三甲曲沙 | 52128-35-5

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 三甲曲沙
• 英文名称: trimetrexate
• 英文别名: 5-methyl-6-(((3,4,5-trimethoxyphenyl)amino)methyl)quinazoline-2,4-diamine；2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyphenylamino)methyl]quinazoline；5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline-2,4-diamine
• CAS: 52128-35-5
• 化学式: C₁₉H₂₃N₅O₃
• 分子量: 369.423
• InChiKey: NOYPYLRCIDNJJB-UHFFFAOYSA-N

物化性质

• 熔点：
  215-217 °C
• 沸点：
  647.0±65.0 °C(Predicted)
• 密度：
  1.305±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：≥ 61.5 mg/mL（166.48 mM）
• 物理描述：
  Solid
• 稳定性/保质期：
  Bulk: A sample stored at 60 °C for 30 days showed no decomposition (UV, HPLC). Solution: A solution in 5% methanol (0.5 mg/mL) showed no decomposition after 9 days (UV). A solution in 5% dimethylacetamide /pH 4 acetate buffer showed no decomposition after 48 hours(HPLC).

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  118
• 氢给体数：
  3
• 氢受体数：
  8

ADMET

代谢

肝脏。临床前数据强烈表明，主要的代谢途径是氧化O-脱甲基化，然后与葡萄糖醛酸或硫酸盐结合。

Hepatic. Preclinical data strongly suggest that the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the sulfate.

来源:DrugBank

代谢

三甲曲沙在肝脏中高度代谢。至少有2种代谢物通过尿液排出。已经识别出一种代谢物，为三甲曲沙的4'-O-葡萄糖苷酸苷，这是由于4'-位的氧化O-二甲化和随后与葡萄糖醛酸结合形成的。大约15%的剂量以未改变的三甲曲沙形式通过尿液排出，而另外20%显然是以代谢物形式排出。

Trimetrexate is highly metabolized by the liver. At least 2 metabolites are excreted in urine. One metabolite has been identified a 4'-O-glucuronide conjugate of trimetrexate, which is formed as a result of oxidative O-dimethylation at the 4'-position and subsequent conjugation with glucuronic acid. About 15% of a dose is excreted in urine as unchanged trimetrexate, while another 20% apparently excreted as metabolites.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏。临床前数据强烈表明，主要的代谢途径是氧化O-脱甲基化，然后与葡萄糖醛酸或硫酸盐结合。 消除途径：给药剂量的10%到30%以原形从尿液中排出。 半衰期：11到20小时

Hepatic. Preclinical data strongly suggest that the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the sulfate. Route of Elimination: Ten to 30% of the administered dose is excreted unchanged in the urine. Half Life: 11 to 20 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

体外研究表明，三甲曲沙是对细菌、原生动物和哺乳动物来源的二氢叶酸还原酶（DHFR）的竞争性抑制剂。DHFR催化细胞内二氢叶酸还原为活性辅酶四氢叶酸。抑制DHFR导致这种辅酶的耗竭，直接干扰胸腺嘧啶生物合成，以及抑制叶酸依赖的形式转移酶，间接抑制p.r.n.生物合成。最终结果是DNA、RNA和蛋白质合成的中断，从而导致细胞死亡。

In vitro studies have shown that trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of p.r.n. biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

当不给与亚叶酸钙保护时，三甲曲沙治疗与血清酶升高的中等发生率相关，高达20%的患者血清ALT或AST升高超过5倍ULN。然而，当与亚叶酸钙一起使用时，三甲曲沙的副作用较少，尽管仍可能发生血清酶升高。在HIV感染和耶氏肺孢子菌肺炎患者的临床试验中，ALT升高超过5倍ULN的发生率为1%至8%，但通常不比使用甲氧苄啶和磺胺甲恶唑的标准化疗更频繁。这些升高通常是暂时的，没有伴随症状或黄疸，尽管继续治疗，但已解决或改善。文献中没有报告三甲曲沙引起的临床明显急性肝损伤的实例。此外，三甲曲沙没有与窦状阻塞综合征或乙型肝炎的再激活相关。尽管如此，三甲曲沙可能具有肝毒性潜力，但由于其使用有限，给予时间短且与亚叶酸钙一起使用，因此没有令人信服地将其与黄疸的临床明显肝损伤病例联系起来。

When given without leucovorin protection, trimetrexate therapy is associated with a moderate rate of serum enzyme elevations, serum ALT or AST elevations above 5 times ULN in up to 20% of patients. When given with leucovorin, however, trimetrexate has fewer side effects although serum enzyme elevations can still occur. In clinical trials in patients with HIV infection and Pneumocystis jirovecii pneumonia, ALT elevations above 5 times ULN occurred in 1% to 8% of patients, but were usually no more frequent than with standard therapy using trimethoprim with sulfamethoxazole. The elevations were typically transient, without accompanying symptoms or jaundice and resolved or improved despite continuation of therapy. No instances of clinically apparent acute liver injury attributed to trimetrexate have been reported in the literature. In addition, trimetrexate has not been linked to sinusoidal obstruction syndrome or to reactivation of hepatitis B. Nevertheless, trimetrexate probably has hepatotoxic potential, but because it has limited use, is given for short periods of time and is administered with leucovorin, it has not been convincingly linked to cases of clinically apparent liver injury with jaundice.

来源:LiverTox

毒理性

• 药物性肝损伤

三甲曲沙

Compound:trimetrexate

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous 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

• 消除途径

给药剂量的10%到30%以原形从尿液中排出。

Ten to 30% of the administered dose is excreted unchanged in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

20 ± 8 升/平方米

20 ± 8 L/m2

来源:DrugBank

吸收、分配和排泄

• 清除

38 +/- 15 mL/min/m2 [获得性免疫缺陷综合症（艾滋病）患者，其中4例患有卡氏肺孢子虫肺炎或2例患有弓形虫病。三甲曲嗪通过静脉注射以30 mg/m2/天的剂量给药，同时每6小时给予亚叶酸钙20 mg/m2，持续21天] 53 +/- 41 mL/min/m2 [患有晚期实体瘤的癌症患者，使用各种剂量方案，接受单次给药，剂量为10至130 mg/m2] 30 +/- 8 mL/min/m2 [患有晚期实体瘤的癌症患者，在使用各种剂量方案后，经过五天的输注]

38 +/- 15 mL/min/m2 [patients with acquired immunodeficiency syndrome (AIDS) who had Pneumocystis carinii pneumonia (4 patients) or toxoplasmosis (2 patients). Trimetrexate was administered intravenously as a bolus injection at a dose of 30 mg/m2/day along with leucovorin 20 mg/m2 every 6 hours for 21 days] 53 +/- 41 mL/min/m2 [Cancer patients with advanced solid tumors using various dosage regimensreceiving a single-dose administration of 10 to 130 mg/m2] 30 +/- 8 mL/min/m2 [Cancer patients with advanced solid tumors using various dosage regimensafter a five-day infusion]

来源:DrugBank

吸收、分配和排泄

癌症患者的临床药代动力学研究表明，三甲曲嗪的血药浓度-时间曲线呈双相或三相形式。终末消除半衰期平均为13.6小时。稳态下平均总血浆清除率和分布容积分别为27.9毫升/分钟/平方米和21.1升/平方米。脑脊液浓度是血浆的3.4%，这表明三甲曲嗪不易透过血脑屏障。三甲曲嗪有86%至94%与血浆蛋白结合。

Clinical pharmacokinetic studies in cancer patients show that trimetrexate plasma concentration-time curves are biphasic or triphasic in form. The terminal elimination half-life averages 13.6 hr. Mean total plasma clearance and volume of distribution as steady-state values were 27.9 ml/min/sq m and 21.1 l/sq m, respectively. Cerebrospinal fluid concentration was 3.4% of that in plasma, which shows that trimetrexate does not cross the blood-brain barrier well. Trimetrexate is 86 to 94% bound to plasma proteins.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉注射溶液（葡萄糖醛酸）在艾滋病患者中的平均口服生物利用度为42%，平均最大血浆浓度为1182 ng/ml（3.2微摩尔/升），在给药后1.8小时达到。/三甲曲沙葡萄糖醛酸/

Mean oral bioavailability of the parenteral solution (glucuronate) in AIDS patients was 42%, with a mean maximum plasma concentration of 1182 ng/ml (3.2 umole/l) achieved 1.8 hr postdose. /Trimetrexate glucuromate/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933990090
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性方面， Trimetrexate 是一种抗生素，能够抑制哺乳动物的二氢叶酸还原酶。

反应信息

• 作为反应物：
  描述：

  三甲曲沙 生成 2,4-Diamino-5-methylquinazoline-6-carbaldehyde
  参考文献：
  名称：

  STETSON, P. L.;SHUKLA, U. A.;ENSMINGER, W. D., J. CHROMATOGR., 464,(1989) N, C. 163-171

  摘要：

  DOI：
• 作为产物：
  描述：

  2,4-二氨基-5-甲基喹唑啉-6-甲腈 在 2,4-二氨基-5-甲基喹唑啉-6-甲腈 作用下， 以52的产率得到三甲曲沙
  参考文献：
  名称：

  J. Labelled. Compd. Rad. 1991, 29, 415-429

  摘要：

  DOI：

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] METALLOENZYME INHIBITOR COMPOUNDS<br/>[FR] COMPOSÉS INHIBITEURS DE MÉTALLOENZYMES
  申请人：VPS 3 INC

  公开号：WO2018165520A1

  公开（公告）日：2018-09-13

  Provided are compounds having HDAC6 modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by HDAC6.

  提供具有HDAC6调节活性的化合物，以及通过HDAC6介导的治疗疾病、疾病或症状的方法。
• [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)