甲基苄肼 | 671-16-9

• 物质功能分类: 原料药 - 抗肿瘤药 - 抗肿瘤辅助用药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 甲基苄肼
• 中文别名: N-异丙基-4-((2-甲基肼)甲基)苯甲酰胺；甲肼苄甲酰异丙胺；甲苄肼；丙卡巴肼；异丙酰胺苄肼；普罗卡巴兴；普鲁苄肼
• 英文名称: Procarbazine
• 英文别名: 4-[(2-methylhydrazinyl)methyl]-N-propan-2-ylbenzamide
• CAS: 671-16-9
• 化学式: C₁₂H₁₉N₃O
• mdl: MFCD00866411
• 分子量: 221.302
• InChiKey: CPTBDICYNRMXFX-UHFFFAOYSA-N

物化性质

• 沸点：
  362.36°C (rough estimate)
• 密度：
  1.0490 (rough estimate)
• 物理描述：
  Solid
• 熔点：
  223 °C
• 溶解度：
  In water, 1,400 mg/L @ 25 °C /Estimated/
• 蒸汽压力：
  8.4X10-7 mm Hg @ 25 °C /Estimated/
• 稳定性/保质期：
  Procarbazine hydrochloride is unstable in aqueous solution. /Procarbazine hydrochloride/
• 解离常数：
  pKa = 6.6
• 保留指数：
  1990;1975;2000;1990

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  16
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.416
• 拓扑面积：
  53.2
• 氢给体数：
  3
• 氢受体数：
  3

ADMET

代谢

普罗卡巴嗪主要在肝脏和肾脏中代谢。该药物似乎被自动氧化成偶氮衍生物，并释放过氧化氢。偶氮衍生物异构成腙，经过水解分解成一个苄醛衍生物和甲基肼。甲基肼进一步降解为CO₂和CH₄，可能还有肼，而醛被氧化为N-异丙基酞酸，通过尿液排出体外。

Procarbazine is metabolized primarily in the liver and kidneys. The drug appears to be auto-oxidized to the azo derivative with the release of hydrogen peroxide. The azo derivative isomerizes to the hydrazone, and following hydrolysis splits into a benzylaldehyde derivative and methylhydrazine. The methylhydrazine is further degraded to CO₂ and CH₄ and possibly hydrazine, whereas the aldehyde is oxidized to N-isopropylterephthalamic acid, which is excreted in the urine.

来源:DrugBank

代谢

它会在人体内迅速代谢...。异环磷酰胺的氧化产生相应的偶氮化合物和过氧化氢。进一步的代谢，可能发生在肝脏，产生在血液中循环并具有强效细胞毒活性的氧化偶氮衍生物。

It is rapidly metabolized in man ... . Oxidation of procarbazine produces the corresponding azo compound and hydrogen peroxide. Further metabolism, presumably in the liver, yields azoxy derivatives that circulate in the bloodstream and have potent cytotoxic activity.

来源:Hazardous Substances Data Bank (HSDB)

代谢

普罗卡巴嗪在大鼠体内可能产生去甲基普罗卡巴嗪；在大鼠体内产生N-异丙基-α-甲基偶氮-p-甲酰胺和对苯二甲酸异丙酰胺。

Procarbazine yields demethylprocarbazine probably in rats; yields n-isopropyl-alpha-methylazo-p-toluamide and terephthalic isopropylamide in rats. /from table/

来源:Hazardous Substances Data Bank (HSDB)

代谢

大鼠在注射后3分钟内将(14)C-甲基肼生物转化为(14)C-甲烷。在90分钟内，大鼠产生了25%的(14)C-CH4和3%的(14)C-CO2。而(14)C-丙卡巴肼的生物转化为CH4的速率较低。90分钟后，剂量的4%以(14)C-CH4的形式排出。/盐酸/

Rats biotransformed ip dose of (14)C-monomethylhydrazine to (14)C-methane within 3 min of injection. ... Rats produced 25% (14)C-CH4 and 3% (14)C-CO2 in 90 min. ...(14)C-procarbazine ... was less readily biotransformed to CH4. After 90 min, 4% of dose...excreted as (14)C-CH4. /hydrochloride/

来源:Hazardous Substances Data Bank (HSDB)

代谢

NADPH依赖的微粒体代谢[14C]肼苯哒嗪，标记在末端N-甲基上，导致药物与外源性添加的DNA共价结合；此反应被美托拉酮抑制。肼苯哒嗪的代谢还显示出药物甲基基团在代谢过程中与微粒体蛋白质共价结合，但蛋白质结合的程度至少比其主要氧化代谢物N-异丙基-α-(2-甲基偶氮)-对甲苯酰胺小一个数量级。导致偶氮衍生物的N-甲基基团与微粒体蛋白质共价结合的反应及其代谢形成甲烷的特征，在表观动力学参数（Km和Vmax）、诱导和抑制模式上显示出许多相似性，表明形成活性中间体的共同代谢途径，并涉及细胞色素p450。还原型谷胱甘肽刺激甲烷的形成并抑制与蛋白质的共价结合。

The NADPH-dependent microsomal metabolism of [14C]procarbazine labeled on the terminal N-methyl group resulted in the covalent binding of the drug to exogenously added DNA; this reaction was inhibited by metyrapone. Procarbazine metabolism was also shown to result in covalent binding of the methyl group of the drug to microsomal protein upon metabolism but the extent of protein binding was at least an order of magnitude smaller than that see with its primary oxidative metabolite. N-isopropyl-alpha-(2-methylazo)-p-toluamide. The characteristics of the reactions leading to the covalent binding of the N-methyl group of the azo derivative to microsomal protein and its metabolism to form methane, possessed a number of similarities in the apparent kinetic parameters (Km and Vmax), induction and inhibition patterns indicating a common pathway of metabolism to form a reactive intermediate and the involvement of cytochrome p450. Reduced glutathione stimulated methane formation and inhibited covalent binding to protein.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

普罗卡巴嗪的细胞毒性作用的确切机制尚未明确。有证据表明，该药物可能通过抑制蛋白质、RNA和DNA的合成发挥作用。研究表明，普罗卡巴嗪可能抑制蛋氨酸的甲基转移到t-RNA。功能性t-RNA的缺失可能导致蛋白质合成停止，进而导致DNA和RNA合成停止。此外，普罗卡巴嗪可能直接损害DNA。在药物自动氧化的过程中形成的过氧化氢，可能会攻击与DNA紧密结合的残留蛋白质中的蛋白质巯基团。

The precise mode of cytotoxic action of procarbazine has not been clearly defined. There is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis. Studies have suggested that procarbazine may inhibit transmethylation of methyl groups of methionine into t-RNA. The absence of functional t-RNA could cause the cessation of protein synthesis and consequently DNA and RNA synthesis. In addition, procarbazine may directly damage DNA. Hydrogen peroxide, formed during the auto-oxidation of the drug, may attack protein sulfhydryl groups contained in residual protein which is tightly bound to DNA.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

轻度和暂时性的血清转氨酶水平升高在系统性联合化疗过程中并不少见，而丙卡巴嗪在这些异常中的作用常常不太明确。超过一半的患者会出现转氨酶升高，而在10%到20%的患者中，转氨酶水平会超过正常上限的5倍。然而，由于血清酶升高而调整剂量的情况很少见。有报道出现临床上明显的肝脏疾病，表现为发热和血清转氨酶水平的显著升高，但没有黄疸，但这种情况非常罕见。一份单独的病例报告描述了在第二次联合治疗过程中自限性的、无黄疸的肝细胞损伤，并在重新使用丙卡巴嗪后复发，但没有在使用其他抗肿瘤药物时复发。

Mild and transient elevations in serum aminotransferase levels are not uncommon during courses of systemic combination chemotherapy and the role of procarbazine in these abnormalities is often not clear. Aminotransferase elevations arise in more than half of patients and rise above 5 times ULN in 10 to 20% of patients. However, dose modification for serum enzyme elevations is rarely necessary. Clinically apparent liver disease with fever and marked elevations in serum aminotransferase levels without jaundice has been reported but is very rare. A single case report described self-limited, hepatocellular injury without jaundice during a second course of combination therapy and recurrence upon rechallenge with procarbazine, but not with the other antineoplastic agents being used.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：丙卡巴肼

Compound:procarbazine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

普罗卡巴嗪能迅速且完全吸收。

Procarbazine is rapidly and completely absorbed.

来源:DrugBank

吸收、分配和排泄

盐酸丙卡巴肼口服给药后能迅速且几乎完全从胃肠道吸收。单次口服30毫克放射性标记的盐酸丙卡巴肼后，药物在1小时内达到血浆放射性浓度峰值。口服给药通常产生的血浆浓度与静脉给药后达到的浓度相似。

Procarbazine hydrochloride is rapidly and nearly completely absorbed from the GI tract following oral administration. Following oral administration of a single 30 mg dose of radiolabeled procarbazine hydrochloride, peak plasma radioactive concentrations of the drug were attained within 1 hour. Oral administration generally results in plasma concentrations similar to those achieved following IV administration of the drug. /Procarbazine hydrochloride/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

大约45%到70%的剂量在最初的24小时内以代谢物的形式通过尿液排出。

Approximately 45% to 70% of a dose is excreted in the urine during the first 24 hr as metabolites.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

从给药后前24小时内,25到70%的口服或静脉给药剂量可在尿液中回收;不到5%以未改变的形式排出,其余大部分以代谢物N-异丙基对苯二甲酸的形式存在。

From 25 to 70% of an oral or parenteral dose given to man is recovered from the urine during the first 24 hours after administration; less than 5% is excreted as the unchanged compound, and the rest is mostly in the form of a metabolite, N-isopropylterephthalanic acid.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

使用放射性标记的盐酸异环磷酰胺进行的动物和人体分布研究表明，放射性活性物质存在于肝脏、肾脏、肠壁和皮肤中。该药物能穿过血脑屏障并分布到脑脊液中。口服给药后，异环磷酰胺在血浆和脑脊液之间迅速达到平衡。目前尚不清楚异环磷酰胺是否分布到乳汁中。

Distribution studies in animals and humans using radiolabeled procarbazine hydrochloride administered IV have shown concentrations of radioactivity to be present in the liver, kidneys, intestinal wall and skin. The drug crosses the blood-brain barrier and distributes into CSF. Equilibration of procarbazine between plasma and CSF occurs rapidly following oral administration. It is not known whether procarbazine is distributed into milk.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2928000090
• 储存条件：
  温度：20°C，存放于惰性气体中，并避免光照。

制备方法与用途

甲基苄肼主要用作抗肿瘤药物和医药中间体。

反应信息

• 作为反应物：
  描述：

  甲基苄肼 在 溶剂黄146 、 sodium nitrite 作用下， 生成 4-甲酰基-N-异丙基苯甲酰胺 、 4-(N-Methyl-N-nitroso-hydrazonomethyl)-benzoesaeureisopropylamid
  参考文献：
  名称：

  Hanefeld, W.; Hunz, I., Archiv der Pharmazie, 1991, vol. 324, # 9, p. 682

  摘要：

  DOI：
• 作为产物：
  描述：

  对甲基苯甲酰氯 在 ammonium cerium (IV) nitrate 、 硝酸 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 33.5h， 生成 甲基苄肼
  参考文献：
  名称：

  一种抗癌药物丙卡巴肼的合成工艺

  摘要：

  本发明提供了一种抗癌药物丙卡巴肼的合成工艺，包括：对甲基苯甲酰氯的合成、N‑异丙基对甲苯甲酰胺的合成、4‑甲酰基‑N‑异丙基苯甲酰胺的合成、丙卡巴肼的合成；所述对甲基苯甲酰氯的合成步骤为：称取对甲苯甲酸136 mg(1.0 mmol)于10 mL的圆底烧瓶中，加入过量的二氯亚砜约3.0 mL,于80℃油浴加热回流3 h，减压蒸馏除去过量的二氯亚砜，得酰氯化合物，不经纯化，直接使用；本发明通过对抗癌药物丙卡巴肼的合成工艺的改进，具有设计合理，简化了合成方法，单元反应收率高、条件温和，降低能耗，节约资源的优点，从而有效的解决了现有装置中出现问题和不足。

  公开号：

  CN110283094A

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。
• 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] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
  申请人：CANCER RESEARCH TECH LTD

  公开号：WO2018215798A1

  公开（公告）日：2018-11-29

  The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.

  本发明涉及作为BCL6（B细胞淋巴瘤6）活性抑制剂的I式化合物：式中X1、X2、X3、R1、R2、R3、R4和R5分别如本文所定义。本发明还涉及制备这些化合物的方法，包括含有它们的药物组合物，以及它们在治疗增生性疾病（如癌症）以及其他BCL6活性所涉及的疾病或病况中的用途。
• [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。

表征谱图