达沙替尼 | 302962-49-8

• 物质功能分类: 原料药 - 抗肿瘤药 - 替尼类抗肿瘤药
• 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: 达沙替尼
• 中文别名: 达沙替尼无水物；达沙替尼(无水)；5-噻唑甲酰胺,N-(2-氯-6-甲基苯基)-2-[[6-[4-(2-羟基乙基)-1-哌嗪基]-2-甲基-4-嘧啶基]氨基]；达沙替尼中间体；N-(2-氯-6-甲基苯基)-2-[[6-[4-(2-羟乙基)哌嗪-1-基]-2-甲基嘧啶-4-基]氨基]-1,3-噻唑-5-甲酰胺；DASA锡IB
• 英文名称: dasatinib
• 英文别名: N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide；BMS‐354825；N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide；Sprycel；N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide；BMS-354825；DAS
• CAS: 302962-49-8
• 化学式: C₂₂H₂₆ClN₇O₂S
• 分子量: 488.013
• InChiKey: ZBNZXTGUTAYRHI-UHFFFAOYSA-N

物化性质

• 熔点：
  275-286°C
• 密度：
  1.408±0.06 g/cm3(Predicted)
• 溶解度：
  溶于DMSO（高达200mg/ml）。
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  135
• 氢给体数：
  3
• 氢受体数：
  9

ADMET

代谢

Dasatinib在人体内被广泛代谢，主要由细胞色素P450酶3A4代谢。

Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4

来源:DrugBank

毒理性

• 肝毒性

在大规模的临床试验中，达沙替尼治疗期间血清氨基转移酶水平升高的情况发生在多达50%的患者中，但通常是轻微且自限性的。超过正常上限5倍（ULN）的升高发生在1%至9%的患者中，通常对剂量调整或暂时停药并在较低剂量重新开始治疗有反应，如果肝功能测试结果显著升高（ALT或AST持续大于5倍ULN或胆红素超过3倍ULN），建议这样做。虽然有报告称出现了伴有症状的血清氨基转移酶显著升高的情况，但没有已发表的关于因达沙替尼治疗而导致的具有黄疸症状的临床明显肝损伤的报告。当然，用于治疗CML的其他酪氨酸激酶受体抑制剂，如伊马替尼、尼洛替尼和波纳替尼，已与急性肝损伤伴黄疸的病例有关。使用这些药物时，肝损伤通常在治疗数月后出现，血清酶升高的模式通常是肝细胞型。免疫过敏特征（皮疹、发热和嗜酸性粒细胞增多）和自身抗体的形成通常不存在。 达沙替尼以及伊马替尼和尼洛替尼治疗中也有报告乙型肝炎病毒再激活的情况。再激活通常发生在HBsAg阳性的人使用酪氨酸激酶抑制剂治疗3到6个月后，表现为黄疸、血清氨基转移酶显著升高和HBV DNA水平增加。乙型肝炎病毒再激活可能是严重的，已有在使用伊马替尼和尼洛替尼治疗后的致命病例报告。在开始癌症化疗之前，有时建议对患者进行HBsAg和抗-HBc筛查，并为HBsAg阳性的人提供口服抗病毒药物如拉米夫定、替诺福韦或恩替卡韦的预防治疗。 可能性评分：D（可能是临床明显肝损伤的原因）。

In large clinical trials, elevations in serum aminotransferase levels during dasatinib therapy occurred in up to 50% of patients, but were usually mild and self-limited. Elevations above 5 times the upper limit of normal (ULN) occurred in 1% to 9% of patients and generally responded to dose adjustment or temporary discontinuation and restarting at a lower dose, which is recommended if liver test results are markedly elevated (ALT or AST persistently greater than 5 times ULN or bilirubin more than 3 times ULN). While episodes of marked serum aminotransferase elevations with symptoms have been reported, there have been no published reports of clinically apparent liver injury with jaundice attributed to dasatinib therapy. Certainly other tyrosine kinase receptor inhibitors used in the therapy of CML such as imatinib, nilotinib and ponatinib have been associated with cases of acute liver injury with jaundice. With these agents, the liver injury typically arises after several months of therapy and the pattern of serum enzyme elevations is typically hepatocellular. Immunoallergic features (rash, fever and eosinophilia) and autoantibody formation are usually not present. Reactivation of hepatitis B has been reported with dasatinib as well as imatinib and nilotinib therapy. Reactivation typically occurs in an HBsAg positive person treated with the tyrosine kinase inhibitor for 3 to 6 months, presenting with jaundice, marked serum aminotransferase elevations and an increase in HBV DNA levels. Reactivation of hepatitis B can be severe and fatal instances have been reported after imatinib and nilotinib therapy. Screening of patients for HBsAg and anti-HBc is sometimes recommended before starting cancer chemotherapy and those with HBsAg offered prophylaxis with oral antiviral agents, such as lamivudine, tenofovir or entecavir. Likelihood score: D (possible cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：达沙替尼

Compound:dasatinib

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：低药物性肝损伤关注

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：4

Severity Grade:4

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

不良反应部分

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 消除途径

Dasatinib在人体内被广泛代谢，主要由细胞色素P450酶3A4进行。消除主要通过粪便进行。

Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. Elimination is primarily via the feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

2505 L

2505 L

来源:DrugBank

安全信息

• 海关编码：
  29341000
• WGK Germany：
  3
• 包装等级：
  III
• 危险类别：
  9
• 危险性防范说明：
  P201,P202,P260,P264,P270,P273,P280,P302+P352,P305+P351+P338+P310,P308+P313,P332+P313,P391,P405,P501
• 危险品运输编号：
  3077
• 危险性描述：
  H315,H318,H351,H361,H372,H410
• 储存条件：
  -20°C冷冻库

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Dasatinib
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: Dasatinib
CAS number: 302962-49-8

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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, refrigerated.
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: C22H26ClN7O2S
Molecular weight: 488.0

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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, hydrogen chloride, sulfur 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

达沙替尼概述

• 作用机制: 一种强效口服的致癌激酶抑制剂，能够阻断癌症细胞加速复制的信号。
• 适应症:
  • 慢性髓细胞白血病（CML）各期。
  • 对甲磺酸伊马替尼等治疗方案耐药或不能耐受的慢性髓细胞样白血病。
  • 费城染色体阳性急性淋巴细胞白血病（Ph+ALL）。
  • 实体瘤患者。

生产流程

1. 粗品制备:
   • 将主要原料加入反应釜，通过一系列步骤最终得到达沙替尼粗品。
2. 精制过程:
   • 使用无水甲醇作为溶剂进行结晶，进一步去除杂质，并达到所需的纯度标准。

药物疗效与安全性

• 治疗效果: 临床试验显示对慢性髓细胞白血病具有较好的治疗效果。
• 不良反应:
  • 骨髓抑制（导致红细胞、白细胞和血小板含量下降）。
  • 水肿。
  • 腹泻。
  • 头痛。
  • 肌肉骨骼疼痛。
  • 皮疹。

特别注意事项

• 肺动脉高压风险: 在2011年，FDA报告指出达沙替尼可能会增加患者患肺动脉高压的风险。该疾病导致心脏泵血到肺部更加困难，并且可能导致呼吸短促、疲劳和腿部肿胀等症状。
• 监管与审批:
  • 2009年5月，美国食品与药品管理局（FDA）正式批准达沙替尼上市销售。
  • 2010年10月28日，再次扩大其适应症范围至费城染色体阳性的慢性髓细胞白血病患者。

化学性质和用途

• 化学性质: 白色固体。
• 适用范围: 主要用于对甲磺酸伊马替尼等治疗方案耐药或不能耐受的慢性髓细胞样白血病患者的治疗。

反应信息

• 作为反应物：
  描述：

  达沙替尼 在 双氧水 作用下， 以 N-甲基吡咯烷酮 为溶剂， 生成 达沙替尼N-氧化物
  参考文献：
  名称：

  [EN] SOLID STATE FORMS OF DASATINIB AND PROCESSES FOR THEIR PREPARATION
  [FR] FORMES SOLIDES DE DASATINIB ET LEURS PROCÉDÉS DE PRÉPARATION

  摘要：

  本发明提供了达沙替尼的(R)-丙二醇溶剂晶型形式。

  公开号：

  WO2017134615A1
• 作为产物：
  描述：

  N-(2-chloro-6-methylphenyl)-2-[[6-[4-[2-(2-ethoxyethoxy)ethyl]piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide 在 三氯化硼 作用下， 以 二氯甲烷 为溶剂， 以72.5%的产率得到达沙替尼
  参考文献：
  名称：

  SYNTHESIS PROCESS OF DASATINIB AND INTERMEDIATE THEREOF

  摘要：

  公开了达沙替尼的合成过程，其中包括将式I的化合物与式II的化合物反应，以获得式III的化合物。还公开了式III的化合物，该化合物用作合成达沙替尼的中间体。式I、II或III中的R1、R2、R3或R4的取代基如描述所定义。

  公开号：

  US20130030177A1
• 作为试剂：
  描述：

  N-羟乙基哌嗪 、 2-(6-bromo-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-formamide 、 N,N-二异丙基乙胺 在 达沙替尼 作用下， 以 异丙醇 为溶剂， 反应 5.0h， 以to give crude Dasatinib (Compound 1) (purity: 95.4%)的产率得到达沙替尼
  参考文献：
  名称：

  SYNTHESIS PROCESS OF DASATINIB AND INTERMEDIATE THEREOF

  摘要：

  公开了达沙替尼的合成过程，其中包括使用公式I的化合物与公式II的化合物反应，以获得公式III的化合物。还公开了公式III的化合物，该化合物用作合成达沙替尼的中间体。在公式I、II或III中的R1、R2、R3或R4的取代基如描述中所定义。

  公开号：

  US20130030177A1

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。
• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• [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] 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。
• SULFONAMIDE, SULFAMATE, AND SULFAMOTHIOATE DERIVATIVES
  申请人：Wang Zhong

  公开号：US20120077814A1

  公开（公告）日：2012-03-29

  The disclosure provides biologically active compounds of formula (I): and pharmaceutically acceptable salts thereof, compositions containing these compounds, and methods of using these compounds in a variety applications, such as treatment of diseases or disorders associated with E1 type activating enzymes, and with Nedd8 activating enzyme (NAE) in particular.

  该披露提供了化学式(I)的生物活性化合物及其药用盐，含有这些化合物的组合物，以及在各种应用中使用这些化合物的方法，例如用于治疗与E1型激活酶相关的疾病或紊乱，特别是与Nedd8激活酶(NAE)相关的疾病或紊乱。