WO2017128163A1 - 含笑内酯二甲基胺的应用 - Google Patents

含笑内酯二甲基胺的应用 Download PDF

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WO2017128163A1
WO2017128163A1 PCT/CN2016/072445 CN2016072445W WO2017128163A1 WO 2017128163 A1 WO2017128163 A1 WO 2017128163A1 CN 2016072445 W CN2016072445 W CN 2016072445W WO 2017128163 A1 WO2017128163 A1 WO 2017128163A1
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Prior art keywords
pulmonary fibrosis
lung
act001
group
lactone
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PCT/CN2016/072445
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English (en)
French (fr)
Inventor
孙涛
陈悦
杨诚
周红刚
刘慧娟
刘艳荣
王静
张成玉
张强
张向明
秦源
荆学双
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天津国际生物医药联合研究院
天津尚德药缘科技股份有限公司
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Priority to AU2016390488A priority Critical patent/AU2016390488B9/en
Application filed by 天津国际生物医药联合研究院, 天津尚德药缘科技股份有限公司 filed Critical 天津国际生物医药联合研究院
Priority to DK16887050.9T priority patent/DK3320901T3/da
Priority to HUE16887050A priority patent/HUE050456T2/hu
Priority to CA2995132A priority patent/CA2995132C/en
Priority to PCT/CN2016/072445 priority patent/WO2017128163A1/zh
Priority to PL16887050T priority patent/PL3320901T3/pl
Priority to PT168870509T priority patent/PT3320901T/pt
Priority to EP16887050.9A priority patent/EP3320901B1/en
Priority to JP2018510880A priority patent/JP6642892B2/ja
Priority to ES16887050T priority patent/ES2783879T3/es
Priority to US15/748,624 priority patent/US10220019B2/en
Publication of WO2017128163A1 publication Critical patent/WO2017128163A1/zh
Priority to HRP20200473TT priority patent/HRP20200473T1/hr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

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  • the present invention relates to the field of medicinal chemistry, and in particular to the use of ridolamine-containing dimethylamine.
  • the lactone lactam dimethylamine is a derivative containing a lactone, which is obtained by using the natural extract, parthenolide, as a raw material, and is simply referred to herein as ACT001.
  • Parthenolide is a sesquiterpene lactone compound purified from the herbaceous plant, Chrysanthemum, which has anti-inflammatory, anti-tumor and anti-platelet aggregation characteristics.
  • ACT001 The current research focuses on the treatment of skin infections, migraine, rheumatism and the treatment of cancer. Studies have shown that ACT001 and parthenolide are characterized by anti-inflammatory, anti-tumor, anti-platelet aggregation, inhibition of proliferation of vascular smooth muscle cells, inhibition of osteoclast activity, etc.
  • tumor necrosis factor TNF- ⁇
  • interleukin- 1 interleukin-1, IL-1
  • IL-12 cyclooxygenase-2
  • COX-2 cyclooxygenase-2
  • Cytokines related to pulmonary fibrosis include transforming growth factor- ⁇ (TGF- ⁇ ), epidermal growth factor (EGF), platelet derived growth factor (PDGF), and insulin-like Growth factor-like growth factors (IGF-1), interleukin (IL), connective tissue growth factor (CTGF), tumor necrosis factor alpha (TNF- ⁇ ) matrix metal Protease (matrix metalloproteinases, MMPs) and the like.
  • TGF- ⁇ transforming growth factor- ⁇
  • EGF epidermal growth factor
  • PDGF platelet derived growth factor
  • IGF-1 insulin-like Growth factor-like growth factors
  • IGF-1 insulin-like Growth factor-like growth factors
  • IL interleukin
  • CTGF connective tissue growth factor
  • TNF- ⁇ tumor necrosis factor alpha
  • MMPs matrix metal Protease
  • pulmonary fibrosis The clinical manifestations of pulmonary fibrosis are dyspnea. In mild pulmonary fibrosis, dyspnea often occurs during strenuous exercise. When pulmonary fibrosis progresses, breathing difficulties occur at rest, and severe lungs Patients with fibrosis may have progressive dyspnea, severe consequences of pulmonary fibrosis, leading to structural changes in normal lung tissue, loss of function; when a large number of fibrous tissue without gas exchange function replaces alveolar, the gas exchange capacity in the lung is weakened, resulting in oxygen Can not enter the blood, patients with poor breathing, hypoxia, acidosis, loss of labor, severe cases can eventually lead to death.
  • Pulmonary fibrosis is characterized by the proliferation of fibroblasts in the lung compartment and the deposition of extracellular matrix. Fibrocytes can not replace alveolar cells for gas exchange, and the accumulation of blood in the lungs can cause harmful substances to be metabolized in the lungs in time, which will damage the alveolar cells and form a vicious circle. Excessive deposition of extracellular matrix causes capillary damage. Compression, causing blood circulation in the lungs is not smooth, leading to blood deposition in the lungs, which in turn leads to a decrease in blood supply to the lungs, causing problems such as difficulty in breathing.
  • Pulmonary disease caused by pulmonary fibrosis is a high-risk disease. Since pulmonary fibrosis is caused by persistent lung injury, once pulmonary fibrosis occurs, it is difficult to cure, which is a great hazard to human health. There is currently no specific drug for the treatment of pulmonary fibrosis. Clinically, anti-inflammatory drugs and / or immunosuppressive agents, anti-fibrotic drugs, anticoagulant drugs, lung transplantation and other measures are mainly used for treatment. Commonly used drugs include glucocorticosteroids, nitroimidazopyridine, cyclosporine, Mycophenolate mofetil, and colchicine and penicillamine which can affect collagen formation.
  • Glucocorticoids have been used in the treatment of idiopathic pulmonary fibrosis for more than 50 years. The results of various clinical studies have found that glucocorticoids are the most effective in patients with idiopathic pulmonary fibrosis. More than 16%. Nitroimidazolium has been used in the treatment of idiopathic pulmonary fibrosis for more than 20 years, and its effectiveness remains controversial. The clinical effectiveness of other drugs is also controversial to varying degrees. Pulmonary fibrosis disease is serious, the mortality rate is high, and clinical treatment measures are lacking. Therefore, it is extremely urgent to develop a new type of medicine for treating pulmonary fibrosis based on an in-depth understanding of its pathogenesis.
  • the invention provides the application of the lactone-containing dimethylamine in the preparation of a medicament for treating pulmonary fibrosis, wherein the molecular structural formula of the lactone-containing dimethylamine is:
  • the medicament for treating pulmonary fibrosis comprises: leucine-containing dimethylamine, glycerol-containing dimethylamine in a pharmaceutically acceptable salt, ester, hydrate or a combination thereof and an adjuvant.
  • the dosage form of the medicament for treating pulmonary fibrosis is selected from the group consisting of a tablet, a capsule, a pill, a suppository, an aerosol, an oral liquid preparation, a granule, a powder, an injection, a syrup, a wine, a tincture, and a lotion. , a film or a combination thereof.
  • the administration of the drug for treating pulmonary fibrosis includes oral administration, injection, implantation, external application, spraying, inhalation, or a combination thereof.
  • the advantage of the present invention for treating pulmonary fibrosis drugs is that the lactide-containing dimethylamine (ACT001) can reverse and inhibit the pulmonary fibrosis level of the body, inhibit the extracellular deposition of the extracellular matrix of the lung, improve the blood supply to the lungs, and increase the lungs.
  • the blood supply thus relieves dyspnea and has a good therapeutic effect on pulmonary fibrosis.
  • the patient is not only easy to accept, but also has low toxicity, low cost, wide source, easy access, and easy understanding of the patient's response to the drug. .
  • ACT001 will change the market pattern of existing treatments for pulmonary fibrosis, and become a clinical drug that can be taken for a long time and effectively inhibits pulmonary fibrosis and improves lung function.
  • the ACT001 used in the present invention is ACT001 fumarate, white powder, which is provided by Tianjin Suntech Pharmaceutical Technology Co., Ltd., batch number: 20131112, and the chemical structural formula of ACT001 fumarate is:
  • Figure 1 is a section of a lung tissue of a normal mouse
  • Figure 2 is a diagram showing the effect of lung tissue section of mice on the third week of mouse pulmonary fibrosis modeling
  • Figure 3A is a perspective view of the external morphology of mouse lung tissue in the second week after ACT001 administration
  • Figure 3B is a graph showing the effect of lung tissue section of mice in the second week after ACT001 administration
  • Figure 4A is a perspective view of the external morphology of mouse lung tissue in the third week after ACT001 administration
  • Figure 4B is a graph showing the effect of tissue sectioning of mice in the third week after ACT001 administration.
  • test materials and sources used in the present invention include:
  • the animals After the animals arrive, the animals are received by the special person in the double-corridor barrier environment mouse breeding room 2, and the "Test Animal Reception Record Form" (BG-017-V00) is filled in.
  • the general condition of the animals is observed at the time of receiving, and the animals are randomly selected. Weighing ensures that the test animals are basically in line with the introduction criteria.
  • ACT001 fumarate white powder, purchased from Tianjin Suntech Pharmaceutical Technology Co., Ltd., batch number 20131112.
  • Methyl Violet Hydrate White crystal, purchased from Beijing Bailingwei Technology Co., Ltd., manufacturer: BEHRINGER TECHNOLOGY CO., LTD. Brand: J&K, purity: 98%, product number: 6045559, MDL: MFCD00150001, CAS number: 1910-42 -5.
  • ACT001 solution Preparation of ACT001 solution: Weigh 1g of ACT001 powder, dissolve it in 100mL of 0.9% physiological saline solution, prepare 10mg/mL solution, and after it is fully dissolved, filter it with 0.22 ⁇ m filter and use it after use. It is now available. The preparation and use of the solution should be carried out in a sterile biosafety cabinet.
  • methyl viologen hydrate solution 2 g of methyl viologen hydrate is weighed, dissolved in 100 ml of 0.9% physiological saline, and placed in a solution of 20 mg/ml. After it is fully dissolved, a 0.22 ⁇ m filter is used. It is used after filtration and sterilization, and it is used now when it is used. The preparation and use of the solution should be carried out in a sterile biosafety cabinet.
  • Example 1 Establishment of a mouse pulmonary fibrosis model and pharmacodynamic testing of ACT001
  • mice Thirty-six mice were randomly divided into three groups: the normal group, the control group (pulmonary fibrosis model group), and the ACT001 group (administered ACT001 after modeling), with 12 rats in each group.
  • the normal group 0.15 mL of 0.9% physiological saline was administered once per dose; in the control group and the ACT001 group, 0.15 mL of an aqueous solution of methyl viologen hydrate was administered once.
  • mice were given drug treatment, and the normal group and the control group used 0.1 mL each time. 0.9% saline was intragastrically administered, and the ACT001 group was intragastrically administered with 0.1 mL of ACT001 aqueous solution. Once every 2 days.
  • mice were taken from each group of normal group, control group and ACT001 group, and the neck was sacrificed and the lung tissue was taken. After fixing for 10% formalin for two days, the fixed liquid on the surface of the lung tissue was washed away with running water, and the lung tissue was dehydrated by a pathological tissue dehydrator, embedded in paraffin, and the embedded tissue was sectioned and stained by HE. Cover the slide and observe changes in lung tissue under a microscope.
  • Figure 1 is a section of a normal mouse lung tissue section.
  • Fig. 2 is a diagram showing the effect of lung tissue sectioning of mice in the third week of mouse pulmonary fibrosis modeling.
  • pulmonary fibrosis there was significant pulmonary fibrosis in the modeling group: extracellular matrix components in alveolar and interstitial deposition, excessive fibrous tissue repair, pulmonary fibrosis, pulmonary interstitial fibrosis, collagen deposition, alveolar Structural changes.
  • Fig. 3A is a perspective view of the external morphology of the lung tissue of the mouse in the second week after the administration of ACT001, as shown in Fig. 3A: compared with the control group, The lung tissue of the ACT001 group was more rosy, the blood supply to the lung tissue was significantly improved, the color of the lung tissue was bright red, and the surface of the lung tissue was more rosy, which was comparable to that of the normal group of mice. However, the color of the lung tissue of the mice in the model-imparted group was dim.
  • the surface of the lung tissue is not rosy. It can be seen that the blood supply to the lung tissue of mice in the group containing lactone dimethylamine (ACT001) was significantly improved. It can be seen that administration of ACT001 can improve blood supply to the lungs, thereby alleviating symptoms such as difficulty in breathing of the body.
  • the lungs were observed under a stereoscopic microscope, and the surface of the lung tissue was pale in the modeled non-administered group.
  • the blood vessels at the edge of the lung tissue were small and rare, and the lung tissue showed consolidation.
  • the alveolar structure of the fibrous tissue was extensively destroyed.
  • Fig. 3B The lung tissue section of the mouse is shown in Fig. 3B, and Fig. 3B is the effect of the lung tissue section of the mouse in the second week after the administration of ACT001. It can be seen from Fig. 3B that the injection of methyl viologen hydrate is compared with healthy normal mice. In the latter control group (ie, the non-administered group), fibrosis appeared in the lungs; in the ACT001 group, the lung tissue did not appear. In reality, there is no fibrosis in the lung parenchyma, and the alveolar structure is not destroyed; the degree of fibrosis in the lung is significantly improved, the interstitial deposition is significantly reduced, and the alveolar tissue is restored to normal.
  • FIGs. 4A and 4B The pictures of lung tissue and lung tissue sections after the third week of ACT001 administration are shown in Figs. 4A and 4B, wherein Fig. 4A is a perspective view of the external morphology of the mouse lung tissue in the third week after ACT001 administration; Fig. 4B It is the effect of tissue sectioning of mice in the third week after ACT001 administration.
  • Fig. 4A and Fig. 4B the degree of pulmonary fibrosis in the ACT001 group was significantly improved compared with the control group, and the lung fibers of the mice were improved.
  • the level of chemistry was significantly reduced, which was comparable to that of the normal group.
  • the body weights of the normal group, the control group, and the mice administered with the ACT001 group were observed, and the lung coefficients of the respective groups were calculated.
  • the average body weight of each group of mice was as follows: the average body weight of the mice in the normal group was 49.2352 g, the average body weight of the control mice was 45.4575, and the average weight of the mice administered the ACT001 group was 47.576.
  • the average lung weight of each group of mice was: the average lung weight of the normal group was 0.4012 g, the average lung weight of the control mice was 0.5983 g, and the average lung weight of the mice administered the ACT001 group was 0.4034 g.
  • lung coefficient lung wet weight (mg) / body weight (g) * 100%, calculated by the lung coefficient of each group of mice: the average lung coefficient of the normal group of mice was 0.81%, control mice The mean lung coefficient was 1.32%, and the mean lung coefficient of the ACT001 group was 0.85%. The lung coefficient of the control group was significantly higher than that of the normal group. There was no significant difference in the lung coefficient between the ACT001 group and the normal group.
  • the mean lung coefficient of the ACT001 group was 0.85%, a decrease of 0.47% compared with the control group, which was close to the average lung coefficient of the normal group of mice, which was 0.81%, indicating that ACT001 can Reversing and improving the level of fibrosis in the lungs, improving excessive deposition of extracellular matrix and inhibiting excessive proliferation of fibrotic cells in the lungs.
  • ACT001 can reverse and inhibit the lung fibrosis level of the body, inhibit the excessive deposition of extracellular matrix in the lung, improve the blood supply to the lung, increase the blood supply to the lungs and relieve the dyspnea, and have the effect of treating pulmonary fibrosis.

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Abstract

本发明提供了含笑内酯二甲基胺在制备治疗肺纤维化的药物中的应用。

Description

含笑内酯二甲基胺的应用 技术领域
本发明涉及药物化学领域，具体而言，涉及含笑内酯二甲基胺的应用。
背景技术
含笑内酯二甲基胺是含笑内酯的衍生物，是由天然提取物小白菊内酯为原料制取而来，在本文中将其简称为ACT001。小白菊内酯是从草本类植物艾菊中纯化出的一种倍半萜烯内酯化合物，具有抗炎、抗肿瘤、抗血小板聚集等特征。关于ACT001目前研究主要是集中在治疗皮肤感染、偏头痛、风湿病以及治疗肿瘤等疾病。研究表明ACT001及小白菊内酯是具有抗炎、抗肿瘤、抗血小板聚集、抑制血管平滑肌细胞的增殖、抑制破骨细胞的活性等特征，其通过抑制肿瘤坏死因子(TNF-α)、白介素-1(interleukin-1，IL-1)、IL-12及环氧化酶-2(COX-2)等的表达而具有抗炎作用；通过抑制NF-κB的活化以及磷酸化来促进癌细胞的凋亡，同时抑制L-8、血管内皮生长因子(vascular endothelial groth factor，VEGF)的产生，起到抗肿瘤的作用；
到目前为止，ACT001在肺纤维化中的应用尚无明确报道。与肺纤维化有关的细胞因子有转化生长因子(transforming growth factor-β，TGF-β)、表皮生长因子(epidermal growth factor，EGF)、血小板衍生生长因子(platelet derived growth factor，PDGF)、胰岛素样生长因子(insulin-like growth factors，IGF-1)、白细胞介素(interleukin，IL)、结缔组织生长因子(connective tissue growth factor，CTGF)、肿瘤坏死因子(tumor necrosis factorα，TNF-α)基质金属蛋白酶(matrix metalloproteinases，MMPs)等。肺纤维化的特征是肺间隔内成纤维细胞的增生，导致ECM沉积，因此抑制成纤维细胞生长是研制抗纤维化药物的重要环节。
肺纤维化的临床表现为呼吸困难，轻度肺纤维化时，呼吸困难常在剧烈运动时出现，当肺纤维化进展时，在静息时也发生呼吸困难，严重的肺 纤维化患者可出现进行性呼吸困难，肺纤维化的严重后果，导致正常肺组织结构改变，功能丧失；当大量没有气体交换功能的纤维组织代替肺泡，使肺部中气体交换能力减弱，导致氧气不能进入血液，患者呼吸不畅、缺氧、酸中毒、丧失劳动力，严重者最后可导致死亡。肺纤维化的特征是肺间隔内成纤维细胞的增生，细胞外基质的沉积过大。纤维细胞不能代替肺泡细胞进行气体交换，而肺部血液的淤积会造成有害物质在肺部不能及时代谢，进而会对肺泡细胞造成损伤，形成一个恶性循环；细胞外基质的过度沉积对毛细血管造成压迫，造成肺部血液循环不流畅，导致肺部血液淤积，进而导致肺部的供血水平下降，造成呼吸困难等问题。
由肺纤维化导致的肺病是高发性疾病，由于肺纤维化是由持续性的肺损伤导致的，因此一旦发生肺纤维化，则难以治愈，会对人类健康造成的很大的危害。肺纤维化的治疗目前并没有特效药物。临床上主要采用抗炎药和/或免疫抑制剂、抗纤维化药物、抗凝血药物、肺移植等措施进行治疗，常用的药物包括糖皮质类固醇、硝基咪唑硫嘧啶、环孢霉素、霉酚酸酯，以及可以影响胶原形成的秋水仙碱和青霉胺等。糖皮质激素类药物用于治疗特发性肺纤维化已有超过50年的历史，对各项临床研究的结果汇总发现，糖皮质激素类药物对特发性肺纤维化患者的显效率最高不超过16％。硝基咪唑硫嘌呤用于治疗特发性肺纤维化已经超过20多年，其有效性仍存在争议。其他药物在临床上的有效性也存在不同程度上的争议。肺纤维化疾病维护严重、病死率高、临床治疗措施匮乏，因此在深入了解其发病机制的基础上开发新型的治疗肺纤维化的药物迫在眉睫。
发明内容
本发明的目的在于提供含笑内酯二甲基胺在制备治疗肺纤维化的药物中的应用。
本发明提供了含笑内酯二甲基胺在制备治疗肺纤维化的药物中的应用，其中，所述含笑内酯二甲基胺的分子结构式为：
Figure PCTCN2016072445-appb-000001
在上述应用中，包括：所述含笑内酯二甲基胺在制备逆转及抑制机体的肺纤维化水平、抑制肺部细胞外基质过度沉积以及改善肺部供血的药物中的应用。
在上述应用中，治疗肺纤维化的药物包括：含笑内酯二甲基胺、含笑内酯二甲基胺在药学上可接受的盐、酯、水合物或它们的组合以及辅料。
在上述应用中，治疗肺纤维化的药物的剂型选自片剂、胶囊剂、丸剂、栓剂、气雾剂、口服液体制剂、颗粒剂、散剂、注射剂、糖浆剂、酒剂、酊剂、露剂、膜剂或它们的组合。
在上述应用中，治疗肺纤维化的药物的给药方式包括：口服、注射、植入、外用、喷雾、吸入或它们的组合。
本发明提供的治疗肺纤维化药物的优势在于：含笑内酯二甲基胺(ACT001)可以逆转及抑制机体的肺纤维化水平、抑制肺部细胞外基质过度沉积、改善肺部供血、增加肺供血量从而缓解呼吸困难，对肺纤维化具有很好的治疗效果，此外，该药物患者不仅容易接受，且毒副作用小、价格低廉、来源广泛、容易获取，还便于了解患者对药物的反应。此外，ACT001将改变已有治疗肺纤维化药物的市场格局，成为一种可长期服用，且有效抑制肺纤维化、改善肺功能状况的临床药物。
本发明所使用的ACT001为ACT001富马酸盐，白色粉末，由天津尚德药缘科技股份有限公司提供，批号：20131112，ACT001富马酸盐的化学结构式为：
Figure PCTCN2016072445-appb-000002
附图说明
图1是正常小鼠肺组织切片图；
图2是小鼠肺纤维化建模第三周小鼠肺组织切片效果图；
图3A是ACT001给药后第二周小鼠肺组织外部形态立体显微镜下效果图；
图3B是ACT001给药后第二周小鼠肺组织切片效果图；
图4A是ACT001给药后第三周小鼠肺组织外部形态立体显微镜下效果图；以及
图4B是ACT001给药后第三周小鼠组织切片效果图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员所获得的所有其他实施例，都属于本发明保护的范围。
本发明使用的试验材料及其来源包括：
(1)小鼠
昆明小鼠(雄性)：由中国人民解放军军事医学科学院试验动物中心和北京维通利华实验动物技术有限公司提供。
动物到达后，由专人接收动物于双走廊屏障环境小鼠饲养室2内，填写《试验动物接收记录表》(BG-017-V00)，接收时对动物大体情况进行观察，并随机抽取动物进行称重，确保试验动物与引进标准基本吻合。实验动物使用许可证号：SYXK(津)2012-0003。
(2)供试品
ACT001富马酸盐：白色粉末，购自天津尚德药缘科技股份有限公司，批号20131112。
甲基紫精水合物：白色晶体，购自北京百灵威科技有限公司，生产厂家：百灵威科技有限公司，品牌：J&K，纯度：98％，产品编号：6045559，MDL：MFCD00150001，CAS号：1910-42-5。
供试品保存：4℃
(3)所用药物及试剂的配制方法包括：
a)ACT001溶液的配制：称取ACT001粉末1g，溶于100mL的0.9％生理盐水溶液中，配制成10mg/mL溶液，待其充分溶解后，用0.22μm滤器过滤除菌后使用，每次使用时现用现配。溶液的配制及使用均应在无菌生物安全柜中操作。
b)甲基紫精水合物溶液的配置：称取甲基紫精水合物2g，溶于100ml的0.9％生理盐水中，配置成20mg/ml的溶液，待其充分溶解后，用0.22μm滤器过滤除菌后使用，每次使用时现用现配。溶液的配制及使用均应在无菌生物安全柜中操作。
c)10％福尔马林固定液的配置：将100ml的福尔马林与900ml的纯净水混匀。
实施例1  小鼠肺纤维化模型的建立和ACT001药效学检测
实验方法及步骤：
1.小鼠肺纤维化模型的建立及给药治疗
1.1小鼠肺纤维化模型的建立
将36只小鼠随机分为三组，正常组、对照组(肺纤维化模型组)、ACT001组(建模后给药ACT001)，每组12只。正常组每只一次性灌胃0.15mL的0.9％生理盐水；对照组以及ACT001组每只一次性灌胃0.15mL的甲基紫精水合物的水溶液。
1.2肺纤维化小鼠的给药治疗
在建模后第三周，给予小鼠药物治疗，正常组以及对照组每次用0.1mL 的0.9％的生理盐水灌胃，ACT001组每次用0.1mL的ACT001水溶液灌胃。每2天一次。
1.3小鼠肺纤维化的病理检测
在建模的第三周、给药后第二周、给药后第三周，分别从正常组、对照组、ACT001组每组取四只小鼠，断颈处死，取其肺组织，经10％福尔马林固定两天后，用流水冲洗掉肺组织表面的固定液，用病理组织脱水机对肺组织进行脱水处理，经石蜡进行包埋，对包埋组织进行切片，经H.E染色，盖片，在显微镜下观察肺组织的变化。
实验结果及评价
1)模型建立结果
如附图1所示，图1是正常小鼠肺组织切片图。如附图2所示，图2是小鼠肺纤维化建模第三周小鼠肺组织切片效果图。从图2中可以看出，建模组出现了明显的肺纤维化：细胞外基质成分在肺泡和间质内沉积，纤维组织过度修复，肺纤维增生，肺间质纤维化，胶原沉积，肺泡结构改变。
2)ACT001药效学检测
给药ACT001第二周后对小鼠进行解剖，检测ACT001对肺纤维化的药效。解剖后观察小鼠的肺组织，结果如图3A所示，图3A是ACT001给药后第二周小鼠肺组织外部形态立体显微镜下效果图，由图3A可知：与对照组相比，给药ACT001组的肺组织更加红润，肺组织供血明显改善，肺组织颜色鲜红，肺组织表面更加红润，与正常组小鼠的表观相当；而建模不给药组小鼠肺组织表面颜色暗淡，肺组织表面不红润。可见给药含笑内酯二甲基胺(ACT001)组小鼠肺组织供血明显改善。可见给药ACT001可以改善肺部供血，从而可以缓解机体的呼吸困难等症状。
立体显微镜下观察肺，而建模不给药组肺组织表面颜色苍白，肺组织边缘血管细小且少见，肺组织出现实变，在肺实质有较大范围纤维增生肺泡结构破坏明显。
小鼠的肺组织切片如图3B所示，图3B是ACT001给药后第二周小鼠肺组织切片效果图，由图3B可知：与健康正常小鼠相比，注射甲基紫精水合物后对照组(即不给药组)肺明显出现纤维化；给药ACT001组，肺组织未出 现实变，在肺实质无纤维增生现象，肺泡结构未被破坏；肺部的纤维化程度明显改善，肺间质沉积明显减少，肺泡组织恢复正常。
ACT001给药第三周后的肺组织图片及肺组织切片的图片如图4A及4B所示，其中图4A是ACT001给药后第三周小鼠肺组织外部形态立体显微镜下效果图；图4B是ACT001给药后第三周小鼠组织切片效果图，由图4A和图4B可知，给药组与对照组相比，给药ACT001组的肺纤维化程度明显改善，小鼠的肺部纤维化水平明显降低，与正常组的肺表观相当。
此外，在给药第三周后，对正常组、对照组以及给药ACT001组的小鼠体重进行观察，并计算各组的肺系数。各组小鼠平均体重如下：正常组小鼠的平均体重为49.2352g，对照组小鼠的平均体重为45.4575，给药ACT001组的小鼠平均体重为47.576。各组小鼠的平均肺重为：正常组小鼠的平均肺重为0.4012g，对照组小鼠的平均肺重为0.5983g，给药ACT001组的小鼠的平均肺重为0.4034g。根据公式：肺系数＝肺湿重(mg)/体重(g)*100％，经计算，各组小鼠的肺系数分别为：正常组小鼠的平均肺系数为0.81％，对照组小鼠的平均肺系数为1.32％，给药ACT001组的平均肺系数为0.85％。对照组的肺系数明显高于正常组，给药ACT001组的肺系数与正常组的肺系数无明显差异。由于肺系数代表肺纤维化程度，相比于对照组，给药ACT001组的平均肺系数为0.85％，降低了0.47％，接近于正常组小鼠的平均肺系数0.81％，由此表明ACT001可以逆转和改善肺部的纤维化水平，改善细胞外基质过度沉积，抑制肺部纤维化细胞的过度增生。
以上实施例表明：ACT001可以逆转及抑制机体的肺纤维化水平、抑制肺部细胞外基质过度沉积、改善肺部供血增加肺供血量和缓解呼吸困难，具有治疗肺纤维化的作用。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (5)

  1. 含笑内酯二甲基胺在制备治疗肺纤维化的药物中的应用，其中，所述含笑内酯二甲基胺的分子结构式为：
    Figure PCTCN2016072445-appb-100001
  2. 根据权利要求1所述的应用，其特征在于，包括：所述含笑内酯二甲基胺在制备逆转及抑制机体的肺纤维化水平、抑制肺部细胞外基质过度沉积以及改善肺部供血的药物中的应用。
  3. 根据权利要求1所述的应用，其特征在于，所述治疗肺纤维化的药物包括：所述含笑内酯二甲基胺、所述含笑内酯二甲基胺在药学上可接受的盐、酯、水合物或它们的组合以及辅料。
  4. 根据权利要求1-3中任一项所述的应用，其特征在于，所述治疗肺纤维化的药物的剂型选自片剂、胶囊剂、丸剂、栓剂、气雾剂、口服液体制剂、颗粒剂、散剂、注射剂、糖浆剂、酒剂、酊剂、露剂、膜剂或它们的组合。
  5. 根据权利要求4所述的应用，其特征在于，所述治疗肺纤维化的药物的给药方式包括：口服、注射、植入、外用、喷雾、吸入或它们的组合。
PCT/CN2016/072445 2016-01-28 2016-01-28 含笑内酯二甲基胺的应用 WO2017128163A1 (zh)

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