葡磷酰胺 | 132682-98-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 葡磷酰胺
• 中文别名: (2S,3R,4S,5S,6R)-2-二(2-氯乙基氨基)膦酰氧基-6-(羟甲基)氧杂环己烷-3,4,5-三醇；葡膦酰胺
• 英文名称: glufosfamide
• 英文别名: β-D-glucosylisophosphoramide mustard；D 19575；(2S,3R,4S,5S,6R)-2-bis(2-chloroethylamino)phosphoryloxy-6-(hydroxymethyl)oxane-3,4,5-triol
• CAS: 132682-98-5
• 化学式: C₁₀H₂₁Cl₂N₂O₇P
• 分子量: 383.166
• InChiKey: PSVUJBVBCOISSP-SPFKKGSWSA-N

物化性质

• 沸点：
  569.9±60.0 °C(Predicted)
• 密度：
  1.56±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  -2
• 重原子数：
  22
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  141
• 氢给体数：
  6
• 氢受体数：
  9

ADMET

毒理性

• 解毒与急救

/SRP:/ 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，并在需要时辅助通气。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，并在必要时进行治疗……监测休克，并在必要时进行治疗……预计癫痫发作，并在必要时进行治疗……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、有强烈的呕吐反射且不流口水，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/

/SRP:/ 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)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或呼吸停止的患者，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。监测心率和必要时治疗心律失常。开始静脉输液，使用D5W（5%葡萄糖溶液）/SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用乳酸钠林格液。注意液体过载的迹象。考虑使用药物治疗肺水肿。对于伴有低血容量迹象的低血压，谨慎输液。注意液体过载的迹象。使用地西泮（安定）治疗癫痫。使用丙美卡因氢氯化物协助眼部冲洗。/毒药A和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 respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

本研究的目标是通过MMT分析法比较糖福酰胺与其他氧化磷酰胺在106份儿童急性白血病样本中的体外药物耐药性。测试的药物包括：糖福酰胺，4-HOO-异磷酰胺，4-HOO-环磷酰胺，马福酰胺环己胺盐，泼尼松龙，长春碱，L-天冬酰胺酶，多柔比星和阿糖胞苷。在这组初始急性淋巴细胞白血病（ALL）样本中，糖福酰胺、4-HOO-异磷酰胺、4-HOO-环磷酰胺和马福酰胺的等效细胞毒性值分别为5.95、9.92、4.60和3.90微克/毫升。与初始ALL样本相比，复发ALL样本中糖福酰胺和4-HOO-异磷酰胺的相对耐药性分别为1.9（p=0.049）和1.3（ns），在初始急性髓细胞白血病（AML）样本中分别为31（p<0.001）和5（p=0.001）。所有氧化磷酰胺均表现出高度显著的交叉耐药性。结论是，糖福酰胺与异磷酰胺相当。糖福酰胺在诊断和复发时对淋巴细胞均有较高的活性，然而它无法克服对其他氧化磷酰胺的耐药性。

... The objective of this study was to /compare/ the in vitro drug resistance proflile of glufosamide with other oxazaphosphorines in 106 samples of childhood acute leukemia by means of the MMT assay. The following drugs were tested: glufosfamide, 4-HOO-ifosfamide, 4-HOO-cyclophosphamide, mafosfamide cyclohexylamine salt, prednisolone, vincristine, L-asparaginase, daunorubicin and cytarabine. In this group of initial acute lymphoblastic leukemia (ALL) samples, equivalent cytotoxicity values for glufosfamide, 4-HOO-ifosfamide, 4-HOO-cyclophosphamide and mafosfamide were 5.95, 9.92, 4.60 and 3.90 ug/ml, respectively. In comparison to initial ALL samples, the relative resistance for glufosfamide and 4-HOO-ifosfamide in relapsed ALL samples were 1.9 (p= 0.049) and 1.3 (ns), and in initial acute myleoblastic leukemia (AML) samples, respectively, 31 (p< 0.001)and 5 (p= 0.001). All oxazaphosphorines showed highly significant cross resistance. In conclusion, glufosfamide is comparable to ifosfamide. Glufosfamide shows high activity against lymphoblasts both on diagnosis and relapse, however it cannot circumvent resistance to other oxazaphosphorines.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

进行了一项研究，以确定6小时输注的葡萄糖苷磷酰胺的最大耐受剂量（MTD）、主要毒性和药代动力学。葡萄糖苷磷酰胺是一种新型的烷化剂，具有针对葡萄糖转运系统的潜力。21名患者（10名女性，11名男性；中位年龄56岁）接受了800至6,000毫克/平方米的剂量治疗，这些患者均对难治性实体瘤无反应。该药物每三周通过六小时的静脉输注（快速/慢速两步法）给药。所有患者在第一个疗程都进行了药代动力学采样。最大耐受剂量为6,000毫克/平方米。在此剂量下，六名患者中有两名出现了可逆的、剂量限制性的肾小管酸中毒，在第二次和第三次治疗后的第一周，血清肌酐略有升高，而六名患者中有三名出现了短暂的4级中性粒细胞减少/白细胞减少。6小时输注的葡萄糖苷磷酰胺的主要毒性是可逆的肾小管酸中毒。

... /A study was conducted/ to determine the maximum tolerated dose (MTD), the principal toxicities, and the pharmacokinetics of 6 hr infusion of glufosfamide ... a novel alkylating agent with the potential to target the glucose transporter system. Twenty-one patients (10 women, 11 men; median age 56 yr) with refractory solid tumors were treated with doses ranging from 800 to 6,000 mg/sq m. /The drug/ was admin very three weeks as a two step (fast/slow) iv infusion over a 6 hr period. All patients went under pharmacokinetic sampling at the first course. The MTD was 6,000 mg/sq m. At this dose, two of six patients developed a reversible, dose limiting renal tubular acidosis and a slight incr in serum creatinine the week after the second and third courses of treatment, respectively, whereas three of six patients experienced short lived grade 4 neutropenia/leukopenia. ... The principal toxicity of the 6 hr infusion of glufosfamide is reversible renal tubular acidosis.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

为了研究抗癌药物戊糖酰胺的细胞毒性的分子方面，调查了该药物诱导凋亡和DNA断裂的潜力。戊糖酰胺能产生DNA星际交联...在体外模型系统中，使用了一对同源的中国仓鼠V79细胞，它们对交联剂的敏感性不同。CL-V5B细胞对戊糖酰胺的细胞毒性作用比亲本V79B细胞更敏感（根据D(10)值，敏感度高出30倍）。在药物脉冲治疗48小时后，敏感细胞而非抵抗性亲本细胞发生凋亡和坏死，凋亡是主要的细胞死亡形式（凋亡和坏死分别占70%和20%）。凋亡随着剂量的增加而增加，并伴随着超敏感细胞中DNA双链断裂的诱导。...观察到Bcl-2蛋白水平显著下降和caspases-3、-8、-9的激活。抵抗性亲本细胞对这些参数有抗性。敏感细胞中Bc1-2的下降先于凋亡，而通过转染介导的Bc1-2过表达至少部分地保护了细胞免于凋亡。从数据中确定，戊糖酰胺诱导的未修复交联转化为双链断裂，通过Bc1-2依赖途径触发凋亡。

To study the molecular aspects of cytotoxicity of the anticancer drug ... glufosfamide the potential of the agent /was investigated/ to induce apoptosis and DNA breakage. Glufosfamide generates DNA interstarand crosslinks ... an in vitro model system a pair of isogenic Chinese hamster V79 cells differing in their sensitivity to crosslinking agents /were utilized/. CL-V5B cells are ... more sensitive (30 fold based on D(10) values to the cytotoxic effects of glufosfamide as compared to parental V79B cells. After 48 hr of pulse treatment with the agent, sensitive cells but not the resistant parental line undergo apoptosis and necrosis, with apoptosis being the predominant form of cell death (70 and 20% of apoptosis and necrosis, respectively). Apoptosis incr as a function of dose and was accompanied by induction of DNA double strant breaks in the hypersensitive cells. ... A strong decline in the level of Bcl-2 protein and activation of caspases-3, -8, and -9 were observed. The resistant parental cells were refractory to all these parameters. Bc1-2 decline in the sensitive cells preceded apoptosis, and transfection mediated over expression of Bc1-2 protected at least in part from apoptosis. From the data /it was determined/ that non-repaired crosslinks induced by glufosfamide are transformed into double strand breaks which trigger apoptosis via Bc1-2 dependent pathway.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

生物活性方面，Glufosfamide 是一种新颖的烷化剂，通过糖苷键与 β-D-葡萄糖相连。

反应信息

• 作为反应物：
  描述：

  乙酸酐 、 葡磷酰胺 在 吡啶 作用下， 反应 1.0h， 生成 [(2R,3R,4S,5R,6S)-3,4,5-triacetyloxy-6-bis(2-chloroethylamino)phosphoryloxyoxan-2-yl]methyl acetate
  参考文献：
  名称：

  WO2008/11588

  摘要：

  公开号：
• 作为产物：
  描述：

  [(2R,3R,4S,5R,6S)-3,4,5-triacetyloxy-6-bis(2-chloroethylamino)phosphoryloxyoxan-2-yl]methyl acetate 在 sodium methylate 甲醇 作用下， 反应 0.5h， 以89%的产率得到葡磷酰胺
  参考文献：
  名称：

  WO2008/11588

  摘要：

  公开号：

文献信息

• PURINE DERIVATIVES
  申请人：PFIZER INC.

  公开号：US20150141402A1

  公开（公告）日：2015-05-21

  The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Q, G, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , and m are defined herein. The novel purine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.

  本发明涉及式(I)的化合物或其药用盐，其中Q、G、环A、环B、R1、R2、R3、R4、R5、R5a、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24和m在此定义。这些新颖的嘌呤衍生物在治疗哺乳动物中的异常细胞生长，如癌症方面具有用途。另外，还涉及含有这些化合物的药物组合物，以及在治疗哺乳动物中的异常细胞生长方面使用这些化合物和组合物的方法。
• PROTEIN KINASE INHIBITORS
  申请人：Sheppard S. George

  公开号：US20070203143A1

  公开（公告）日：2007-08-30

  Compounds that inhibit protein kinases, compositions containing the compounds and methods of treating diseases using the compounds are disclosed.

  抑制蛋白激酶的化合物、含有这些化合物的组合物以及利用这些化合物治疗疾病的方法被披露。
• [EN] ASH1L INHIBITORS AND METHODS OF TREATMENT THEREWITH<br/>[FR] INHIBITEURS DE ASH1L ET MÉTHODES DE TRAITEMENT AU MOYEN DE CEUX-CI
  申请人：UNIV MICHIGAN REGENTS

  公开号：WO2017197240A1

  公开（公告）日：2017-11-16

  Provided herein are small molecule inhibitors of ASH1L activity and small molecules that facilitate ASH1L degradation and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASH1L.

  本文提供了ASH1L活性的小分子抑制剂，促进ASH1L降解的小分子以及它们的使用方法，用于治疗疾病，包括急性白血病、实体肿瘤和其他依赖于ASH1L活性的疾病。
• [EN] ERK INHIBITORS<br/>[FR] INHIBITEURS D'ERK
  申请人：MERCK SHARP & DOHME

  公开号：WO2016100050A1

  公开（公告）日：2016-06-23

  The present invention provides a compound of Formula (I) or the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are ERK2 inhibitors. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.

  本发明提供了一种化合物(I)或其药学上可接受的盐、酯和前药，这些化合物是ERK2抑制剂。该发明还提供了一种包括至少一种化合物(I)和药学上可接受的载体的有效量的药物组合物。该发明还提供了一种包括至少一种化合物(I)的有效量和至少一种其他药学活性成分的有效量（例如，化疗药物等）以及药学上可接受的载体的药物组合物。
• [EN] PYRROLOPYRIMIDINES AS FAK AND ALK INHIBITERS FOR TREATMENT OF CANCERS AND OTHER DISEASES<br/>[FR] PYRROLOPYRIMIDINES À TITRE D'INHIBITEURS DE FAK ET D'ALK POUR LE TRAITEMENT DES CANCERS ET AUTRES MALADIES
  申请人：ABBOTT LAB

  公开号：WO2012045195A1

  公开（公告）日：2012-04-12

  Disclosed are compounds which inhibit the activity of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK), compositions containing the compounds, and methods of treating diseases during which FAK and ALK are expressed. The diseases are, for example, cancers.

  揭示了抑制焦点粘附激酶（FAK）和间变性淋巴瘤激酶（ALK）活性的化合物，含有这些化合物的组合物，以及治疗在其中FAK和ALK表达的疾病的方法。这些疾病例如包括癌症。