment group is significantly lower than that of the TAA model group.
  • Alanine aminotransferase is mainly present in the hepatocyte cytoplasm, and its intracellular concentration is higher than 1000-3000 times in serum.
  • liver fibrosis develops to a large amount of hepatocyte necrosis in the later stage. Therefore, it can also be used as an indicator to measure liver fibrosis.
  • Table 1 after treatment, the alanine aminotransferase value of the treatment group was significantly lower than that of the TAA model group. It can be seen that I3C and DIM and their derivative compounds can significantly reduce hepatocyte necrosis, delay the onset of liver fibrosis, and reduce disease damage.
  • mice were randomly divided into four groups, that is, the mice were randomly divided into four groups, namely, TAA model group, I3C treatment group, DIM treatment group, 5-methoxy DIM treatment. group.
  • the model was established for the week, and the I3C treatment group, the DIM treatment group, and the 5-methoxy DIM treatment group were injected with DIM at 20 mg/kg, and the TAA model group was given the same amount of physiological saline twice a week.

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Description

二吲哚甲垸及前体和衍生物在制备治疗肝病药物中的应用
一、 技术领域
本发明属于生物医药技术领域, 具体涉及 3,3'-二吲哚甲烷和吲哚 -3-甲醇及其衍 生化合物在制备治疗病毒性肝炎, 或酒精性肝炎, 或药物性肝炎, 或脂肪肝, 或 肝纤维化, 或肝硬化的药物中的应用。
二、 背景技术
肝纤维化是指肝脏内弥漫性细胞外基质 (特别是胶原)过度沉积。 它不是一个 独立的疾病,许多慢性肝脏疾病均可引起肝纤维化,其病因大致可分为感染性 (慢 性乙型、 丙型和丁型病毒性肝炎, 血吸虫病等), 先天性代谢缺陷 (肝豆状核变 性、 血色病、 αΐ-抗胰蛋白酶缺乏症等), 化学代谢缺陷 (慢性酒精性肝病、 慢性 药物性肝病)以及自身免疫性肝炎、原发性胆汁性肝硬化和原发性硬化性胆管炎 等。 其临床症状主要包括疲乏无力、 食欲减退、 消化不良、 出血等, 而且病程迁 延不愈, 甚至有癌变可能。针对肝纤维化治疗过去主要集中在糖皮质类固醇、秋 水仙素、 干扰素等, 但是传统的治疗存在靶点尚不明确, 副作用较大, 停药后易 复发, 成本较高等缺点。
近年来研究表明肝纤维化的发生主要是由于肝星状细胞 (Hepatic stellate cell HSC)被激活, 激活的 HSC可以转化为成肌纤维细胞 (myofibroblast), 其重要标志 之一是开始表达平滑肌 α-肌动蛋白 (α-SMA), 并大量表达分泌 I型胶原, 导致胞 外基质(extracellular matrix, ECM) 的合成与降解失衡, 造成大量的胶原在细胞 外沉积。 自由基主要包括超氧阴离子自由基 (02 _)、 羟自由基 (OH'_)、 过氧化 氢 (H202) 等, 在肝纤维化发生过程中, 肝脏中的巨噬细胞大量分泌自由基, 自由基的危害在于其一方面可以直接作用于各种信号分子, 促使 HSC增殖活化, 诱导肝纤维化的发生, 另一方面还能攻击肝细胞的各种膜相结构, 引起脂质过氧 化链式反应, 形成一系列脂质过氧化物, 而脂质过氧化物质可通过影响胶原代谢 导致肝纤维化的形成。3,3'-二吲哚甲烷(DIM)及其母体化合物吲哚 -3-甲醇(I3C) 最早被报道具有抗癌作用。 吲哚 -3-甲醇 (I3C) 在体内胃酸环境中很不稳定, 可 发生缩合反应形成低聚物 3,3'-二吲哚甲烷。 3,3'-二吲哚甲烷虽有文献报道其可以 保护机体免受自由基损伤, 但尚未有将其用于治疗肝纤维化的相关研究结果报 道。 三、 发明内容
本发明需要解决的问题就是公开了一类可以有效保护机体免受自由基损伤, 从而阻断肝纤维化发作的小分子药物, 具体涉及到吲哚 -3-甲醇和二吲哚甲烷以 及衍生化合物以及其水溶液注射制剂在肝纤维化中的治疗。
本项发明提供的是具有以下结构的化合物:
Figure imgf000003_0001
这种化合物的 Rl, R2, R4, R5, R6, R7位可以分别是一个氢原子, 或者 是一个选自以下基团组的取代基, 这个基团组包括卤素, 硝基, 和主链长约一到 十个碳原子首选一到五个碳原子的直链或者支链的烷或烷氧基,上述的化合物至 少有一个取代基。
在首选的 I3C衍生物中, Rl, R2, R4, R6, R7上是氢原子, R5是一个选 自氯, 溴, 氟的卤素。 相应的, 首选的 I3C衍生物包括 5-氯 -吲哚 -3-甲醇, 5-溴- 吲哚 -3-甲醇, 5-氟 -吲哚 -3-甲醇。 其他的首选 I3C衍生物包括 Rl, R2, R4, R6, R7上是氢原子, R5为一到十个碳原子首选一到五个碳原子的烷或烷氧基的化合 物。 这些化合物包括但是不限于: 5-甲基 -吲哚 -3-甲醇, 5-乙基 -吲哚 -3-甲醇, 5- 丙基』引哚 -3-甲醇, 5-丁基』引哚 -3-甲醇, 5-戊基 -吲哚 -3-甲醇。 这些化合物还包 括但是不限于: 5-甲氧基 -吲哚 -3-甲醇, 5-乙氧基 -吲哚 -3-甲醇, 5-丙氧基 -吲哚 -3- 甲醇, 5-丁氧基 -吲哚 -3-甲醇, 5-戊氧基 -吲哚 -3-甲醇。 其他的首选 I3C衍生物包 括 R2, R4, R5, R6, R7上是氢原子, R1为一到十个碳原子首选一到五个碳原 子的烷或烷氧基的化合物。 这些化合物包括但是不限于: N-甲基 -吲哚 -3-甲醇, N-乙基 -吲哚 -3-甲醇, N-丙基 -吲哚 -3-甲醇, N-丁基 -吲哚 -3-甲醇, N-戊基 -吲哚 -3- 甲醇。 还有一类 I3C的衍生物包括 Rl, R4, R5, R6, R7上是氢原子, R2为一 到十个碳原子首选一到五个碳原子的烷或烷氧基的化合物。这些化合物包括但是 不限于: 2-甲基 -吲哚 -3-甲醇, 2-乙基 -吲哚 -3-甲醇, 2-丙基 -吲哚 -3-甲醇, 2-丁基 -吲哚 -3-甲醇, 2-戊基 -吲哚 -3-甲醇。 在另一种结构中, Rl, R2, R4, R6, R7上 是氢原子, R5是硝基。 本项发明还提供了一个具有如下结构的化合物:
Figure imgf000004_0001
这个化合物的 Rl, R2, R4, R5, R6, R7, Rl', R2', R4', R5', R6'和 R7' 位可以分别是一个氢原子, 或者是一个选自以下基团组的取代基,这个基团组包 括卤素,硝基,和主链长约一到十个碳首选一到五个碳的直链或者支链的烷或烷 氧基, 上述的化合物至少有一个取代基。 卤素由氯, 溴, 氟的组合中选出。 这样 的化合物被称作 DIM衍生物或者 DIM类似物。
在首选的 DIM衍生物中, Rl, R2, R4, R6, R7, Rl', R2', R4', R6'和 R7' 位是氢原子, R5和 R5'是一个由氯, 溴, 氟的组合中选出的卤素。 相应的, 首选 的 DIM衍生物包括 5, 5'-二氯-二吲哚甲烷; 5, 5'-二溴-二吲哚甲烷; 5, 5'-二氟- 二吲哚甲烷。 其他的首选 DIM衍生物包括 Rl, R2, R4, R6, R7, Rl', R2', R4', R6'和 R7'位是氢原子, R5和 R5'是一到十个碳原子首选一到五个碳原子的 烷或烷氧基的化合物。 这些化合物包括但是不限于: 5, 5'-二甲基-二吲哚甲烷; 5, 5'-二乙基-二 D引哚甲烷; 5, 5'-二丙基-二 D引哚甲烷; 5, 5'-二丁基-二 D引哚甲烷; 5, 5'-二戊基-二吲哚甲烷。 其他首选的 DIM衍生物包括 R2, R4, R5, R6, R7, R2', R4', R5', R6'和 R7'位是氢原子, Rl和 Rl'是一到十个碳原子首选一到五个 碳原子的烷或烷氧基的化合物。这些化合物包括但是不限于: Ν, Ν'-二甲基 -二吲 哚甲烷; Ν, Ν'-二乙基-二吲哚甲烷; Ν, Ν'-二丙基-二吲哚甲烷; Ν, Ν'-二丁基- 二吲哚甲烷; Ν, Ν'-二戊基-二吲哚甲烷。另一种首选的 DIM衍生物包括 Rl, R4, R5, R6, R7, Rl', R4', R5', R6'和 R7'位是氢原子, R2和 R2'是一到十个碳原 子首选一到五个碳原子的烷或烷氧基的化合物。 这些化合物包括但是不限于: 2, 2'—二甲基-二吲哚甲烷; 2, 2'-二乙基-二吲哚甲烷; 2, 2'-二丙基-二吲哚甲烷; 2, T- 二丁基-二吲哚甲焼; 2, 2'-二戊基-二吲哚甲烷。 在另一种结构中, Rl, R2, R4, R6, R7, Rl', R2', R4', R6'和 R7'位是氢原子, R5禾 P R5'是硝基。
使用商业上可得的吲哚取代物来合成 I3C的取代衍生物可能是获得这些化合 物最便捷的方法。 DIM的衍生物同样可以通过甲醛缩合吲哚取代物的方法制备。 然而, 后者的劣势在于副产物的形成使得分离纯化所需要的 DIM衍生物更为复 杂。本专利提供的化合物通过二甲基甲酰胺缩合一种合适的吲哚取代物来制备取 代了的吲哚 -3-乙醛。 合适的吲哚衍生物在 Rl, R2, R4, R5, R6, R7位上有取 代基。 这些吲哚衍生物包括但是不限于: 5-甲氧基, 5-氯, 5-溴, 5-氟, 5'-甲基, 5-硝基, N-甲基和 2-甲基吲哚。 被取代的吲哚 -3-乙醛产物通过使用一种合适的 醇如甲醇以及硼氢化钠处理还原其醛基从而得到 I3C的取代衍生物。 DIM的取 代衍生物通过缩合吲哚 -3-甲醇的取代产物加以合成,这可以通过采取例如 PH值 5.5左右的磷酸盐缓冲液处理等方法实现。
本项发明还提供了一种由具有生物活性的剂量的有以下结构的化合物构成 的药物制剂:
Figure imgf000005_0001
这种化合物的 Rl, R2, R4, R5, R6, R7位可以分别是一个氢原子, 或者 是一个选自以下基团组的取代基, 这个基团组包括卤素, 硝基, 和主链长约一到 十个碳原子首选一到五个碳原子的直链或者支链的烷或烷氧基,上述的化合物至 少有一个取代基。 卤素由氯, 溴, 氟的组合中选出。
本项发明的另一个目标在于通过给予具有生物活性的剂量的以下化合物提 供一种肝纤维化的治疗方法:
Figure imgf000005_0002
这种化合物的 Rl, R2, R4, R5, R6, R7位可以分别是一个氢原子, 或者 是一个选自以下基团组的取代基, 这个基团组包括卤素, 硝基, 和主链长约一到 十个碳原子首选一到五个碳原子的直链或者支链的烷或烷氧基 上述的化合物至 少有一个取代基。 卤素由氯, 溴, 氟的组合中选出。 本项发明还提供了一种由具有生物活性剂量的有以下结构的化合物构成的 药物制剂:
Figure imgf000006_0001
这个化合物的 Rl, R2, R4, R5, R6, R7, Rl', R2', R4', R5', R6'和 R7' 位可以分别是一个氢原子, 或者是一个选自以下基团组的取代基,这个基团组包 括卤素,硝基,和主链长约一到十个碳首选一到五个碳的直链或者支链的烷或烷 氧基, 上述的化合物至少有一个取代基。 卤素由氯, 溴, 氟的组合中选出。
本项发明的更进一步的目标在于通过给予具有生物活性的剂量的以下化合 物提供一种治疗肝纤维化的方法:
Figure imgf000006_0002
这个化合物的 Rl, R2, R4, R5, R6, R7, Rl', R2', R4', R5', R6'和 R7' 位可以分别是一个氢原子, 或者是一个选自以下基团组的取代基,这个基团组包 括卤素,硝基,和主链长约一到十个碳首选一到五个碳的直链或者支链的烷或烷 氧基, 上述的化合物至少有一个取代基。 卤素由氯, 溴, 氟的组合中选出。
本项发明的这个试剂可以通过口腔, 静脉, 鼻腔, 直肠或其他任何可以输送 有效剂量的活性物质的方式给药。合适的剂量是那些能得到所需要的最终量的剂 量。而治疗不同的疾病也可能需要不同的剂量。该试剂的有效量是能导致肝纤维 化程度明显降低的量。
具有常规技术的研究人员将能够确定本项发明所提供的试剂的最有效的给 药剂量和时间考虑给药方式, 药物代谢, 以及其他一些药代动力学参数例如药物 分布, 清除率等。
活性的试剂可以通过一个药物载体或者稀释液给药。这项发明所提供的试剂 还可以和其他试剂例如化疗或者免疫激活药物或者治疗药物联合给药。对这项发 明适用的药物载体或者稀释液的实例包括任何溶有水溶性有机载体的生理缓冲 液, 例如环糊精磷酸盐缓冲液以及 pH7.0到 7.4的含有合适的水溶性有机载体其 它缓冲液。 合适的水溶性有机载体包括但是不限于环糊精, 玉米油, DMSO, 胶 囊等。
这项发明通过体内对肝纤维化模型进行例证。 此处的动物包括但是不限于: 小鼠, 大鼠, 驯养动物包括但是不限于猫, 狗, 以及其它一些动物例如但是不限 于牛, 羊, 猪, 马, 灵长类动物例如但是不限于猴子和人。 小鼠肝纤维化模型的 体内检测是被广泛认可和接受的体内药物活性检测的模型,同时也可以为其它生 物例如人, 但是不仅限于人提供参考。
下面的例子用以解释这项发明的具体细节, 但是不应被视作对这项发明的功 能范围的限定。
本发明所述的吲哚 -3-甲醇和二吲哚甲烷及其衍生化合物在肝纤维化治疗中 的应用:
1. 使用硫代乙酰胺( thioacetamide, TAA)的磷酸缓冲溶液于 ICR小鼠腹腔注射, 建立 TAA型肝纤维化模型。
2. 将吲哚 -3-甲醇和二吲哚甲烷及其衍生化合物溶解到玉米油中, 在建立 TAA 型肝纤维化模型同时进行灌胃, 对肝纤维化进行治疗。
3. TAA与吲哚 -3-甲醇和二吲哚甲烷及其衍生化合物每周给药 2次,给药 4周后 处死小鼠, 取出肝脏分别做羟脯氨酸测定以及谷丙转氨酶测定。
本发明所述的吲哚 -3-甲醇和二吲哚甲烷及其衍生化合物的水溶液注射制剂 在肝纤维化模型治疗中的应用:
1. 使用硫代乙酰胺( thioacetamide, TAA)的磷酸缓冲溶液于 ICR小鼠腹腔注射, 建立 TAA型肝纤维化模型。
2. 将配制好的吲哚 -3-甲醇和二吲哚甲烷及其衍生化合物的水溶液注射制剂在 建立 TAA型纤维化模型同时进行注射, 对肝纤维化进行治疗。
3. TAA与吲哚 -3-甲醇和二吲哚甲烷及其衍生化合物每周给药 2次,给药 4周后 处死小鼠, 取出肝脏分别做羟脯氨酸测定以及谷丙转氨酶测定。
本发明的有效成果是提供一种新的治疗肝纤维化的方法, 通过给予吲哚 -3-甲 醇和二吲哚甲烷及其衍生化合物以及相关的水溶液注射制剂来保护机体免受自 由基损伤, 从而抑制和阻断肝纤维化的发作。 同时, 本发明所使用的小分子药物 易于获取, 价格低廉, 性质稳定, 便于保存和运输。
四、 具体实施方式
1. 吲哚 -3-甲醇和二吲哚甲烷及其衍生化合物的准备
吲哚类衍生物 (比如, 5-甲氧基, 5-氯, 5-溴, 5-氟, 5'-甲基, 5-硝基, N- 甲基和 2-甲基吲哚) 可以通过商业购买获得 (南京锐马精细化工有限公司), 被 取代的吲哚 -3-乙醛产物通过使用一种合适的醇比如甲醇以及硼氢化钠来还原醛 基得到 I3C的取代衍生物。 通过冰盐浴将 2.9ml二甲基甲酰胺冷却至 0°C, 然后 缓慢加入 0.86ml磷酰氯(时间大于 30min)。将 8.6mmol吲哚类衍生物溶解在 1.0ml 的二甲基甲酰胺,然后将其缓慢加入到前面已经冷却的磷酰氯溶液中(时间大于 lOmin), 所形成的悬浮液, 37°C加热 60min-90min, 直至澄清的黄色溶液变成微 黄色的糊状物。然后向此糊状物中加入 1ml的冰水,再缓慢加入 10ml含有 3.75g KOH的水溶液 (时间大于 30min)。 将此混合物加热至沸点后冷却。 过滤得到吲 哚 -3-乙醛衍生物, 水洗, 空气中干燥。 所得的产物用于准备 I3C的衍生物。
l.Og吲哚 -3-乙醛衍生物溶于 5.0ml的甲醇, 持续加入固体硼氢化钠, 直至所 有的醛基均被还原。 然后向反应物中加入 50mlH2O, 冷却至 0°C, 过滤得到 I3C衍生物, 暗处真空干燥。
lg I3C衍生物加入到 pH5.5磷酸盐缓冲液, 室温搅拌 6h, 整个反应过程通过 薄层层析(TLC)加以检测。 过滤得到 DIM衍生物, 真空干燥, 放置于暗处(得 率 80%-90%), 得率经气相色谱, 液相色谱以及薄层层析加以确认。
2.口服 I3C和 DIM及其衍生化合物对 TAA导致的小鼠肝纤维化模型的治疗
将 I3C、 DIM, 甲氧基 DIM用玉米油溶解, 配成 2.0mg/ml储液备用。 按照 文献报道方法建立小鼠 TAA型肝纤维化模型, 即取雄性 ICR小鼠 40只, 体重 16-18g, 将小鼠随机分成四组即 TAA模型组、 I3C治疗组、 DIM治疗组、 5-甲氧 基 DIM治疗组, 每组小鼠腹腔注射 TAA的磷酸缓冲液 (200mg/kg), 每周给药 两次。 建立模型当周开始治疗, I3C治疗组、 DIM治疗组、 5-甲氧基 DIM治疗 组按 20mg/kg灌胃给药, TAA模型组给相应量的玉米油, 每周给药两次。 模型 建立四周后处死, 取病变肝脏组织, 做羟脯氨酸测定和谷丙转氨酶测定。 ( 1 ) 肝脏羟脯氨酸测定
取病变肝脏组织匀浆后取上清, 采用碱水解法测定羟脯氨酸含量。
(2) 肝脏谷丙转氨酶结果
取小鼠血清, 测定谷丙转氨酶含量。
肝纤维化时,肝内主要增加的成分为胶原纤维,羟脯氨酸为胶原纤维所特有, 为此肝羟脯氨酸的含量在一定程度上反应了肝纤维化的程度。由表 1可以发现口 服 I3C和 DIM及其衍生化合物可以有效缓解小鼠肝纤维化发作, 治疗组的羟脯 氨酸值明显低于 TAA模型组。 谷丙转氨酶主要存在于肝细胞浆内, 其细胞内浓 度高于血清中 1000-3000倍, 当肝细胞坏死时, 血清中谷丙转氨酶含量会大幅上 升, 而肝纤维化发展到后期肝细胞大量坏死,所以也可以作为衡量肝纤维化的指 标。 由表 1可见, 经过治疗, 治疗组的谷丙转氨酶值明显低于 TAA模型组。 由 此可见, I3C和 DIM及其衍生化合物可以显著减少肝细胞坏死, 延缓肝纤维化 发作, 减轻疾病损害。
表 1 肝脏羟脯氨酸以及血清中谷丙转氨酶活力测定
5-甲氧基 DIM治疗 组别 TAA模型组 13 C治疗组 DIM治疗组
组 羟脯氨酸 ( g/g liver) 356±43 237±11* 176±21* 194±17* 谷丙转氨酶 (U/mgprot) 372±24 245±32* 204±37* 236±12* 数据均以平均值±标准差的形式加以显示, 显著性差异通过 ANOVA检验加 以确定。
*代表 P<0.05
3. DC和 DIM及其衍生化合物的水溶液注射制剂对 TAA导致的小鼠肝纤维化模 型的治疗
将 I3C、 DIM, 甲氧基 DIM用环糊精和生理盐水配制成 1.0mg/kg的储液备 用。 小鼠 TAA肝纤维化模型建立参照实施 1, 建模当日, 将小鼠随机分成四组 即将小鼠随机分成四组即 TAA模型组、 I3C治疗组、 DIM治疗组、 5-甲氧基 DIM 治疗组。 建立模型当周开始治疗, I3C治疗组、 DIM治疗组、 5-甲氧基 DIM治 疗组按 20mg/kg注射给 DIM, TAA模型组给同等量的生理盐水, 每周给药两次。
模型建立四周后处死, 取病变肝脏组织, 做羟脯氨酸测定和谷丙转氨酶测定。羟 脯氨酸测定和谷丙转氨酶测定见实施 1。
如表 2所示, 腹腔注射 I3C和 DIM及其衍生化合物的水溶液注射制剂同样可以 减缓小鼠肝纤维化发作。
表 2肝脏羟脯氨酸以及血清中谷丙转氨酶活力测定
5-甲氧基 DIM治疗 组别 TAA模型组 13 C治疗组 DIM治疗组
组 羟脯氨酸 ( g/g liver) 363±32 253±21* 195±24* 203±14* 谷丙转氨酶 (U/mgprot) 392±31 239±21* 187±29* 226±19* 数据均以平均值±标准差的形式加以显示, 显著性差异通过 ANOVA检验加 以确定。
*代表 P<0.05
上述实例用以解释这项发明的具体细节, 但是不应被视作对这项发明的功能 范围的限定。

Claims

权利 要 求 书
1. 一种 3, 3'-二吲哚甲烷及其衍生物在制备治疗病毒性肝炎, 或酒精性肝炎, 或药物性肝炎, 或脂肪肝, 或肝纤维化, 或肝硬化的药物中的应用, 小分子 化合物 3, 3'-二吲哚甲烷及其衍生物的结构如下:
Figure imgf000011_0001
其中 R, R2, , R5, Re, R7, Ri', R2', ', R5', 和 R7'是氢原子, 或 卤素, 或硝基, 或主链长约一到十个碳的直链或者支链的烷或烷氧基。
2. 根据权利要求 1所述, 直链或者支链烷或烷氧基其特征是一到五个碳原子。
3. 根据权利要求 1所述, 卤素为氯, 或溴, 或氟。
4. 根据权利要求 1所述,小分子化合物 3,3'-二吲哚甲烷及其衍生物为 5,5'-二氯 -二吲哚甲烷, 或 5,5'-二溴-二吲哚甲烷, 或 5,5'-二氟-二吲哚甲烷, 或 5,5'- 二甲基-二吲哚甲烷, 或 5,5'-二乙基-二吲哚甲烷, 或 5, 5'-二丙基-二吲哚甲 烷, 或 5,5'-二丁基-二吲哚甲烷, 或 5,5'-二戊基-二吲哚甲烷, 或 5,5'-二甲氧 基-二吲哚甲焼,或 5,5'-二乙氧基-二吲哚甲焼,或 5,5'-二丙氧基-二吲哚甲焼, 或 5,5'-二丁氧基-二吲哚甲烷, 或 5,5'-二戊氧基-二吲哚甲烷, 或 Ν,Ν'-二甲 基-二吲哚甲烷, 或 Ν,Ν'-二乙基-二吲哚甲烷, 或 Ν,Ν'-二丙基-二吲哚甲烷, 或 Ν,Ν'-二丁基-二吲哚甲烷, 或 Ν,Ν'-二戊基-二吲哚甲烷, 或 2,2'-二甲基- 二吲哚甲烷,或 2,2'-二乙基 -二吲哚甲烷,或 2,2'-二丙基 -二吲哚甲烷,或 2,2'- 二丁基-二吲哚甲烷, 或 2,2'-二戊基-二吲哚甲烷。
5. 根据权利要求 1所述, 适用的药物制剂材料为玉米油, 或二甲基亚砜, 或环 糊精, 或明胶胶囊。
6. 一种吲哚 -3-甲醇及其衍生物治在制备治疗病毒性肝炎, 或酒精性肝炎, 或药 物性肝炎, 或脂肪肝, 或肝纤维化, 或肝硬化的药物中的应用, 小分子化合 物吲哚 -3-甲醇及其衍生物, 其结构式如下:
1
Figure imgf000012_0001
其中, Ri , R2, , R5, , R7位是氢原子, 或卤素, 或硝基, 或主链长为 一到十个碳原子的直链或者支链的烷或烷氧基。
7. 根据权利要求 8所述, 直链或者支链烷或烷氧基其特征为一到五个碳原子。
8. 根据权利要求 8所述, 卤素为氯, 或溴, 或氟。
9. 根据权利要求 8所述, 小分子化合物吲哚 -3-甲醇及其衍生物为 5-甲基 -吲哚 -3-甲醇, 或 5-乙基 -吲哚 -3-甲醇, 或 5-丙基 -吲哚 -3-甲醇, 或 5-丁基 -吲哚 -3- 甲醇, 或 5-戊基 -吲哚 -3-甲醇, 或 5-甲氧基 -吲哚 -3-甲醇, 或 5-乙氧基 -吲哚 -3-甲醇, 或 5-丙氧基 -吲哚 -3-甲醇, 或 5-丁氧基 -吲哚 -3-甲醇, 或 5-戊氧基- 吲哚 -3-甲醇, 或 N-甲基 -吲哚 -3-甲醇, 或 N-乙基 -吲哚 -3-甲醇, 或 N-丙基- 吲哚 -3-甲醇, 或 N-丁基 -吲哚 -3-甲醇, 或 N-戊基 -吲哚 -3-甲醇, 或 2-甲基- 吲哚 -3-甲醇, 或 2-乙基 -吲哚 -3-甲醇, 或 2-丙基 -吲哚 -3-甲醇, 或 2-丁基-吲 哚 -3-甲醇, 或 2-戊基 -吲哚 -3-甲醇。
10. 根据权利要求 7所述, 适用的药物制剂材料为玉米油, 或二甲基亚砜, 或环 糊精, 或明胶胶囊。
2
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3017816A4 (en) * 2013-05-28 2016-11-16 Vsevolod Ivanovich Kiselev DIINDOLYLMETHANE-BASED MEDICAMENT AND USE THEREOF FOR THE TREATMENT OF INFLUENZA AND VIRAL AIRWAY INFECTIONS

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105963295A (zh) * 2016-06-18 2016-09-28 张阳康 吲哚-3-甲醇、二吲哚甲烷及其衍生物在制备治疗强直性脊柱炎物中的应用
CN105853410A (zh) * 2016-06-18 2016-08-17 张阳康 吲哚-3-甲醇、二吲哚甲烷及其衍生物在制备治疗脂溢性脱发药物中的应用
CN105963294A (zh) * 2016-06-18 2016-09-28 张阳康 吲哚-3-甲醇、二吲哚甲烷及其衍生物在制备治疗红斑狼疮药物中的应用
CN105853409A (zh) * 2016-06-18 2016-08-17 张阳康 吲哚-3-甲醇、二吲哚甲烷及其衍生物在制备治疗器官移植排斥反应药物中的应用
CN108245509A (zh) * 2018-01-29 2018-07-06 南京大学 Dim及其衍生物在制备防治化疗引发损伤药物中的应用
RU2740377C1 (ru) * 2020-03-18 2021-01-13 Всеволод Иванович Киселёв Способ лечения эндометриоза и сопутствующего спаечного процесса лекарственным средством на основе 3,3'-дииндолилметана в комплексе с B-циклодекстрином

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004093871A1 (en) * 2003-03-27 2004-11-04 Lankenau Institute For Medical Research Novel methods for the treatment of cancer
KR20090042689A (ko) * 2007-10-27 2009-04-30 한림대학교 산학협력단 3,3’-디인돌릴메탄을 유효성분으로 함유하는 염증 질환의예방 및 치료용 조성물
CN101428016A (zh) * 2008-12-23 2009-05-13 南京大学 二吲哚甲烷及其衍生物在类风湿关节炎治疗中的应用
KR20100070664A (ko) * 2008-12-18 2010-06-28 연세대학교 산학협력단 인돌-3-카비놀 유도체를 유효성분으로 포함하는 비만, 고지혈증, 지방간 또는 당뇨의 예방 또는 치료용 조성물

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1795187A (zh) * 2003-03-27 2006-06-28 兰肯瑙医学研究所 新型ido抑制剂及其使用方法
WO2006047716A2 (en) * 2004-10-26 2006-05-04 Bioresponse Llc Use of diindolylmethane-related indoles and growth factor receptor inhibitors for the treatment of human cytomegalovirus associated disease

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004093871A1 (en) * 2003-03-27 2004-11-04 Lankenau Institute For Medical Research Novel methods for the treatment of cancer
KR20090042689A (ko) * 2007-10-27 2009-04-30 한림대학교 산학협력단 3,3’-디인돌릴메탄을 유효성분으로 함유하는 염증 질환의예방 및 치료용 조성물
KR20100070664A (ko) * 2008-12-18 2010-06-28 연세대학교 산학협력단 인돌-3-카비놀 유도체를 유효성분으로 포함하는 비만, 고지혈증, 지방간 또는 당뇨의 예방 또는 치료용 조성물
CN101428016A (zh) * 2008-12-23 2009-05-13 南京大学 二吲哚甲烷及其衍生物在类风湿关节炎治疗中的应用

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
PING JIE ET AL.: "Effect of indole-3-carbinol on activation, proliferation and collagen secretion of rat hepatic stellate cells.", CHINESE JOURNAL OF PHARMACOLOGY AND TOXICOLOGY., vol. 21, no. 4, August 2007 (2007-08-01), pages 333, XP008168130 *
WEI XIAONING ET AL.: "Molecular Mechanisms of Anti-Fibrotic Effect of Indole-3-Carbinol by Protein Array Assays.", MEDICAL JOURNAL OF WUHAN UNIVERSITY., vol. 31, no. 6, November 2010 (2010-11-01), pages 709 - 712,738, XP008168158 *
WU XIAOQIAN ET AL.: "Effects of indole-3-carbinol on hepatic stellate cells activated by acetaldehyde in precision-cut liver slices.", CHINESE PHARMACOLOGICAL BULLETIN., vol. 23, no. 4, April 2007 (2007-04-01), pages 441 - 445, XP008168129 *
ZHANG CHUN ET AL.: "Protection of indole-3-carbinol against ethanol-induced hepatotoxicity in precision liver-cut slices of rats.", CHINESE PHARMACOLOGICAL BULLETIN., vol. 20, no. 6, June 2004 (2004-06-01), pages 660 - 663, XP008168128 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3017816A4 (en) * 2013-05-28 2016-11-16 Vsevolod Ivanovich Kiselev DIINDOLYLMETHANE-BASED MEDICAMENT AND USE THEREOF FOR THE TREATMENT OF INFLUENZA AND VIRAL AIRWAY INFECTIONS

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