帕唑帕尼 | 444731-52-6

• 物质功能分类: 原料药 - 循环系统用药 - 抗高血压病药
• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 帕唑帕尼
• 中文别名: VEGFR抑制剂；5-[[4-[(2,3-二甲基-2H-吲唑-6-基)(甲基)氨基]嘧啶-2-基]氨基]-2-甲基苯磺酰胺
• 英文名称: pazopanib
• 英文别名: Votrient；5-((4-((2,3-dimethyl-2H-indazol-6- yl)(methyl)amino)pyrimidin-2-yl)amino)-2-methylbenzenesulfonamide；GW-786034；5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide；5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzolsulfonamide；5-[[4-[(2,3-dimethylindazol-6-yl)-methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide
• CAS: 444731-52-6
• 化学式: C₂₁H₂₃N₇O₂S
• 分子量: 437.525
• InChiKey: CUIHSIWYWATEQL-UHFFFAOYSA-N

物化性质

• 熔点：
  285-289°C (dec.)
• 沸点：
  728.8±70.0 °C(Predicted)
• 密度：
  1.40
• 闪点：
  359℃
• 溶解度：
  可溶于酸水溶液（轻微）、DMSO（轻微、加热）、甲醇（轻微、加热）
• 蒸汽压力：
  3.21X10-14 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Based on the stability data a shelf-life of 24 months will be applied to the product, with no special storage conditions requirements.
• 分解：
  Thermal decomposition may produce toxic gases such as carbon monoxide, carbon dioxide, and nitrogen oxides. /Pazopanib hydrochloride/
• 解离常数：
  pKa1 = 2.29 (amine); pKa2 = 5.07 (amine); pKa3 = 10.41 (amide) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  127
• 氢给体数：
  2
• 氢受体数：
  8

ADMET

代谢

通过CYP3A4代谢，其次通过CYP1A2和CYP2C8代谢。代谢物的活性低于帕唑帕尼（活性降低10到20倍）。其三个代谢物可以在系统中观察到，占血浆放射活性的不到10%。

Metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C8. Metabolites are less active than pazopanib (10 to 20-fold less active). Three of its metabolites can be observed in the systemic and account for <10% of plasma radioactivity.

来源:DrugBank

代谢

体外研究显示，帕唑帕尼通过CYP3A4代谢，CYP1A2和CYP2C8有较小的贡献。

In vitro studies demonstrated that pazopanib is metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C8.

来源:Hazardous Substances Data Bank (HSDB)

代谢

pazopanib(Votrient)是一种口服酪氨酸激酶抑制剂,最近被批准用于治疗肾细胞癌和软组织肉瘤。在这项为期两部分的的研究中,研究了(14)C-pazopanib的代谢、处置以及pazopanib片剂在晚期癌症患者中的口服生物利用度。在A部分,三名男性各接受了一次口服(14)C-pazopanib悬浊液(400毫克,70微居里)。有两个来自羟基化反应的代谢物和一个来自N-脱甲基反应的代谢物在循环中,但都很少,每个代谢物占血浆放射活性的<5%。

Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. In this two-part study, ... the metabolism, disposition of (14)C-pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer /was investigated. In part A, three men each received a single oral dose of (14)C-pazopanib in suspension (400 mg, 70 uCi). Two metabolites derived from hydroxylation and one from N-demethylation were ,,, circulating, but were minor, each accounting for <5% of plasma radioactivity. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

在人肝脏微粒体和肝细胞中观察到的代谢途径包括单氧合作用、双氧合作用，以及可能氧化成羧酸。在人肝细胞中还检测到了单氧合代谢物的葡萄糖苷酸化。在肝脏微粒体或肝细胞培养中并没有观察到独特的人类一期代谢物。然而，一个二期代谢物，即可能来源于羧酸代谢物的葡萄糖苷酸，仅在人类肝细胞中观察到。其假定的前体在体内被识别为来自插管猴子胆管的胆汁中的重要组成部分（<19%）。总之，体外和体内的代谢数据表明，在代谢方面没有主要的物种差异。

The routes of metabolism observed in human liver microsomes and hepatocytes were monooxygenation, di-oxygenation, and possibly oxidation to a carboxylic acid. Glucuronidation of a monooxygenated metabolite was also detected in human hepatocytes. There were no unique human phase I metabolites observed in either liver microsomal or hepatocyte incubations. However, a phase II metabolite, i.e., a glucuronide potentially derived from a carboxylic acid metabolite, was observed only in human hepatocytes. Its presumed precursor was identified in vivo as a significant component (<19%) in bile from bile duct cannulated monkeys. In conclusion, the combined in vitro and in vivo metabolic data indicated no major species differences in metabolism.

来源:Hazardous Substances Data Bank (HSDB)

代谢

pazopanib 在人肝微粒体和肝细胞培养物中的代谢程度较低，在大多数临床前物种中也是如此。与研究中其他物种相比，pazopanib 在兔和狗肝细胞中的代谢更为广泛。口服给药后，在所有物种（包括人类）的粪便中，未改变的 pazopanib 是主要成分。

The extent of metabolism of pazopanib was low in human liver microsomal and hepatocyte incubations as well as in most of the preclinical species. Pazopanib was more extensively metabolized by rabbit and dog hepatocytes than by those from the other species studied. Following PO administration, unchanged pazopanib was the predominant component in feces from all species including humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：帕唑帕尼是一种白色至略带黄色的固体，制成薄膜包衣片。帕唑帕尼是一种多受体酪氨酸激酶抑制剂，是一种抗肿瘤药物。它用于治疗晚期肾细胞癌，以及用于已接受过化疗的晚期软组织肉瘤患者。人类暴露和毒性：在接受帕唑帕尼治疗的患者中，曾报告出现严重的或致命的肝毒性，表现为血清转氨酶和胆红素浓度升高。如果出现肝毒性，应减少帕唑帕尼的剂量，或中断或永久停止治疗。孕妇应避免使用帕唑帕尼。尽管没有对孕妇进行充分且良好控制的研究，但动物研究已显示帕唑帕尼具有致畸性、胚胎毒性、胎儿毒性和流产作用。如果在怀孕期间使用或患者在接受帕唑帕尼治疗期间怀孕，应告知患者可能对胎儿造成的危害。在接受帕唑帕尼治疗的患者中，还报告了QT间期延长、尖端扭转型室性心动过速以及严重且有时致命的出血事件。最后，使用帕唑帕尼还与可能导致致命的胃肠道穿孔或瘘管有关。动物研究：尽管没有进行帕唑帕尼的致癌性研究，但在小鼠的13周研究中，雌性小鼠在1000毫克/千克/天的剂量下出现了肝脏的增殖性病变，包括嗜酸性灶，另一只雌性小鼠观察到单个腺瘤病例。帕唑帕尼在大鼠的剂量水平低至3毫克/千克/天时，产生了胎儿致畸效应（包括心血管畸形和骨化延迟），减少了胎儿体重，并导致胚胎死亡。在兔子的研究中，剂量低至30毫克/千克/天时就观察到了母体毒性（体重减轻、食物消耗减少和流产），而剂量低至3毫克/千克/天时胎儿体重就减轻了。帕唑帕尼在300毫克/千克/天的剂量下也降低了雌性大鼠的生育能力。在剂量低至10毫克/千克/天时，就注意到了着床前和着床后损失以及早期吸收增加。在猴子和老鼠中观察到黄体减少，在大鼠中注意到卵巢萎缩。尽管帕唑帕尼没有影响雄性大鼠的交配或生育能力，但在15周的剂量低至100毫克/千克/天时，观察到精子生产率、精子活力以及附睾和睾丸精子浓度的降低。在26周给药后，给予30毫克/千克/天或更高剂量的雄性大鼠表现出睾丸和附睾重量减轻，睾丸萎缩和退化，伴有无精子症、精子减少和附睾的筛状变化。在大鼠的毒理学研究中，出现了多种组织（骨骼、牙齿、骨髓、指甲床、生殖器官、血液组织、肾脏、肾上腺、淋巴结、垂体和胰腺）的影响，这些影响与血管内皮生长因子受体（VEGFR）抑制和/或VEGF信号通路的破坏一致，其中一些影响在3毫克/千克/天的剂量下发生。帕唑帕尼在一组标准的遗传毒性研究中进行了测试。在细菌细胞（Ames）试验、人外周淋巴细胞染色体畸变试验和大鼠微核试验中，帕唑帕尼被发现不具有致突变性和断裂性。

IDENTIFICATION AND USE: Pazopanib is a white to slightly yellow solid formulated into film-coated tablets. Pazopanib, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent. It is used for the treatment of advanced renal cell carcinoma and for patients with advanced soft tissue sarcoma who have received prior chemotherapy. HUMAN EXPOSURE AND TOXICITY: Severe or fatal hepatotoxicity, manifested as increases in serum concentrations of aminotransferases and bilirubin, has been reported in patients receiving pazopanib. If hepatotoxicity occurs, pazopanib dosage should be reduced, or therapy should be interrupted or permanently discontinued. Woman should avoid the use of pazopanib during pregnancy. While there are no adequate and well-controlled studies in pregnant women, pazopanib has been shown to be teratogenic, embryotoxic, fetotoxic, and abortifacient in animal studies. If used during pregnancy or if the patient becomes pregnant while receiving pazopanib, the patient should be apprised of the potential fetal hazard. Prolongation of the QT interval and torsades de pointes and severe and sometimes fatal hemorrhage events have been reported in patients receiving pazopanib. Finally, GI perforation or fistula which can be fatal has also been associated with the use of pazopanib. ANIMAL STUDIES: While carcinogenicity studies with pazopanib have not been conducted, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci occurred in 2 females and a single case of adenoma in another female was observed at a dose of 1000 mg/kg/day. Pazopanib produced fetal teratogenic effects (including cardiovascular malformations and delayed ossification), reduced fetal body weight, and embryo lethality in rats at a dose level as low as 3 mg/kg/day. In rabbits, maternal toxicity (body weight loss, reduced food consumption, and abortion) was observed at doses as low as 30 mg/kg/day, while fetal weight was reduced at doses as low as 3 mg/kg/day. Pazopanib also reduced fertility in female rats at a dose of 300 mg/kg. Increased pre- and post-implantation loss and early resorptions were noted at doses as low as 10 mg/kg/day. Decreased corpora lutea were observed in monkeys and mice and ovarian atrophy was noted in rats. While pazopanib did not affect mating or fertility in male rats, reductions in sperm production rates, sperm motility, and epididymal and testicular sperm concentration was observed at doses as low as 100 mg/kg/day for 15 weeks. Following 26 weeks of dosing, male rats given doses of 30 mg/kg/day or greater exhibited decreased testicular and epididymal weights, atrophy and degeneration of the testes with aspermia, hypospermia and cribriform change in the epididymis. In toxicology studies in rats, there were effects in a variety of tissues (bone, teeth, bone marrow, nail beds, reproductive organs, hematological tissues, kidney, adrenal glands, lymph node, pituitary, and pancreas) consistent with vascular endothelial growth factor receptor (VEGFR) inhibition and/or disruption of VEGF signaling pathways with some effects occurring at doses of 3 mg/kg/day. Pazopanib was tested in a standard battery of genotoxicity studies. Pazopanib was found to be nonmutagenic and non-clastogenic when tested in a bacterial cell (Ames) assay, human peripheral lymphocyte chromosome aberration assay and rat micronucleus assay.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在大规模临床试验中，接受帕唑帕尼治疗的患者的常规肝功能检测常常出现异常，其中高达一半的患者出现血清转氨酶升高，约三分之一的患者出现总胆红素升高。谷丙转氨酶（ALT）和谷草转氨酶（AST）值超过正常上限（ULN）5倍的情况发生在8%的患者中，ALT和胆红素同时升高的组合在1%到2%的患者中出现。在帕唑帕尼用于各种实体瘤的初步试验中，有罕见报告出现黄疸的肝炎。

In large clinical trials, abnormalities in routine liver tests were common in patients treated with pazopanib, with serum aminotransferase elevations occurring in up to half of patients and total serum bilirubin in approximately one-third. ALT and AST values greater than 5 times the upper limit of normal (ULN) occurred in 8% of patients and combinations of ALT and bilirubin elevations in 1% to 2%. In preliminary trials of pazopanib in various solid tumors, there were rare reports of hepatitis with jaundice in

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：帕唑帕尼

Compound:pazopanib

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

pazopanib在癌症患者中的吸收缓慢且不完全。在实体瘤患者中，剂量在50-2000毫克范围内，吸收是非线性的。在连续22天每天一次接受800毫克 pazopanib的患者中，也可以观察到显著的药物积累。压碎药片可能会增加暴露量（Cmax和AUC增加，而Tmax减少2小时）。生物利用度，口服片800毫克，癌症患者= 21％；由于从胃肠道吸收不完全，生物利用度可能较低。在系统中循环的主要药物成分是pazopanib，而不是其代谢物。平均最高血浆浓度= 58.1 µg/mL；平均AUC = 1037 µg · h/mL；

Absorption of pazopanib in cancer patients is slow and incomplete. In patients with solid tumour, over a dose range of 50-2000 mg, absorption is nonlinear. Significant accumulation of pazopanib can also be observed in patients receiving 800 mg once daily for 22 days. Crushing tablets may increase exposure (increase in Cmax and AUC, while Tmax decreases by 2 hours). Bioavailability, oral tablet 800 mg, cancer patient = 21%; Bioavailability may be low due to incomplete absorption from the gastrointestinal tract. The major circulating component of the drug in the systemic is pazopanib, and not its metabolites. Mean maximum plasma concentration= 58.1 µg/mL; Mean AUC= 1037 µg · h/mL;

来源:DrugBank

吸收、分配和排泄

• 消除途径

主要通过粪便排出（82.2%），在癌症患者中通过尿液排出的量微不足道（<4%）。大部分给药剂量以原形排出。大约10%的剂量是氧化代谢物，主要通过粪便消除。

Primarily excreted via feces (82.2%) and to a negligible extent via urine (<4%) in cancer patients. Most of the administered dose is excreted unchanged. Approximately 10% of dose are oxidative metabolites and are mostly eliminated via the feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

稳态下，静脉注射5毫克，癌症患者=11.1升（范围9.15-13.4）

Vd steady state, IV administration 5 mg, cancer patient = 11.1 L (range of 9.15 - 13.4)

来源:DrugBank

吸收、分配和排泄

• 清除

CL,癌症患者，静脉注射5毫克=4毫升/分钟，吸收剂量的一半通过氧化代谢清除。

CL, cancer patient, IV administration 5 mg = 4mL/min Half of the absorbed dose is cleared via oxidative metabolism.

来源:DrugBank

吸收、分配和排泄

当与食物一起服用时，帕唑帕尼的系统暴露量会增加。高脂肪或低脂肪餐时服用帕唑帕尼会导致AUC和Cmax大约增加2倍。因此，帕唑帕尼应在餐前至少1小时或餐后2小时服用。

Systemic exposure to pazopanib is increased when administered with food. Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2 fold increase in AUC and Cmax. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S28B,S36/37/39
• 危险类别码：
  R43,R62/63
• 海关编码：
  29350090
• 危险性防范说明：
  P264,P270,P273,P301+P312,P330
• 危险性描述：
  H302,H413
• 储存条件：
  Refrigerator

制备方法与用途

产品描述 帕唑帕尼是由葛兰素史克公司研发的一种新型口服血管生成抑制剂，专门针对顽固肿瘤的新血管生成过程。它靶向作用于血管内皮生长因子受体（VEGFR），通过抑制对肿瘤供血的新血管生成来发挥其药效。该药物适用于治疗晚期肾细胞癌、软组织肉瘤（STS）、上皮性卵巢癌和非小细胞肺癌。

梅奥临床研究中心的美国明尼苏达州罗彻斯特市的研究显示，帕唑帕尼（商品名Votrient）不仅能有效治疗甲状腺癌，还能使一半患者的肿瘤体积缩小。相比常用药物，它更能长时间稳定病情，并维持较长的治疗效果，是目前治疗甲状腺癌应答率最高的药物之一。

美国食品药品监督管理局于2009年10月19日批准帕唑帕尼（商品名Votrient）上市，它是自2005年以来第六个获批用于治疗肾细胞癌的药物。数据显示，2009年约有3万名患者被诊断为肾细胞癌。

不良反应

使用该药物可能出现腹泻、高血压、毛发颜色改变、恶心、食欲不振、呕吐、疲劳、虚弱、腹痛及头痛等不良反应。此外，帕唑帕尼还可能引发严重的肝脏问题，因此在治疗前和期间应进行血液检测以监测肝功能。孕妇禁用此药，因为对胎儿有害。用药期间还需要定期检查心电图和电解质水平，以防出现心律不齐。

生物活性

Pazopanib（GW786034）是一种新型多靶点的VEGFR1、VEGFR2、VEGFR3、PDGFR、FGFR、c-Kit 和 c-Fms/CSF1R抑制剂，IC50值分别为10 nM、30 nM、47 nM、84 nM、74 nM、140 nM 和 146 nM。此外，它还能够诱导cathepsin B的活化和自噬。

靶点

• VEGFR1（无细胞试验）：10 nM
• VEGFR2（无细胞试验）：30 nM
• VEGFR3（无细胞试验）：47 nM
• c-Kit（无细胞试验）：74 nM

体外研究

Pazopanib有效抑制VEGF诱导的HUVEC细胞中VEGFR2磷酸化作用，IC50为8 nM。在所有滑膜肉瘤细胞系中，包括SYO-1和HS-SY-II细胞，它表现出剂量依赖性生长抑制作用。SYO-1和HS-SY-II细胞的增殖在1微克/毫升Pazopanib下被抑制，在5微克/毫升时完全停止。Pazopanib引起G1期阻滞，并且因此抑制滑膜肉瘤细胞的生长。与载体处理的细胞相比，Akts、GSK-3β、JNKs、p70 S6 激酶和mTOR的磷酸化作用在Pazopanib处理的SYO-1细胞中被抑制。

体内研究

与用载体或10毫克/千克Pazopanib处理的小鼠相比，使用30毫克/千克或100毫克/千克剂量Pazopanib的小鼠肿瘤负荷显著降低。Pazopanib治疗具有良好的耐受性，并且每组小鼠的体重差异没有明显不同。

反应信息

• 作为反应物：
  描述：

  帕唑帕尼 在 2-均三甲苯基-2,5,6,7-四氢吡咯并[2,1-C][1,2,4]三唑-4-鎓氯化物 、 potassium carbonate 、 苯甲醛 作用下， 以 乙醇 为溶剂， 反应 18.0h， 生成 C₂₁H₂₁N₆O₂S^(1-)*K⁽¹⁺⁾
  参考文献：
  名称：

  NHC 催化的伯磺酰胺脱氨基：后期功能化的平台

  摘要：

  在此，我们描述了一种将初级磺胺类药物温和、后期转化为其他几个官能团的方法的开发和应用。这些反应通过磺酰胺的初始还原脱氨基作用发生，通过 NHC 催化的瞬时形成的 N-磺酰亚胺反应生成亚磺酸盐。这里描述的方法几乎可以容忍所有常见的官能团，例如几种复杂药物化合物的后期衍生化。基于含磺酰胺药物和构建块的流行，我们开发了一种方法，使磺酰胺能够用作合成化学的多功能合成手柄。

  DOI：

  10.1021/jacs.8b11800
• 作为产物：
  描述：

  N,2,3-三甲基-2H-吲唑-6-胺 在 盐酸 、 sodium carbonate 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 8.0h， 生成 帕唑帕尼
  参考文献：
  名称：

  A Novel Practical Synthesis of Pazopanib: An Anticancer Drug

  摘要：

  本文报告了一种合成帕唑帕尼的新方法。在我们的合成路线中，避免使用如二甲基硫酸酯和碘甲烷等具有强致突变性的烷基化试剂。报道了一种对3-甲基-6-硝基-1H-吲唑的2位进行区域选择性甲基化的新方法。这条新路线比之前报道的路线少了一步。

  DOI：

  10.2174/157017812800233714

文献信息

• Switching on prodrugs using radiotherapy
  作者：Jin Geng、Yichuan Zhang、Quan Gao、Kevin Neumann、Hua Dong、Hamish Porter、Mark Potter、Hua Ren、David Argyle、Mark Bradley

  DOI：10.1038/s41557-021-00711-4

  日期：2021.8

  Chemotherapy is a powerful tool in the armoury against cancer, but it is fraught with problems due to its global systemic toxicity. Here we report the proof of concept of a chemistry-based strategy, whereby gamma/X-ray irradiation mediates the activation of a cancer prodrug, thereby enabling simultaneous chemo-radiotherapy with radiotherapy locally activating a prodrug. In an initial demonstration, we show the activation of a fluorescent probe using this approach. Expanding on this, we show how sulfonyl azide- and phenyl azide-caged prodrugs of pazopanib and doxorubicin can be liberated using clinically relevant doses of ionizing radiation. This strategy is different to conventional chemo-radiotherapy radiation, where chemo-sensitization of the cancer takes place so that subsequent radiotherapy is more effective. This approach could enable site-directed chemotherapy, rather than systemic chemotherapy, with ‘real time’ drug decaging at the tumour site. As such, it opens up a new era in targeted and directed chemotherapy. Prodrugs offer one route to treat cancer, but they require activation once they have been delivered to the tumour. Now, a simultaneous chemo-radiotherapy strategy has been demonstrated in mice that uses gamma or X-ray irradiation to locally activate an anticancer prodrug.

  化疗是抗击癌症的有力武器，但由于其全身性的毒性，存在诸多问题。在此，我们报告了一种基于化学的策略的概念验证，该策略通过γ射线/X射线辐射介导激活一种癌症前药，从而实现化疗与局部激活前药的放射疗法的同步进行。在初步演示中，我们展示了利用这种方法激活荧光探针的过程。在此基础上，我们展示了如何利用临床相关剂量的电离辐射释放pazopanib和doxorubicin的磺酰叠氮化物和苯基叠氮化物笼蔽前药。这种策略与传统化疗-放射疗法中通过化疗增敏使后续放射疗法更有效的辐射不同。这种方法可能实现靶向局部化疗，而非全身性化疗，在肿瘤部位实现“实时”药物释放。因此，它开启了靶向和定向化疗的新纪元。 前药为治疗癌症提供了一条途径，但一旦送达肿瘤后需要激活。现在，在小鼠身上展示了一种同步化疗-放射疗法策略，使用γ或X射线辐射在局部激活抗癌前药。
• [EN] BENZOTHIADIAZINE COMPOUNDS<br/>[FR] COMPOSÉS BENZOTHIADIAZINE
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2017098421A1

  公开（公告）日：2017-06-15

  The invention is directed to substituted benzothiadiazine derivatives. Specifically, the invention is directed to compounds according to Formula (I):wherein R, R1, R2, R3, R4 and R5 are as defined herein. The compounds of the invention are inhibitors of CD73 and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with CD73 inhibition, such as AIDS, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting CD73 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

  本发明涉及取代苯并噻二嗪衍生物。具体而言，本发明涉及式(I)化合物：其中R、R1、R2、R3、R4和R5定义如下。本发明的化合物是CD73的抑制剂，可用于治疗癌症、前癌综合症和与CD73抑制相关的疾病，如艾滋病、自身免疫病、感染、动脉粥样硬化和缺血-再灌注损伤。因此，本发明进一步涉及包含本发明化合物的药物组合物。本发明更进一步的涉及使用本发明化合物或包含本发明化合物的药物组合物抑制CD73活性和治疗相关疾病的方法。
• [EN] 5-(1 H-BENZO[D]IMIDAZO-2-YL)-PYRIDIN-2-AMINE AND 5-(3H-IMIDAZO[4,5-B]PYRIDIN-6-YL)-PYRIDIN-2-AMINE DERIVATIVES AS C-MYC AND P300/CBP HISTONE ACETYLTRANSFERASE INHIBITORS FOR TREATING CANCER<br/>[FR] DÉRIVÉS DE 5-(1 H-BENZO[D]IMIDAZO-2-YL)-PYRIDIN-2-AMINE ET DE 5-(3H-IMIDAZO[4,5-B]PYRIDIN-6-YL)-PYRIDIN-2-AMINE UTILISÉS EN TANT QU'INHIBITEURS D'HISTONE ACÉTYLTRANSFÉRASE DE C-MYC ET P300/CBP POUR LE TRAITEMENT DU CANCER
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2019049061A1

  公开（公告）日：2019-03-14

  The invention is directed to substituted 5-(1H-benzo[d]imidazo-2-yl)- pyridin-2-amine and 5-(3H-imidazo[4,5-b]pyridin-6-yl)-pyridin-2-amine derivatives. Specifically, the invention is directed to compounds according to Formula (lb) wherein R', R2', R3', R4', Rs', R6', R7', and X1' are as defined herein; or a salt thereof including a pharmaceutically acceptable salt thereof. The compounds of the invention decrease MYC protein (c-MYC) in cells and/or inhibit p300/CBP histone acetyltransferase and can be useful in the treatment of cardiac hypertrophy, diabetes, obesity & nonalcoholic fatty liver disease, HIV, polycystic kidney disease, inflammatory diseases, ankylosing spondylitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, cancer and pre-cancerous syndromes, and diseases associated with dysregulation of Myc or inhibition of p300/CBP histone acetyltransferase. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention still further discloses methods of reducing MYC protein (c-MYC) in cells and inhibiting p300/CBP histone acetyltransferase activity, and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

  本发明涉及取代的5-(1H-苯并[d]咪唑-2-基)-吡啶-2-胺和5-(3H-咪唑[4,5-b]吡啶-6-基)-吡啶-2-胺衍生物。具体而言，本发明涉及根据公式(lb)的化合物，其中R'、R2'、R3'、R4'、Rs'、R6'、R7'和X1'按本说明书中定义；或其盐，包括药用可接受的盐。本发明的化合物能够降低细胞中的MYC蛋白（c-MYC）和/或抑制p300/CBP组蛋白乙酰转移酶，可用于治疗心肌肥大、糖尿病、肥胖和非酒精性脂肪肝疾病、HIV、多囊肾疾病、炎症性疾病、强直性脊柱炎、银屑病、银屑病关节炎、类风湿性关节炎、克罗恩病、多发性硬化症、癌症和前癌症综合症，以及与Myc失调或p300/CBP组蛋白乙酰转移酶抑制相关的疾病。因此，本发明进一步涉及包含本发明化合物的药物组合物。本发明还进一步公开了使用本发明的化合物或包含本发明化合物的药物组合物，降低细胞中MYC蛋白（c-MYC）和抑制p300/CBP组蛋白乙酰转移酶活性的方法，以及治疗与之相关的疾病的方法。
• [EN] 5-SULFAMOYL-2-HYDROXYBENZAMIDE DERIVATIVES<br/>[FR] DÉRIVÉS DE 5-SULFAMOYL-2-HYDROXYBENZAMIDE
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2017153952A1

  公开（公告）日：2017-09-14

  The invention is directed to substituted salicylamide derivatives. Specifically, the invention is directed to compounds according to Formula (I): wherein R, R1 and R2 are as defined herein, or a pharmaceutically acceptable salt thereof. The compounds of the invention are inhibitors of CD73 and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with CD73 inhibition, such as AIDS, the treatment of HIV, autoimmune diseases, infections, atherosclerosis, and ischemia–reperfusion injury. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting CD73 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

  本发明涉及取代水杨酰胺衍生物。具体而言，本发明涉及根据公式(I)的化合物：其中R、R1和R2如本文所述，或其药用可接受的盐。本发明的化合物是CD73的抑制剂，可用于治疗癌症、前癌症综合症以及与CD73抑制相关的疾病，例如艾滋病、治疗HIV、自身免疫疾病、感染、动脉粥样硬化和缺血再灌注损伤。因此，本发明进一步涉及包含本发明化合物的药物组合物。本发明还进一步涉及使用本发明化合物或包含本发明化合物的药物组合物来抑制CD73活性和治疗与之相关的疾病的方法。
• [EN] IMIDAZOLIDINONE DERIVATIVES AS INHIBITORS OF PERK<br/>[FR] DÉRIVÉS D'IMIDAZOLIDINONE COMME INHIBITEURS DE PERK
  申请人：GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTD

  公开号：WO2017046739A1

  公开（公告）日：2017-03-23

  The invention is directed to substituted imidazolidinone derivatives. Specifically, the invention is directed to compounds according to Formula I (I) wherein R1, R2, R3, R4, R5, R6, R7, X, Y1, Y2 and Z are defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, pre-cancerous syndromes, as Alzheimer's disease, neuropathic pain, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, Parkinson disease, diabetes, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob Disease, fatal familial insomnia, Gerstmann-Sträussler-Scheinker syndrome, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis, chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, frontotemporal dementias, tauopathies, Pick's disease, Neimann-Pick's disease, amyloidosis, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

  这项发明涉及取代咪唑烷酮衍生物。具体而言，该发明涉及根据式I（I）中R1、R2、R3、R4、R5、R6、R7、X、Y1、Y2和Z所定义的化合物。该发明的化合物是PERK的抑制剂，可用于治疗癌症、癌前综合征、阿尔茨海默病、神经病性疼痛、脊髓损伤、创伤性脑损伤、缺血性中风、中风、帕金森病、糖尿病、代谢综合征、代谢紊乱、亨廷顿病、克雅氏病、致命性家族性失眠、格斯特曼-施特劳斯勒-谢因克症候群及相关朊蛋白病、肌萎缩侧索硬化、进行性核上性麻痹、心肌梗死、心血管疾病、炎症、器官纤维化、肝脏慢性和急性疾病、脂肪肝病、肝脂肪变性、肝纤维化、肺部慢性和急性疾病、肺纤维化、肾脏慢性和急性疾病、肾脏纤维化、慢性创伤性脑病（CTE）、神经退行性疾病、痴呆症、额颞叶痴呆症、tau蛋白病、皮克氏病、尼曼-皮克氏病、淀粉样变性、认知障碍、动脉粥样硬化、眼部疾病、心律失常、器官移植以及器官移植用途中的运输。因此，该发明进一步涉及包含该发明化合物的药物组合物。该发明还进一步涉及使用该发明化合物或包含该发明化合物的药物组合物抑制PERK活性和治疗相关疾病的方法。