5-氟-2'-脱氧脲核苷 | 50-91-9

• 物质功能分类: 原料药 - 抗肿瘤药 - 抗代谢类抗肿瘤药
• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 中文名称: 5-氟-2'-脱氧脲核苷
• 中文别名: 氟尿苷；2'-脱氧-5-氟尿苷；5-氟-2'-脱氧尿苷；氟脲脱氧核苷；5-氟-2"-脱氧脲核苷；氟苷；5-氟去氧尿苷；2'-脱氧-5-氟尿嘧啶核苷；氟脲苷；5-氟-2-脱氧脲核苷
• 英文名称: 5-Fluoro-2'-deoxyuridine
• 英文别名: floxuridine；5-fluorodeoxyuridine；FUdR；2'-deoxy-5- fluorouridine；5-fluoro-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione；2′-deoxy-5-fluoruridine；5-fluoro-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione
• CAS: 50-91-9
• 化学式: C₉H₁₁FN₂O₅
• mdl: MFCD00006530
• 分子量: 246.195
• InChiKey: ODKNJVUHOIMIIZ-RRKCRQDMSA-N

物化性质

• 熔点：
  148 °C(lit.)
• 比旋光度：
  35.9 º (c=1, water)
• 沸点：
  150 °C
• 密度：
  1.3751 (estimate)
• 溶解度：
  在水中溶解度为 100 mM，在 DMSO 中溶解度为 100 mM
• 物理描述：
  Inhibits DNA synthesis. (NTP, 1992)
• 颜色/状态：
  Crystals from butyl acetate
• 气味：
  ODORLESS
• 蒸汽压力：
  7.6X10-13 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation for D (sodium) line = +37 deg (water); +48.6 deg (DMF)
• 分解：
  When heated to decomposition it emits very toxic fumes of /hydrogen fluoride and nitrogen oxides/.
• 解离常数：
  pKa = 7.44 (imide nitrogen)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.2
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.555
• 拓扑面积：
  99.1
• 氢给体数：
  3
• 氢受体数：
  6

ADMET

代谢

肝脏的。

Hepatic.

来源:DrugBank

代谢

生物转化/在/肝脏和组织中，广泛地转化为单磷酸衍生物和氟尿嘧啶；在连续动脉内输注后，转化为单磷酸衍生物增强；在快速静脉或动脉内注射后，大部分转化为氟尿嘧啶。

Biotransformation /is/ hepatic and in tissues, extensive, to the monophosphate derivative and fluorouracil; after continuous intra-arterial infusion, conversion to the monophosphate derivative is enhanced; largely converted to fluorouracil after rapid intravenous or intra-arterial injection.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在注入小剂量氟尿嘧啶后，大部分药物似乎被代谢为FUDR-MP，该药物的有效代谢物。当单剂量快速给药时，氟尿嘧啶显然会迅速分解为氟尿嘧啶。

Following infusion of small doses of floxuridine, most of the drug appears to be anabolized to FUDR-MP, the active metabolite of the drug. When single doses are administered rapidly, floxuridine is apparently rapidly catabolized to fluorouracil.

来源:Hazardous Substances Data Bank (HSDB)

代谢

氟尿嘧啶和氟尿嘧啶在肝脏中代谢。与单次注射相比，连续输注氟尿嘧啶时，其代谢降解较少。该药物以原形和尿素、氟尿嘧啶、α-氟-β-脲丙酸、二氢氟尿嘧啶、α-氟-β-胍丙酸以及α-氟-β-丙氨酸的形式在尿液中排出，并作为呼吸二氧化碳排出。

Floxuridine and fluorouracil are metabolized in the liver. Metabolic degradation of floxuridine is less when the drug is given by continuous infusion than when given by single injections. The drug is excreted intact and as urea, fluorouracil, a-fluoro-ß-ureidopropionic acid, dihydrofluorouracil, alpha-fluoro-beta-guanidopropionic acid, and alpha-fluoro-beta-alanine in the urine and as respiratory carbon dioxide.

来源:Hazardous Substances Data Bank (HSDB)

代谢

代谢降解发生，尤其是在肝脏中。氟尿嘧啶通过胸腺嘧啶或脱氧尿嘧啶磷酸化酶转化为5-氟尿嘧啶。5-氟尿嘧啶通过嘧啶环的还原被灭活；这个反应由二氢尿嘧啶脱氢酶执行，这种酶存在于肝脏、肠道粘膜和其他组织中。这种酶的遗传性缺乏会导致对药物的高度敏感。这个反应的产物，5-氟-5,6-二氢尿嘧啶最终降解为α-氟-β-丙氨酸...。

Metabolic degradation occurs, particularly in the liver. Floxuridine is converted by thymidine or deoxyuridine phosphorylases into 5-fluorouracil. 5-Fluorouracil is inactivated by reduction of the pyrimidine ring; this reaction is carried out by dihydrouracil dehydrogenase, which is found in liver, intestinal mucosa, and other tissues. Inherited deficiency of this enzyme leads to greatly increased sensitivity to the drug. The product of this reaction, 5-fluoro-5,6-dihydrouracil is ultimately degraded to alpha-fluoro-beta-alanine ... .

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

血清转氨酶升高在通过肝动脉输注氟尿嘧啶的患者中发生的比例很高，报告的发生率从25%到100%不等。这些升高通常在严重程度上是轻微到中等，并在停止治疗后得到解决。"化学性肝炎"，然而，经常是剂量调整或治疗周期延期的原因。此外，长期或重复的肝动脉内氟尿嘧啶输注可能导致无结石性胆囊炎和多发性胆管狭窄，这些情况可能引起黄疸和慢性硬化性胆管炎样综合征。在通过肝动脉输注氟尿嘧啶治疗的患者中，有5%到25%的患者会出现有症状的胆管狭窄，伴随疼痛和黄疸。这些症状通常在治疗2到6个月后出现，但可能会在更晚的时间出现，甚至在开始氟尿嘧啶治疗一年多后。胆管狭窄通常影响肝门区域的中心胆管，通常在胆总管分叉处及其周围。类似的炎症和纤维化是氟尿嘧啶治疗时可能发生的无结石性胆囊炎的原因，但通过在肝转移切除或放置肝动脉内输注泵时进行胆囊切除术可以避免。胆管狭窄通常在停止治疗后有所改善，但可能会进展或需要内镜或手术治疗。由于进行性胆管狭窄和胆汁淤积性肝损伤导致的死亡已经有过描述，并且可能是这种转移性肿瘤幸存者死亡的主要原因。通过同时给予地塞米松和通过肝脏和胆管成像监测，氟尿嘧啶治疗后胆管狭窄的发生率可能会降低。然而，由于新的、更有效的系统性抗癌药物的问世，肝动脉内灌注化疗的许多并发症已经减少了人们对这种治疗的热情。

Serum aminotransferase elevations occur in a high proportion of patients given floxuridine by infusion into the hepatic artery, the reported rates ranging from 25% to 100%. These elevations are generally mild to moderate in severity and resolve with stopping therapy. "Chemical hepatitis," however, not infrequently is a cause of dose modification or delay in cycles of treatment. In addition, prolonged or repeated hepatic arterial infusions of FUDR can cause acalculous cholecystitis and multiple biliary strictures that can cause jaundice and a chronic sclerosing cholangitis-like syndrome. Between 5% and 25% of patients treated with hepatic arterial infusions of FUDR will develop symptomatic biliary strictures with pain and jaundice. These typically arise after 2 to 6 months of therapy, but can appear later, even more than a year after initiating FUDR therapy. The biliary strictures typically affect central bile ducts in the area of the porta hepatis, generally in and around the bifurcation of the common hepatic duct. Similar inflammation and fibrosis account for the acalculous cholecystitis that can occur with FUDR therapy, but which can be avoided by cholecystectomy at the time of hepatic resection of metastases or placement of the intraarterial infusion pump. The biliary strictures generally improve with stopping therapy, but can progress or require endoscopic or surgical intervention. Deaths from progressive biliary strictures and cholestatic liver injury have been described and can be a major cause of death among survivors of this metastatic tumor. The frequency of biliary strictures after FUDR therapy may be decreased by concurrent administration of dexamethasone and avoided by monitoring with hepatic and biliary imaging. However, the many complications of hepatic arterial infusion chemotherapy have decreased enthusiasm for this therapy, particularly with newer, more potent systemic antineoplastic agents.

来源:LiverTox

毒理性

• 相互作用

氟尿嘧啶可能增加与血液病原因药物同时或近期治疗的白细胞减少和/或血小板减少的副作用；如果需要，应根据血细胞计数调整氟尿嘧啶的剂量。

Leukopenic and/or thrombocytopenic effects of floxuridine may be increased with concurrent or recent therapy /with blood dyscrasia-causing medications/ if these medications cause the same effects; dosage adjustment of floxuridine, if necessary, should be based on blood counts.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

附加性骨髓抑制可能会发生；当同时或连续使用两种或更多包括放射治疗在内的骨髓抑制剂时，可能需要减少剂量/与氟尿嘧啶合用/。

Additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively /with floxuridine/.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

由于正常的防御机制可能被氟尿嘧啶治疗所抑制，患者对灭活病毒疫苗的抗体反应可能会降低。停用导致免疫抑制的药物与患者恢复对疫苗反应的能力之间的时间间隔取决于所用免疫抑制药物的程度和类型、基础疾病以及其他因素；估计从3个月到1年不等。

Because normal defense mechanisms may be suppressed by floxuridine therapy, the patients antibody response to killed virus vaccines may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patients ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

由于氟尿嘧啶治疗可能会抑制正常的防御机制，与活病毒疫苗同时使用可能会增强疫苗病毒的复制，可能会增加疫苗病毒的副作用/不良反应，和/或可能会降低患者对疫苗的抗体反应；只有在仔细审查患者的血液学状态并得到管理氟尿嘧啶治疗的医生的知识和同意后，才应谨慎地对这些患者进行免疫接种。停用导致免疫抑制的药物与患者恢复对疫苗反应的能力之间的时间间隔取决于使用的免疫抑制药物的类型和强度、基础疾病和其他因素；估计从3个月到1年不等。与患者密切接触的人，尤其是家庭成员，也应推迟口服脊髓灰质炎疫苗的免疫接种。

Because normal defense mechanisms may be suppressed by floxuridine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patients antibody repose to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematological status and only with the knowledge and consent of the physician managing the floxuridine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patients ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 消除途径

氟尿嘧啶可以通过肾脏以不变的药物、尿素、氟尿嘧啶、α-氟-β-脲基丙酸、二氢氟尿嘧啶、α-氟-β-胍基丙酸和α-氟-β-丙氨酸的形式排出。氟尿嘧啶还可能通过呼吸以二氧化碳的形式排出。

Floxuridine can be excreted as unchanged drug, urea, fluorouracil, a-fluoro-bureidopropionic acid, dihydrofluorouracil, a-fluoro-b-guanidopropionic acid and a-fluoro-b-alanine via the kidneys. Floxuridine may also be excreted as respiratory carbon dioxide.

来源:DrugBank

吸收、分配和排泄

...氟尿嘧啶/是/...通过 parenterally(非口服途径)给药，因为口服后的吸收...是不可预测和不完整的。

... Floxuridine /is/ ... administered parenterally, since absorption after ingestion ... is unpredictable and incomplete.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

氟尿嘧啶是否分布进入乳汁尚不清楚。

It is not known whether floxuridine is distributed into milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

一些氟尿嘧啶可以穿过血脑屏障；活性代谢物在细胞内定位。

Some /Floxuridine/ crosses the blood-brain barrier; active metabolites are localized intracellularly.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

消除途径主要是呼吸系统（以二氧化碳形式），约占60%。肾脏消除占10到13%（以未改变的药物和代谢物形式）。

Elimination /is/ respiratory (as carbon dioxide), about 60%. Renal /elimination accounts for/ 10 to 13% (as unchanged drug and metabolites).

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1
• 危险品标志：
  Xn
• 安全说明：
  S22,S26,S36,S36/37/39
• 危险类别码：
  R22,R68,R36/37/38
• WGK Germany：
  3
• 海关编码：
  2934999090
• 危险品运输编号：
  UN 2811 6.1/PG 3
• 危险类别：
  6.1
• RTECS号：
  YU7525000
• 包装等级：
  III
• 危险标志：
  GHS06
• 危险性描述：
  H301
• 危险性防范说明：
  P261,P301+P312,P302+P352,P304+P340,P305+P351+P338

制备方法与用途

生物活性

Floxuridine（脱氧氟尿苷、FUDR，NSC 27640）是一种前体药物，在体内迅速分解为5-氟尿嘧啶。该药物可用于治疗多种癌症，特别是肝脏转移的癌症。它能够抑制Poly(ADP-Ribose)聚合酶、诱导DNA损伤和凋亡，并对HSV和CMV具有抗病毒作用。

体外研究

Floxuridine相较于相应的5'-O-单氨基酸酯前药，在与PEPT1的亲和力上更高。在人T淋巴细胞白血病细胞中，它与Leucovorin联用可产生协同抑制效果。Floxuridine显著抑制了[(3)H]-inosine和[(3)H]腺苷的摄取（对照组的60-70%），而其氨基酸酯前体，包括缬氨酸、苯丙氨酸、Asp和赖氨酸酯，则仅能提供较低程度的抑制效果（对照组的10-30%）。在持续36天的实验中，Floxuridine显著抑制了细胞增值超过50%，使细胞数量增加了4倍。此外，它还延长了体外培养的人眼球筋膜囊成纤维细胞的增殖时间。由于其短半衰期、陡峭的剂量反应曲线、高总清除率和高效的肝脏提取作用，Floxuridine是理想的肝动脉灌注（HAI）药物。

化学性质

Floxuridine是一种白色结晶，无气味，易溶于水和甲醇，几乎不溶于氯仿和乙醚。熔点为150-151℃。比旋度为+37°至+48.6°（在DMF中测量）。其紫外吸收最大波长分别为268 nm（pH 7.2）和270 nm（pH 14）。

用途

Floxuridine是一种抗肿瘤药物，适用于治疗肝癌、胃肠道癌、乳腺癌及头颈部癌。它可能引起骨髓抑制、胃肠道反应以及皮肤局部反应等副作用，并可能导致碱性磷酸酶、血清转氨酶、血清胆红质和乳酸脱氢酶水平升高。

生产方法

Floxuridine的制备过程如下：首先，甲基-2-去氧-D-呋喃核糖苷进行对甲苯甲酰化处理；然后，在乙酸-盐酸条件下水解以使1位甲氧基被氯取代；之后，与1-乙酰氧汞-5-氟尿嘧啶缩合生成产物，再经水解去掉对甲苯甲酰基而得。

反应信息

• 作为反应物：
  描述：

  5-氟-2'-脱氧脲核苷 在 4-二甲氨基吡啶 、 水 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.0h， 生成 3',5'-di-O-D-valyl-floxuridine trifluoroacetate
  参考文献：
  名称：

  氟尿苷的氨基酸酯前药：合成及结构，立体化学和酯化的位置对水解速率的影响。

  摘要：

  目的合成氟尿苷（FUdR）的氨基酸酯前药，并研究结构，立体化学和蛋白质的酯化部位对这些前药在Caco-2细胞匀浆中水解速率的影响。方法采用既定程序合成FUdR的氨基酸酯前药。在人腺癌细胞系（Caco-2）匀浆和pH 7.4磷酸盐缓冲液中评估了前药水解的动力学。结果合成并表征了以脯氨酸，L-缬氨酸，D-缬氨酸，L-苯丙氨酸和D-苯丙氨酸为原基的FUdR的3'-单酯，5'-单酯和3'，5'-二酯前药。在Caco-2细胞匀浆中，L-氨基酸酯前药的水解速度是相应D-氨基酸酯前药的10到75倍。Pro和Phe酯前药的水解速度比相应的Val酯前药快得多（3至30倍）。此外，5'-单酯前药的水解明显快于3'，5'-二酯前药的水解（3倍）。结论成功合成了新型的FUdR氨基酸酯前药。此处显示的结果清楚地表明，Caco-2细胞匀浆中FUdR前药的活化速率受该结构的结构，立体化学和酯化部位的影响。最后，5'-V

  DOI：

  10.1023/a:1025745824632
• 作为产物：
  描述：

  3,5-二-O-p-氯苯甲酰基氟尿苷 在 氨 作用下， 以 甲醇 为溶剂， 反应 16.0h， 生成 5-氟-2'-脱氧脲核苷
  参考文献：
  名称：

  5-取代的2'-脱氧尿苷异头体的立体选择性合成

  摘要：

  研究了5-取代的2,4-双(三甲基甲硅烷氧基)嘧啶与3,5-双(Op-氯苯甲酰基)-2-脱氧-α-D-呋喃核糖基氯的取代反应。在对硝基苯酚的存在下，β端基异构体立体选择性地形成，而有机碱的加入导致α端基异构体的立体选择性形成。反应的立体选择性取决于二甲硅烷基嘧啶的 5 位取代基、添加剂和每种试剂的浓度。5-取代的2'-脱氧-尿苷的α和β异头通过5-取代3',5'-二-O-(对-氯苯甲酰基)-2'-脱氧尿苷的α和β异头脱酰化合成。

  DOI：

  10.1246/bcsj.60.2073

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。
• Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
  申请人：——

  公开号：US20020143182A1

  公开（公告）日：2002-10-03

  The invention relates to certain heterocyclic compounds useful for the treatment of cancer and other diseases, having the Formula (I): 1 wherein: (a) m is an integer 0 or 1; (b) R 12 is an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocyclic, a substituted heterocyclic, a heteroaryl, a substituted heteroaryl, an aryl or a substituted aryl residue; (c) Ar 3 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (d) Ar 4 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (e) R 5 is hydrogen, hydroxy, alkyl or substituted alkyl; (f) - - - - - represents a bond present or absent; and (g) W, X, Y and Z are independently or together C(O)—, C(S), S, O, or NH; or a pharmaceutically acceptable salt thereof.

  该发明涉及某些对治疗癌症和其他疾病有用的杂环化合物，其具有以下式（I）： 1 其中： (a) m是整数0或1； (b) R12是烷基，取代烷基，环烷基，取代环烷基，杂环基，取代杂环基，杂芳基，取代杂芳基，芳基或取代芳基残基； (c) Ar3是芳基，取代芳基，杂芳基或取代杂芳基残基； (d) Ar4是芳基，取代芳基，杂芳基或取代杂芳基残基； (e) R5是氢，羟基，烷基或取代烷基； (f) - - - - - 代表存在或不存在的键；以及 (g) W、X、Y和Z独立或一起是C(O)、C(S)、S、O或NH；或其药学上可接受的盐。
• [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。
• Cobalamin conjugates for anti-tumor therapy
  申请人：Weinshenker M. Ned

  公开号：US20050054607A1

  公开（公告）日：2005-03-10

  The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.

  本发明提供了一种适用于治疗肿瘤相关疾病的钴胺素-药物结合物。钴胺素通过可切割的连接剂间接共价结合到抗肿瘤药物上，还可以通过一个或多个可选的间隔物。钴胺素通过其核糖环的5'-OH与第一间隔物或可切割连接剂共价结合。药物通过其现有或添加的功能基团与可切割连接剂的第二间隔物结合。在给药后，结合物与转钴胺素（其任何同工异构体）形成复合物。然后，该复合物结合到细胞膜上的受体并被细胞摄取。一旦进入细胞，细胞内酶将切割结合物，从而释放药物。根据结合物的结构，特定类别或类型的细胞内酶影响切割。由于生长细胞对钴胺素的需求量较高，肿瘤细胞通常摄取结合物的比例高于正常非生长细胞。本发明的结合物与相应的游离药物相比，具有较低的全身毒性和增强的疗效。
• [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。

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