福莫司汀 | 92118-27-9

• 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 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 中文名称: 福莫司汀
• 中文别名: 福泰氮芥；[1-[[[(2-氯乙基)亚硝基胺]羰基]氨基]乙基]膦酸二乙酯；1-[3-(2-氯乙基)-3-亚硝基脲]-乙基磷酸二乙酯
• 英文名称: fotemustine
• 英文别名: 1-(2-chloroethyl)-3-(1-diethoxyphosphorylethyl)-1-nitrosourea
• CAS: 92118-27-9
• 化学式: C₉H₁₉ClN₃O₅P
• mdl: MFCD00866278
• 分子量: 315.694
• InChiKey: YAKWPXVTIGTRJH-UHFFFAOYSA-N

物化性质

• 熔点：
  85°
• 密度：
  1.37±0.1 g/cm3(Predicted)
• 溶解度：
  H2O：≥1mg/mL
• 颜色/状态：
  Solid
• 蒸汽压力：
  9.1X10-7 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  19
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.888
• 拓扑面积：
  97.3
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

静脉输注的14C-福莫司汀（大约100毫克/平方米）在2名癌症患者中的药代动力学和代谢被研究。福莫司汀的代谢物在血浆中被识别为氯乙醇和N-亚硝基-1-咪唑啉酮-乙基-二乙基膦酸盐，在尿液中为1-海蒽环-乙基-二乙基膦酸盐和醋酸。

The pharmacokinetics and metabolism of intravenously infused (14)C-fotemustine (about 100 mg/sq m) were examined in 2 cancer patients. ... Metabolites of fotemustine were identified as chloroethanol and N-nitroso-1-imidazolone-ethyl-diethylphosphonate in plasma and as 1-hydantoin-ethyl-diethyl-phosphonate and acetic acid in urine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

肺毒性（急性呼吸窘迫综合征）在连续组合使用达卡巴嗪和福莫司汀后观察到，这很可能是由于高剂量的达卡巴嗪引起的O6-烷基转移酶的抑制。应避免这种联合用药方式。

Pulmonary toxicity (acute respiratory distress syndrome) has been observed after the sequential combination dacarbazine and fotemustine, likely due to O6 alkyltransferase inhibition provoked by a high dose of dacarbazine. This mode of combination should be avoided.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

保持呼吸道通畅，必要时协助通气。如果出现昏迷、抽搐、低血压和心律失常，则进行治疗。使用甲氧氯普胺治疗恶心和呕吐，使用静脉晶体液治疗胃肠炎引起的液体丢失。对于骨髓抑制，应在经验丰富的血液学家或肿瘤学家的帮助下进行治疗。外渗：立即停止输液，并通过注射器的负压尽可能多地抽回液体。然后给予以下特定治疗：在区域上放置加热垫，间歇加热24小时；抬高肢体。局部注射透明质酸酶可能有益。不要使用冰袋。/对于/去污，如果条件适当，口服活性炭。在小到中等摄入量后，如果可以迅速给予活性炭，则无需进行胃灌洗。由于这些药物的快速细胞内结合，透析和其他体外清除程序通常无效。/抗肿瘤药物/

Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Extravasation: Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. Then give the following specific treatment: Place a heating pad over the area and apply heat intermittently for 24 hours; elevate the limb. Local injection of hyaluronidase may be beneficial. Do not use ice packs. /For/ decontamination administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of the rapid intracellular incorporation of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者向前倾或将其置于左侧（如果可能的话，头部向下），以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。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……。预期癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，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/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). 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 0.9% saline (NS) 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 ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。 /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉输注放射性碳14标记的福莫司汀（大约100 mg/平方米）的药代动力学和代谢在2名癌症患者中进行了研究。当输注停止时，血浆中的放射性水平增加到最大4.1和5.5微克当量/克，然后以三指数方式下降，初始、中期和终末相的平均半衰期分别约为0.5、10和80小时。完整药物的血浆水平较低，最大水平为1.1和2.8微克/毫升，并以单指数方式下降，半衰期约为24分钟。血浆清除率较高（1426和764毫升/分钟），分布容积基于面积为47.7和26.4升。大部分放射性物质在7天内通过尿液排出（50.1%和61.3%），粪便中含量较少（6.8%和0.3%），作为呼出的二氧化碳的量仅微乎其微（不到0.1%）。...

The pharmacokinetics and metabolism of intravenously infused (14)C-fotemustine (about 100 mg/sq m) were examined in 2 cancer patients. Plasma levels of radioactivity increased to a maximum of 4.1 and 5.5 ug equivalents per g when the infusion stopped then declined triexponentially with mean half-lives of about 1/2, 10 and 80 hr for the initial, mid and terminal phases, respectively. Plasma levels of intact drug were lower, with maximum levels of 1.1 and 2.8 micrograms/ml, and declined monophasically with a half-life of about 24 min. Plasma clearance was high (1426 and 764 mL/min) with the volume of distribution based on areas of 47.7 and 26.4 L. Most of the radioactivity was eliminated in urine (50.1 and 61.3%) over 7 days with smaller amounts in the feces (6.8 and 0.3%) and only minimal quantities (under 0.1%) as expired carbon dioxide. ...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在给人类使用标记有(14)C的氯乙基团的药物后，放射性物质会缓慢消除，终末半衰期为83小时。大约50至60%的放射性物质在尿液中检测到，其中30至40%在最初的24小时内检测到，但未改变的分子在尿液中未检测到。5%的放射性物质通过粪便排出，以呼出的CO2形式排出的不到0.2%。

After administration in /humans/ of the drug labelled with (14)C on the chloroethyl group, the radioactivity is slowly eliminated with a terminal half-life of 83 hours. About 50 to 60% of the radioactivity administered is detected in the urine, 30 to 40% of which is detected during the first 24 hours, but the unchanged molecule is not detected in the urine. 5% of the radioactivity is eliminated in the feces and less than 0.2% in the form of expired CO2.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在/humans/中，通过静脉输液给药时，福莫司汀的血浆水平在大约45分钟后接近稳态值。输液结束后，血浆水平迅速下降，三小时后血液中无法再检测到该分子。

In /humans/, during administration by intravenous infusion, the plasma levels of fotemustine are close to the steady-state value after 45 minutes. After the end of the infusion, plasma levels go down rapidly and three hours later the molecule can no longer be detected in the blood.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在动物中，组织的分布是迅速且非常广泛的。福莫司汀能穿过血脑屏障（在大鼠中，注射后2到5分钟内在脑中检测到足够高的水平以发挥活性）。

In animals, the tissue distribution is rapid and very extensive. Fotemustine crosses the blood-brain barrier (2 to 5 minutes after bolus administration in the rat, it is detected in the brain at sufficiently high levels to be active).

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S16,S26,S36,S36/37
• 危险类别码：
  R10,R36/37,R43,R40
• WGK Germany：
  3
• 危险类别：
  6.1(b)
• 包装等级：
  III

制备方法与用途

亚硝脲类抗肿瘤药——福莫司汀

福莫司汀是一种亚硝脲类抗肿瘤药物，具有烷基化和氨甲酰化活性。动物实验显示其具有广谱的抗肿瘤作用。它的化学结构中含有一个丙氨酸生物电子等配体（氨基-1-乙基磷酸），这使得它能够容易穿透细胞及通过血脑屏障，在所有亚硝脲类药物中，福莫司汀的穿透力最强；然而，它的体内清除速度相对较慢。

福莫司汀的作用机制类似于氮芥，因此被称为“福泰氮芥”。它能够在体内与DNA酶作用，抑制DNA和RNA合成。相比氮芥，福莫司汀的毒性和致突变性较低。临床应用上主要用于治疗原发性恶性脑肿瘤、播散性恶性黑色素瘤（包括脑内部位），同时也适用于中枢神经系统肿瘤、非小细胞肺癌、恶性淋巴瘤及肾癌等。

化学性质

福莫司汀为结晶状固体，熔点为85℃。

用途

福莫司汀是一种新型的亚硝脲化合物，主要用于治疗分散性恶性黑色素瘤。

生产方法

合成福莫司汀的方法是：在水中与过量的氯乙基异氰酸酯反应，在0°C条件下，用亚硝酸钠进行亚硝化处理。

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。
• [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] SUBSTITUTED BENZYLAMINE COMPOUNDS, THEIR USE IN MEDICINE, AND IN PARTICULAR THE TREATMENT OF HEPATITIS C VIRUS (HCV) INFECTION<br/>[FR] COMPOSÉS DE BENZYLAMINE SUBSTITUÉS, LEUR UTILISATION EN MÉDECINE, EN PARTICULIER DANS LE TRAITEMENT D'UNE INFECTION PAR LE VIRUS DE L'HÉPATITE C (VHC)
  申请人：ASTEX THERAPEUTICS LTD

  公开号：WO2013064538A1

  公开（公告）日：2013-05-10

  The invention provides compounds of the formula (I): or a salt, N-oxide or tautomer thereof, wherein A is CH, CF or nitrogen; E is CH, CF or nitrogen; and R0 is hydrogen or C1-2 alkyl; R1a is selected from CONH2; CO2H; an optionally substituted acyclic C1-8 hydrocarbon group; and an optionally substituted monocyclic carbocyclic or heterocyclic group of 3 to 7 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S; R2 is selected from hydrogen and a group R2a; R2a is selected from an optionally substituted acyclic d-8 hydrocarbon group; an optionally substituted monocyclic carbocyclic or heterocyclic group of 3 to 7 ring members, of which 0, 1 or 2 ring members are heteroatom ring members selected from O, N and S; and an optionally substituted bicyclic heterocyclic group of 9 or 10 ring members, of which 1 or 2 ring members are nitrogen atoms; wherein at least one of R1 and R2 is other than hydrogen; R3 is an optionally substituted 3- to 10-membered monocyclic or bicyclic carbocyclic or heterocyclic ring containing 0, 1, 2 or 3 heteroatom ring members selected from N, O and S; R4a is selected from halogen; cyano; C1-4 alkyl optionally substituted with one or more fluorine atoms; C1-4 alkoxy optionally substituted with one or more fluorine atoms; hydroxy-C1-4 alkyl; and C1-2 alkoxy-C1-4 alkyl; R5 is selected from hydrogen and a substituent R5a; and R5a is selected from C1-2 alkyl optionally substituted with one or more fluorine atoms; C1-3 alkoxy optionally substituted with one or more fluorine atoms; halogen; cyclopropyl; cyano; and amino, The compounds have activity against hepatitis C virus and can be used in the prevention or treatment of hepatitis C viral infections.

  该发明提供了以下式（I）的化合物，或其盐、N-氧化物或互变异构体，其中A为CH、CF或氮；E为CH、CF或氮；R0为氢或C1-2烷基；R1a选自CONH2；CO2H；一个可选择取代的非环状C1-8碳氢化合物基团；以及一个可选择取代的含有3至7个环成员的单环碳环或杂环基团，其中0、1、2、3或4个是从O、N和S中选择的杂原子环成员；R2选自氢和一个基团R2a；R2a选自一个可选择取代的非环状d-8碳氢化合物基团；一个可选择取代的含有3至7个环成员的单环碳环或杂环基团，其中0、1或2个环成员是从O、N和S中选择的杂原子环成员；以及一个可选择取代的含有9或10个环成员的双环杂环基团，其中1或2个环成员是氮原子；其中R1和R2中至少一个不是氢；R3选自一个可选择取代的含有0、1、2或3个从N、O和S中选择的杂原子环成员的3至10个成员的单环或双环碳环或杂环环；R4a选自卤素；氰基；C1-4烷基，可选择取代一个或多个氟原子；C1-4烷氧基，可选择取代一个或多个氟原子；羟基-C1-4烷基；和C1-2烷氧基-C1-4烷基；R5选自氢和一个取代基R5a；R5a选自C1-2烷基，可选择取代一个或多个氟原子；C1-3烷氧基，可选择取代一个或多个氟原子；卤素；环丙基；氰基；和氨基。这些化合物对丙型肝炎病毒具有活性，并可用于预防或治疗丙型肝炎病毒感染。
• [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。