1,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-bis(oxidanyl)anthracene-9,10-dione; hydron; dichloride

• 分子结构分类: 有机化合物 - 苯类化合物 - 蒽
• 英文名称: 1,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-bis(oxidanyl)anthracene-9,10-dione; hydron; dichloride
• 英文别名: 1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione;hydron;dichloride
• 化学式: C22H30Cl2N4O6
• mdl: MFCD00242943
• 分子量: 517.4
• InChiKey: ZAHQPTJLOCWVPG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.65
• 重原子数：
  34
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.363
• 拓扑面积：
  163
• 氢给体数：
  10
• 氢受体数：
  10

ADMET

代谢

盐酸米托蒽醌（诺万特龙）在人和动物体内的药代动力学研究被讨论。静脉注射的诺万特龙以多指数动力学和终末半衰期从38小时到数天不等的速度从人和动物的血浆中消失。它通过广泛地进入组织而从血浆中被迅速清除；然而，重新分布回到血浆和从体内消除是缓慢的过程。在动物和人体内，诺万特龙被代谢为单羧酸和二羧酸衍生物，以及这些酸的葡萄糖醛酸苷结合物。静脉给药后，大部分组织中结合的是未改变的诺万特龙。消除过程缓慢，主要通过肾脏。与多柔比星（II）的相互作用研究表明，预先给予多柔比星可能会延长诺万特龙的半衰期，但同时给药在第一次剂量后可能不会涉及问题。

... Pharmacokinetic studies in humans and animals with mitoxantrone hydrochloride (Novantrone) are /discussed/ Intravenously administered novantrone disappears from the plasma of humans and animals with multiexponential kinetics and with a terminal half life ranging from 38 hr to several days. It is rapidly cleared from the plasma by extensive sequestration into the tissues; however, redistribution back into the plasma and elimination from the body are slow processes, In both animals and humans, novantroneis metabolized to the mono and dicarboxylic acid derivatives, as well as the glucuronide conjugates of these acids. Following IV administration, it is unchanged novantrone that binds to most tissues. Elimination is slow and predominantly via the kidney. Interaction studies with doxorubicin (II) indicate that prior administration of doxorubicin may prolong the half life of novantrone but that concurrent administration may not involve problems after the first dose.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间的总结使用：大多数资料认为，在母体抗肿瘤药物疗法期间，如米托蒽醌，母乳喂养是禁忌的。在间歇性治疗期间，可能可以在适当的禁乳期安全地进行母乳喂养，但禁乳期的持续时间尚不清楚。在一例病人中，米托蒽醌在每平方米6毫克剂量的28天后仍然能在乳汁中检测到。化疗可能会不利地影响母乳的正常微生物组和化学成分。在怀孕期间接受化疗的妇女更有可能在哺乳婴儿时遇到困难。 ◉ 对哺乳婴儿的影响：一位母亲静脉注射了3天每天每平方米6毫克的米托蒽醌，以及5天每天每平方米80毫克的依托泊苷和每平方米170毫克的阿糖胞苷。她在第三次米托蒽醌注射后的3周恢复了哺乳，此时米托蒽醌在乳汁中仍然可以检测到。婴儿在16个月大时没有明显的异常。 ◉ 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:Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy, such as mitoxantrone. It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence, but the duration of abstinence is not clear. In one patient, mitoxantrone was still detectable in milk 28 days after a dose of 6 mg per square meter. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant. ◉ Effects in Breastfed Infants:One mother received 3 daily doses of 6 mg/sq. m. of mitoxantrone intravenously along with 5 daily doses of etoposide 80 mg/sq. m. and cytarabine 170 mg/sq. m. intravenously. She resumed breastfeeding her infant 3 weeks after the third dose of mitoxantrone at a time when mitoxantrone was still detectable in milk. The infant had no apparent abnormalities at 16 months of age. ◉ 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

• 副作用

哮喘 - 由吸入刺激性或过敏原物质引发的 可逆性支气管收缩（支气管小管狭窄）。

Asthma - Reversible bronchoconstriction (narrowing of bronchioles) initiated by the inhalation of irritating or allergenic agents.

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

毒理性

• 相互作用

肿瘤化疗中的支持性护理是一个深入研究的主题。细胞抑制疗法的并发症是广泛研究其药物相互作用和副作用的原因。伴随肿瘤的免疫学和生化变化是最可能导致宿主生理状况恶化的因素。在许多情况下，甚至用于预防肝毒性的治疗方案中包含了肉碱及其乙酰衍生物。我们的假设是验证乙酰-L-肉碱盐酸盐（ALC）在联合米托蒽醌（MX）和肝毒性细胞抑制药物（包括烷化剂）治疗中的支持性代谢效果。本文报告描述了ALC与MX联合对携带可移植的L1210白血病且对MX有抗性的DBA/2雄性小鼠的影响。评估效果的准则是实验动物的存活时间长度。使用药物剂量为二次方的比例风险模型（7）来评估存活时间并计算最佳剂量。在每组数据经过对数转换后，使用威布尔分布确定了风险函数和相对风险指数。剂量-反应曲线由没有常数项的二次多项式表示。联合治疗显示，ALC的最佳剂量为186 mg/kg皮下注射。在携带对MX有抗性的实验性白血病L1210/MX的小鼠中，ALC（皮下注射）与MX（6 mg/kg静脉注射）联合治疗的效果在概率水平p <或= 0.001上得到了证实。ALC在单疗法中的效果不明显。

Supportive care in tumour chemotherapy is a subject of intensive research. The complications of cytostatic therapy are a cause of extensive research of their pharmacological interactions and side effects. The immunologic and biochemical changes accompanying tumours are the factor that is most responsible for the worsening of the physiology of the host. Regimens containing carnitine and it's acetyl-derivative are used in many cases, among others even for preventing hepatotoxicity. Our hypothesis was to verify the supporting metabolic effects of acetyl-L-carnitine hydrochloride (ALC) in combined therapy with mitoxantrone (MX) and hepatotoxic cytostatic drugs including alkylating agents. This present report describes the effect of ALC in combination with MX on DBA/2 male mice bearing a transplantable L1210 leukemia resistant to MX. The criterion for evaluation of effect was the length of survival time of experimental animals. The proportional-hazards model quadratic in the drug dose (7) was used for survival time evaluation and optimal dose calculation. The hazard functions and the index of relative hazard were determined using Weibull distribution after logarithmic transformation of the entered data in each particular group. The dose-response curve was represented by a second-degree polynomial without absolute term. The combination therapy revealed that the optimal dose of ALC was 186 mg/kg s.c. A significant effect of ALC (s.c.) in combined therapy with MX (6 mg/kg i.v.) given to animals bearing an experimental form of leukemia L1210/MX resistant to MX was proven at a level of probability p < or = 0.001. The effect of ALC in monotherapy was not demonstrable.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

...研究了双嘧达莫增强盐酸米托蒽醌细胞毒性的能力，实验是在体外培养的仓鼠卵巢细胞中进行的。克隆形成实验表明，1、2.5和5微摩尔的双嘧达莫剂量依赖性地降低了用5-25纳摩尔米托蒽醌处理的细胞的存活率。1和5微摩尔双嘧达莫的剂量分别将在3天内抑制细胞生长50%所需的米托蒽醌浓度从3.2降低到1.8纳摩尔，以及从3降低到0.5纳摩尔。双嘧达莫使指数生长的细胞在暴露于米托蒽醌时米托蒽醌的积累增加了1.8倍。因此，得出结论双嘧达莫在体外增强了米托蒽醌的细胞毒性。

... The ability of dipyridamole to /enhance/ the cytotoxic effects of mitoxantrone hydrochloride was studied in hamster ovary cells in vitro. Clonogenic assays indicated that one, 2.5, and 5 uM decreased the survival of cells treated with 5-25 nM mitoxantrone in a dose dependent manner. Doses of one and 5 uM dipyridamole decreased the mitoxantrone concentration required for 50% inhibition of cell growth from 3.2 to 1.8 and from 3 to 0.5 nM, respectively, over 3 days. Dipyridamole increased the accumulation of mitoxantrone by 1.8 fold in exponentially growing cells exposed to mitoxantrone. It was concluded that dipyridamole augments the cytotoxic effects of mitoxantrone in vitro.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

肿瘤对弱酸性和弱碱性化疗药物的摄取受到肿瘤细胞外/间质pH（pH(e)）、肿瘤细胞维持的细胞内pH（pH(i)）以及药物本身的离子化特性的极大影响。肿瘤中的酸性外细胞膜pH梯度会排除如蒽环类、蒽醌类和长春花碱类等弱碱性药物进入细胞，导致肿瘤中出现相当程度的“生理性药物抵抗”。我们在C3H/hen小鼠的C3H肿瘤中通过灌胃和腹腔注射（i.p.）NaHCO(3)诱导了急性代谢性碱中毒。(31)P磁共振光谱测量3-氨基丙基磷酰化物显示，在腹腔注射NaHCO(3)后2小时内，肿瘤pH(e)增加了多达0.6个pH单位，后腿组织pH(e)增加了0.2到0.3个pH单位。根据测得的pH(e)和pH(i)值，对米托蒽醌在肿瘤和正常（后腿）组织中的摄取进行理论计算，表明通过NaHCO(3)预处理可以获得高达3.3倍的治疗指数增益。用12 mg/kg米托蒽醌治疗C3H肿瘤携带小鼠导致肿瘤生长延迟9天，而联合NaHCO(3)--米托蒽醌治疗使TGD增强到16天。

Uptake of weak acid and weak base chemotherapeutic drugs by tumors is greatly influenced by the tumor extracellular/interstitial pH (pH(e)), the intracellular pH (pH(i)) maintained by the tumor cells, and by the ionization properties of the drug itself. The acid-outside plasmalemmal pH gradient in tumors acts to exclude weak base drugs like the anthracyclines, anthraquinones, and vinca alkaloids from the cells, leading to a substantial degree of "physiological drug resistance" in tumors. We have induced acute metabolic alkalosis in C3H tumor-bearing C3H/hen mice, by gavage and by intraperitoneal (i.p.) administration of NaHCO(3). (31)P magnetic resonance spectroscopic measurements of 3-aminopropylphosphonate show increases of up to 0.6 pH units in tumor pH(e), and 0.2 to 0.3 pH units in hind leg tissue pH(e), within 2 hours of i.p. administration of NaHCO(3). Theoretical calculations of mitoxantrone uptake into tumor and normal (hind leg) tissue at the measured pH(e) and pH(i) values indicate that a gain in therapeutic index of up to 3.3-fold is possible with NaHCO(3) pretreatment. Treatment of C3H tumor-bearing mice with 12 mg/kg mitoxantrone resulted in a tumor growth delay of 9 days, whereas combined NaHCO(3)--mitoxantrone therapy resulted in an enhancement of the TGD to 16 days.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

建立了一种优化程序，用于通过乳化加热固化法制备米托蒽醌白蛋白微球（DHAQ-BSA-MS）。研究了载药白蛋白微球的形态、粒径、载药量、释放特性、稳定性以及在体内的分布。结果显示，微球表面规则，平均直径为0.99微米，平均表面积直径为1.24微米，平均体积直径为1.44微米，表观载药量为2.558 ± 0.101微克/毫克（n = 5），有效载药量为1.503% ± 0.127%（n = 5），包封率为92.82% ± 6.48%（n = 5），释放特性符合“双相动力学方程”：1 - Q = 0.6428e^(-0.2132t) + 0.3988e^(-0.00150t)（γ1 = -0.9951，γ2 = -0.9982）；T1/2 α = 3.250小时，T1/2 β = 461.7小时。载药白蛋白微球在室温下储存三个月后稳定性良好。高效液相色谱（HPLC）的结果显示，给小鼠静脉注射后20分钟，药物在大约77.6% ± 1.38%的剂量积累在肝脏中。这表明DHAQ-BSA-MS对肝脏具有显著的靶向性，对于提高米托蒽醌的抗肝癌效果和降低其毒性似乎具有重要作用。

An optimum procedure was established for preparing mitoxantrone albumin microspheres (DHAQ-BSA-MS) with emulsion-heating solidification. The morphology, diameters, drug loading, release characteristics, stability and its distribution in vivo of the drug-loaded albumin microspheres were studied. The results showed that the surface was regular, the average diameter was 0.99 micron, mean surface diameter was 1.24 microns and mean volume diameter was 1.44 microns, apparent drug loading was 2.558 +/- 0.101 micrograms.mg-1 (n = 5), effective drug loading was 1.503% +/- 0.127% (n = 5), embedding ratio was 92.82% +/- 6.48% (n = 5), and the release characteristics were in accord with "biphase kinetics equation": 1 - Q = 0.6428e-0.2132t + 0.3988e-0.00150t (gamma 1 = -0.9951, gamma 2 = -0.9982); T1/2 alpha = 3.250 h, T1/2 beta = 461.7 h. The stability of the drug-loaded albumin microspheres was good after three months storage at room temperature. The results determined by HPLC showed that the drug accumulated about 77.6% +/- 1.38% of the dose in the liver 20 minutes after intravenous injection to mice. This indicates that DHAQ-BSA-MS showed remarkable targeting for liver, and it seems to have important value for increasing the antihepatoma effect and decreasing the toxicity of mitoxantrone.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

... /药物动力学/ 1,4-二羟基-5,8-双((2-((2-羟基乙基)氨基)乙基)氨基)-9,10-蒽二酮盐酸盐（I；NSC 301739；米托蒽醌盐酸盐）在6名转移性癌症患者中进行了测定，每位患者接受了100-200 mCi的I，每平方米1至3毫克的I溶解在12毫升正常生理盐水中，通过静脉推注15分钟。I的血浆清除呈现双相模式，调和平均初始半衰期为13.7分钟，终末半衰期为37.4小时。在24小时和72小时时，尿液中未改变药物的回收率分别为6.8%和7.3%，而相应总放射活性的回收率为9.4%和11.3%。I的表观分布容积约为13.8 + 2.9升/千克。总清除率为238.7毫升/千克/小时，是肌酐清除率的两倍。

... /Pharmacokinetics/ 1,4 dihydroxy 5,8 bis((2 ((2 hydroxyethyl)amino)ethyl)amino) 9,10 an6 thracenedione hydrochloride (I; NSC 301739; mitoxantrone hydrochloride) were determined in 6 metastatic cancer patients who each received 100 200 mCi, one to 3 mg/sq m of I in 12 ml of normal saline solution as an IV bolus over 15 min. Plasma clearance of I followed a biphasic pattern with a harmonic mean initial half life of 13.7 min and a terminal half life of 37.4 hr. Recovery of unchanged drug in the urine was 6.8% at 24 hr and 7.3% at 72 hr, while the corresponding recovery of total radioactivity was 9.4% and 11.3%. The apparent volume of distribution of I was about 13.8 + 2.9 liters/kg. Total clearance was 238.7 ml/kg/hr, twice the creatinine clearance.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

盐酸米托蒽醌（诺万特龙）在人和动物体内的药代动力学研究被讨论。静脉注射的诺万特龙以多指数动力学和终末半衰期从38小时到数天不等的速度从人和动物的血浆中消失。它通过广泛地进入组织而从血浆中被迅速清除；然而，重新分布回到血浆和从体内消除是缓慢的过程。在动物和人体内，诺万特龙被代谢为单羧酸和二羧酸衍生物，以及这些酸的葡萄糖醛酸苷结合物。静脉给药后，大部分组织中结合的是未改变的诺万特龙。消除过程缓慢，主要通过肾脏。与多柔比星（II）的相互作用研究表明，预先给予多柔比星可能会延长诺万特龙的半衰期，但同时给药在第一次剂量后可能不会涉及问题。

... Pharmacokinetic studies in humans and animals with mitoxantrone hydrochloride (Novantrone) are /discussed/ Intravenously administered novantrone disappears from the plasma of humans and animals with multiexponential kinetics and with a terminal half life ranging from 38 hr to several days. It is rapidly cleared from the plasma by extensive sequestration into the tissues; however, redistribution back into the plasma and elimination from the body are slow processes, In both animals and humans, novantroneis metabolized to the mono and dicarboxylic acid derivatives, as well as the glucuronide conjugates of these acids. Following IV administration, it is unchanged novantrone that binds to most tissues. Elimination is slow and predominantly via the kidney. Interaction studies with doxorubicin (II) indicate that prior administration of doxorubicin may prolong the half life of novantrone but that concurrent administration may not involve problems after the first dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

肿瘤对弱酸性和弱碱性化疗药物的摄取受到肿瘤细胞外/间质pH（pH(e)）、肿瘤细胞维持的细胞内pH（pH(i)）以及药物本身的离子化特性的极大影响。肿瘤中的酸性外细胞膜pH梯度会排除如蒽环类、蒽醌类和长春花碱类等弱碱性药物进入细胞，导致肿瘤中出现相当程度的“生理性药物抵抗”。我们在C3H/hen小鼠的C3H肿瘤中通过灌胃和腹腔注射（i.p.）NaHCO(3)诱导了急性代谢性碱中毒。(31)P磁共振光谱测量3-氨基丙基磷酰化物显示，在腹腔注射NaHCO(3)后2小时内，肿瘤pH(e)增加了多达0.6个pH单位，后腿组织pH(e)增加了0.2到0.3个pH单位。根据测得的pH(e)和pH(i)值，对米托蒽醌在肿瘤和正常（后腿）组织中的摄取进行理论计算，表明通过NaHCO(3)预处理可以获得高达3.3倍的治疗指数增益。用12 mg/kg米托蒽醌治疗C3H肿瘤携带小鼠导致肿瘤生长延迟9天，而联合NaHCO(3)--米托蒽醌治疗使TGD增强到16天。

Uptake of weak acid and weak base chemotherapeutic drugs by tumors is greatly influenced by the tumor extracellular/interstitial pH (pH(e)), the intracellular pH (pH(i)) maintained by the tumor cells, and by the ionization properties of the drug itself. The acid-outside plasmalemmal pH gradient in tumors acts to exclude weak base drugs like the anthracyclines, anthraquinones, and vinca alkaloids from the cells, leading to a substantial degree of "physiological drug resistance" in tumors. We have induced acute metabolic alkalosis in C3H tumor-bearing C3H/hen mice, by gavage and by intraperitoneal (i.p.) administration of NaHCO(3). (31)P magnetic resonance spectroscopic measurements of 3-aminopropylphosphonate show increases of up to 0.6 pH units in tumor pH(e), and 0.2 to 0.3 pH units in hind leg tissue pH(e), within 2 hours of i.p. administration of NaHCO(3). Theoretical calculations of mitoxantrone uptake into tumor and normal (hind leg) tissue at the measured pH(e) and pH(i) values indicate that a gain in therapeutic index of up to 3.3-fold is possible with NaHCO(3) pretreatment. Treatment of C3H tumor-bearing mice with 12 mg/kg mitoxantrone resulted in a tumor growth delay of 9 days, whereas combined NaHCO(3)--mitoxantrone therapy resulted in an enhancement of the TGD to 16 days.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  1,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-bis(oxidanyl)anthracene-9,10-dione; hydron; dichloride 生成 米托蒽醌
  参考文献：
  名称：

  MURDOCK, K. C.

  摘要：

  DOI：
• 作为产物：
  描述：

  米托蒽醌 生成 1,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-bis(oxidanyl)anthracene-9,10-dione; hydron; dichloride
  参考文献：
  名称：

  MIQURDOCK, KEITH C.;DURR, FREDERICK E.

  摘要：

  DOI：

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] 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] BRUTON'S TYROSINE KINASE INHIBITORS<br/>[FR] INHIBITEURS DE LA TYROSINE KINASE DE BRUTON
  申请人：PFIZER

  公开号：WO2014068527A1

  公开（公告）日：2014-05-08

  Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (BTK). Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the BTK inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions. (Formula I)

  本文披露了一种与Bruton's酪氨酸激酶（BTK）形成共价键的化合物。公开了制备这些化合物的方法。还披露了包括这些化合物的药物组合物。公开了使用BTK抑制剂的方法，单独或与其他治疗剂联合治疗自身免疫疾病或症状、异源免疫疾病或症状、癌症，包括淋巴瘤，以及炎症性疾病或症状的方法。 (化学式I)
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。