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WO2021036495A1 - 新型苯乙酸衍生物、其制备方法及其作为药物的用途 - Google Patents

新型苯乙酸衍生物、其制备方法及其作为药物的用途 Download PDF

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WO2021036495A1
WO2021036495A1 PCT/CN2020/099650 CN2020099650W WO2021036495A1 WO 2021036495 A1 WO2021036495 A1 WO 2021036495A1 CN 2020099650 W CN2020099650 W CN 2020099650W WO 2021036495 A1 WO2021036495 A1 WO 2021036495A1
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fibrosis
compound
organs
pharmaceutically acceptable
acceptable salt
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French (fr)
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李政
张陆勇
刘冰
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广东药科大学
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    • C—CHEMISTRY; METALLURGY
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic 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
    • 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
    • A—HUMAN NECESSITIES
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    • A61P13/00—Drugs for disorders of the urinary system
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    • A—HUMAN NECESSITIES
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    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention relates to a deuterated 3-pentylphenylacetic acid derivative, a preparation method and application thereof, and belongs to the technical field of medicine.
  • the structure of the deuterated derivative involved in the present invention is unique and novel in this field.
  • Organ fibrosis refers to the accumulation of infection, inflammation, fat and other substances in the living body caused by various reasons such as microorganisms, chemical substances, immune responses, eating habits, environment, genetic background and other reasons (including unknown causes). After the degeneration of tissues or cells causes organ damage, necrosis, etc., it cannot fully regenerate, and connective tissue proliferation and fibrosis occur. It is known to occur in various organs such as the liver, lungs, heart, kidney, cranial nervous system, and many organs and tissues such as muscles, bones, and skin. Liver cirrhosis is a typical pathological state of fibrosis in the liver.
  • liver function is significantly reduced.
  • liver cirrhosis in addition to fibrosis caused by lung injury accompanied by pneumonia such as interstitial pneumonia, there is also idiopathic pulmonary fibrosis of unknown cause.
  • Myocardial fibrosis is a disease in which the tissues of the myocardium and heart valves become fibrotic.
  • the primary disease is cardiomyopathy and valvular disease caused by coronary circulatory failure, infection or immune response, etc., and can progress to a state of heart failure.
  • fibrosis is caused in the kidney tissue along with the development of chronic kidney disease, it will cause the kidney function to deteriorate rapidly and reach an irreversible state.
  • organ fibrosis is a serious disease that causes irreversible deterioration of the function of the organ and tissue and has a very poor prognosis.
  • liver transplantation is the only effective treatment method for liver cirrhosis, but liver transplantation has many problems such as insufficient organ donors, high medical costs, and health risks to the donor in the case of living donor liver transplantation. Therefore, the development of drugs for organ fibrosis has become a research hotspot in this field, in order to bring more economical, safe and effective new drugs to patients with organ fibrosis.
  • Pirfenidone has anti-inflammatory, anti-fibrotic and antioxidant properties, and can significantly delay the rate of forced expiratory vital capacity (FVC) decline. It was approved for the treatment of idiopathic pulmonary fibrosis (IPF) in 2008 and is recommended for light It is not clear whether IPF patients with moderate pulmonary dysfunction and severe pulmonary dysfunction can benefit. Nintanib is a VEGFR/FGFR/PDGFR inhibitor, which can significantly reduce the absolute value of FVC decline in patients with IPF and relieve the disease process to a certain extent. It was approved for IPF in the United States and the European Union in 2014 and 2015, respectively. Like pirfenidone, this product is recommended for patients with mild and moderate pulmonary dysfunction. Whether severe patients can benefit or not requires further research.
  • FVC forced expiratory vital capacity
  • the present invention uses a deuteration strategy to block the potential metabolic sites of PBI-4050, which has better drug metabolism properties and anti-organ fibrosis effects in vivo. Therefore, the deuterated PBI-4050 and its pharmaceutically acceptable salts can be potentially used to treat or prevent organ fibrosis-related diseases, and have broad development prospects.
  • the purpose of the present invention is to provide deuterated PBI-4050 derivatives and their medical applications, and provide a solution for the prevention or/and treatment of organ fibrosis-related diseases. Class of new potential drugs.
  • the deuterated PBI-4050 derivative of the present invention contains an effective amount of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 and R 3 are each independently selected from hydrogen and deuterium, and at least one of the R 1 , R 2 and R 3 groups is a deuterium atom;
  • More preferred compounds of the invention include, but are not limited to:
  • the pharmaceutically acceptable salt involved in the present invention is a sodium salt, a potassium salt or a lithium salt.
  • Another aspect of the present invention relates to a pharmaceutical composition, which contains a therapeutically effective dose of the compound or a pharmaceutically acceptable salt thereof and a suitable carrier, diluent or excipient.
  • the present invention also relates to the use of the compound or its pharmaceutically acceptable salt or its pharmaceutical composition in the preparation of a medicament for the prevention or/and treatment of organ fibrotic diseases, wherein the organ fibrosis occurs in the digestive organs, respiratory organs, Fibrosis of circulatory organs, genitourinary organs, motor organs, cranial nervous system, endocrine organs, or skin; including prevention or/and treatment of fatty liver, liver fibrosis, pulmonary fibrosis, kidney fibrosis, heart fibrosis, Syndrome and other organ fibrosis-related diseases in medicine for at least one disease.
  • the present invention can be measured by using the test system described below.
  • test examples of the present invention are usually in accordance with the conventional conditions or in accordance with the conditions recommended by the commercial manufacturer.
  • the reagents without specific sources are commonly used reagents purchased on the market.
  • Test Example 2 The in vivo anti-hepatic fibrosis effect of the compound of the present invention can be measured by using the following measurement system:
  • mice were sacrificed on the 61st day, serum was collected, and serum AST and ALT levels were determined by an automatic biochemical analyzer; the liver was removed, and the content of hydroxyproline in the liver was determined by alkaline hydrolysis, and the liver fibrosis of mice was observed by Masson staining status.
  • AST, ALT and hydroxyproline levels are shown in Table 2. See Figure 1 for the results of Masson staining.
  • Test Example 3 The in vivo anti-kidney fibrosis effect of the compound of the present invention can be measured by using the measurement system described below:
  • **P ⁇ 0.01 is the result of Student’s t test relative to the blank control group.
  • test compound can significantly improve the renal function indicators of the renal fibrosis model.
  • Masson staining (figure 2) shows that the model control group has dilated renal tubules, thickened glomerular basement membrane, and increased fibrous proliferation. Renal fibrosis of the group was significantly improved, and the compound of the present invention showed a better anti-renal fibrosis effect.
  • Figure 1 Masson staining results of liver fibrosis model induced by CCl 4
  • Figure 2 Masson staining results of adenine-induced renal fibrosis model kidney
  • Step 1 In the sealed tube, add Pd(PPh 3 ) 2 Cl 2 (0.6g, 0.78mmol), 1-pentyne (5.4g, 78.6mmol), and (3-bromophenyl) methyl acetate (6g , 26.2mmol) and tetrabutylammonium fluoride hydrate (20.6g, 78.6mmol), mixed well and heated at 80°C for 3h. The mixture was added with 50 mL of water, and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was evaporated under reduced pressure.
  • Step 2 Mix 10% Pd/C (0.36g) with D 2 O (30 mL), after replacing hydrogen, react at room temperature for 24 hours, add (3-(pentyn-1-yl)phenyl)acetate to the reaction flask Ester (3.6g) in methanol dilution, continue to react at room temperature for 6h, the reaction solution was filtered with diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was collected, 20mL of water was added, ethyl acetate extracted, and the organic phases were combined with anhydrous sodium sulfate Dry, filter, and evaporate the organic solvent under reduced pressure.
  • Step 3 Dissolve methyl 2-(3-(pentyl-1,1,2,2-D 4 )phenyl)acetate (3.2g, 14.3mmol) in a mixture of THF/CH 3 OH/H 2 O LiOH (1.7g, 71.4mmol) was added to the solvent. After the addition, the reaction was carried out at room temperature for 5h. The solvent was evaporated under reduced pressure, acidified with 1N HCl, and extracted with ethyl acetate. The combined organic phases were dried with anhydrous sodium sulfate, filtered, and reduced under reduced pressure. The organic solvent is evaporated.
  • the active ingredients, pregelatinized starch and microcrystalline cellulose are sieved, mixed thoroughly, added to the polyvinylpyrrolidone solution, mixed, soft materials are made, sieved, wet granules are made, dried at 50-60°C, and the carboxymethyl starch
  • the sodium salt, magnesium stearate and talc are sieved and added to the above granules to form a tablet.

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Abstract

本发明涉及一类通式(I)所示的新型氘代3-戊基苯乙酸衍生物、其制备方法及含有该衍生物的药物组合物作为制备预防或/和治疗器官纤维化相关疾病的药物用途。所述的本发明化合物具有更优异的药物代谢性质和体内抗器官纤维化效果，可应用于制备预防或/和治疗脂肪肝、肝纤维化，肺纤维化、肾纤维化、心纤维化、Alström综合征等器官纤维化相关疾病的药物，具有广阔的应用前景。

Description

新型苯乙酸衍生物、其制备方法及其作为药物的用途 技术领域
本发明涉及氘代3-戊基苯乙酸衍生物、其制备方法及其应用，属于医药技术领域。本发明中涉及的氘代衍生物结构在该领域具有独特性和新颖性。
背景技术
器官纤维化是指由于微生物、化学物质、免疫反应等活体内的反应、饮食习惯、环境、遗传背景等各种原因(也包括原因不明)引起的感染、炎症、脂肪等活体内物质的蓄积、组织或细胞的变性等导致器官受到损伤、发生坏死等之后，无法充分再生，发生结缔组织增生形成纤维化。已知在肝、肺、心脏、肾脏、脑神经系统等各种器官，以及肌肉、骨骼、皮肤等众多器官、组织中均可发生。肝硬化是肝脏中发生纤维化的典型病理状态，是各种原因(如药物性肝损伤，脂肪肝，慢性肝炎等)导致的肝病慢性发展到最终的病态，由于功能性的肝细胞减少和纤维组织增生，肝功能显著降低。全球有约2000万肝硬化患者，但目前尚无有效的治疗药物。当前，主要预防手段是如何通过各种对症疗法来延缓慢性肝病向肝硬化的发展。肺纤维化中，除了由间质性肺炎等肺炎伴随的肺损伤引起的纤维化以外，还存在原因不明的特发性肺纤维化，该疾病出现咳嗽、胸痛、呼吸困难等症状，严重影响患者生活质量，且预后不良。心肌纤维化为心肌、心脏瓣膜的组织发生纤维化的疾病，其以由冠状动脉循环功能衰竭、感染或免疫反应等引起的心肌病及瓣膜病等为原发病，可发展至心力衰竭状态。在肾脏中，如果伴随慢性肾病的发展而在肾脏组织内造成纤维化，会导致肾功能急剧恶化而到达不可恢复的状态。总之，器官纤维化的发展是引起该器官、组织的功能的不可逆的恶化而预后极其不良的严重病情，但目前尚缺乏有效药物。作为对肝硬化唯一有效的治疗方法是肝移植，但肝移植存在器官供体不足、医疗成本高、在活体肝移植的情况下具有对供体的健康风险等众多问题。因此，针对器官纤维化药物的开发成为该领域的研究热点，以期为器官纤维化患者带来更经济、安全、有效的新型药物。
吡非尼酮具有抗炎、抗纤维化和抗氧化特性，能够显著延缓用力呼气肺活量(FVC)下降速率，2008年获批用于特发性肺纤维化(IPF)治疗，推荐应用于轻、中度肺功能障碍IPF患者，重度肺功能受损患者能否获益尚不明确。尼达尼布为VEGFR/FGFR/PDGFR抑制剂，可显著减少IPF患者FVC下降的绝对值，一定程度上缓解疾病进程，分别于2014及2015年在美国和欧盟获批用于IPF。与吡非尼酮相同，本品被推荐用于轻、中度肺功能障碍患者，重度病患能否获益需要进一步研究。但吡非尼酮和尼达尼布副作用较大，患者耐受性较差。近年来，一系列临床研究表明PBI-4050(WO2012097428)能够显著改善多种器官纤维化，且副作用较小(Nat Rev Drug Discov,2017,16,755-772及Eur Respir J,2019,53,1800663)，但其苄位在体内易被氧化代谢，从而加重肝脏代谢负担，且影响其药物代谢动力学性质，并最终影响体内抗纤 维化效果。
Figure PCTCN2020099650-appb-000001
本发明运用氘代策略封闭PBI-4050的潜在代谢位点，其具有更优异的药物代谢性质和体内抗器官纤维化效果。因此，所述氘代PBI-4050及其可药用盐可以潜在的用于治疗或者预防器官纤维化相关疾病，具有广阔的开发前景。
发明内容
针对现有技术中PBI-4050易于代谢的缺陷和未满足的临床需求，本发明的目的是提供氘代PBI-4050衍生物及其医药应用，为预防或/和治疗器官纤维化相关疾病提供一类新的潜在药物。
本发明所述的氘代PBI-4050衍生物，是含有有效量的通式(I)所示的化合物或其可药用的盐：
Figure PCTCN2020099650-appb-000002
其中：
R 1，R 2和R 3各自独立选自氢、氘，且R 1，R 2和R 3基团中至少有一个基团为氘原子；
更优选的本发明化合物包括，但不限于：
2-(3-(戊基-1,1,2,2-D 4)苯基)乙酸(I-1)；
2-(3-(戊基-1,1-D 2)苯基)-2,2-D 2乙酸(I-2)；
2-(3-(戊基-1,1,2,2-D 4)苯基)-2,2-D 2乙酸(I-3)；
2-(3-(戊基-1,1,2,2-D 4)苯基)乙酸钠(I-4)。
本发明涉及的药学上可接受的盐是钠盐、钾盐或锂盐。
本发明的另一方面涉及一种药物组合物，其含有治疗有效剂量的所述化合物或其可药用的盐及适当的载体、稀释剂或赋形剂。
本发明同时涉及所述化合物或其可药用的盐或其药物组合物在制备预防或/和治疗器官纤维化疾病的药物中的用途，其中，器官纤维化为发生于消化器官、呼吸器官、循环器官、泌尿生殖器官、运动器官、脑神经系统、内分泌器官、或皮肤的纤维化；包括预防或/和治疗脂肪肝、肝纤维化，肺纤维化、肾纤维化、心纤维化、
Figure PCTCN2020099650-appb-000003
综合征等器官纤维化相关疾病中至少一种疾病的药物中的用途。
本发明可以通过使用如下所述的测试系统测定。
以下生物学测试实施例描述解释本发明。
本发明测试例中具体条件的实验方法通常按常规条件或按照商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常用试剂。
测试例1本发明化合物对人肝脏微粒体稳定性研究
用DMSO配置受试化合物母液，并用0.1％BSA溶液稀释至待测浓度。人肝微粒体在含有0.1M Tris缓冲液(pH 7.4)，5.0mM MgCl 2溶液，0.005％BSA，和1.0mM NADPH的96-孔板中37℃下孵育，每孔微粒体蛋白终浓度为0.5mg/mL，孵育5min后，加入受试药物，分别在0、10、20、30、60、90min后加入甲醇终止反应。用LC-MS/MS测定样品中化合物的浓度，并计算化合物的半衰期。实施例化合物肝脏微粒体稳定性结果见表1。
表1：化合物对人肝脏微粒体稳定性
Figure PCTCN2020099650-appb-000004
结论：本发明所有化合物对人肝脏微粒体稳定性均强于PBI-4050，具有降低用药剂量、改善体内药物疗效的潜能。
测试例2本发明中化合物的体内抗肝纤维化作用可以通过使用如下所述的测定系统测定：
8周龄C57BL/6小鼠，雄性，随机分为6组，每组6只，每周两次给予2mL/kg四氯化碳橄榄油溶液(10％含量)，造模60天，在造模期间，空白对照组(空白溶媒：0.5％的羧甲基纤维素钠溶液)，受试化合物组(200mg/kg)每天一次分别灌胃给予空白溶媒及受试化合物，连续给药60天，于第61天处死小鼠，收集血清，以自动生化分析仪测定血清AST，ALT水平；摘取肝脏，以碱水解法测定肝中羟脯氨酸含量，并以Masson染色观察小鼠肝纤维化状态。AST，ALT及羟脯氨酸水平见表2。Masson染色结果见附图1。
表2：化合物对血清AST，ALT及肝脏羟脯氨酸水平的影响(
Figure PCTCN2020099650-appb-000005
n＝6)
Figure PCTCN2020099650-appb-000006
注：*P≤0.05为相对于PBI-4050组的Student’s t检验结果。
结果表明：本发明化合物及其药用钠盐I-4能够明显改善肝纤维化小鼠模型的肝功能，及降低肝脏羟 脯氨酸水平；Masson染色(附图1)结果表明，模型对照组肝小叶纤维间隔形成，中央静脉周围及汇管区纤维沉积增多，而给药组肝纤维化程度得到明显改善，表现出较好的抗肝纤维化作用。其中，化合物I-1、I-3及I-4的AST水平显著低于PBI-4050组，I-3组的ALT及羟脯氨酸水平显著低于PBI-4050组，表现出更优异的药用价值。
测试例3本发明中化合物的体内抗肾纤维化作用可以通过使用如下所述的测定系统测定：
8周龄C57BL/6小鼠，雄性，随机分为6组，每组6只，给予0.25％腺嘌呤饲料喂养四周制备肾纤维化模型，在给予腺嘌呤饲料一周后，开始给予空白对照组，受试化合物组(200mg/kg)每天一次分别灌胃空白溶媒及受试化合物，连续给药三周后处死小鼠，收集血清，测定血清尿素氮(BUN)，血肌酐(Scr)水平；摘取肾脏以Masson染色观察小鼠肾纤维化状态。BUN，Scr水平见表3。Masson染色结果见附图2。
表3：化合物对BUN，Scr水平的影响(
Figure PCTCN2020099650-appb-000007
n＝6)
Figure PCTCN2020099650-appb-000008
注：**P≤0.01为相对于空白对照组的Student’s t检验结果。
结果表明：受试化合物能够明显改善肾纤维化模型的肾功能指标，Masson染色(附图2)结果表明模型对照组肾小管扩张，肾小球基底膜增厚，纤维增生较明显，而给药组肾纤维化得到明显改善，本发明化合物表现出较好的抗肾纤维化作用。
附图说明
图1：CCl 4诱导的肝纤维化模型肝脏Masson染色结果
图2：腺嘌呤诱导的肾纤维化模型肾脏Masson染色结果
具体实施方式
下面结合实施例对本发明作进一步说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
2-(3-(戊基-1,1,2,2-D 4)苯基)乙酸(I-1)
Figure PCTCN2020099650-appb-000009
步骤一：在密封管中，依次加入Pd(PPh 3) 2Cl 2(0.6g，0.78mmol)，1-戊炔(5.4g，78.6mmol)，(3-溴苯基)乙酸甲酯(6g，26.2mmol)和四丁基氟化铵水合物(20.6g，78.6mmol)，混合均匀后80℃下加热反应3h。混合物加水50mL，乙酸乙酯萃取(20mL×3)。合并有机相以无水硫酸钠干燥，过滤，减压蒸除有机溶剂。柱层析纯化(乙酸乙酯/石油醚，5:95，v/v)，得淡黄色油状(3-(戊炔-1-基)苯基)乙酸甲酯(3.6g，65％)。
1H NMR(300MHz,DMSO-d 6)δ7.33–7.28(m,3H),7.27–7.22(m,1H),3.70(s,2H),3.63(s,3H),2.41(t,J＝7.0Hz,2H),1.58(h,J＝7.2Hz,2H),1.02(t,J＝7.3Hz,3H).
步骤二：10％Pd/C(0.36g)与D 2O(30mL)混合，置换氢气后，室温反应24h，往反应瓶中加入(3-(戌炔-1-基)苯基)乙酸甲酯(3.6g)的甲醇稀释液，继续室温反应6h，反应液以硅藻土抽滤，乙酸乙酯洗涤滤饼，收集滤液，加水20mL，乙酸乙酯萃取，合并有机相以无水硫酸钠干燥，过滤，减压蒸除有机溶剂。柱层析纯化(乙酸乙酯/石油醚，3:97，v/v)，得2-(3-(戊基-1,1,2,2-D 4)苯基)乙酸甲酯(3.2g，89％)。
步骤三：将2-(3-(戊基-1,1,2,2-D 4)苯基)乙酸甲酯(3.2g，14.3mmol)溶于THF/CH 3OH/H 2O的混合溶剂中，加入LiOH(1.7g，71.4mmol)，加完后常温反应5h，减压蒸除溶剂，加1N HCl酸化，乙酸乙酯萃取，合并有机相以无水硫酸钠干燥，过滤，减压蒸除有机溶剂。残留物经柱层析纯化(乙酸乙酯/石油醚，1:3，v/v)，得白色固体2-(3-(戊基-1,1,2,2-D 4)苯基)乙酸2.9g，产率为91％。
1H NMR(300MHz,CD 3OD)δ:7.23–7.19(m,1H),7.09–7.04(m,3H),3.57(s,2H),1.36–1.32(m,4H),0.88(t,J＝7.2Hz,3H).ESI-MS m/z:209.1[M-H] -.
实施例2
2-(3-(戊基-1,1-D 2)苯基)-2,2-D 2乙酸(I-2)
Figure PCTCN2020099650-appb-000010
在圆底烧瓶中依次加入间戊基苯乙酸(3g)，10％钯碳(0.3g)及重水(25mL)，氢气置换后，50度加热反应72h，反应液以硅藻土抽滤，乙酸乙酯洗涤滤饼，收集滤液，加水20mL，乙酸乙酯萃取，合并有机相以无水硫酸钠干燥，过滤，减压蒸除有机溶剂。残余物经柱层析纯化(乙酸乙酯/石油醚，1:3，v/v)，得到白色固体2.6g，产率为86％。
1H NMR(300MHz,CD 3OD)δ:7.25–7.20(m,1H),7.08–7.04(m,3H),1.62(t,J＝7.4Hz,2H),1.37–1.32(m,4H),0.87(t,J＝7.1Hz,3H).ESI-MS m/z:209.1[M-H] -.
实施例3
2-(3-(戊基-1,1,2,2-D 4)苯基)-2,2-D 2乙酸(I-3)
Figure PCTCN2020099650-appb-000011
在圆底烧瓶中依次加入I-1(2g)，10％钯碳(0.2g)及重水(20mL)，氢气置换后，50度加热反应72h，反应液以硅藻土抽滤，乙酸乙酯洗涤滤饼，收集滤液，加水20mL，乙酸乙酯萃取，合并有机相以无水硫酸钠干燥，过滤，减压蒸除有机溶剂。残余物经柱层析纯化(乙酸乙酯/石油醚，1:3，v/v)，得到白色固体1.6g，产率为80％。
1H NMR(300MHz,CD 3OD)δ:7.28–7.22(m,1H),7.09–7.04(m,3H),1.36–1.32(m,4H),0.89(t,J＝7.3Hz,3H).ESI-MS m/z:211.1[M-H] -.
实施例4
2-(3-(戊基-1,1,2,2-D 4)苯基)乙酸钠(I-4)
Figure PCTCN2020099650-appb-000012
在乙醇和水的混合溶液(4:1，v/v)中，依次加入I-1(2g，3.5mmol)，碳酸氢钠(0.8g，3.5mmol)。反应混合物室温下搅拌过夜。减压蒸除溶剂，将所得白色黏状固体溶解于水中，并将溶液冻干，得白色固体1.9g，产率为86％。
实施例5
含活性剂I-4的片剂：
Figure PCTCN2020099650-appb-000013
将活性成分、预胶化淀粉和微晶纤维素过筛，充分混合，加入聚乙烯吡咯烷酮溶液，混合，制软材，过筛，制湿颗粒，于50-60℃干燥，将羧甲基淀粉钠盐、硬脂酸镁和滑石粉过筛加入至上述颗粒中压片成型。

Claims (6)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    Figure PCTCN2020099650-appb-100001
    其中：
    R 1，R 2和R 3各自独立选自氢、氘，且R 1，R 2和R 3基团中至少有一个基团为氘原子。
  2. 权利要求2所定义的通式(I)化合物或其可药用的盐，所述化合物选自：
    2-(3-(戊基-1,1,2,2-D 4)苯基)乙酸；
    2-(3-(戊基-1,1-D 2)苯基)-2,2-D 2乙酸；
    2-(3-(戊基-1,1,2,2-D 4)苯基)-2,2-D 2乙酸；
    2-(3-(戊基-1,1,2,2-D 4)苯基)乙酸钠。
  3. 权利要求1-2任一项所述的通式(I)化合物的药学上可接受的盐是钠盐、钾盐或锂盐。
  4. 一种药物组合物，含有权利要求1-3之一所述的化合物或其可药用盐及适当的载体或赋形剂。
  5. 权利要求1-4任意一项所定义的化合物或其可药用的盐或其药物组合物在制备预防或/和治疗器官纤维化疾病的药物中的用途，其中，器官纤维化为发生于消化器官、呼吸器官、循环器官、泌尿生殖器官、运动器官、脑神经系统、内分泌器官、或皮肤的纤维化。
  6. 权利要求1-4任意一项所定义的化合物或其可药用的盐或其药物组合物在制备预防或/和治疗脂肪肝、肝纤维化，肺纤维化、肾纤维化、心纤维化、
    Figure PCTCN2020099650-appb-100002
    综合征等器官纤维化相关疾病中至少一种疾病的药物中的用途。
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CN102421742A (zh) * 2009-05-04 2012-04-18 普罗米蒂克生物科学公司 3-戊基苯乙酸的盐及其药物用途
WO2012097428A1 (en) * 2010-10-27 2012-07-26 Prometic Biosciences Inc. Compounds and pharmaceutical compositions for uses in diabetes
CN105143170A (zh) * 2013-03-15 2015-12-09 普罗米蒂克生物科学公司 用于治疗肺纤维化、肝纤维化、皮肤纤维化和心脏纤维化的经取代的芳族化合物

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WO2012097428A1 (en) * 2010-10-27 2012-07-26 Prometic Biosciences Inc. Compounds and pharmaceutical compositions for uses in diabetes
CN105143170A (zh) * 2013-03-15 2015-12-09 普罗米蒂克生物科学公司 用于治疗肺纤维化、肝纤维化、皮肤纤维化和心脏纤维化的经取代的芳族化合物

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