Nothing Special   »   [go: up one dir, main page]

WO2021000527A1 - 三环类xor抑制剂及其制备方法和应用 - Google Patents

三环类xor抑制剂及其制备方法和应用 Download PDF

Info

Publication number
WO2021000527A1
WO2021000527A1 PCT/CN2019/125525 CN2019125525W WO2021000527A1 WO 2021000527 A1 WO2021000527 A1 WO 2021000527A1 CN 2019125525 W CN2019125525 W CN 2019125525W WO 2021000527 A1 WO2021000527 A1 WO 2021000527A1
Authority
WO
WIPO (PCT)
Prior art keywords
tricyclic
xor
group
xor inhibitor
inhibitor
Prior art date
Application number
PCT/CN2019/125525
Other languages
English (en)
French (fr)
Inventor
李晶
李媛媛
李晓雷
张雷
关溯
Original Assignee
华南理工大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 华南理工大学 filed Critical 华南理工大学
Publication of WO2021000527A1 publication Critical patent/WO2021000527A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the invention belongs to the technical field of medicine and chemical engineering, and specifically relates to a tricyclic XOR inhibitor and a preparation method and application thereof.
  • Gout is caused by the continuous increase of blood uric acid levels, resulting in the deposition of monosodium urate crystals in joints and other tissues.
  • the level of blood uric acid is the core factor for the occurrence and development of gout.
  • the blood uric acid level exceeds the saturated dissolution amount in the blood, increased urate crystals are deposited in the joints, and a little crystal shedding can stimulate the surrounding tissues to produce inflammation. It causes redness, swelling, heat, and pain in the joints, and brings great pain and inconvenience to the patient's daily life.
  • hyperuricemia and gout are closely related, and controlling the blood uric acid level is the key to preventing and treating the disease. Studies have found that hyperuricemia or gout is also closely related to the occurrence of hypertension, hyperlipidemia, atherosclerosis, diabetes and other diseases.
  • uric acid Decreased excretion or increased production of uric acid is the main cause of primary hyperuricemia.
  • uric acid has two important sources, exogenous and endogenous. Exogenous uric acid accounts for 20% of the source of uric acid. Almost all purines ingested from food are converted into uric acid in the body. Endogenous uric acid accounts for 80% of the source of uric acid, and the main reason for its increase is the deficiency of enzymes in purine metabolism, which affects the feedback regulation of purine metabolism and uric acid synthesis. Enzyme defects have the following manifestations: 1. Increased phosphoribose pyrophosphate synthase activity; 2.
  • uric acid cannot be metabolized into urea sacs and can only be excreted as a prototype, with the intestinal tract accounting for 30% and the kidney accounting for 70%. In the kidneys, the excreted uric acid is completely filtered by the glomeruli. 90% of the uric acid is reabsorbed by the renal proximal tubules, and only 10% of the uric acid is excreted in the urine.
  • uric acid transporters play an important role in the excretion of uric acid, including urate anion transporter (Universal Asynchronous Receiver/Transmitter, URAT1), uric acid transport related protein (Glucose transporter 9, GLUT9),
  • URAT1 Universal Asynchronous Receiver/Transmitter
  • uric acid transport related protein Glucose transporter 9, GLUT9
  • OATs organic anion transporter family
  • a proper amount of uric acid plays a pivotal role in plasma. It can resist oxidation, inhibit the decomposition and synthesis of special enzymes, and can also chelate metal ions. Therefore, controlling the stability of blood uric acid levels in the body plays a vital role.
  • the treatment of gout is divided into the treatment of acute gout and the treatment of chronic gout.
  • the standard treatment of acute gout is to reduce and control the inflammatory response, such as the use of colchicine, non-steroidal anti-inflammatory drugs, glucocorticoids (oral, intra-articular or intramuscular injection); inhibition of interleukin-1 ⁇ (IL-1 ⁇ ) ) Of biological products such as anakinra, linacipr, kanazumab and so on.
  • the treatment of chronic gout is mainly to control the blood uric acid level ⁇ 6mg/dL through uric acid-lowering therapy.
  • uric acid-lowering agents can be divided into three categories: xanthine oxidoreductase inhibitors (XORIs), such as allopurinol and non Busostat, topipristat; uric acid excretion drugs, such as probenecid, benzbromarone, and Recinade; uricase, such as polyethylene glycol recombinant uricase.
  • XORIs xanthine oxidoreductase inhibitors
  • uric acid excretion drugs such as probenecid, benzbromarone, and Recinade
  • uricase such as polyethylene glycol recombinant uricase.
  • Allopurinol is a kind of purine XORIs. It was marketed in the 1960s. It can be rapidly oxidized in the body to Oxypurinol, which has a stronger XOR inhibitory effect. It has also been marketed for use.
  • Allopurinol can competitively inhibit the action of XOR and natural purine bases and block the production of uric acid, but it will produce many side effects, such as fever, allergic rash, diarrhea and abdominal pain.
  • Febuxostat (Febuxostat) was developed by Teijin Pharmaceutical Company of Japan and was approved in the United States in 2008. It is the first non-purine XORIs approved by the US FDA for more than 40 years since the application of allopurinol. Its inhibitory ability is stronger than Allopurinol. Clinical studies have shown that febuxostat can significantly inhibit the production of uric acid, with small side effects and good safety, but it may still increase the risk of cardiovascular events. It has recently been warned by the FDA.
  • Topiroxostat is a new type of aryltriazole-based competitive XORIs developed by Fuji Yakuhin, Japan. It was approved for marketing in Japan in August 2013.
  • Piraxostat Y-700
  • Y-700 is a type of mixed XORIs developed by Welfide. It has a strong and long-lasting effect on XOR to inhibit the production of uric acid.
  • Y-700 is metabolized by the liver, and in vivo pharmacokinetic experiments show that it has good oral bioavailability. Degree, is still in the clinical research stage.
  • the primary purpose of the present invention is to provide a tricyclic XOR inhibitor.
  • Another object of the present invention is to provide a method for preparing the above tricyclic XOR inhibitor.
  • Another object of the present invention is to provide the application of the above-mentioned tricyclic XOR inhibitor in the preparation of uric acid or gout-lowering drugs.
  • B is imidazolyl, pyrazolyl, thiazolyl or triazolyl
  • R is an "electron-donating group” such as C1-C9 alkyl, alkoxy, amino or hydroxyl, or R is an "electron-withdrawing group” such as cyano, halogen substituent, aldehyde, carboxyl, sulfonic acid or nitro group.
  • B is imidazolyl
  • R is a meta or para substitution; more preferably, it is a para substitution.
  • R is a C1-C9 saturated aliphatic linear alkyl, branched alkyl or alkoxy group, or R is a cyano group, a nitro group; more preferably a tert-butyl group, a methoxy group or a cyano group.
  • ring B is
  • the tricyclic XOR inhibitor is a compound as described in any one of the following:
  • the preparation method of the above tricyclic XOR inhibitor includes the following steps:
  • the organic solvent in steps (1) and (2) refers to DMF (N,N-dimethylformamide), and the inorganic base refers to K 2 CO 3 .
  • the alkaline hydrolysis and acidification in step (3) refers to adding NaOH aqueous solution to the mixed solution (EtOH/THF) of ethanol and tetrahydrofuran to hydrolyze, and then adding HCl aqueous solution to acidify.
  • the uric acid or gout-lowering drug includes as an active ingredient a tricyclic XOR inhibitor or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable salt includes a salt formed by a tricyclic XOR inhibitor, a metal ion, an organic base, and a salt that can retain the biological effectiveness and properties of the parent compound.
  • the metal ion is an alkali metal ion, an alkaline earth metal ion or an aluminum ion
  • the organic base is ethanolamine, diethanolamine, triethanolamine, tromethamine, piperidine or piperazine.
  • the tricyclic XOR inhibitors of the present invention have a completely different chemical structure from the known XOR inhibitors, and are a new type of XOR inhibitors; as demonstrated in the following experimental examples, they are effective against gout-related yellow Purine oxidase shows an excellent inhibitory effect, and shows an excellent uric acid-lowering effect in acute and long-term hyperuricemia mouse models; therefore, they can be used to prevent and treat xanthine oxidase-related diseases, For example, hyperuricemia, heart failure, cardiovascular disease, hypertension, kidney disease, inflammation, arthropathy, etc.
  • Figure 1 is a synthetic route diagram of the tricyclic XOR inhibitor of the present invention.
  • Figure 2 is a graph showing changes in plasma uric acid content over time after administration of the compound D 1 group of Example 1, the model control group, and the positive control group to acute hyperuricemia mice.
  • Fig. 3 is a graph showing the determination results of plasma uric acid, urea nitrogen and creatinine after administration of the compound D 1 group of Example 1 and the normal control group, the model control group, and the positive control group to long-term hyperuricemia mice.
  • Buffer Dilute 10 ⁇ PBS (pH 7.4) to 1 ⁇ PBS. Unless otherwise specified, the PBS in the reaction system refers to 1 ⁇ PBS.
  • Substrate Weigh 15.2 mg of xanthine, add 45 mL of PBS to ultrasonically dissolve, and then add PBS to make the volume to 200 mL to obtain a substrate solution of 0.5 mmol/L.
  • Enzyme solution Under ice bath, dilute 10.2 ⁇ L xanthine oxidoreductase mother solution with 20mL PBS to obtain 0.5 ⁇ g/100 ⁇ L enzyme solution.
  • the compound D 1 -D 3 obtained in the present invention has the following structure-activity relationship: 1.
  • the benzene rings of compounds D 1 , D 2 , and D 3 are substituted with 4-tert-butylphenyl, 4-methoxyphenyl, and 3-methoxyphenyl, respectively, and their inhibitory activity decreases sequentially , Suggesting that alkyl substitution on benzene ring is better than alkoxy substitution.
  • the inhibitory activity of compound D 2 is about twice that of compound D 3 , suggesting that para-substitution on the benzene ring is better than meta-substitution.
  • mice After 18-22g SPF grade ICR mice were adaptively fed for one week, they were randomly divided into a model control group (potassium oxazinate 250 mg ⁇ kg -1 + hypoxanthine 400 mg ⁇ kg -1 ) and a positive control group (oxazine Potassium 250mg ⁇ kg -1 + Hypoxanthine 400mg ⁇ kg -1 + Febuxostat 5mg ⁇ kg -1 ), group D 1 (potassium oxazine 250mg ⁇ kg -1 + hypoxanthine 400mg ⁇ kg -1 +D 1 compound 5 mg ⁇ kg -1 ), 8 rats in each group.
  • a model control group potassium oxazinate 250 mg ⁇ kg -1 + hypoxanthine 400 mg ⁇ kg -1
  • a positive control group oxazine Potassium 250mg ⁇ kg -1 + Hypoxanthine 400mg ⁇ kg -1 + Febuxostat 5mg ⁇ kg -1
  • group D 1 potassium oxazin
  • mice were weighed before the experiment, and the model control group and each administration group were given a subcutaneous injection of 250 mg ⁇ kg -1 of potassium oxazinate + intraperitoneal injection of 400 mg ⁇ kg -1 of hypoxanthine. After 1 hour, the blood uric acid level was measured (recorded as 1h). Blood uric acid), and immediately give each drug group the drug to be tested. The model control group is given the same amount of solvent. 1h, 2h, 3h, 4h, 5h, 6h, 7h after administration, the uric acid value is measured (respectively Recorded as 2h, 3h, 4h, 5h, 6h, 7h, 8h blood uric acid). The results obtained are plotted with graphpad 6.0 and statistically analyzed by one-tailed Students t-test. The results are shown in Figure 2 (*P ⁇ 0.05 compared with model control group, **P ⁇ 0.01 compared with model control group).
  • mice After 18-22g SPF grade ICR mice were adaptively fed for one week, they were randomly divided into normal control group (normal saline) and model control group (potassium oxazine 250mg ⁇ kg -1 + hypoxanthine 150mg ⁇ kg -1 ), positive control group (potassium oxazine 250 mg ⁇ kg -1 + hypoxanthine 150 mg ⁇ kg -1 + febuxostat 5 mg ⁇ kg -1 ), group D 1 (potassium oxazine 250 mg ⁇ kg -1 + Hypoxanthine 150 mg ⁇ kg -1 + D 1 compound 5 mg ⁇ kg -1 ), 8 rats in each group.
  • normal control group normal saline
  • model control group potassium oxazine 250mg ⁇ kg -1 + hypoxanthine 150mg ⁇ kg -1
  • positive control group potassium oxazine 250 mg ⁇ kg -1 + hypoxanthine 150 mg ⁇ kg -1 + febuxostat 5 mg ⁇ kg
  • mice were weighed before the experiment, and the model control group and each administration group were given subcutaneous injection of 250 mg ⁇ kg -1 of potassium oxonate + intraperitoneal injection of hypoxanthine 150 mg ⁇ kg -1 at 9:00 every day, and the normal control group was given
  • the above experiment was 7 days. On the seventh day after the treatment drug was administered for 1 hour, the eyeballs were taken immediately, and the blood was collected at 0-4°C for 10 minutes.
  • the blood was centrifuged at 10000 r/min for 5 minutes.
  • the upper plasma was carefully drawn and used with an automatic biochemical analyzer (Beckman Coulter, AU5811, Tokyo). , Japan) Measure the values of Uric acid, Urea Nitrogen and Crea in plasma.
  • the results are plotted in graphpad 6.0 to two-tailed Student's t-test statistical analysis, the results as shown in (# 3 as compared with the normal group, P ⁇ 0.05, ## as compared with the normal group, P ⁇ 0.01, * and Model P ⁇ 0.05 compared with group, **P ⁇ 0.01 compared with model group).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明属于医药化工技术领域，公开了一种三环类XOR抑制剂及其制备方法和应用。所述三环类XOR抑制剂的结构如式(I)所示，式中B为咪唑基、吡唑基、噻唑基或三氮唑基；R为C1～C9的烷基、烷氧基、氨基或羟基，或R为氰基、卤素取代基、醛基、羧基、磺酸基或硝基。以5-溴-2-碘-苯甲腈、R取代芳基硼酸、五元芳杂环-4-甲酸乙酯为起始原料，依次经过C-C偶联、C-N偶联及水解反应得到产物。本发明化合物具有与已知XOR抑制剂完全不同的化学结构，且对与痛风有关的XOR表现出优良的抑制作用，为抗高尿酸血症或痛风药物的制备提供了新途径。

Description

三环类XOR抑制剂及其制备方法和应用 技术领域
本发明属于医药化工技术领域，具体涉及一种三环类XOR抑制剂及其制备方法和应用。
背景技术
近年来，随着全球经济的飞速发展，人们的生活水平有了极大程度的提高，伴随而来的是与不良饮食习惯、生活方式有关的慢性病患病率攀升，其中痛风作为一种严重影响患者生活质量的疾病，越来越得到大家的关注和重视。
痛风是由于血尿酸水平持续升高导致单钠尿酸盐结晶沉积在关节和其它组织中所致。血尿酸的水平高低是痛风发生发展的核心因素，当血尿酸水平超过其血液中的饱和溶解量时，增高的尿酸盐结晶便在关节沉积，少许结晶脱落便可刺激周围组织产生炎症反应，引起关节的红、肿、热、痛，给患者日常生活带来极大的痛苦和不便。由此可见，高尿酸血症与痛风有着密不可分的关系，控制血尿酸水平是防治该病的关键。研究发现，高尿酸血症或者痛风与高血压、高脂血症、动脉粥样硬化、糖尿病等疾病的发生也有密切相关性。
尿酸排泄减少或生成增加是原发性高尿酸血症的主要病因。在人体内尿酸有外源性和内源性两个重要来源，其中外源性尿酸占尿酸来源的20％，从食物中摄入的嘌呤在体内几乎都转变成尿酸。内源性尿酸占尿酸来源的80％，其增多的主要原因是嘌呤代谢中酶的缺陷，从而影响嘌呤代谢的反馈调节和尿酸合成。酶缺陷则有以下几种表现：1、磷酸核糖焦磷酸合成酶活性增高；2、磷酸核糖焦磷酸酰胺转移酶活性增高；3、次黄嘌呤-鸟嘌呤磷酸核糖转移酶活性降低；4、黄嘌呤氧化还原酶活性增高。另一方面，由于人类缺少尿酸分解酶，所以尿 酸无法代谢为尿素囊，只能以原型排出，其排出比例肠道占30％、肾脏占70％。在肾脏中，排出的尿酸完全经肾小球滤过，其中90％的尿酸被肾脏近曲小管重吸收，只有10％尿酸随尿液排出体外。近年来研究显示，多种尿酸转运体在尿酸的排泄过程中扮演着重要角色，其中尿酸盐阴离子转运体(Universal Asynchronous Receiver/Transmitter，URAT1)、尿酸转运相关蛋白(Glucose transporter 9，GLUT9)、有机阴离子转运体(Organic anion transporter family，OATs)家族对尿酸的排泄影响最为重要。事实上适量的尿酸在血浆中有着举足轻重的作用，它能抗氧化、抑制特殊酶的分解和合成，并且还能螯合金属离子。因此，控制体内血尿酸水平稳定有着至关重要的作用。
痛风的治疗分为急性痛风的治疗和慢性痛风的治疗。急性痛风的标准治疗方法是减轻与控制炎症反应，例如使用秋水仙碱、非甾体抗炎药、糖皮质激素(口服，关节内或肌肉内注射)；抑制白细胞介素-1β(IL-1β)的生物制品如阿那白滞素、利那西普、卡纳单抗等。慢性痛风治疗主要是通过降尿酸治疗控制血尿酸水平<6mg/dL，常见的降尿酸试剂可分为三类：黄嘌呤氧化还原酶抑制剂(xanthine oxidoreductase inhibitors，XORIs)，如别嘌醇、非布索坦、托匹司他；促尿酸排泄药，如丙磺舒、苯溴马隆、雷西钠德；尿酸酶，如聚乙二醇重组尿酸酶。
长期以来，临床使用的抗痛风药物普遍表现出疗效差、副作用大、适用人群窄等缺点，而新兴的尿酸酶类药物由于免疫原性、长期使用的安全性及价格昂贵等问题也影响了其广泛使用。XORIs由于作用机理明确，疗效明显，副作用小的优点，倍受关注。别嘌醇(Allopurinol)是一种嘌呤类XORIs，于20世纪60年代上市，它在体内可以快速氧化成对XOR抑制作用更强的奥西嘌醇(Oxypurinol)，也已上市使用。别嘌醇可竞争性地抑制XOR与天然嘌呤碱的作用，阻断尿酸的生成，但是会产生许多副作用，例如发热、过敏性皮疹、腹泻及腹痛等症状。非布索坦(Febuxostat)由日本Teijin制药公司研发，于2008年在美国获得批准，是自别嘌醇应用40多年来美国FDA批准的第一个非嘌呤类的XORIs，它的抑制能力强于别嘌醇。临床研究表明，非布索坦可以显著抑制尿酸 的产生同时副作用小且安全性好，但仍有可能增加心血管事件发生风险，近期已被FDA黑框警告。托匹司他(Topiroxostat)是日本Fuji Yakuhin公司研发的一类新型芳基三唑类竞争性XORIs，于2013年8月在日本批准上市。Piraxostat(Y-700)是由Welfide公司研发的一类混合型XORIs，对XOR具有较强和长效抑制尿酸生成的效果，Y-700经肝脏代谢，体内药代实验显示具有良好的口服生物利用度，目前仍处于临床研究阶段。
随着对XOR研究的深入，人们发现，抑制XOR的活性除可治疗高尿酸血症外，对缺血、再灌注损伤、尤其是心衰也有一定疗效，高效低毒的XORIs具有巨大开发潜力和应用价值。就痛风这一顽疾而言，以XOR为作用靶点的新药设计已经得到广泛重视，多种高活性化合物已经进入临床试验，但仍面临毒副作用较大等诸多问题，有待更深入的研究。
发明内容
针对以上现有技术存在的缺点和不足之处，本发明的首要目的在于提供一种三环类XOR抑制剂。
本发明的另一目的在于提供上述三环类XOR抑制剂的制备方法。
本发明的再一目的在于提供上述三环类XOR抑制剂在制备降尿酸或痛风药物中的应用。
本发明目的通过以下技术方案实现：
一种三环类XOR抑制剂，其结构如式(I)所示：
Figure PCTCN2019125525-appb-000001
式(I)中，B为咪唑基、吡唑基、噻唑基或三氮唑基；
R为C1～C9的烷基、烷氧基、氨基或羟基等“供电子基团”，或R为氰基、卤素取代基、醛基、羧基、磺酸基或硝基等“吸电子基团”。
进一步优选的，B为咪唑基。
进一步优选的，R为间位或对位取代；更优选为对位取代。
进一步优选的，R为C1～C9的饱和脂肪直链烷基、支链烷基或烷氧基，或R为氰基、硝基；更优选为叔丁基、甲氧基或氰基。
进一步优选的，B环的结构为
Figure PCTCN2019125525-appb-000002
进一步优选的，所述三环类XOR抑制剂为如下任一项所述的化合物：
1-[4’-叔丁基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸；
1-[4’-甲氧基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸；
1-[3’-甲氧基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸。
上述三环类XOR抑制剂的制备方法，包括以下步骤：
(1)氩气保护下，将
Figure PCTCN2019125525-appb-000003
R取代苯基硼酸、无机碱、四三苯基磷钯加到有机溶剂中加热反应，得到
Figure PCTCN2019125525-appb-000004
(2)氩气保护下，将
Figure PCTCN2019125525-appb-000005
CuI、无机碱、(E)-N’N-二甲基-1,2-环己二胺在有机溶剂中，经C-N偶联反应，得到
Figure PCTCN2019125525-appb-000006
(3)
Figure PCTCN2019125525-appb-000007
经碱催化水解、酸化后得到
Figure PCTCN2019125525-appb-000008
上述制备方法的合成路线图如图1所示。
优选地，步骤(1)和(2)中所述的有机溶剂是指DMF(N,N-二甲基甲酰胺)，所述的无机碱是指K 2CO 3。
优选地，步骤(3)中所述碱性水解、酸化是指在乙醇和四氢呋喃的混合溶液(EtOH/THF)加入NaOH水溶液水解，再加入HCl水溶液酸化。
上述三环类XOR抑制剂在制备降尿酸或痛风药物中的应用。
优选地，所述降尿酸或痛风药物包括作为有效成分的三环类XOR抑制剂或其药学上可接受的盐、酯和药学上可接受的载体。
优选地，所述药学上可接受的盐包括三环类XOR抑制剂与金属离子、有机碱形成的盐，可以保留母体化合物的生物有效性和性质的盐。
更优选地，所述金属离子是碱金属离子、碱土金属离子或铝离子，所述有机碱是乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、哌啶或哌嗪。
本发明的三环类XOR抑制剂具有如下优点及有益效果：
本发明的三环类XOR抑制剂具有与已知XOR抑制剂完全不同的化学结构，是一类新颖结构的XOR抑制剂；如在下面的实验例中所证实的，它们对与痛风有关的黄嘌呤氧化酶表现出优良的抑制作用，并在急性和长期高尿酸血症小鼠模型中，表现出优良的降尿酸效果；因此，它们可以用于预防和治疗与黄嘌呤氧化酶相关的疾病，例如，高尿酸血症、心力衰竭、心血管疾病、高血压、肾疾病、炎症、关节病等。
附图说明
图1为本发明三环类XOR抑制剂的合成路线图。
图2为急性高尿酸血症小鼠给予实施例1的化合物D 1组和模型对照组、阳 性对照组后血浆中尿酸含量随时间的变化图。
图3为长期高尿酸血症小鼠给予实施例1的化合物D 1组和正常对照组、模型对照组，阳性对照组后血浆中尿酸、尿素氮和肌酐的测定结果图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例1
1-[4’-叔丁基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸(D 1)的合成：
(1)氩气保护下，将5-溴-2-碘-苯甲腈(1.5g，5mmol)，叔丁基苯硼酸(1.3g，7.5mmol)，K 2CO 3(2.8g，20mmol)，四三苯基磷钯(0.3g，0.3mmol)以及DMF(6mL)加入到30mL二颈瓶中，120℃下反应24h，TLC监测反应完全后，冷至室温，加入乙酸乙酯30mL稀释，加入30mL水，振荡分层，水相用乙酸乙酯(25mL×3)萃取，合并有机相，饱和食盐水(100mL×2)洗涤，无水硫酸镁干燥，减压蒸出溶剂，硅胶柱纯化(V 乙酸乙酯:V 石油醚＝1:20)得白色固体2-(4’-叔丁基-苯基)-5-溴-苯甲腈(a 1)1.3g，收率82.0％。
(2)氩气保护下，a 1(0.4g，1.2mmol)、咪唑-4-甲酸乙酯(0.14g，1.0mmol)、CuI(19mg，0.1mmol)、K 2CO 3(0.3g，2.1mmol)、及(E)-N’N-二甲基-1，2-环己基二胺(28mg，0.2mmol)和DMF(5mL)加入到25mL烧瓶中，110℃下反应24h。冷至室温，15mL水稀释，乙酸乙酯(15mL×3)萃取，饱和食盐水(10mL)洗涤，无水硫酸镁干燥，减压蒸除溶剂，硅胶柱纯化(V 乙酸乙酯:V 石油醚＝1:6)，得白色固体1-[4’-叔丁基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸乙酯(b 1)0.1g，收率52.0％。
(3)b 1(0.19g，0.5mmol)溶入体积比为1:1的四氢呋喃(4mL)和乙醇(4mL)的混合溶液中，加入1M NaOH 2mL，70℃下反应完全后，冷至室温，加入1M HCl调节pH为2-3，加水稀释，固体析出，抽滤，滤饼用水洗至中性，干 燥，得白色固体1-[4’-叔丁基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸(D 1)0.17g，收率95.0％。
产物的结构表征数据如下：
1H NMR(600MHz,DMSO-d 6)δ8.58(d,J＝1.1Hz,1H,-NCH),8.52(d,J＝1.1Hz,1H,-NCH),8.46(d,J＝2.4Hz,1H,ArH),8.18(dd,J＝8.5,2.4Hz,1H,ArH),7.78(d,J＝8.5Hz,1H,ArH),7.60-7.56(m,4H,ArH),1.35(s,9H,-C 6H 4C(C H 3) 3). 13C NMR(151MHz,DMSO-d 6)δ163.80,152.10,143.68,137.30,136.01,135.39,134.42,132.02,128.89,126.13,126.07,125.94,124.38,118.31,111.74,34.96,31.60,31.50。
实施例2
1-[4’-甲氧基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸(D 2)的合成：
(1)氩气保护下，5-溴-2-碘-苯甲腈(1.5g，5mmol)，4-甲氧基苯硼酸(1.1g，7.5mmol)，K 2CO 3(2.8g，20mmol)，四三苯基磷钯(0.3g，0.3mmol)以及DMF(6mL)加入到30mL二颈瓶中，120℃下反应24h，TLC监测反应完全后，冷至室温，加入乙酸乙酯30mL稀释，加入30mL水，振荡分层，水相用乙酸乙酯(25mL×3)萃取，合并有机相，饱和食盐水(100mL×2)洗涤，无水硫酸镁干燥，减压蒸出溶剂，硅胶柱纯化(V 乙酸乙酯:V 石油醚＝1:20)得白色固体2-(4’-甲氧基-苯基)-5-溴-苯甲腈(a 2)1.1g，收率78.6％。
(2)氩气保护下，a 2(0.4g，1.2mmol)、咪唑-4-甲酸乙酯(0.1g，1.0mmol)、CuI(19mg，0.1mmol)、K 2CO 3(0.3g，2.1mmol)、(E)-N’N-二甲基-1，2-环己基二胺(28mg，0.2mmol)和DMF(5mL)加入到25mL烧瓶中，110℃下反应24h。冷至室温，15mL水稀释，乙酸乙酯(15mL×3)萃取，饱和食盐水(10mL)洗涤，无水硫酸镁干燥，减压蒸除溶剂，硅胶柱纯化(V 乙酸乙酯:V 石油醚＝1:6)，得白色固体1-[4’-甲氧基-2-氰基-(1，1’-联苯)]-1H-咪唑-4-甲酸乙酯(b 2)0.1g，收率63.0％。
(3)b 2(0.17g，0.5mmol)溶入体积比为1:1的四氢呋喃(4mL)和乙醇(4mL)的混合溶液中，加入1M NaOH 2mL，70℃下反应完全后，冷至室温，加入 1M HCl调节pH为2-3，加水稀释，固体析出，抽滤，滤饼用水洗至中性，干燥，得白色固体1-[4’-甲氧基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸(D 2)0.15g，收率96.5％。
产物的结构表征数据如下：
1H NMR(600MHz,DMSO-d 6)δ8.56(s,1H,-NCH),8.51(s,1H,-NCH),8.44(d,J＝2.3Hz,1H,ArH),8.16(dd,J＝8.5,2.3Hz,1H,ArH),7.74(d,J＝8.5Hz,1H,ArH),7.58(d,J＝8.7Hz,2H,ArH),7.12(d,J＝8.7Hz,2H,ArH),3.84(s,3H,-C 6H 4OC H 3). 13C NMR(151MHz,DMSO-d 6)δ163.87,160.43,143.58,137.21,135.75,135.62,131.84,130.53,129.51,125.95,125.86,124.23,118.37,114.78,111.67,55.81。
实施例3
1-[3’-甲氧基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸(D 3)的合成：
(1)氩气保护下，5-溴-2-碘-苯甲腈(1.5g，5mmol)，3-甲氧基苯硼酸(1.1g，7.5mmol)，K 2CO 3(2.8g，20mmol)，四三苯基磷钯(0.3g，0.3mmol)以及DMF(6mL)加入到30mL二颈瓶中，120℃下反应24h，TLC监测反应完全后，冷至室温，加入乙酸乙酯30mL稀释后，加入30mL水，振荡分层，水相用乙酸乙酯(25mL×3)萃取，合并有机相，饱和食盐水(100mL×2)洗涤，无水硫酸镁干燥，减压蒸出溶剂，硅胶柱纯化(V 乙酸乙酯:V 石油醚＝1:20)得白色固体2-(3’-甲氧基-苯基)-5-溴-苯甲腈(a 3)1.0g，收率68.5％。
(2)氩气保护下，a 3(0.4g，1.2mmol)、咪唑-4-甲酸乙酯(0.1g，1.0mmol)、CuI(19mg，0.1mmol)、K 2CO 3(0.3g，2.1mmol)、(E)-N’N-二甲基-1，2-环己基二胺(28mg，0.2mmol)和DMF(5mL)加入到25mL烧瓶中，110℃下反应24h。冷至室温，15mL水稀释，乙酸乙酯(15mL×3)萃取，饱和食盐水(10mL)洗涤，无水硫酸镁干燥，减压蒸除溶剂，硅胶柱纯化(V 乙酸乙酯:V 石油醚＝1:6)，得白色固体1-[3’-甲氧基-2-氰基-(1，1’-联苯)]-1H-咪唑-4-甲酸乙酯(b 3)0.1g，收率63.0％。
(3)b 3(0.17g，0.5mmol)溶入体积比为1:1的四氢呋喃(4mL)和乙醇(4 mL)的混合溶液中，加入1M NaOH 2mL，70℃下反应完全后，冷至室温，加入1M HCl调节pH为2-3，加水稀释，固体析出，抽滤，滤饼用水洗至中性，干燥，得白色固体1-[3’-甲氧基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸(D 3)0.14g，收率90.0％。
产物的结构表征数据如下：
1H NMR(600MHz,DMSO-d 6)δ8.61(d,J＝4.7Hz,2H,-NCH),8.49(d,J＝1.8Hz,1H,ArH),8.20(dd,J＝8.4,1.9Hz,1H,ArH),7.81(d,J＝8.5Hz,1H,ArH),δ7.48(t,J＝7.9Hz,1H,ArH),7.19(d,J＝7.2Hz,1H,ArH),7.11-7.08(m,1H,ArH),3.84(s,2H,-C 6H 4OC H 3). 13C NMR(151MHz,DMSO-d 6)δ163.60,159.84,143.70,138.60,137.35,136.17,135.04,132.07,130.45,126.04,125.89,124.43,121.41,118.11,115.14,114.76,112.02,55.77。
以上实施例所得产物的活性评价：
一、化合物D 1-D 3对XOR的体外抑制活性评价
(1)溶液配制
缓冲液：将10×PBS(pH 7.4)稀释为1×PBS。除特别说明，反应体系中所指PBS均指1×PBS。
底物：称取15.2mg黄嘌呤，加入45mL PBS超声促溶，再加PBS定容至200mL，即得0.5mmol/L的底物溶液。
酶液：冰浴下，用20mL的PBS稀释10.2μL黄嘌呤氧化还原酶母液，即得到0.5μg/100μL的酶液。
待测化合物：分别准确称取实施例1～3中的产物D 1-D 3，用DMSO配制成1mmol/L的溶液贮备，于20℃避光储存。使用前用PBS稀释至所需浓度，DMSO含量要控制在5％以内以保证其对酶活无影响。
(2)测定
将上述配好的PBS溶液、样品或空白溶液(空白溶液为PBS溶液)、100μL酶液依次加入96孔板，在酶标仪中37℃下孵育3min，接着向孵化好的微孔 板中加入底物启动反应，295nm处每隔1min读数一次，共读5min，每组实验平行测定三次。将在各浓度下的试验化合物的初速度转化为基于没有抑制剂存在下的初速度的抑制率百分比(％)，计算IC 50值，结果如表1所示。
表1化合物D 1-D 3对XOR的抑制活性(n＝3)
Figure PCTCN2019125525-appb-000009
由表1结果可知，本发明所得化合物D 1-D 3具有以下构效关系：1、化合物D 1的抑酶活性最强(IC 50＝7.2nM)，与非布索坦相当(P>0.05)；2、化合物D 1、D 2、D 3的苯环分别为4-叔丁基苯基、4-甲氧基苯基、3-甲氧基苯基取代，它们的抑酶活性依次降低，提示苯环上烷基取代优于烷氧基取代。另外，化合物D 2的抑酶活性大约是化合物D 3的2倍，提示苯环上对位取代优于间位取代。
二、化合物D 1在急性高尿酸血症小鼠模型中的降尿酸活性评价
18-22g的SPF级ICR小鼠适应性喂养一周后，随机分组，分为模型对照组(氧嗪酸钾250mg·kg -1+次黄嘌呤400mg·kg -1)，阳性对照组(氧嗪酸钾250mg·kg -1+次黄嘌呤400mg·kg -1+非布索坦5mg·kg -1)，D 1组(氧嗪酸钾250mg·kg -1+次黄嘌呤400mg·kg -1+D 1化合物5mg·kg -1)，每组8只。
实验前称量小鼠体重，给予模型对照组及各给药组皮下注射氧嗪酸钾250mg·kg -1+腹腔注射次黄嘌呤400mg·kg -1，1h后测定血尿酸水平(记为1h血尿酸)，并立即对各药物组分别灌胃给予待测药物，模型对照组灌胃给予等量溶媒，给药后1h、2h、3h、4h、5h、6h、7h分别测定尿酸值(分别记为2h、3h、4h、5h、6h、7h、8h血尿酸)。所得结果以graphpad 6.0作图，以one-tailed Students t-test统计分析，结果如图2所示(*与模型对照组相比P<0.05，**与模型对照组相比P<0.01)。
由图2可知，在给药后的8h内，化合物D 1可以非常显著地降低急性高尿酸血症小鼠的血尿酸水平。
三、化合物D 1在长期高尿酸血症小鼠模型中的降尿酸活性评价
18-22g的SPF级ICR小鼠适应性喂养一周后，随机分组，分为正常对照组(生理盐水)，模型对照组(氧嗪酸钾250mg·kg -1+次黄嘌呤150mg·kg -1)，阳性对照组(氧嗪酸钾250mg·kg -1+次黄嘌呤150mg·kg -1+非布索坦5mg·kg -1)，D 1组(氧嗪酸钾250mg·kg -1+次黄嘌呤150mg·kg -1+D 1化合物5mg·kg -1)，每组8只。
实验前称量小鼠体重，每天于9:00分别给予模型对照组及各给药组皮下注射氧嗪酸钾250mg·kg -1+腹腔注射次黄嘌呤150mg·kg -1，正常对照组给予等量生理盐水，1h后分别测定血尿酸水平(记为1h血尿酸)，并立即对各药物组分别灌胃给予待测药物，正常对照组和模型对照组灌胃给予等量溶媒，连续重复上述实验7天。于第七天给予治疗药物1h后，立即摘眼球取血，血液于0-4℃静置10min，以10000r/min离心5min，小心吸取上层血浆，以自动生化分析仪(Beckman Coulter，AU5811，Tokyo，Japan)测定血浆中尿酸(Uric acid)、尿素氮(Urea Nitrogen)和肌酐(Crea)值。所得结果以graphpad 6.0作图，以two-tailed Student’s t-test统计分析，结果如图3所示( #与正常组相比P<0.05， ##与正常组相比P<0.01，*与模型组相比P<0.05，**与模型组相比P<0.01)。
由图3可知，模型对照组的血尿酸水平显著高于正常组，造模成功(P<0.001)，模型对照组的血肌酐和尿素氮水平均显著高于正常组，提示长期高尿酸血症会对小鼠的肾功能造成一定损伤(P<0.05)。与模型对照组做比较，D 1和非布索坦都对高尿酸血症小鼠有显著的降尿酸作用(P<0.05)，此外，化合物D 1显示了一定的降尿素氮和降肌酐作用(P<0.05)，说明化合物D 1在降低血尿酸活性之外，也能在一定程度上改善肾功能损伤。因此，基于化合物D 1降尿酸活性评价的结果，化合物D 1有待做进一步的研究，而且有望成为新型的降尿酸药物。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其它的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 一种三环类XOR抑制剂，其特征在于：所述三环类XOR抑制剂的结构如式(I)所示：
    Figure PCTCN2019125525-appb-100001
    式(I)中，B为咪唑基、吡唑基、噻唑基或三氮唑基；
    R为C1～C9的烷基、烷氧基、氨基或羟基，或R为氰基、卤素取代基、醛基、羧基、磺酸基或硝基。
  2. 根据权利要求1所述的一种三环类XOR抑制剂，其特征在于：B为咪唑基。
  3. 根据权利要求1所述的一种三环类XOR抑制剂，其特征在于：R为间位或对位取代；R为C1～C9的饱和脂肪直链烷基、支链烷基或烷氧基，或R为氰基、硝基。
  4. 根据权利要求1所述的一种三环类XOR抑制剂，其特征在于：B环的结构为
    Figure PCTCN2019125525-appb-100002
  5. 根据权利要求1所述的一种三环类XOR抑制剂，其特征在于：所述三环类XOR抑制剂为如下任一项所述的化合物：
    1-[4’-叔丁基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸；
    1-[4’-甲氧基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸；
    1-[3’-甲氧基-2-氰基-(1,1’-联苯)]-1H-咪唑-4-甲酸。
  6. 权利要求1～5任一项所述的一种三环类XOR抑制剂的制备方法，其特征在于包括以下步骤：
    (1)氩气保护下，将
    Figure PCTCN2019125525-appb-100003
    R取代苯基硼酸、无机碱、四三苯基磷钯加到有机溶剂中加热反应，得到
    Figure PCTCN2019125525-appb-100004
    (2)氩气保护下，将
    Figure PCTCN2019125525-appb-100005
    CuI、无机碱、(E)-N’N-二甲基-1,2-环己二胺在有机溶剂中，经C-N偶联反应，得到
    Figure PCTCN2019125525-appb-100006
    (3)
    Figure PCTCN2019125525-appb-100007
    经碱催化水解、酸化后得到
    Figure PCTCN2019125525-appb-100008
  7. 根据权利要求6所述的一种三环类XOR抑制剂的制备方法，其特征在于：步骤(1)和(2)中所述的有机溶剂是指DMF，所述的无机碱是指K 2CO 3。
  8. 根据权利要求6所述的一种三环类XOR抑制剂的制备方法，其特征在于：步骤(3)中所述碱性水解、酸化是指在乙醇和四氢呋喃的混合溶液加入NaOH水溶液水解，再加入HCl水溶液酸化。
  9. 权利要求1～5任一项所述的一种三环类XOR抑制剂在制备降尿酸或痛风药物中的应用。
  10. 根据权利要求9所述的一种三环类XOR抑制剂在制备降尿酸或痛风药物中的应用，其特征在于：所述降尿酸或痛风药物包括作为有效成分的三环类XOR抑制剂或其药学上可接受的盐、酯和药学上可接受的载体；所述药学上可 接受的盐包括三环类XOR抑制剂与金属离子或有机碱形成的盐；所述金属离子是碱金属离子、碱土金属离子或铝离子，所述有机碱是乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、哌啶或哌嗪。
PCT/CN2019/125525 2019-07-01 2019-12-16 三环类xor抑制剂及其制备方法和应用 WO2021000527A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910583434.1A CN110204493B (zh) 2019-07-01 2019-07-01 三环类xor抑制剂及其制备方法和应用
CN201910583434.1 2019-07-01

Publications (1)

Publication Number Publication Date
WO2021000527A1 true WO2021000527A1 (zh) 2021-01-07

Family

ID=67795630

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/125525 WO2021000527A1 (zh) 2019-07-01 2019-12-16 三环类xor抑制剂及其制备方法和应用

Country Status (2)

Country Link
CN (1) CN110204493B (zh)
WO (1) WO2021000527A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110204493B (zh) * 2019-07-01 2021-05-14 华南理工大学 三环类xor抑制剂及其制备方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101282934A (zh) * 2005-10-07 2008-10-08 安斯泰来制药株式会社 三芳基羧酸衍生物
WO2008126770A1 (ja) * 2007-04-05 2008-10-23 Astellas Pharma Inc. トリアリールカルボン酸誘導体の製造方法
WO2008126772A1 (ja) * 2007-04-05 2008-10-23 Astellas Pharma Inc. 高血圧治療剤
CN101389352A (zh) * 2006-02-24 2009-03-18 安斯泰来制药株式会社 治疗或预防消化道溃疡的药物
CN103848796A (zh) * 2012-11-30 2014-06-11 镇江新元素医药科技有限公司(中外合资) 一类氘代2-苯基噻唑化合物及其药物组合物
CN110204493A (zh) * 2019-07-01 2019-09-06 华南理工大学 三环类xor抑制剂及其制备方法和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101282934A (zh) * 2005-10-07 2008-10-08 安斯泰来制药株式会社 三芳基羧酸衍生物
CN101389352A (zh) * 2006-02-24 2009-03-18 安斯泰来制药株式会社 治疗或预防消化道溃疡的药物
WO2008126770A1 (ja) * 2007-04-05 2008-10-23 Astellas Pharma Inc. トリアリールカルボン酸誘導体の製造方法
WO2008126772A1 (ja) * 2007-04-05 2008-10-23 Astellas Pharma Inc. 高血圧治療剤
CN103848796A (zh) * 2012-11-30 2014-06-11 镇江新元素医药科技有限公司(中外合资) 一类氘代2-苯基噻唑化合物及其药物组合物
CN110204493A (zh) * 2019-07-01 2019-09-06 华南理工大学 三环类xor抑制剂及其制备方法和应用

Also Published As

Publication number Publication date
CN110204493B (zh) 2021-05-14
CN110204493A (zh) 2019-09-06

Similar Documents

Publication Publication Date Title
JP6635527B2 (ja) 高尿酸血症又は痛風の治療又は予防用化合物
CN107001320A (zh) 1‑烷基‑6‑氧代‑1,6‑二氢吡啶‑3‑基化合物及其用途
EP2927219B1 (en) 2-aryl selenazole compound and pharmaceutical composition thereof
KR20210097100A (ko) 2-(1-아실옥시-n-펜틸)벤조산 및 염기성 아미노산 또는 아미노구아니딘이 형성하는 염, 이의 제조 방법 및 용도
WO2016148114A1 (ja) 酸化ストレス誘導神経細胞死抑制化合物
JP2024516040A (ja) キサンチンオキシダーゼ抑制剤
WO2017071479A1 (zh) 一种谷氨酰胺酰基环化酶抑制剂
JP2019510744A (ja) 置換オキサジアゾール系化合物、当該化合物を含む組成物およびその応用
CN108727267A (zh) 一类urat1抑制剂及其应用
WO2021000527A1 (zh) 三环类xor抑制剂及其制备方法和应用
JP7050009B2 (ja) ハロゲン化合物およびその軸性キラリティ異性体
CN106632245B (zh) 氮取代基苯基吡唑类黄嘌呤氧化还原酶抑制剂及制备与应用
CN106478619B (zh) 一类黄嘌呤氧化酶抑制剂及其应用
KR20240004634A (ko) 삼환식 유비퀴틴 특이적 프로테아제 1 억제제 및 이의 용도
CN108484600A (zh) 促尿酸排泄的urat1抑制剂
WO2018001197A1 (zh) 一种尿酸转运体1抑制剂的制备方法
CN110078668B (zh) 一种苯基咪唑类xor抑制剂及制备与应用
CN105272984B (zh) 吡唑并[3,4-d]嘧啶-4-酮衍生物、其制备方法和应用
CN103601674B (zh) 一种抑制二肽激肽酶的化合物及制备方法和用途
CN114805192B (zh) 一种含2-羟基苯甲酸的三环类xor/urat1双重抑制剂及其制备方法与应用
CN108218777A (zh) 一种硫取代苯基吡唑类xor抑制剂及制备与应用
CN106459053B (zh) 吡唑并[3,4-d]嘧啶-4-酮衍生物、其制备方法和应用
CN114920663A (zh) 一种联苯类奥司他韦衍生物及其制备方法与应用
CN118026948A (zh) 三联芳环类化合物及其制备方法、药物组合物和应用
CN108276418A (zh) 化合物、含有该化合物的药用组合物及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19936157

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19936157

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 25/05/2022)

122 Ep: pct application non-entry in european phase

Ref document number: 19936157

Country of ref document: EP

Kind code of ref document: A1