培美曲塞 | 137281-23-3

• 物质功能分类: 生物化工 - 提取物 - 植物提取物
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 培美曲塞
• 中文别名: N-[4-[2-(2-氨基-4,7-二氢-4-氧代-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酰基]-L-谷氨酸；培美曲赛酸；N-(4-[2-(2-氨基-4,7-二氢-4-氧-1H-吡咯[2,3-D]嘧啶-5-基)乙基]苯甲酰)-L-谷氨酸；N-[4-[2-(2-胺基-4,7-二氢-4-氧-1H吡咯[2,3-D]嘧啶-5基)乙基]苯甲酰]-L-谷氨酸；培美曲塞酸；4-[2-(2-胺基-4,7二氢-4-氧-1H吡咯[2,3-d]嘧啶-5基)乙基]苯甲酸；培美曲赛；培美曲塞二钠盐；培美曲塞二酸
• 英文名称: pemetrexed
• 英文别名: alimta；LY231514；PMX；N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid；(2S)-2-{[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino}pentanedioic acid；N-(4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-D]pyrimidin-5-yl)ethyl)benzoyl)-L-glutamic acid；pemetrexed disodium；pemetrexed diacid；Pemetrexed；(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioic acid
• CAS: 137281-23-3
• 化学式: C₂₀H₂₁N₅O₆
• 分子量: 427.417
• InChiKey: WBXPDJSOTKVWSJ-ZDUSSCGKSA-N

物化性质

• 密度：
  1.59±0.1 g/cm3(Predicted)
• 溶解度：
  微溶于在甲醇中
• 颜色/状态：
  Crystals from 50% methanol/methylene chloride
• 蒸汽压力：
  6X10-21 mm Hg at 25 °C at 25 °C /Estimated/
• 亨利常数：
  Henry's Law constant: 2.08X10-29 atm-cu m/mole at 25 °C /Estimated/
• 解离常数：
  pKa1 = 3.6; pKa2 = 4.4 (carboxylic moieties) /Estimated/

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  187
• 氢给体数：
  6
• 氢受体数：
  7

ADMET

代谢

由细胞色素P450酶代谢

Metabolized by Cytochrome P450 Enzymes

来源:DrugBank

代谢

培美曲塞没有被显著代谢，70%到90%的剂量以原形恢复...

Pemetrexed is not metabolised to an appreciable extent and ... 70% to 90% of the dose recovered unchanged ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

培美曲塞治疗与血清酶水平低至中等程度的升高有关，但这些通常都是轻微的、短暂的，并且不伴有症状或黄疸。血清ALT或AST升高超过5倍ULN的患者比例为1%至6%，但通常病程自限，很少需要调整剂量或停药。没有报告因培美曲塞引起的临床上明显的急性肝损伤的案例。此外，培美曲塞并未与肝窦阻塞综合征或乙型肝炎的复发有关联，但它在高剂量的恶性肿瘤治疗或骨髓移植预处理方案中很少使用，而这些情况下其他抗肿瘤药物常与这些并发症有关。

Pemetrexed therapy is associated with a low-to-moderate rate of serum enzyme elevations, but these are generally mild, transient and without accompanying symptoms or jaundice. Serum ALT or AST elevations above 5 times ULN occur in 1% to 6% of patients, but are usually self-limited in course and rarely require dose modification or discontinuation. No instances of clinically apparent acute liver injury attributed to pemetrexed have been reported. In addition, pemetrexed has not been linked to sinusoidal obstruction syndrome or to reactivation of hepatitis B, but it is rarely used in high doses in neoplastic disease or in conditioning regimens for bone marrow transplantation, situations in which other neoplastic agents are commonly associated with these complications.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：培美曲塞

Compound:pemetrexed

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

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

不良反应部分

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 消除途径

培美曲塞不会被显著代谢，并且主要通过尿液排出，给药后24小时内，约70%至90%的剂量以原形在尿液中回收。

Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration.

来源:DrugBank

吸收、分配和排泄

• 分布容积

16.1升

16.1 L

来源:DrugBank

吸收、分配和排泄

• 清除

91.8毫升/分钟【肾功能正常的癌症患者在10分钟内接受0.2至838毫克/平方米的静脉输液】

91.8 mL/min [Cancer patients with normal renal function receiving 0.2 to 838 mg/m2 infusion over a 10-minute period]

来源:DrugBank

吸收、分配和排泄

培美曲塞主要通过尿液在给药后最初的24小时内排出体外。

Pemetrexed ... is primarily eliminated in the urine ... within the first 24 hours following administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

pemetrexed的总系统清除率为91.8毫升/分钟，适用于肾功能正常（肌酐清除率为90毫升/分钟）的患者。随着肾功能下降，清除率降低，暴露量（AUC）增加。Pemetrexed的总系统暴露量（AUC）和最大血浆浓度（Cmax）随剂量成比例增加。

The total systemic clearance of pemetrexed is 91.8 mL per min in patients with normal renal function (creatinine clearance of 90 mL per min). The clearance decreases, and exposure (AUC) increases, as renal function decreases. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• WGK Germany：
  3
• 海关编码：
  2933990090
• RTECS号：
  LZ9950100
• 危险性防范说明：
  P261,P280,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H332,H335
• 储存条件：
  0-10°C；避免加热

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Pemetrexed
Synonyms: (S)-2-(4-(2-(2-Amino-4-oxo-4,7-dihydro-1h-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzamido)pentanedioic
acid

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: Pemetrexed
137281-23-3
CAS number:

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Inhalation:
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Storage: Store in closed vessels, refrigerated.

---

Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
No data
Boiling point:
Melting point: No data
Flash point: No data
Density: No data
Molecular formula: C20H21N5O6
Molecular weight: 427.4

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

---

Section 14. Transportation information
Non-harzardous for air and ground transportation.

---

Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

生物活性

Pemetrexed (LY231514) 是一种叶酸拮抗剂，抑制胸苷酸合成酶 (TS)、二氢叶酸还原酶 (DHFR) 和甘氨酰胺核苷酸甲酰转移酶 (GARFT)，Ki 分别为 1.3 nM、7.2 nM 和 65 nM。

靶点

• Ki: 1.3 nM (TS), 7.2 nM (DHFR), 65 nM (GARFT)

体外研究

Pemetrexed (LY231514) 硫酸盐是一种新颖的经典叶酸拮抗剂，其抗肿瘤活性可能源于通过其多谷氨酰胺代谢物同时和多重抑制几种关键的叶酸依赖酶。Pemetrexed (LY231514) 是已知 FPGS 酶的最佳底物（Km = 1.6 μM，Vmax/Km = 621）。多谷氨酰胺化及其代谢物很可能是决定这一新型药物的选择性和抗肿瘤活性的关键因素。尽管 LY23l5l4 只能适度抑制 TS (Ki = 340 nM, 重组小鼠)，但其五谷氨酰胺类似物的效力提高了100倍（Ki = 3.4 nM），使其成为最有效的叶酸基TS抑制剂之一。

体内研究

接受 PC61 加 Pemetrexed 治疗的小鼠表现出统计学上更长的生存时间。在存活分析中，与单独使用 PC61、rat IgG 加 Pemetrexed 或未治疗组相比，接受 PC61 和 Pemetrexed 联合治疗的小鼠显示出显著更好的存活率。

反应信息

• 作为反应物：
  描述：

  培美曲塞 在 双氧水 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 32.0h， 生成 N-[4-[2-[2-amino-4,7-dihydro-4-oxo-1,5,6-trihydroxy-1H-pyrrolo[2,3-d]pyrimidin-5-yl ]ethyl]benzoyl]-L-glutamic acid
  参考文献：
  名称：

  培美曲塞氧化物及其制备方法

  摘要：

  本发明涉及一种培美曲塞或其二钠盐的氧化杂质化合物，即培美曲塞氧化物A及其二钠盐化物和美曲塞氧化物B及其二钠盐，以及它们的制备和在培美曲塞二钠质量控制中的用途。

  公开号：

  CN102838602B
• 作为产物：
  描述：

  N-[4-[2-(2-氨基-4,7-二氢-4-氧代-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酰]-L-谷氨酸二乙酯对甲苯磺酸盐 在 sodium hydroxide 作用下， 以 水 为溶剂， 生成 培美曲塞
  参考文献：
  名称：

  抗癌药物培美曲塞二钠杂质的合成及理化表征

  摘要：

  对与培美曲塞二钠合成相关的工艺相关杂质进行了物理化学表征。文献中已经提到形成培美曲塞杂质的可能性，但尚未发表对其结构的研究。本文描述了这些化合物的合成方法的发展，并讨论了基于二维 NMR 实验和 MS 数据的结构解析。这些杂质的鉴定应有助于培美曲塞二钠盐生产过程中的质量控制。

  DOI：

  10.3390/molecules200610004

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] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2010144486A1

  公开（公告）日：2010-12-16

  Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

  揭示了式(I)的JAK抑制剂，其中G1、R1、R2、R3、R4、R5、R6和R7在规范中定义。还披露了含有这些化合物的药物组合物、试剂盒和制造物品，制备这些化合物的方法和材料，以及使用这些化合物治疗涉及免疫系统和炎症的疾病、紊乱和症状的方法，包括类风湿关节炎、血液恶性肿瘤、上皮癌（即癌症）和其他与JAK相关的疾病、紊乱或症状。
• SULFONAMIDE, SULFAMATE, AND SULFAMOTHIOATE DERIVATIVES
  申请人：Wang Zhong

  公开号：US20120077814A1

  公开（公告）日：2012-03-29

  The disclosure provides biologically active compounds of formula (I): and pharmaceutically acceptable salts thereof, compositions containing these compounds, and methods of using these compounds in a variety applications, such as treatment of diseases or disorders associated with E1 type activating enzymes, and with Nedd8 activating enzyme (NAE) in particular.

  该披露提供了化学式(I)的生物活性化合物及其药用盐，含有这些化合物的组合物，以及在各种应用中使用这些化合物的方法，例如用于治疗与E1型激活酶相关的疾病或紊乱，特别是与Nedd8激活酶(NAE)相关的疾病或紊乱。
• [EN] COMPOUNDS AND METHODS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR LE TRAITEMENT DE MALADIES NEURODÉGÉNÉRATIVES
  申请人：TAVARES FRANCIS XAVIER

  公开号：WO2016168118A1

  公开（公告）日：2016-10-20

  Novel compounds of formula (II) are disclosed. Compounds of formula (II) comprise ornithine derivatives or compounds that may metabolize to ornithine. Also disclosed are methods for the treatment of neurodegenerative diseases such as Alzheimer's Disease using compounds of formula (II).

  公开了化学式（II）的新化合物。化学式（II）的化合物包括鸟氨酸衍生物或可能代谢成鸟氨酸的化合物。还公开了使用化学式（II）的化合物治疗神经退行性疾病，如阿尔茨海默病的方法。
• [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。