吉列替尼 | 1254053-43-4

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 吉列替尼
• 中文别名: 吉利替尼
• 英文名称: gilteritinib
• 英文别名: ASP-2215；(6-ethyl-3-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide)；6-ethyl-3-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide
• CAS: 1254053-43-4
• 化学式: C₂₉H₄₄N₈O₃
• 分子量: 552.72
• InChiKey: GYQYAJJFPNQOOW-UHFFFAOYSA-N

物化性质

• 熔点：
  >157°C (dec.)
• 沸点：
  696.9±55.0 °C(Predicted)
• 密度：
  1.242±0.06 g/cm3(Predicted)
• 溶解度：
  溶于 DMSO (25 mg/ml)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  40
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  121
• 氢给体数：
  3
• 氢受体数：
  10

ADMET

代谢

吉特替尼主要通过肝脏中的CYP3A4酶活性代谢。其代谢主要由N-脱烷基化和氧化反应驱动，形成M17、M16和M10等代谢物。从血浆浓度来看，主要形式是未改变的药物。

Gilteritinib is primarily metabolized in the liver by the activity of CYP3A4. Its metabolism is driven by reactions of N-dealkylation and oxidation which forms the metabolite M17, M16 and M10. From the plasma concentration, the major form is the unchanged drug.[L4835]

来源:DrugBank

毒理性

• 肝毒性

血清氨基转移酶水平升高在吉尔特尼布治疗期间很常见，发生在78%的患者中，并且有12%的患者升高超过正常上限的5倍。吉尔特尼布的临床使用有限，但并未与急性肝损伤伴有症状或黄疸的实例相关联。由于FLT3抑制剂的使用在临床经验上有限，它们导致肝损伤的潜力尚未得到很好的定义。

Elevations in serum aminotransferase levels are common during gilteritinib therapy occurring in 78% of patients and rising above 5 times the upper limit of the normal range in 12%. Gilteritinib has had limited clinical use but has not been linked to instances of acute liver injury with symptoms or jaundice. Because of the limited clinical experience with the use of FLT3 inhibitors, their potential for causing liver injury is not well defined.

来源:LiverTox

毒理性

• 毒性总结

吉特替尼布在小鼠细菌突变分析中未报告具有突变性，在中国仓鼠肺细胞异常试验中也没有报告具有断裂性。然而，它在小鼠骨髓中诱导了微核，并且在睾丸中引起了生殖细胞和精母细胞巨细胞形成的退化和坏死，以及附睾管上皮细胞的单个细胞坏死。[FDA标签]

Gilteritinib is not reported to be mutagenic in bacterial mutagenesis assays nor clastogenic in aberration test assays in Chinese hamster lung cells. However, it resulted positive for the induction of micronuclei in mouse bone marrow and for the degeneration and necrosis of germ cells and spermatid giant cell formation in testis as well as single cell necrosis of the epididymal duct epithelia.[FDA label]

来源:DrugBank

毒理性

• 蛋白质结合

吉特替尼被报告与血浆蛋白高度结合，占剂量的94%。根据这个比例，主要的结合蛋白是血清白蛋白。

Gilteritinib is reported to be highly bound to plasma proteins, representing 94% of the dose. From this ratio, the main protein-bound is serum albumin.[L4834]

来源:DrugBank

吸收、分配和排泄

• 吸收

在临床前试验中，口服给药后2小时观察到吉瑞替尼的最大血浆浓度，随后在4-8小时后达到肿瘤组织中的最大浓度。最大浓度以及药时曲线下面积（AUC）随剂量相应改变，分别报告为374 ng/ml和6943 ng·h/ml。在连续给药15天后达到稳态血浆水平，大约有10倍的生物累积。在人类空腹状态下，报告tmax为4-6小时。与高脂肪餐同服时，Cmax和AUC分别降低了26%和10%，tmax延迟了2小时。

In preclinical trials, the maximal plasma concentration of gilteritinib was observed 2 hours after oral administration and followed by a maximal intratumor concentration after 4-8 hours. The maximum concentration, as well as the AUC, were modified correspondingly with the dose and were reported to be 374 ng/ml and 6943 ng.h/ml, respectively.[A40048] The steady-state plasma level is reached within 15 days of dosing with an approximate 10-fold bioaccumulation.[L4833] In a fasted state in humans, the tmax is reported to be of 4-6 hours. The Cmax and AUC were decreased by 26% and 10% respectively by the co-ingestion of a high-fat meal with a tmax delay of 2 hours.[L4834]

来源:DrugBank

吸收、分配和排泄

• 消除途径

从给药剂量来看，吉特替尼主要在粪便中排泄，占给药剂量的64.5%，而16.4%的药物原形或其代谢物在尿液中回收。[L4835]

From the administered dose, gilteritinib is mainly excreted in feces which represents 64.5% of the administered dose while 16.4% is recovered in urine either as the unchanged drug or as its metabolites.[L4835]

来源:DrugBank

吸收、分配和排泄

• 分布容积

估计的表观中央和周围分布体积分别为1092升和1100升。这个值表明了广泛的组织分布。

The estimated apparent central and peripheral volume of distribution is 1092 L and 1100 L respectively. This value indicated an extensive tissue distribution.[L4834]

来源:DrugBank

吸收、分配和排泄

• 清除

吉特利替尼的估计清除率是14.85 L/h。[L4834]

The estimated clearance of gilteritinib is 14.85 L/h.[L4834]

来源:DrugBank

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  -20℃

制备方法与用途

吉列替尼是一种FLT3酪氨酸激酶抑制剂，能够对携带FLT3-ITD基因变异和FLT3酪氨酸激酶蛋白域基因变异的FLT3产生抑制作用，并在AML细胞系中抑制AXL受体的活性。

适应症

吉列替尼是一种有效的、选择性FLT3口服抑制剂，靶向FTL3与Axl。它获批用于携带FLT3突变的复发或难治性急性髓系白血病成人患者，并用于治疗约三分之一的携带FLT3基因突变的复发/难治性急性骨髓性白血病（AML）成人患者。基因突变需通过FDA批准的伴随诊断确认。

临床试验

吉列替尼（Gilteritinib，ASP2215）是一种口服的FLT3/AXL抑制剂，具有抗FLT3-ITD和FLT3-TKD活性。前期临床试验显示该药在复发难治性FLT3阳性的AML患者中表现出疗效。一项新的I期临床试验将吉列替尼加入标准“3+7”方案诱导、大剂量阿糖胞苷巩固治疗，并以此单药进行维持，在每天服药大于等于80mg的27例FLT3突变阳性患者中，24例（88.9%）达完全缓解或完全缓解伴部分血液学恢复。其中17位患者接受120mg/天的剂量，耐受良好，并得到100%的CRc。目前该试验仍在继续当中，而该药已经分别在日本和美国FDA获批上市。

生物活性

Gilteritinib (ASP2215)是小分子FLT3/AXL抑制剂，对FLT3和AXL的IC50值分别为0.29 nM和0.73 nM。其抑制c-KIT的IC50值约为抑制FLT3的800倍。

靶点

• FLT3 (细胞自由实验)： 0.29 nM
• AXL (细胞自由实验)： 0.73 nM

体外研究

在表达突变型FLT3的MV4-11和MOLM-13、Ba/F3细胞中，Gilteritinib对FLT3-ITD（内部串联重复）和FLT3-D835Y具有有效的抑制活性。Gilteritinib在细胞实验和动物模型中可降低FLT3及其下游靶点的磷酸化水平。在所检测的78种激酶中，浓度为1 nM或5 nM的Gilteritinib可抑制其中8种激酶活性（即抑制程度超过50%）。对MV4-11细胞进行Gilteritinib处理，处理48小时可诱导细胞凋亡。Gilteritinib处理24小时后还能下调抗凋亡蛋白如MCL-1、BCL2L10、survivin的表达。

体内研究

在体内实验中，gilteritinib经口服后可在异种移植瘤组织中高水平地分布。在FLT3驱动的AML模型中，gilteritinib在肿瘤组织中的富集使FLT3活性降低、肿瘤消退并改善生存。gilteritinib的抗肿瘤活性与它对磷酸化FLT3和磷酸化STAT5的双重抑制相关。此外，在小鼠IBMT模型中，gilteritinib可降低白血病负担并延长生存时间。在小鼠模型中gilteritinib的处理没有明显毒性作用。

反应信息

• 作为反应物：
  描述：

  富马酸 、 吉列替尼 以 甲醇 为溶剂， 反应 0.5h， 以1.6 g的产率得到6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate
  参考文献：
  名称：

  [EN] PROCESS FOR THE PREPARATION OF GILTERITINIB FUMARATE
  [FR] PROCÉDÉ DE PRÉPARATION DE FUMARATE DE GILTÉRITINIB

  摘要：

  The present invention provides process for the preparation of 2-pyrazine carboxamide, 6-ethyl-3-[[3-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl] phenyl] amino]-5-[ (tetra hydro-2H-pyran-4-yl) amino]-, (2E)-2-butenedioate (2:1) of formula (I) and its crystalline and / or amorphous forms there of. 2-Pyrazinecarboxamide, 6-ethyl-3-[ [ 3- methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl] phenyl] amino]-5-[(tetrahydro-2H-pyran-4-yl) amino]-, (2E)-2-butenedioate (2:1) (I) is represented by the following structural formula.

  公开号：

  WO2022009235A1
• 作为产物：
  描述：

  6-ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carbonitrile 在 双氧水 、 sodium hydroxide 作用下， 以 乙醇 、 二甲基亚砜 为溶剂， 反应 3.0h， 以85%的产率得到吉列替尼
  参考文献：
  名称：

  一种3，5-二取代-吡嗪-2-甲酰胺化合物的合 成方法

  摘要：

  本发明公开了一种3,5‑二取代‑吡嗪‑2‑甲酰胺化合物的合成方法，具体的说，是一种对参与癌细胞生长的FLT3‑Axl的受体酪氨酸激酶具有优异抑制活性的3,5‑二取代‑吡嗪‑2‑甲酰胺化合物的合成方法，其特征是包含以下步骤：将化合物5进行水解反应，即可；本发明方法反应条件温和，操作简单，后处理简便，反应收率大幅度提高，是一条全新的可工业化的合成路线。

  公开号：

  CN106083821B

文献信息

• DIAMINO HETEROCYCLIC CARBOXAMIDE COMPOUND
  申请人：Shimada Itsuro

  公开号：US20120040968A1

  公开（公告）日：2012-02-16

  Provided is a compound useful as an inhibitor against the kinase activity of EML4-ALK fusion protein. As a result of intensive and extensive studies on compounds having inhibitory activity against the kinase activity of EML4-ALK fusion protein, the present inventors found that the diamino heterocyclic carboxamide compounds of the present invention had inhibitory activity against the kinase activity of EML4-ALK fusion protein. By this finding, the present invention was completed. The compounds of the present invention can be used as a pharmaceutical composition for preventing and/or treating cancer, such as lung cancer, non-small cell lung cancer, and small cell lung cancer.

  提供的是一种化合物，可作为抑制EML4-ALK融合蛋白激酶活性的抑制剂。通过对具有抑制EML4-ALK融合蛋白激酶活性的化合物进行深入广泛的研究，本发明人发现本发明的二氨基杂环羧酰胺化合物对EML4-ALK融合蛋白激酶活性具有抑制作用。通过这一发现，完成了本发明。本发明的化合物可用作预防和/或治疗癌症，如肺癌、非小细胞肺癌和小细胞肺癌的药物组合物。
• [EN] COMBINATION THERAPY WITH AN ANTI-AXL ANTIBODY-DRUG CONJUGATE<br/>[FR] POLYTHÉRAPIE AVEC UN CONJUGUÉ ANTICORPS ANTI-AXL-MÉDICAMENT
  申请人：ADC THERAPEUTICS SA

  公开号：WO2018193102A1

  公开（公告）日：2018-10-25

  The present disclosure relates to combination therapies for the treatment of pathological conditions, such as cancer. In particular, the present disclosure relates to combination therapies comprising treatment with an Antibody Drug Conjugate (ADC) and a secondary agent.

  本公开涉及用于治疗病理状况，如癌症的联合疗法。具体而言，本公开涉及包括抗体药物结合物（ADC）治疗和辅助药物治疗的联合疗法。
• PHARMACEUTICAL COMPOSITION COMPRISING DIAMINO HETEROCYCLIC CARBOXAMIDE COMPOUND AS ACTIVE INGREDIENT
  申请人：ASTELLAS PHARMA INC.

  公开号：US20160339020A1

  公开（公告）日：2016-11-24

  A pharmaceutical composition is suitable for treating AXL-related cancer. The cancer can be cancer with high expression of AXL. The cancer can also be cancer which has acquired resistance by the activation of AXL against therapy with an anticancer agent. Specific diamino heterocyclic carboxamide compounds have an AXL inhibitory action, and pharmaceutical compositions comprising these compounds as an active ingredient have a therapeutic effect on AXL-related cancer. This AXL-related cancer can be cancer with high expression of AXL and/or cancer which has acquired resistance by the activation of AXL against therapy with an anticancer agent.

  一种药物组合适用于治疗与AXL相关的癌症。该癌症可以是AXL表达高的癌症。该癌症也可以是通过激活AXL对抗抗癌药物治疗而获得耐药性的癌症。特定的二氨基杂环羧酰胺化合物具有抑制AXL的作用，含有这些化合物作为活性成分的药物组合物对与AXL相关的癌症具有治疗作用。这种与AXL相关的癌症可以是AXL表达高和/或通过激活AXL对抗抗癌药物治疗而获得耐药性的癌症。
• MEDICINAL COMPOSITION COMPRISING DIAMINO HETEROCYCLIC CARBOXAMIDE COMPOUND AS ACTIVE INGREDIENT
  申请人：Astellas Pharma Inc.

  公开号：EP3103453A1

  公开（公告）日：2016-12-14

  [Problem] To provide: a medicinal composition for treating an AXL-related cancer; in another embodiment, a medicinal composition for treating a cancer with high expression of AXL; and, in still another embodiment, a medicinal composition for treating a cancer that has acquired resistance through activation of AXL against anticancer agent therapy. [Solution] As the results of an examination on compounds having AXL inhibitory effect, the present inventors confirmed that specific diamino heterocyclic carboxamide compounds have AXL inhibitory effect and medicinal compositions comprising such a compound as an active ingredient have therapeutic effect on an AXL-related cancer, on a cancer with high expression of AXL in another embodiment, and on a cancer that has acquired resistance through activation of AXL against anticancer agent therapy in still another embodiment, thereby completing the present invention.

  [问题]提供：一种用于治疗AXL相关癌症的药物组合物；在另一个实施方案中，一种用于治疗AXL高表达癌症的药物组合物；以及在另一个实施方案中，一种用于治疗通过激活AXL对抗癌剂治疗产生耐药性的癌症的药物组合物。[解]作为对具有 AXL 抑制作用的化合物进行研究的结果，本发明人确认特定二氨基杂环羧酰胺化合物具有 AXL 抑制作用，并且包含这种化合物作为活性成分的药物组合物对 AXL 相关癌症、在另一个实施方案中对 AXL 高表达癌症以及在另一个实施方案中对通过激活 AXL 获得抗癌剂治疗耐药性的癌症具有治疗效果，从而完成了本发明。
• STABLE PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION
  申请人：Astellas Pharma Inc.

  公开号：EP3318259A1

  公开（公告）日：2018-05-09

  Provided is a stable pharmaceutical composition for oral administration comprising 6-ethyl-3-(3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide (hereinafter referred to as compound A) or a pharmaceutically acceptable salt thereof, wherein the generation of related substances during storage is inhibited. In the stable pharmaceutical composition for oral administration, the proportion of crystals of compound A or a pharmaceutically acceptable salt thereof is 60% or more with respect to the total amount of compound A or a pharmaceutically acceptable salt thereof.

  本发明提供了一种用于口服的稳定药物组合物，该组合物包含 6-乙基-3-(3-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}氨基)-5-(四氢-2H-吡喃-4-基氨基)吡嗪-2-甲酰胺（以下简称化合物 A）或其药学上可接受的盐，其中相关物质在储存期间的生成受到抑制。在用于口服的稳定药物组合物中，化合物 A 或其药学上可接受的盐的晶体比例占化合物 A 或其药学上可接受的盐总量的 60% 或以上。