泼尼莫司汀 | 29069-24-7

• 物质功能分类: 原料药 - 抗肿瘤药 - 烷化剂类抗肿瘤药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 泼尼莫司汀
• 英文名称: Prednimustine
• 英文别名: [2-[(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] 4-[4-[bis(2-chloroethyl)amino]phenyl]butanoate
• CAS: 29069-24-7
• 化学式: C₃₅H₄₅Cl₂NO₆
• 分子量: 646.651
• InChiKey: HFVNWDWLWUCIHC-GUPDPFMOSA-N

物化性质

• 熔点：
  163-164°
• 比旋光度：
  D24 +92.9° (c = 1.06 in chloroform)
• 沸点：
  791.5±60.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)
• 颜色/状态：
  Crystals from methanol
• 旋光度：
  Optical rotation: + 92.9 degrees @ 24 °C (c = 1.06 in chloroform)

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  44
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  7

ADMET

代谢

泼尼松和苯丁酸氮芥（氯安布西林）及其β-氧化代谢物苯乙酸氮芥（PAM）的药代动力学特性在口服200毫克泼尼莫司汀（Sterecyt）和分别给予20毫克泼尼松加20毫克苯丁酸氮芥的方案后在血浆中进行了研究。共有12名癌症患者完成了这项试验。药物在交叉研究中作为单次剂量给药，并收集了32小时的连续血浆样本。通过气相色谱/质谱法测定苯丁酸氮芥和PAM，通过放射免疫分析法测定泼尼松。泼尼莫司汀中泼尼松和苯丁酸氮芥部分的平均相对利用度分别为19%和16%。与单独使用苯丁酸氮芥和泼尼松相比，泼尼莫司汀治疗后泼尼松以及苯丁酸氮芥和PAM在血浆中出现较晚且浓度显著较低。我们还发现，与单独使用苯丁酸氮芥相比，泼尼莫司汀给药后苯丁酸氮芥和PAM在血浆中的消除期延长。相比之下，泼尼莫司汀中泼尼松部分的消除与单独使用泼尼松片剂的消除似乎没有差异。泼尼莫司汀给药后烷化成分的修改血浆谱可能对泼尼莫司汀的临床疗效很重要。

The pharmacokinetic characteristics of prednisolone & of chlorambucil & its beta-oxidized metabolite, phenylacetic mustard (PAM) were studied in plasma after the oral admin of 200 mg prednimustine (Sterecyt) & a regimen consisting of 20 mg prednisolone plus 20 mg chlorambucil, respectively. A total of 12 cancer patients completed this trial. The drugs were given in a cross-over study as single doses, & serial plasma samples were collected for 32 h. Chlorambucil & PAM were assayed by a gas chromatographic/mass spectrometry method & prednisolone, by radioimmunoassay. The median relative availability of the prednisolone & chlorambucil moiety in prednimustine was 19% & 16%, respectively. Prednisolone, as well as chlorambucil & PAM, appeared later & at a significantly lower concn in plasma after treatment with prednimustine as compared with the mixture of chlorambucil & prednisolone. We also found that the elimination phase of chlorambucil & PAM in plasma is prolonged after the admin of prednimustine as compared with chlorambucil per se. In contrast, the elimination of the prednisolone moiety of prednimustine & that following the admin of a plain prednisolone tablet did not seem to differ. The modified plasma profile of the alkylating components following prednimustine admin may be important for the clinical efficacy of prednimustine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

这份报告描述了7种氯ambucil酯的理化性质和药代动力学参数，与氯ambucil进行了比较。这些酯被设计为氯ambucil的前药，以增加氯ambucil在大脑中的渗透和在CNS中的浓度与时间曲线，用于潜在治疗脑瘤。它们包括四种碳链长度从1-8的脂肪族酯（氯ambucil-甲基，-丙基，-己基和-辛酯）和三种芳香族酯，包括氯ambucil的苯甲基，苯乙基和泼尼松龙酯，泼尼莫司汀。这些酯具有亲脂性，并具有从4.05到>8.0的辛醇:水分配系数（log P值）。所有酯保留了烷化活性，但与氯ambucil相比有所降低。此外，所有酯在大鼠体内代谢，只产生氯ambucil。测量这些化合物在大鼠血浆中水解成氯ambucil的体外速率表明，短链脂肪族和芳香族氯ambucil酯被迅速分解为其母化合物。随着酯链长度和复杂性的增加，化合物的血浆半衰期增加。这可能与长链酯与血浆蛋白的结合增加有关，保护酯免受非特异性血浆酯酶的作用，以及血浆酯酶对这些酯的亲和力降低有关。通过HPLC对氯ambucil-己基，-辛基和-泼尼松龙酯的药代动力学分析表明，在大鼠中静脉注射（剂量相当于等摩尔氯ambucil，10 mg/kg）后，它们在血浆和大脑中只产生了低浓度的活性化合物。这些的大脑:血浆比率较低，与氯ambucil相似，没有一种酯显示出比等摩尔氯ambucil（5 mg/kg静脉注射，第1-5天）对大鼠脑内Walker 256肉瘤更优越的抗癌活性。

This report describes the physicochemical & pharmacokinetic parameters of 7 chlorambucil esters, which were compared with those of chlorambucil. These esters were designed as chlorambucil prodrugs to incr the brain penetration & concn vs time profile of chlorambucil within the CNS for potential treatment of brain tumors. They include four aliphatic esters from 1-8 carbon chains in length (chlorambucil-methyl, -propyl, -hexyl, & -octyl esters) & 3 aromatic esters, including the phenylmethyl, phenylethyl & prednisolone ester of chlorambucil, prednimustine. The esters were lipophilic & possessed log octanol:water partition coefficients (log P values) that ranged from 4.05 to >8.0. All retained alkylating activity, which was reduced compared with that of chlorambucil. In addition, all were metabolized in vivo in the rat to yield chlorambucil alone. Measurement of the in vitro rate of ester hydrolysis of the cmpds to yield chlorambucil in rat plasma demonstrated that short-chain aliphatic & aromatic chlorambucil esters were rapidly broken down to their parent compound. The plasma half-lives of the compounds increased with the increasing length & complexity of their ester chain. This may have been related to an incr in the binding of the long-chain esters to plasma proteins, protecting the ester from nonspecific plasma esterases, & to a reduced affinity of plasma esterases to these esters. Pharmacokinetic analysis of chlorambucil-hexyl, -octyl, & -prednisolone esters by HPLC demonstrated that following their iv admin in the rat (in doses equivalent to equimolar chlorambucil, 10 mg/kg), they yielded only low concns of active compounds in plasma & brain. The brain:plasma ratio of these was low & similar to that of chlorambucil, & no ester demonstrated anticancer activity superior to that obtained after the admin of equimolar chlorambucil (5 mg/kg i.v., days 1-5) against brain-sequestered Walker 256 carcinosarcoma in the rat.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌剂：泼尼莫司汀

IARC Carcinogenic Agent:Prednimustine

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：第3组：无法归类其对人类致癌性

IARC Carcinogenic Classes:Group 3: Not classifiable as to its carcinogenicity to humans

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构专论集：第50卷：（1990年）药物

IARC Monographs:Volume 50: (1990) Pharmaceutical Drugs

来源:International Agency for Research on Cancer (IARC)

毒理性

• 相互作用

本次调查的目的是评估富含半胱氨酸的蛋白质金属硫蛋白（MT）对细胞抵抗氯安布西林和泼尼松龙的酯前尼姆斯坦的细胞毒作用的能力。研究的细胞是富含MT的小鼠成纤维细胞（C1 1D100）和人上皮细胞（HE100），两者在之前的报告中已经被证明对氯安布西尔的抵抗力比其亲本株（C1 1D和HE）高出约3倍。在克隆和生长速率研究中，富含MT的细胞株也显示出对前尼姆斯坦的显著抗性。例如，在克隆研究中，C1 1D细胞的D0（D0=将存活率降至1/e的药物剂量）为8.7微克/毫升前尼姆斯坦，而C1 1D100的D0为12.4微克/毫升，代表抵抗力增加了约1.5倍，P<0.001，t检验。其他克隆研究表明，与等摩尔浓度的单一或联合组分相比，前尼姆斯坦在耐药细胞中具有显著的细胞杀伤活性。在用3H，（14）C-前尼姆斯坦（3H在泼尼松龙部分，（14）C在氯安布西尔部分）处理后，并通过凝胶过滤，大约40%的细胞质氯安布西尔与MT一起洗脱。然而，在MT部分中没有恢复到完整的前尼姆斯坦。数据表明，富含MT的细胞对前尼姆斯坦的抵抗力增强，是因为MT对烷基化部分的隔离。由于这种相互作用可能直到水解后才发生，因此完整的结合物可能绕过这种细胞防御机制。

The purpose of this investigation was to evaluate the ability of the cysteinyl-rich protein metallothionein (MT) to protect cells against the cytotoxic effects of prednimustine, an ester of chlorambucil & prednisolone. The cells studied were MT-rich substrains of murine fibroblasts (C1 1D100) & human epithelial cells (HE100), both demonstrated in an earlier report to exhibit an approx 3-fold incr in resistance to chlorambucil compared to their parent lines (C1 1D & HE) ... . Both in cloning & in growth rate studies the MT-rich strains proved to be significantly more resistant also to prednimustine. E.g. in cloning studies D0 for C1 1D cells (D0= the dose of drug reducing survival to 1/e) was 8.7 ug/ml prednimustine, whereas D0 for C1 1D100 was 12.4 ug/ml, representing an approx 1.5-fold incr in resistance, P<0.001, t-test. Other cloning studies revealed that prednimustine had a significantly higher cell killing activity in the resistant cells than equimolar concns of its components, single or in combination. Following treatment with 3H, (14)C-prednimustine (3H in the prednisolone moiety, (14)C in the chlorambucil moiety) & subsequent gel filtration, about 40% of the cytosolic chlorambucil eluted with MT. However, no intact prednimustine was recovered in the MT fractions. The data indicate that the MT-rich cells possess increased resistance to prednimustine due to a sequestration by MT of the alkylating moiety. Since the interaction probably does not take place until after hydrolysis, it is possible that the intact conjugate may bypass this cellular defence mechanism.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

基本治疗：建立专利气道。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要进行治疗……。监测休克，如有必要进行治疗……。预见并处理癫痫发作……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用生理盐水连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

细胞内浓度的预处理尼穆斯汀（PM）、苯丁酸氮芥（CLB）、苯乙酸氮芥（PAAM）和泼尼松龙（P）在不同实验肿瘤细胞系中被测量，这些细胞系被PM或CLB + P混合物孵化。为了细胞内分析测定，我们修改了一种高效液相色谱法，用于检测血浆中的这些物质。完整的PM可以在孵化肿瘤细胞的细胞内室中检测到。来自PM注射大鼠的PM孵化细胞显示出比暴露于CLB + P混合物或CLB的细胞更高的细胞内浓度-时间积分（PAAM）和更长的浓度-时间曲线，这些药物具有烷化能力。PM孵化后细胞中无法检测到PAAM，而在CLB孵化细胞中，PAAM的AUC超过了母药CLB。因此，我们的体外结果支持PM相对于CLB和CLB + P具有促进细胞内摄取和增加抗增殖效果的概念。

Intracellular concns of prednimustine (PM), chlorambucil (CLB), phenylacetic acid mustard (PAAM) & prednisolone (P) were measured in different experimental tumor cell lines that had been incubated with either PM or CLB + P. For intracellular analytical determination, we modified a high-pressure liquid chromatographic method for the detection of these substances in plasma. Intact PM could be detected in the intracellular compartment of the incubated tumor cells. PM-incubated cells from PM-injected rats exhibited a higher intracellular concn-time integral (PAAM) & longer concn-time profiles for drugs with alkylating capacity than did cells exposed to the CLB + P mixture or to CLB. PAAM was not detectable after incubation of cells with PM, whereas in CLB-incubated cells the AUC of PAAM exceeded that of the parent drug CLB. Our in vitro results therefore favour the concept of a facilitated intracellular uptake & an increased antiproliferative effect for PM versus CLB & CLB + P.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

一个剂量的口服溶液（40毫克/平方米）的(14)C-泼尼莫司汀被给予四位癌症患者。在适当的时间收集血浆、尿液和粪便，并分析总放射性。血浆样本用于分析泼尼莫司汀。在3名患者中，血浆中放射性物质（1-3微克(14)C-泼尼莫司汀当量）的峰值出现在1.5-3小时，在1名患者中出现在5-6小时。在血浆中没有检测到完整的泼尼莫司汀；这意味着如果存在，它的浓度将是0.02微克/毫升或更低，并且会占峰值血浆水平时总药物相关物质的不到1%。可溶剂提取的代谢物在血浆中的半衰期约为8小时或更短。到24小时时，几乎所有血浆中的放射性物质似乎都是共价结合的，并且它以大约10天的估算终末消除半衰期缓慢消除。在最初的24小时内迅速通过尿液排出，72小时内尿液中回收了40%-60%的剂量。尽管泼尼莫司汀吸收良好，但酯在口服给药后受到广泛的预处理，因此在系统循环中不存在。

A single oral soln dose (40 mg/sq m) of (14)C-prednimustine was administered to each of four cancer patients. Plasma, urine, & feces were collected at appropriate times & analyzed for total radioactivity. Plasma samples were analyzed for prednimustine. Peak plasma levels of radioactivity (1-3 ug (14)C-prednimustine equivalents) occurred at 1.5-3 hr in 3 patients & at 5-6 hr in one patient. No intact prednimustine was detected in the plasma; this means that if present, it would be at a concn of 0.02 ug/ml or less & would account for <1% of the total drug-related material at the time of peak plasma levels. Solvent-extractable metabolites had a plasma half-life of about 8 hr or less. By 24 hr essentially all the plasma radioactivity appeared to be covalently bound, & it was eliminated slowly with an estimated terminal elimination half-life of about 10 days. Rapid urinary excretion occurred in the first 24 hr, & 40%-60% of the dose was recovered in the urine in 72 hr. Although prednimustine was well absorbed, the ester was subject to extensive presystemic metab & was not present in the systemic circulation after oral admin.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Prednimustine（Leo 1031），一种泼尼松龙和苯丁酸氮芥的偶联物，被用于人体和狒狒，并确定了该化合物的代谢命运。与泼尼松龙的排泄相比，Prednimustine的排泄更慢且量更少，很大一部分药物保留在体内。口服给药后，Prednimustine分子的水解似乎是以定量的方式进行，但在静脉给药后，相当一部分的Prednimustine似乎仍然完整。与尿液排泄相比，通过粪便排泄的放射性物质很少。在狒狒中，胆汁排泄相对不重要。药物在狒狒的肺和脾脏中的定位表明，这种药物可能对影响这些器官的肿瘤性疾病具有潜在的治疗用途。

Prednimustine (Leo 1031), a conjugate of prednisolone & chlorambucil, was administered to humans & baboons & the metabolic fate of the cmpd ascertained. Compared to the excretion of prednisolone, prednimustine is excreted more slowly & less quantitatively, with a significant part of the cmpd being retained in the body. Hydrolysis of the prednimustine molecule appears to take place quantitatively after oral admin, but a substantial part of prednimustine appears to remain intact after its iv admin. Fecal excretion of radioactivity was minor compared to the urinary route. The biliary excretion in the baboon was relatively insignificant. Localisation within the lung & spleen of the baboon points to a potential therapeutic use of this drug in neoplastic conditions affecting these organs.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为产物：
  描述：

  泼尼松龙 、 苯丁酸氮芥 、 对甲苯磺酸 、 N,N'-二环己基碳二亚胺 在 4-二甲氨基吡啶 尿素 、 乙醇 作用下， 以 二氯甲烷 、 溶剂黄146 为溶剂， 反应 20.0h， 以to give 58.9 g of TLC pure prednimustine (91% yield) without any discolouration的产率得到泼尼莫司汀
  参考文献：
  名称：

  Steroid esters preparation

  摘要：

  本发明涉及一种改进的类固醇酯合成方法，其中使用肼基脲和4-(三级氨基)-吡啶的催化量与酸催化剂相结合作为缩合剂，可以得到高产率的纯净、不变色化合物。

  公开号：

  US04537722A1

文献信息

• [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。
• [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。