托法替尼 | 477600-75-2

• 物质功能分类: 生物化工 - 抑制剂 - 酪氨酸蛋白激酶/信号转导子和转录活化子抑制剂(JAK/STAT)
• 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: 托法替尼
• 中文别名: 3-((3R,4R)-4-甲基-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)-3-氧代丙腈；1,4-二氯-2,5-二甲氧基苯；托法替布；CP 690550；CP-690550；3-((3R,4R)-4-甲基-3-(甲基(7H-吡咯并(2,3-d)嘧啶-4-基)氨基)哌啶-1-基)-3-氧代丙腈
• 英文名称: tasocitinib
• 英文别名: Tofacitinib；(+/-)-CP 690550；3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile；3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile；xeljanz；3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
• CAS: 477600-75-2
• 化学式: C₁₆H₂₀N₆O
• 分子量: 312.374
• InChiKey: UJLAWZDWDVHWOW-YPMHNXCESA-N

物化性质

• 密度：
  1.3
• 溶解度：
  可溶于DMSO（高达100mg/ml）或乙醇（高达100mg/ml）。
• 颜色/状态：
  Yellow foam
• 蒸汽压力：
  1.32X10-10 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions. /Tofacitinib citrate/
• 旋光度：
  Specific optical rotation: +10.4 deg at 25 °C/D (c = 0.64 in methanol)
• 解离常数：
  pKa1 = 8.46 (cyano); pKa2 = 13.56 (secondary amine)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  88.9
• 氢给体数：
  1
• 氢受体数：
  5

ADMET

代谢

在肝脏由CYP3A4和CYP2C19代谢。产生的代谢物是无效的。

Metabolized in the liver by CYP3A4 and CYP2C19. Metabolites produced are inactive.

来源:DrugBank

代谢

托法替尼的清除机制大约是70%通过肝脏代谢和30%通过肾脏排泄原型药物。托法替尼的代谢主要是由CYP3A4介导，CYP2C19有较小的贡献。在一项人体放射性标记研究中，超过65%的总循环放射性是由未改变的托法替尼引起的，剩余的35%归因于8种代谢物，每种代谢物占总放射性的不到8%。托法替尼的药理活性归因于原型分子。

Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和用途：托法替尼是一种黄色泡沫。作为药物Xeljanz，它用于治疗对甲氨蝶呤反应不足或不耐受的中度至重度活动性类风湿性关节炎（RA）成人患者。它可能作为单药治疗或与甲氨蝶呤或其他非生物疾病修饰抗风湿药物（DMARDs）联合使用。人类暴露和毒性：根据流行病学研究，接受托法替尼治疗的RA患者的总体感染（包括严重感染）风险和死亡率似乎与接受生物制剂治疗的RA患者观察到的相似。严重感染率随时间保持稳定。在全球托法替尼RA开发计划中，结核病是最常见的报告的机会性感染，但在低和中结核病发病率的地区却很罕见。在一项遗传毒性研究中，在代谢激活的高细胞毒性浓度下，人类淋巴细胞体外细胞遗传学分析中观察到染色体异常的增加，但在没有代谢激活的情况下没有观察到影响。动物研究：在食蟹猴中，由于急性暴露，观察到呕吐和活动减少。Xeljanz在单次口服剂量大于或等于500 mg/kg时导致大鼠死亡。免疫和造血器官系统被确定为重复剂量毒性研究动物的主要靶标。在大鼠的围产期/产后发育研究中，Xeljanz在口服剂量50 mg/kg/天时减少了交付和活产幼仔的数量，并减少了幼仔在口服剂量下的存活率。Xeljanz在兔子和大鼠的口服剂量分别为30和100 mg/kg/天时具有致畸性（外部、内脏和骨骼异常）。Xeljanz在细菌反向突变试验中不具有致突变性。Xeljanz在哺乳动物细胞（体外CHO/HGPRT试验）中不具有致突变性，并且没有在大鼠肝细胞非计划DNA合成试验中诱导原发性DNA损伤。Xeljanz在体内大鼠微核试验中也为阴性。在一项为期2年的大鼠致癌性研究中，Xeljanz在口服剂量大于或等于30 mg/kg/天时诱导良性Leydig细胞肿瘤和恶性冬眠瘤，在100/75 mg/kg/天时诱导良性胸腺瘤。在一项为期39周的成年猴子重复剂量毒性研究中，在高剂量5 mg/kg每日两次时观察到淋巴瘤，但在较低剂量1 mg/kg每日两次时未观察到（大约相当于人类暴露）。

IDENTIFICATION AND USE: Tofacitinib is a yellow foam. As the drug Xeljanz, it is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). HUMAN EXPOSURE AND TOXICITY: According to epidemiological studies, the overall risk of infection (including serious infection) and mortality rates in RA patients treated with tofacitinib appear to be similar to those observed in RA patients treated with biologic agents. The rates of serious infection were stable over time. Within the global tofacitinib RA development program, tuberculosis was the most common opportunistic infection reported but was rare in regions of low and medium TB incidence. In a genotoxicity study, increases in chromosomal abnormalities were observed in a human lymphocyte in vitro cytogenetic assay, at high cytotoxic concentrations with metabolic activation, but no effects were observed without metabolic activation. ANIMAL STUDIES: In cynomolgus monkeys, emesis and decreased activity were observed as a result of acute exposure. Xeljanz caused death in rats at single oral doses of >/= 500 mg/kg. Immune and hematopoietic organ systems were identified as main targets in repeat-dose toxicity studies on animals. In a peri/postnatal development study in rats, Xeljanz decreased the number of delivered and live born pups, and reduced pup survival at oral doses of 50 mg/kg/day. Xeljanz was teratogenic (external, visceral and skeletal abnormalities) in rabbits and rats at oral doses of 30 and 100 mg/kg/day, respectively. Xeljanz was not mutagenic in the bacterial reverse mutation assay. Xeljanz was not mutagenic in mammalian cells (in vitro CHO/HGPRT assay) and did not induce primary DNA damage in an in vivo/in vitro rat hepatocyte unscheduled DNA synthesis assay. Xeljanz was also negative in the in vivo rat micronucleus test. In a 2-year rat carcinogenicity study, Xeljanz induced benign Leydig cell tumors and malignant hibernomas at oral doses of >/= 30 mg/kg/day and benign thymomas at 100/75 mg/kg/day. In a 39-week repeat-dose toxicity study in adult monkeys, lymphomas were observed at the high dose of 5 mg/kg twice daily, but not at the lower dose of 1 mg/kg twice daily (approximately equivalent to human exposure).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在大规模注册临床试验中，接受托法替尼治疗的受试者血清转氨酶升高的情况发生在28%到34%，而对照组发生率为25%，安慰剂组为10%。这些升高通常是轻微和暂时的，但在托法替尼治疗的患者中，高于正常上限3倍（ULN）的情况发生在1%到2%，而安慰剂组不到1%。这些升高偶尔会导致早期停药，但更多时候即使不调整剂量也能解决。在上市前的研究中，没有因托法替尼导致的临床上明显的肝损伤案例。自从托法替尼获得批准并更广泛使用以来，没有发表过与其使用相关的肝毒性的报告，但一部分患者确实出现了血清转氨酶升高，有时会导致停药。虽然其他Janus激酶抑制剂，如鲁索利替尼，曾与乙型肝炎再激活的案例有关，但在托法替尼治疗期间临床上明显的乙型肝炎再激活的自发报告尚未见报道。另一方面，对HBsAg阳性且肝脏疾病不活跃的患者进行托法替尼治疗的回顾性研究报道，这些患者出现了HBV DNA水平升高和血清转氨酶水平的轻微升高，但没有症状。相比之下，对血清中存在抗-HBc但无HBsAg的患者的研究没有显示出HBV DNA升高和HBsAg出现的证据。因此，在治疗期间乙型肝炎的再激活可能会发生，尽管它通常是轻微的和自限性的。在重度COVID-19肺炎的易感患者中使用托法替尼治疗后乙型肝炎是否会再激活尚不清楚，但迄今为止还没有这样的报告。

In large registration clinical trials, serum aminotransferase elevations occurred in 28% to 34% of tofacitinib treated subjects compared to 25% in comparator arms and 10% in placebo recipients. These elevations were typically mild and transient, but values above 3 times the upper limit of normal (ULN) occurred in 1% to 2% of patients on tofacitinib compared to less than 1% on placebo. The elevations occasionally led to early discontinuations, but more often resolved even without dose adjustment. In prelicensure studies, there were no instances of clinically apparent liver injury attributed to tofacitinib. Since approval and more wide scale availability of tofacitinib, there have been no published reports of hepatotoxicity associated with its use but a proportion of patients do develop serum aminotransferase elevations which in some cases leads to drug discontinuation. While other Janus kinase inhibitors such as ruxolitinib have been associated with episodes of reactivation of hepatitis B, spontaneous reports of clinically apparent reactivation of hepatitis during tofacitinib therapy have not been reported. On the other hand, retrospective studies on patients with HBsAg and inactive liver disease who were treated with tofacitinib have been reported to develop rising levels of HBV DNA and modest elevations in serum aminotransferase levels without symptoms. In contrast, studies of patients with anti-HBc without HBsAg in serum have shown no evidence of HBV DNA rises and appearance of HBsAg. Thus, reactivation of hepatitis B during therapy can occur, although it is generally mild and self-limited in course. Whether reactivation of hepatitis B can arise after therapy of susceptible patients with tofacitinib for severe COVID-19 pneumonia is unknown, but there have been no such reports to date.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概要：目前没有关于在哺乳期间使用托法替尼的临床信息。在获得更多信息之前，特别是在哺乳新生儿或早产儿时，可能更倾向于使用其他药物。制造商和一个专家小组建议在托法替尼治疗期间及最后一次服用Xeljanz后18小时或最后一次服用Xeljanz XR后36小时内停止哺乳。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No information is available on the clinical use of tofacitinib during breastfeeding. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. The manufacturer and an expert panel recommend that breastfeeding be discontinued during tofacitinib therapy and for 18 hours after the last dose of Xeljanz or 36 hours after the last dose of Xeljanz XR. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 在妊娠和哺乳期间的影响

◈ 托法替尼是什么？ 托法替尼是一种处方药，用于治疗类风湿性关节炎、银屑病关节炎和溃疡性结肠炎。关于这些疾病的信息，可以在我们的资料页找到：https://mothertobaby.org/fact-sheets/rheumatoid-arthritis/、https://mothertobaby.org/fact-sheets/psoriasis-and-pregnancy/ 和 https://mothertobaby.org/fact-sheets/inflammatory-bowel-disease-pregnancy/。托法替尼的品牌名为Xeljanz®和Xeljanz XR®。有时人们在发现自己怀孕后，会考虑改变用药方式，或者完全停止用药。然而，在做出任何改变之前，与您的医疗保健提供者交谈是非常重要的。您的医疗保健提供者可以与您讨论治疗您的疾病的好处和孕期未治疗疾病的风险。 ◈ 我正在服用托法替尼。这会让我更难怀孕吗？ 尚未进行研究以查看服用托法替尼是否会使怀孕变得更加困难。 ◈ 服用托法替尼会增加流产的风险吗？ 任何怀孕都可能出现流产。虽然尚未进行充分研究，但有报告称妇女在怀孕早期接触了托法替尼。没有报告显示增加流产的风险。 ◈ 服用托法替尼会增加出生缺陷的风险吗？ 每个怀孕都有3-5%的出生缺陷风险。这被称为背景风险。动物研究显示，在远高于人类使用剂量的情况下，使用托法替尼会增加出生缺陷。在人类中，有报告称妇女在怀孕早期接触了托法替尼。没有报告显示增加出生缺陷的风险。目前没有足够的信息来知道托法替尼是否会在人类中增加出生缺陷的风险。 ◈ 孕期服用托法替尼会增加其他与怀孕相关问题的风险吗？ 尚未进行研究以查看托法替尼是否会增加与怀孕相关问题的风险，如早产（出生在37周之前）或低出生体重（出生时体重低于5磅8盎司）。 ◈ 孕期服用托法替尼会影响孩子的未来行为或学习吗？ 尚未进行研究以查看托法替尼是否会导致孩子的行为或学习问题。哺乳期服用托法替尼：尚未对哺乳期使用托法替尼进行充分研究。制造商和一个专家小组建议在服用托法替尼和最后一次给药后18小时内停止哺乳。对于缓释形式（Xeljanz® XR），他们建议在最后一次给药后36小时再恢复哺乳。请务必与您的医疗保健提供者讨论所有关于哺乳的问题。 ◈ 如果男性服用托法替尼，会影响生育能力（使伴侣怀孕的能力）或增加出生缺陷的风险吗？ 尚未进行研究以查看托法替尼是否会影响男性生育能力或增加出生缺陷的风险。一般来说，父亲或精子捐赠者接触的东西不太可能增加怀孕的风险。更多信息，请参阅MotherToBaby资料页《父亲接触与怀孕》https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/。

◈ What is tofacitinib? Tofacitinib is a prescription medication used to treat rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. More information on these conditions can be found in our fact sheets at https://mothertobaby.org/fact-sheets/rheumatoid-arthritis/, https://mothertobaby.org/fact-sheets/psoriasis-and-pregnancy/ and https://mothertobaby.org/fact-sheets/inflammatory-bowel-disease-pregnancy/. Tofacitinib is marketed under the brand name Xeljanz® and Xeljanz XR®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy. ◈ I take tofacitinib. Can it make it harder for me to get pregnant? Studies have not been done to see if taking tofacitinib could make it harder to get pregnant. ◈ Does taking tofacitinib increase the chance for miscarriage? Miscarriage can occur in any pregnancy. While it has not been well studied, there are reports of women exposed to tofacitinib during early pregnancy. No increase chance for pregnancy loss was reported. ◈ Does taking tofacitinib increase the chance of birth defects? Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Animal studies showed an increase in birth defects with the use of tofacitinib at doses much higher than those used in humans. In humans, there are reports of women exposed to tofacitinib during early pregnancy. No increased chance for birth defects was reported. There is not enough information to know if tofacitinib increases the chance of birth defects in humans. ◈ Does taking tofacitinib in pregnancy increase the chance of other pregnancy related problems? Studies have not been done to see if tofacitinib increases the chance for pregnancy-related problems such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces at birth). ◈ Does taking tofacitinib in pregnancy affect future behavior or learning for the child? Studies have not been done to see if tofacitinib can cause behavior or learning issues for the child.Breastfeeding while taking tofacitinib:Tofacitinib has not been well studied for use during breastfeeding. The manufacturer and an expert panel recommend that breastfeeding be stopped while using tofacitinib and for 18 hours after the last dose. For the extended release form (Xeljanz® XR), they recommend waiting 36 hours after the last dose before resuming breastfeeding. Be sure to talk to your healthcare provider about all your breastfeeding questions. ◈ If a male takes tofacitinib, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects? Studies have not been done to see if tofacitinib could affect male fertility or increase the chance of birth defects. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

来源:Mother To Baby Fact Sheets

毒理性

• 相互作用

在健康个体中，CYP3A诱导剂利福平（每日一次口服600mg，连续7天）分别降低了托法替尼（单次口服剂量30mg）的峰血浆浓度和AUC 74%和84%。同时使用利福平可能会降低托法替尼的疗效。

In healthy individuals, the CYP3A inducer rifampin (600 mg orally once daily for 7 days) decreased peak plasma concentrations and AUC of tofacitinib (single oral dose of 30 mg) by 74 and 84%, respectively. Concomitant use of rifampin may decrease efficacy of tofacitinib.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

74% 口服吸收（绝对生物利用度），在0.5-1小时内达到血浆峰浓度（Tmax）。与高脂肪餐同服不改变AUC，但Cmax降低32%。

74% oral absorption (absolute bioavailability), with peak plasma concentrations (T max) achieved in 0.5-1 hour. Administration with fatty meals does not alter AUC but reduces Cmax by 32%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

70%在肝脏通过CYP3A4（主要）和CYP2C19（次要）代谢。产生的代谢物是无效的。30%以原药形式通过肾脏排出。

70% metabolized in the liver by CYP3A4 (major) and CYP2C19 (minor). Metabolites produced are inactive. 30% renally eliminated as unchanged drug.

来源:DrugBank

吸收、分配和排泄

• 分布容积

静脉给药后，Vd=87L。分布在大红细胞和血浆之间是均等的。

Vd= 87L after intravenous administration. Distribution is equal between red blood cells and plasma.

来源:DrugBank

吸收、分配和排泄

托法替尼的蛋白结合率大约为40%。托法替尼主要与白蛋白结合，并且似乎不与α1-酸性糖蛋白结合。托法替尼在红细胞和血浆之间均匀分布。

The protein binding of tofacitinib is approximately 40%. Tofacitinib binds predominantly to albumin and does not appear to bind to a1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

托法替尼的绝对口服生物利用度为74%。与高脂肪餐同服Xeljanz（托法替尼的商品名）不会改变AUC（药时曲线下面积），而Cmax（最高血药浓度）降低了32%。在临床试验中，Xeljanz的给药不考虑是否与餐食同服。

The absolute oral bioavailability of tofacitinib is 74%. Coadministration of Xeljanz with a high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, Xeljanz was administered without regard to meals.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  29335990
• 储存条件：
  2-8°C

制备方法与用途

枸橼酸托法替布（Tofacitinib）概述

枸橼酸托法替布 (tofacitinib citrate) 的化学系统名称为 3-{(3R,4R)-4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-哌啶-1-基]-3-氧代丙腈枸橼酸盐，是由美国辉瑞公司 (Pfizer) 研发的一种Janus激酶抑制剂。2012年11月6日，该物质经美国食品药品管理局（FDA）批准上市，用于治疗对甲氨蝶呤治疗反应不足或不耐受的中度至重度活动性类风湿关节炎 (RA) 成人患者的治疗。

用途

托法替布适用于甲氨蝶呤疗效不足或对其无法耐受的中度至重度活动性类风湿关节炎（RA）成年患者，可与甲氨蝶呤或其他非生物改善病情抗风湿药（DMARD）联合使用。商品名 Xeljanz 是一种由美国辉瑞制药公司开发的治疗类风湿关节炎药物。

2012年11月6日，FDA和辉瑞公司联合宣布，枸橼酸托法替布获准用于对氨甲蝶呤治疗应答不充分或不耐受的中至重度活动性类风湿关节炎（RA）成人患者。Xeljanz 可作为单一治疗或与氨甲蝶呤或其他非生物疾病缓解性抗风湿药物 (DMARD) 联合使用，但不应与生物性 DMARD 或强免疫抑制剂(如硫唑嘌呤和环孢菌素)联合使用。

经核准的 Xeljanz 剂量为每日2次，每次5mg。7项临床试验在中至重度活动性 RA 成人患者中评估了枸橼酸托法替布的安全性和有效性，结果显示接受Xeljanz治疗的患者均具有临床应答和身体功能上的显著改善。

最常见的不良反应包括上呼吸道感染、头痛、腹泻、鼻充血、咽喉痛和鼻咽炎。使用 Xeljanz 与严重感染风险增加相关，包括机会性感染、结核、癌症和淋巴瘤。Xeljanz 治疗还与胆固醇和肝酶数值增高及血细胞计数降低有关。

为了研究 Xeljanz 对心脏病、癌症和严重感染的长期影响，FDA要求进行一项上市后研究，该研究将对两种剂量的 Xeljanz (枸橼酸托法替尼) 治疗进行评估，并纳入一个接受另一种经核准治疗的患者组作为对照。

生物活性

Tofacitinib（CP-690550, Tasocitinib）是一种新型 JAK3 抑制剂，IC50 为 1 nM。它作用于 JAK2 和 JAK1 选择性低 20 到 100 倍。

体外研究

CP-690550 是一种针对 JAK 的抑制剂，在体外研究中表现出优异的活性和特异性。它能够通过加强 Tb7 分化，加速实验性自身免疫脑脊髓炎的发生（低剂量 CP-690550）。此外，该药物在异位心脏移植的小鼠模型中提高了移植后心脏的寿命，并在非人灵长类动物 (NHPs, 食蟹猴) 中防止同种异体肾移植排斥反应。

体内研究

CP-690550 在小鼠和非人灵长类动物中的体内研究显示了其广泛的免疫调节作用。它能够通过流式细胞仪检测淋巴细胞亚群发生改变，并在低剂量下延迟型过敏反应降低（皮下注射给药敏感小鼠）。这些结果表明，CP-690550 具有潜在的免疫抑制和抗炎作用。

反应信息

• 作为反应物：
  描述：

  托法替尼 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 5-{(E)-{4-{{{{2-{4-{[(3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl](methyl)amino}-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido}ethyl}(methyl)carbamoyl}oxy}methyl}-2-methoxyphenyl}diazenyl}-2-hydroxybenzoic acid
  参考文献：
  名称：

  Discovery of a Colon-Targeted Azo Prodrug of Tofacitinib through the Establishment of Colon-Specific Delivery Systems Constructed by 5-ASA–PABA–MAC and 5-ASA–PABA–Diamine for the Treatment of Ulcerative Colitis

  摘要：

  DOI：

  10.1021/acs.jmedchem.1c02166
• 作为产物：
  描述：

  4-氯-7H-吡咯并[2,3-d]嘧啶-7-羧酸叔丁酯 在 盐酸 、 氢气 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 托法替尼
  参考文献：
  名称：

  一种枸橼酸托法替尼的制备方法

  摘要：

  本发明涉及一种枸橼酸托法替尼的制备方法，具体涉及以4‑氯‑7‑吡咯并[2,3‑d]嘧啶、(BOC)2O、(3R,4R)‑(1‑苄基‑4‑甲基哌啶‑3‑基)甲胺‑L‑二对甲苯甲酰酒石酸盐、Pd/C、氰基乙酸和枸橼酸为原料，经氨基保护反应、氨基化反应、脱苄基反应、缩合反应、脱保护反应和成盐反应六步高产率合成枸橼酸托法替尼。本合成路线提供了一种枸橼酸托法替尼的制备方法是一种高收率、低成本、易操作、适宜工业化的制备方法。

  公开号：

  CN108358930A

文献信息

• [EN] LIPID PRODRUGS OF JAK INHIBITORS AND USES THEREOF<br/>[FR] PROMÉDICAMENTS LIPIDIQUES D'INHIBITEURS DE JAK ET LEURS UTILISATIONS
  申请人：PURETECH LYT INC

  公开号：WO2020176859A1

  公开（公告）日：2020-09-03

  The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, and methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a disclosed lipid prodrug or a pharmaceutical composition thereof.

  本发明提供了淋巴系统定向脂质前药，其药物组成物，生产这种前药和组成物的方法，以及改善作为脂质前药一部分的治疗剂的生物利用度或其他性质的方法。本发明还提供了治疗疾病、紊乱或状况的方法，例如本文所披露的那些，包括向需要的患者施用所披露的脂质前药或其药物组成物。
• [EN] AMINO PYRAZINE DERIVATIVES AS PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS<br/>[FR] DÉRIVÉS AMINÉS DE PYRAZINE UTILISABLES EN TANT QU'INHIBITEURS DE LA PHOSPHATIDYLINOSITOL 3-KINASE
  申请人：NOVARTIS AG

  公开号：WO2015162459A1

  公开（公告）日：2015-10-29

  The present invention provides compounds of formula (I) which inhibit the activity of PI 3-kinase gamma isoform, which are useful for the treatment of diseases mediated by the activation of PI 3-kinase gamma isoform.

  本发明提供了一种公式（I）的化合物，该化合物抑制PI 3-激酶γ同工酶的活性，对于治疗由PI 3-激酶γ同工酶激活介导的疾病是有用的。
• [EN] SUBSTITUTED HETERO-BICYCLIC COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS THEREOF<br/>[FR] COMPOSÉS HÉTÉRO-BICYCLIQUES SUBSTITUÉS, COMPOSITIONS ET LEURS APPLICATIONS MÉDICINALES
  申请人：ADVINUS THERAPEUTICS LTD

  公开号：WO2013157022A1

  公开（公告）日：2013-10-24

  The present disclosure provides hetero-biclyclic compounds of formula (I), their tautomers, polymorphs, stereoisomers, prodrugs, solvates, hydrates, N-oxides, co-crystals, pharmaceutically acceptable salts, pharmaceutical compositions containing them and methods of treating conditions and diseases that are mediated by Bruton's tyrosine kinase (Btk) activity, The disclosure also relates to the process of preparation of compounds of Formula (I). These compounds are useful in the treatment, prevention, prophylaxis, management, or adjunct treatment of all medical conditions related to inhibition of Bruton's tyrosine kinase (Btk), such as inflammatory and/or autoimmune disorder, cell proliferation, rheumatoid arthritis, psoriasis, psoriatic arthritis, transplant rejection, graft-versus-host disease, multiple sclerosis, inflammatory bowel disease, allergic diseases, asthma, type 1 diabetes, myasthenia gravis, hematopoetic disfunction, B-cell malignancies, systemic lupus, erythematosus or other disorders.

  本公开提供了式(I)的杂环双环化合物，它们的互变异构体、多晶形态、立体异构体、前药、溶剂合物、水合物、N-氧化物、共晶体、药学上可接受的盐、含有它们的药物组合物以及治疗由布鲁顿酪氨酸激酶（Btk）活性介导的疾病和病症的方法。该公开还涉及制备式(I)化合物的过程。这些化合物在治疗、预防、预防、管理或辅助治疗与抑制布鲁顿酪氨酸激酶（Btk）有关的所有医学状况方面具有用处，如炎症和/或自身免疫性疾病、细胞增殖、类风湿关节炎、牛皮癣、银屑病性关节炎、移植排斥、移植物抗宿主病、多发性硬化、炎症性肠病、过敏性疾病、哮喘、1型糖尿病、重症肌无力、造血功能障碍、B细胞恶性肿瘤、系统性红斑狼疮或其他疾病。
• [EN] NOVEL AMINO PYRIMIDINE DERIVATIVES<br/>[FR] NOUVEAUX DÉRIVÉS D'AMINOPYRIMIDINE
  申请人：NOVARTIS AG

  公开号：WO2015079417A1

  公开（公告）日：2015-06-04

  The present invention describes new amino pyrimidine derivatives of formula (I) and pharmaceutically acceptable salts thereof which appear to interact with Bruton's tyrosine kinase (Btk). Accordingly, the novel amino pyrimidines may be effective in the treatment of autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection, cancers e.g. of hematopoietic origin or solid tumors.

  本发明描述了新的氨基嘧啶衍生物的化学式(I)及其药用盐，这些衍生物似乎与布鲁顿酪氨酸激酶（Btk）相互作用。因此，这些新型氨基嘧啶可能在治疗自身免疫性疾病、炎症性疾病、过敏性疾病、气道疾病（如哮喘和慢性阻塞性肺病（COPD））、移植排斥、血液起源或实体肿瘤等癌症方面具有有效性。
• Prodrugs of a JAK Inhibitor Compound for Treatment of Gastrointestinal Inflammatory Disease
  申请人：THERAVANCE BIOPHARMA R&D IP, LLC

  公开号：US20170145044A1

  公开（公告）日：2017-05-25

  The invention provides compounds which are prodrugs of a JAK inhibitor agent for the targeted delivery of the JAK inhibitor to the gastrointestinal tract of a mammal. The invention also provides pharmaceutical compositions comprising the compounds, methods of using the compounds to treat gastrointestinal inflammatory diseases, and processes and intermediates useful for preparing the compounds.

  本发明提供了一种前药化合物，它是针对哺乳动物胃肠道靶向输送JAK抑制剂的前药。本发明还提供了包含该化合物的药物组合物，使用该化合物治疗胃肠道炎症性疾病的方法，以及用于制备该化合物的过程和中间体。