leucovorin | 68538-85-2

• 物质功能分类: 有机原料 - 羧酸类化合物及衍生物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 英文名称: leucovorin
• 英文别名: <6S>-N⁵-formyltetrahydrofolic acid；(6S,S)-5-Formyl-5,6,7,8-tetrahydrofolsaeure；6S-folinic acid；5-formyl-(6S)-tetrahydrofolate；N-((S)-5-Formyl-5,6,7,8-tetrahydro-pteroyl)-L-glutaminsaeure；N-((S)-5-formyl-5,6,7,8-tetrahydro-pteroyl)-L-glutamic acid；L-folinic acid；levoleucovorin；5-formyl-THF；5-formyl-(6S)-tetrahydrofolic acid；5-formyltetrahydrofolate；Levoleucovorin；(2S)-2-[[4-[[(6S)-2-amino-5-formyl-4-oxo-3,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioic acid
• CAS: 68538-85-2
• 化学式: C₂₀H₂₃N₇O₇
• 分子量: 473.445
• InChiKey: VVIAGPKUTFNRDU-STQMWFEESA-N

物化性质

• 密度：
  1.68±0.1 g/cm3(Predicted)
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from water with 3 mol of water of crystallization.
• 熔点：
  245 °C (decomp)
• 溶解度：
  Sparingly soluble in water
• 蒸汽压力：
  2.3X10-21 mm Hg at 25 °C at 25 °C /Estimated/
• 亨利常数：
  Henry's Law constant = 4.4X10-27 atm-cu m/mole at 25 °C /Estimated/
• 稳定性/保质期：
  Leucovorin calcium injection, powder for injection, and tablets should be stored at 15-30 °C and protected from light. /Leucovorin calcium/
• 旋光度：
  Off-white to light beige amorphous powder. Odorless. Freely soluble in water. Specific optical rotation = +14.9 deg at 21 °C/D ( c= 1 in water). /Calcium salt pentahydrate/
• 解离常数：
  pKa1= 3.1; pKa2= 4.8; pKa3= 10.4

计算性质

• 辛醇/水分配系数(LogP)：
  -1.2
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  216
• 氢给体数：
  7
• 氢受体数：
  10

ADMET

代谢

广泛转化为四氢叶酸衍生物。

Extensively converted to tetrahydrofolic derivatives.

来源:DrugBank

代谢

活体内，亚叶酸钙迅速并广泛地转化为其他四氢叶酸衍生物，包括5-甲基四氢叶酸，这是体内叶酸的主要运输和储存形式。/亚叶酸钙/

In vivo, leucovorin calcium is rapidly and extensively converted to other tetrahydrofolic acid derivatives including 5-methyl tetrahydrofolate, which is the major transport and storage form of folate in the body. /Leucovorin calcium/

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏和肠道粘膜主要转换为5-甲基四氢叶酸（活性）。口服给药后，亚叶酸钙的代谢非常广泛（大于90%）且迅速（在30分钟内）。而静脉给药后代谢较少（约66%），肌肉注射给药后代谢约为72%，且代谢速度较慢。

Hepatic and intestinal mucosal, mainly to 5-methyltetrahydrofolate (active). After oral administration, leucovorin is substantially (greater than 90%) and rapidly (within 30 minutes) metabolized. Metabolism is less extensive (about 66% after intravenous and 72% after intramuscular administration) and slower with parenteral administration.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

急性静脉LD50值在大鼠和小鼠中分别为575 mg/kg（1725 mg/m²）和378 mg/kg（2268 mg/m²）。

ِAcute intravenous LD50 values in adult mice and rats were 575 mg/kg (1725 mg/m²) and 378 mg/kg ( 2268 mg/m²), respectively.

来源:DrugBank

毒理性

• 肝毒性

既不正常也不过量摄入叶酸与肝脏损伤或肝功能测试异常有关。在长期临床试验中，与安慰剂相比，叶酸治疗并没有更频繁地导致血清酶和胆红素升高。高剂量叶酸（每日达15毫克）的使用并未与显著的不良反应、ALT升高或肝毒性有关联。

Neither normal nor excessively high intakes of folate are associated with liver injury or liver test abnormalities. In long term clinical trials, serum enzyme and bilirubin elevations were no more frequent with folic acid therapy than with placebo. Use of high doses of folic acid (up to 15 mg daily) has not been associated with appreciable adverse reactions, ALT elevations or hepatotoxicity.

来源:LiverTox

毒理性

• 药物性肝损伤

左旋亚叶酸钙

Compound:Levoleucovorin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：没有匹配项

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

静脉快速给药后，血清总四氢叶酸（total-THF）浓度达到平均峰值1722 ng/mL。血清（6S）-5-甲基-5,6,7,8-四氢叶酸浓度达到平均峰值275 ng/mL，达到峰值平均时间为0.9小时。

After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations reached a mean peak of 275 ng/mL and the mean time to peak was 0.9 hours.

来源:DrugBank

吸收、分配和排泄

• 消除途径

尿液。

Urinary.

来源:DrugBank

吸收、分配和排泄

• 分布容积

数据找不到。

Data can't be found.

来源:DrugBank

吸收、分配和排泄

• 清除

数据找不到。

Data can't be found.

来源:DrugBank

吸收、分配和排泄

作用持续时间：所有给药途径：3到6小时。

Duration of action: All routes: 3 to 6 hours.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

左旋叶酸是外消旋亚叶酸的药理活性左旋异构体。在大剂量甲氨蝶呤治疗后，左旋脲佐菌素可作为救援剂，并与氟尿嘧啶联合用于晚期转移性结直肠癌的研究[1]。

反应信息

• 作为反应物：
  描述：

  leucovorin 在 叠氮磷酸二苯酯 、 caesium carbonate 、 三乙胺 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 生成 (S)-2-((S)-4-{4-[((5R,6S)-2-Amino-5-formyl-4-oxo-3,4,5,6,7,8-hexahydro-pteridin-6-ylmethyl)-amino]-benzoylamino}-4-benzyloxycarbonyl-butyrylamino)-pentanedioic acid dibenzyl ester
  参考文献：
  名称：

  Fitzhugh, Anthony L.; Akee, Rhone K.; Ruei, Faith C., Journal of the Chemical Society. Perkin transactions I, 1994, # 7, p. 897 - 902

  摘要：

  DOI：
• 作为产物：
  描述：

  N-<4-<<2(S)--3-<(2-amino-5-nitro-4(3H)-oxopyrimidin-6-yl)amino>propyl>amino>benzoyl>-L-glutamic acid 在 palladium on activated charcoal 盐酸 、 氢气 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 、 盐酸 、 N,N-二甲基甲酰胺 为溶剂， 58.0 ℃ 、310.27 kPa 条件下， 反应 27.5h， 生成 leucovorin
  参考文献：
  名称：

  Synthesis of tetrahydropteridine C6-stereoisomers, including N5-formyl-(6S)-tetrahydrofolic acid

  摘要：

  Chiral N1-protected vicinal diamines derived from amino acids were condensed with 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone, the nitro group reduced, and the amine deprotected. oxidative cyclization of the resulting triaminopyrimidinone via quinoid pyrimidine intermediates gave a quinoid dihydropteridine, which was then reduced to a tetrahydropteridine C6-stereoisomer. Thus, 6(R)- and 6(S)-propyltetrahydropterin were stereospecifically synthesized (99% enantiomeric purity) in good yield from D- and L-norvaline, respectively. Reductive alkylation of (p-aminobenzoyl)-L-glutamate with a nitropyrimidine aldehyde derived from D- or L-serine similarly afforded, after cyclization and reduction, (6R)- or (6S)-tetrahydrofolic acid. The latter was then converted to the natural isomer of leucovorin by regioselective N5-formylation with carbonyl diimidazole/formic acid without loss of enantiomeric purity.

  DOI：

  10.1021/jo00042a030
• 作为试剂：
  描述：

  calcium;(2S)-2-[[4-[[(6S)-2-amino-5-formyl-4-oxo-3,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioate;pentahydrate 、 disodium;carbonate 、 calcium carbonate 、 盐酸 在 钠 、 水 、 异丙醇 、 leucovorin 作用下， 以 水 、 异丙醇 、 溶剂黄146 为溶剂， 反应 1.0h， 生成 leucovorin
  参考文献：
  名称：

  CRYSTALLINE LEVOFOLINIC ACID AND PROCESS FOR ITS PREPARATION

  摘要：

  本发明涉及稳定的晶体(6S)-N(5)-甲酰基-5,6,7,8-四氢叶酸，通常称为左旋叶酸酯，其本质上为纯6S对映体形式，以及其制备方法。

  公开号：

  US20120245177A1

文献信息

• [EN] PYRIMIDINE COMPOUNDS AND PYRIMIDO INDOLE COMPOUNDS AND METHODS OF USE<br/>[FR] COMPOSÉS DE PYRIMIDINE ET COMPOSÉS DE PYRIMIDO INDOLE ET PROCÉDÉS D'UTILISATION DE CEUX-CI
  申请人：UNIV HOLY GHOST DUQUESNE

  公开号：WO2016022890A1

  公开（公告）日：2016-02-11

  The present invention discloses substituted pyrimidine and pyrimido indole compounds and optionally pharmaceutically acceptable salts, hydrates or solvates thereof. A method of treating a patient having cancer or a disease comprising administering to a patient an effective amount of the compound or pharmaceutically acceptable salt, hydrate, or solvate thereof.

  本发明公开了取代嘧啶和嘧啶并吲哚化合物以及可选择的药用盐、水合物或溶剂化合物。一种治疗患有癌症或疾病的患者的方法包括向患者投予化合物或其药用盐、水合物或溶剂化合物的有效量。
• [EN] FOLATE SALTS FOR MEDICAL USE<br/>[FR] SELS DE FOLATE À USAGE MÉDICAL
  申请人：APROFOL AG

  公开号：WO2019063236A1

  公开（公告）日：2019-04-04

  The invention relates to amorphous folate salt. The salt consists of a folate anion and an organic cation. The folate anion is selected from the group consisting of 5-formyl-(6S)-tetrahydrofolic acid, 10-formyl-(6R)-tetrahydrofolic acid, 5-methyl- (6S)-tetrahydrofolic acid, (6S)-tetrahydrofolic acid, 5,10-Methylene-(6R)- tetrahydrofolic acid, and its oxidized derivatives JK12A and Mefox, and the cation is an organic compound selected from the group arginine, choline, acetylcholine, 1,1-dimethyl-biguanidin phenylethylbiguanidin, betaine-methylester and dimethylanninoethanol. The cation is an organic compound with a complementary pharmacological activity.

  该发明涉及非晶态叶酸盐。该盐由叶酸阴离子和有机阳离子组成。叶酸阴离子选自5-甲酰-(6S)-四氢叶酸、10-甲酰-(6R)-四氢叶酸、5-甲基-(6S)-四氢叶酸、(6S)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸及其氧化衍生物JK12A和Mefox等，阳离子选自精氨酸、胆碱、乙酰胆碱、1,1-二甲基-双胍苯乙双胍、甜菜碱甲酯和二甲基氨基乙醇等有机化合物。该阳离子是具有互补药理活性的有机化合物。
• A simple and effective method for preparation of the 6(R)- and 6(S)-diastereoisomers of 5-formyltetrahydrofolate (leucovorin)
  作者：Lilias Rees、Colin J. Suckling、Hamish C. S. Wood

  DOI：10.1039/c39870000470

  日期：——

  Acylation of 6(RS)-tetrahydrofolate with (–)-menthyl chloroformate afforded an N-5 derivative which was separable into its diastereoisomers by extraction with n-butanol; these derivatives were converted separately into the 6(R)- and 6(S)-diastereoisomers of 5-formyltetrahydrofolate by treatment with a mixture of formic acid and hydrogen bromide in acetic acid followed by hydrolysis.

  用（-）-薄荷基氯甲酸酯酰化6（RS）-四氢叶酸，得到N-5衍生物，可通过用正丁醇萃取将其分离成非对映异构体。通过用甲酸和溴化氢在乙酸中的混合物处理，然后水解，将这些衍生物分别转化为5-甲酰基四氢叶酸酯的6（R）-和6（S）-非对映异构体。
• Enantioselektive Katalysen, 135. Mitt. [1]. Stereoselektive Hydrierung von Folsaüure und2-Methylchinoxalin mit optisch aktiven Rhodium(I)-Phosphan-Komplexen
  作者：Henri Brunner、Sabine Rosenboem

  DOI：10.1007/s007060070017

  日期：2000.12.13

   In the hydrogenation of the C*N double bonds of the pyrazine ring of folic acid to 5,6,7,8-tetrahydrofolic acid a new asymmetric center is formed at C6 of the pteridine system. With rhodium(I) catalysts made from optically active phosphanes, which are immobilized on silical gel, the hydrogenation in aqueous solution can be controlled stereoselectively. The highest diastereomeric excess of ca . 40%

   在叶酸的吡嗪环的C * N双键氢化为5,6,7,8-四氢叶酸的过程中，在蝶啶系统的C6处形成新的不对称中心。使用固定在硅胶上的由旋光性膦制成的铑（I）催化剂，可以选择性地控制水溶液中的氢化。 ca 的最高非对映异构体过量 。（-）- BPPM 获得40％ 含有催化剂。还可以用铑（I）-膦催化剂均匀地在水溶液中氢化生物分子叶酸，其配体包含磺酸基和聚醚片段。与非均相催化剂相比，均相氢化进行得较慢并且非对映选择性有所降低。2-甲基喹喔啉的氢化是还原叶酸的模型系统。普通的铑（I）-膦催化剂仅提供小的对映选择性。
• [EN] MULTI-LIGAND DRUG CONJUGATES AND USES THEREOF<br/>[FR] CONJUGUÉS DE MÉDICAMENT MULTI-LIGANDS ET LEURS UTILISATIONS
  申请人：COHERENT BIOPHARMA

  公开号：WO2017025057A1

  公开（公告）日：2017-02-16

  A conjugate compounds or pharmaceutically acceptable salt thereof, comprises a payload and two or more kinds of cell-interacting molecules. The cell-interacting molecules are ligands capable of specifically binding to a cell surface receptor. A method of treating diseases, comprises delivering a payload to a subject.

  一种共轭化合物或其药用可接受的盐，包括载荷和两种或两种以上的细胞相互作用分子。这些细胞相互作用分子是能够特异性结合到细胞表面受体的配体。一种治疗疾病的方法，包括将载荷传递给一个受试者。