来曲唑 | 112809-51-5

• 物质功能分类: 原料药 - 抗肿瘤药 - 激素类抗肿瘤药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 来曲唑
• 中文别名: 1-[双(4-氰基苯基)甲基]-1,2,4-三氮唑；4,4'-(1 H-1,2,4-三唑-1-基亚甲基)-双苯腈
• 英文名称: letrozol
• 英文别名: Letrozole；4,4'-((1H-1,2,4-triazol-1-yl)methylene)dibenzonitrile；Femara；LTZ；1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole；4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]benzonitrile；4,4’-((1H-1,2,4-triazol-1-yl)methylene)dibenzonitrile；4-[(4-cyanophenyl)(1,2,4-triazol-1-yl)methyl]benzonitrile；4,4'-(1H-1,2,4-triazol-1-ylmethylene)bisbenzonitrile；letrazole；4-[(4-cyanophenyl)-(1,2,4-triazol-1-yl)methyl]benzonitrile
• CAS: 112809-51-5
• 化学式: C₁₇H₁₁N₅
• 分子量: 285.308
• InChiKey: HPJKCIUCZWXJDR-UHFFFAOYSA-N

物化性质

• 熔点：
  181-183°C
• 沸点：
  563.5±60.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：>50mg/mL
• 物理描述：
  Solid
• 颜色/状态：
  White to yellowish crystalline powder
• 气味：
  Practically odorless
• 蒸汽压力：
  6.8X10-9 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  78.3
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

代谢

来曲唑通过CYP2A6代谢为酮类似物代谢物，该代谢物进一步通过CYP3A4和CYP2A6代谢为4,4'-(羟甲基)二苯腈。4,4'-(羟甲基)二苯腈通过UGT2B7发生葡萄糖醛酸化。

Letrozole is metabolized by CYP2A6 to a ketone analog metabolite, which is further metabolized by CYP3A4 and CYP2A6 to 4,4'-(hydroxymethylene)dibenzonitrile. 4,4'-(hydroxymethylene)dibenzonitrile is glucuronidated by UGT2B7.

来源:DrugBank

代谢

来曲唑的主要消除途径是在肝脏中缓慢代谢成一种药理学上不活跃的羧醇代谢物（4,4'-羟甲基-双苯腈），随后将这种代谢物的葡萄糖苷酸结合物通过肾脏排泄。羧醇代谢物的形成由细胞色素P-450（CYP）同工酶3A4和2A6介导，而羧醇代谢物的酮类似物的形成则由同工酶2A6介导。

The primary elimination pathway of letrozole consists of slow metabolism in the liver to a pharmacologically inactive carbinol metabolite (4,4'-methanol-bisbenzonitrile) followed by renal excretion of the glucuronide conjugate of this metabolite. Formation of the carbinol metabolite is mediated by cytochrome P-450 (CYP) isoenzymes 3A4 and 2A6, and formation of the ketone analog of the carbinol metabolite is mediated by isoenzyme 2A6.

来源:Hazardous Substances Data Bank (HSDB)

代谢

主要通过CYP3A4和CYP2A6在肝脏代谢。来曲唑通过竞争性地与酶的细胞色素P450亚单位的血红素结合，抑制芳香化酶酶，从而减少所有组织中的雌激素生物合成。它缓慢代谢为一个无活性的代谢物，其葡萄糖醛酸苷结合物通过肾脏排泄，代表主要的清除途径。 半衰期：2天

Primarily hepatic via CYP3A4 and CYP2A6. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. Half Life: 2 days

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

来曲唑是一种非甾体类的芳香化酶酶系统的竞争性抑制剂；它抑制雄激素向雌激素的转化。在成年非肿瘤和携带肿瘤的女性动物中，来曲唑在减少子宫重量、升高血清促黄体生成激素（LH）和导致雌激素依赖性肿瘤的退化方面与卵巢切除一样有效。与卵巢切除相比，来曲唑治疗不会导致血清（卵泡刺激激素（FSH））的增加。来曲唑选择性地抑制性腺类固醇生成，但对肾上腺盐皮质激素或糖皮质激素的合成没有显著影响。有机腈在体内和体外都会分解成氰化物离子。因此，有机腈的主要毒性机制是它们产生有毒的氰化物离子或氢氰酸。氰化物是电子传递链第四复合体（存在于真核细胞线粒体膜中）中的细胞色素c氧化酶的抑制剂。它与这种酶中的三价铁原子形成复合物。氰化物与这种细胞色素的结合阻止了电子从细胞色素c氧化酶传递到氧气。结果，电子传递链被破坏，细胞无法再通过有氧呼吸产生ATP作为能量。主要依赖有氧呼吸的组织，如中枢神经系统和心脏，受到特别影响。氰化物也通过结合过氧化氢酶、谷胱甘肽过氧化物酶、变性血红蛋白、羟钴胺素、磷酸酶、酪氨酸酶、抗坏血酸氧化酶、黄嘌呤氧化酶、琥珀酸脱氢酶和Cu/Zn超氧化物歧化酶来产生一些毒性作用。氰化物与变性血红蛋白中的三价铁离子结合形成无活性的氰化变性血红蛋白。

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumorbearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum Leuteinizing hormone (LH), and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum (folicile stimulating hormone (FSH). Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. Organic nitriles decompose into cyanide ions both in vivo and in vitro. Consequently the primary mechanism of toxicity for organic nitriles is their production of toxic cyanide ions or hydrogen cyanide. Cyanide is an inhibitor of cytochrome c oxidase in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It complexes with the ferric iron atom in this enzyme. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted and the cell can no longer aerobically produce ATP for energy. Tissues that mainly depend on aerobic respiration, such as the central nervous system and the heart, are particularly affected. Cyanide is also known produce some of its toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinic dehydrogenase, and Cu/Zn superoxide dismutase. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin. (L97)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

血清酶在接受来曲唑治疗的女性中据报道有高达1%的升高，但这些升高通常是轻微的、无症状的且自限性的，很少需要调整剂量。长期使用来曲唑治疗与临床上明显的肝损伤有关的病例很少见诸发表。更常见的是与阿那曲唑和依西美坦治疗相关的胆汁淤积性和肝细胞性肝损伤的报道，通常在治疗1到4个月后出现，表现为黄疸。虽然有些病例病情严重，但一旦停药，恢复通常很快。尚未有严重黄疸、急性肝衰竭、慢性肝炎或胆管消失综合征归因于来曲唑使用的病例。与他莫昔芬不同，来曲唑并未与脂肪肝疾病、脂肪肝炎或肝硬化的发生有关联。

Serum enzymes are reported to be elevated in up to 1% of women treated with letrozole, but these elevations are usually mild, asymptomatic and self-limited, rarely requiring dose modification. There have been few published instances of clinically apparent liver injury associated with long term letrozole therapy. More frequent have been reports of cholestatic and hepatocellular liver injury associated with anastrozole and exemestane, typically arising after 1 to 4 months of therapy and presenting with jaundice. While cases have been severe, recovery is usually prompt once the agent is stopped. There have been no cases of severe jaundice, acute liver failure, chronic hepatitis or vanishing bile duct syndrome attributed to letrozole use. Unlike tamoxifen, letrozole has not been associated with development of fatty liver disease, steatohepatitis or cirrhosis.

来源:LiverTox

毒理性

• 药物性肝损伤

来曲唑

Compound:letrozole

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-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：2

Severity Grade:2

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

来曲唑的口服生物利用度为99.9%。2.5毫克的口服剂量可以在8.10小时达到104纳米摩尔/升的最大血药浓度（Cmax），并且药时曲线下面积为7387纳米摩尔*小时/升（AUC）。

Letrozole is 99.9% orally bioavailable. A 2.5mg oral dose reaches a Cmax of 104nmol/L with a Tmax of 8.10h, and an AUC of 7387nmol\*h/L.

来源:DrugBank

吸收、分配和排泄

• 消除途径

来曲唑有90%通过尿液排出体外。其中75%的剂量以葡萄糖苷酸代谢物的形式回收，9%以酮和甲醇代谢物的形式存在，而6%的来曲唑以原形在尿液中回收。

Letrozole is 90% eliminated in the urine. 75% of the dose is recovered as a glucuronide metabolite, 9% is in the form of the ketone and carbinol metabolites, and 6% is recovered in urine as unchanged letrozole.

来源:DrugBank

吸收、分配和排泄

• 分布容积

来曲唑的分布体积为1.87L/kg。

The volume of distribution of letrozole is 1.87L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

单次给药后，来曲唑的平均清除率为1.52L/h，在稳态时为1.20L/h。

The average clearance after a single dose of letrozole was 1.52L/h and at steady state was 1.20L/h.

来源:DrugBank

吸收、分配和排泄

来曲唑口服给药后从胃肠道快速且完全吸收。在接受每日2.5毫克来曲唑治疗的患者中，药物达到稳态血浆浓度需要2-6周。来曲唑在每日重复给予2.5毫克时表现出轻微的非线性药代动力学，稳态血浆浓度比单次给药后测量的血浆浓度预测值高1.5-2倍。然而，来曲唑并不会持续积累，稳态浓度在每日药物给药的延长期间保持不变。食物不会影响该药物的口服吸收。

Letrozole is rapidly and completely absorbed from the GI tract following oral administration. Steady-state plasma concentrations of the drug are reached in 2-6 weeks in patients receiving letrozole 2.5 mg daily. Letrozole exhibits slightly nonlinear pharmacokinetics with repeated administration of 2.5 mg daily, with steady-state plasma concentrations 1.5-2 times higher than predicted based on plasma concentrations measured after a single dose. However, continuous accumulation of letrozole does not occur, and steady-state concentrations are maintained over extended periods of daily drug administration. Food does not affect the oral absorption of the drug.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi,C
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• WGK Germany：
  3
• 海关编码：
  2933990090
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  DI4957000
• 储存条件：
  -20°C 冰箱

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: 4,4’-((1H-1,2,4-triazol-1-yl)methylene)dibenzonitrile
Synonyms:

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: 4,4’-((1H-1,2,4-triazol-1-yl)methylene)dibenzonitrile
CAS number: 112809-51-5

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C17H11N5
Molecular weight: 285.3

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

来曲唑简介

来曲唑是一种新一代高选择性芳香化酶抑制剂，为人工合成的苄三唑类衍生物。通过抑制芳香化酶使雌激素水平下降，从而消除雌激素对肿瘤生长的刺激作用。其体内活性比第一代芳香化酶抑制剂氨鲁米特强150-250倍。由于选择性较高，不影响糖皮质激素、盐皮质激素和甲状腺功能，大剂量使用对肾上腺皮质类固醇物质分泌无抑制作用，因此具有较高的治疗指数。

来曲唑主要用于绝经后雌激素受体（ER/PR阳性）阳性的乳腺癌患者。乳腺癌与雌激素有关，绝经前女性的雌激素主要来源于卵巢，而绝经后主要是由雄激素转化为雌激素，这种转化主要是通过一种酶——芳香化酶进行的。来曲唑正是通过抑制这种酶从而达到降低雌激素水平的目的。

作用机制

来曲唑可以竞争性地与细胞色素P450酶的亚单位血红素结合，从而抑制芳香化酶，导致所有组织中雌激素生物合成减少。由于肿瘤缺少了雌激素这一养分，其转移和复发的风险也会降低。

适应症

多项临床前研究表明来曲唑对全身各系统及靶器官没有潜在毒性，无诱变性和致癌作用，且毒副反应较小、耐受性良好。与其他芳香化酶抑制剂和抗雌激素药物相比，其抗肿瘤作用更强。适用于治疗抗雌激素治疗无效的晚期乳腺癌绝经后患者以及乳腺癌早期的治疗。

来曲唑片与阿那曲唑的区别

来曲唑片：

• 适用于绝经后晚期乳腺癌，多用于治疗抗雌激素治疗失败后的二线治疗。

阿那曲唑：

• 是一种强效的选择性三唑类芳香酶抑制剂。
• 它能抑制细胞色素P-450所依赖的芳香酶从而阻断雌激素的生物合成。本品对人类胎盘芳香酶的50%抑制浓度（IC50）值为15nmol/L。

不良反应与副作用

随机分组试验表明，每天口服来曲唑2.5mg后，与药物相关的不良反应发生率为33%，明显低于对照组46%。不良反应多为轻度或中度，以恶心（2%-9%）、头痛（0%-7%）、骨痛（4%-10%）、潮热（0%-9%）和体重增加（2%-8%）为主要表现；其他少见的还包括便秘、腹泻、瘙痒、皮疹、关节痛、胸痛、腹痛、疲倦、失眠、头晕、水肿、高血压、心律不齐、血栓形成、呼吸困难、阴道流血等。

多数患者服用来曲唑后能较好地耐受，但药三分毒。其副作用主要包括：

1. 精神症状：疲乏、头痛。
2. 恶性、腹痛，相对少见。
3. 骨骼肌疼痛、关节疼痛，发生率最高，许多患者在服用半年左右会出现此类症状。
4. 咳嗽、胸痛，部分患者在服用1年后可能出现干咳和胸部不适，多可耐受。

安全性

来曲唑属于妊娠用药X级，美国FDA未批准该药物用于诱导排卵。但至今的研究表明，来曲唑不会增加先天畸形的风险。国内外各大指南推荐来曲唑作为诱导排卵的一线用药。

根据来曲唑的半衰期，在早卵泡期给药时会在受精卵着床前被清除。尽管如此，该药物与所有诱导排卵的药物一样，医生必须在开始用药前确定患者未妊娠。建议给予来曲唑前进行血液妊娠试验。

化学性质

• 熔点：181～183℃

用途

吡咯型芳构化酶抑制剂，用于治疗乳腺癌。

生产方法

4-溴甲基苯腈（I）和三唑在氯仿-乙腈中反应生成物(Ⅱ)，再与4-氟苯腈，在叔丁醇钾存在下，在二甲基甲酰胺中反应，即得来曲唑。

反应信息

• 作为反应物：
  描述：

  来曲唑 生成 4,4'-(1H-1,2,4-triazol-1-yl)methylenebis(benzoic acid)
  参考文献：
  名称：

  用于高选择性、灵敏和实时检测呋喃西林和铜离子的多响应可再生水稳定二维镉 (II) 荧光探针

  摘要：

  摘要 近年来，发光金属有机框架（MOFs）材料在荧光传感领域引起了广泛关注。在这项工作中，一种新型的二维 (2D) 微孔水稳定配位材料 {[Cd(μ3-HL)2(H2O)]⋅2.3H2O}n (1, H2L = 4,4′-(1H -1,2,4-三唑-1-基）亚甲基-双（苯甲酸））已通过强大的溶剂热方法制备，并已通过单晶 X 射线衍射分析、PXRD、扫描电子显微镜进行表征(SEM) 和透射电子显微镜 (TEM) 表征。晶体结构分析还揭示了部分去旋前的 μ3 配位的 HL− 采用三齿桥接模式，将这些镉 (II) 中心连接起来，最终形成了二维 (2D) 微孔配位框架 1。具有 12.216(3) A × 8.578(11) A 的二元性的一维通道，可以沿晶体学 a 轴观察到。值得注意的是，1 具有良好的化学稳定性，不仅在各种溶剂中，而且在 pH 值从 2 到 12 变化的水溶液中都保持结构完整性。此外，1

  DOI：

  10.1016/j.molstruc.2020.128328
• 作为产物：
  描述：

  4-((4-cyanophenyl)(1H-1,2,4-triazol-1-yl)methyl)benzamide 在 三氟乙酸酐 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.0h， 以90%的产率得到来曲唑
  参考文献：
  名称：

  一种合成基本纯来曲唑的新方法

  摘要：

  本文展示了一种改进的新型和实用的口服非甾体芳香酶抑制剂 (AI) 来曲唑合成方法，该合成方法采用五步合成工艺，收率极佳。合成的关键步骤包括4-(氯(4-氰基苯基)甲基)苯甲酰胺与1H-1,2,4-三唑缩合，并在低温下使用三氟乙酸酐进一步脱水为来曲唑。

  DOI：

  10.24820/ark.5550190.p010.891
• 作为试剂：
  描述：

  1H-1,2,4-三唑 、 、 对氟苯腈 、 、 sodium hexamethyldisilazane 、 四氢呋喃 在 氮气 、 溶剂黄146 、 甲苯 、 来曲唑 作用下， 反应 0.5h， 以yielding 41 grams of product的产率得到来曲唑
  参考文献：
  名称：

  Process for the preparation of letrozole

  摘要：

  本发明提供了一种高产纯度高的莱特罗唑制备工艺，无需在中间阶段去除4-[1-(1,3,4-三唑基)甲基]苯甲腈杂质。本发明还提供了一种莱特罗唑合成工艺，在第一阶段最小化4-[1-(1,3,4-三唑基)甲基]苯甲腈杂质的形成。在该工艺中，4-(卤代甲基)苯甲腈与1H-1,2,4-三唑盐反应，降低了杂质的形成。最好的情况是采用一锅法进行制备。

  公开号：

  US20070066831A1

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• [EN] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
  申请人：CANCER RESEARCH TECH LTD

  公开号：WO2018215798A1

  公开（公告）日：2018-11-29

  The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.

  本发明涉及作为BCL6（B细胞淋巴瘤6）活性抑制剂的I式化合物：式中X1、X2、X3、R1、R2、R3、R4和R5分别如本文所定义。本发明还涉及制备这些化合物的方法，包括含有它们的药物组合物，以及它们在治疗增生性疾病（如癌症）以及其他BCL6活性所涉及的疾病或病况中的用途。
• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。
• [EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2010144486A1

  公开（公告）日：2010-12-16

  Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

  揭示了式(I)的JAK抑制剂，其中G1、R1、R2、R3、R4、R5、R6和R7在规范中定义。还披露了含有这些化合物的药物组合物、试剂盒和制造物品，制备这些化合物的方法和材料，以及使用这些化合物治疗涉及免疫系统和炎症的疾病、紊乱和症状的方法，包括类风湿关节炎、血液恶性肿瘤、上皮癌（即癌症）和其他与JAK相关的疾病、紊乱或症状。