folinic acid | 22350-60-3

• 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: folinic acid
• 英文别名: Folinic acid；2-[[4-[(2-amino-5-formyl-4-oxo-3,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid
• CAS: 22350-60-3
• 化学式: C₂₀H₂₃N₇O₇
• 分子量: 473.445
• InChiKey: VVIAGPKUTFNRDU-UHFFFAOYSA-N

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

活体中，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，亚叶酸钙被大量（大于90%）且快速（在30分钟内）代谢。代谢在非口服给药时较为有限（静脉给药后约66%，肌肉注射后约72%）且速度较慢。

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

• 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

• 相互作用

甲酰四氢叶酸与氟尿嘧啶同时使用可能会增加氟尿嘧啶的治疗效果和毒性；尽管这两种药物可以一起使用以获得治疗优势，但需要谨慎。

Concurrent use of leucovorin /with fluorouracil/ may increase the therapeutic and toxic effects of fluorouracil; although the two medications may be used together for therapeutic advantage, caution is necessary.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

将肿瘤细胞暴露于还原型叶酸（如亚叶酸钙）与氟嘧啶类药物（如5-氟尿嘧啶或5-氟-2'脱氧尿嘧啶）共同使用前或使用中，可以显著提高这些药物的活性。现有证据表明，这种协同作用的机制是动力学稳定了胸苷酸合成酶和氟脱氧尿苷酸之间形成的复合物，并且涉及到胸苷酸合成酶反应的辅因子，5,10-亚甲基四氢叶酸的一个摩尔。这种效应导致胸苷酸核苷酸耗尽的时间延长，从而增加了细胞死亡的水平。

Exposure of tumor cells to reduced folates /like leucovorin/ before or with the fluoropyrimidines, 5-fluorouracil or 5-fluoro-2'deoxyuridine, results in a substantial increase in the activity of these drugs. Available evidence suggests that the mechanism of this synergism is a kinetic stabilization of complex formed between thymidylate synthase and fluorodeoxyuridylate that also involves a mole of the cofactor for the thymidylate synthase reaction, 5,10-methylenetetrahydrofolate. This effect results in an extended time of depletion of thymidine nucleotides with a resultant increased level of cell death.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

大量甲酰四氢叶酸可能会对抗这些药物的抗惊厥作用：/巴比妥类抗惊厥药、乙内酰脲类抗惊厥药、普里米酮/。

Large dose of leucovorin may counteract the anticonvulsant effects of these medications: /barbiturate anticonvulsants, hydantoin anticonvulsants, primidone/.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

Sprague Dawley 大鼠用于展示一氧化二氮对生殖指标和胎儿发育的影响，以及叶酸预处理对此的影响。... 在怀孕的第9天，将动物分组暴露于70-75%的一氧化二氮，有的在暴露前12小时和立即暴露前接受0.1毫克叶酸腹腔注射。随后将胎儿发育情况与对照组进行比较。胎儿的存活率没有显著差异，但是暴露于一氧化二氮的两组胎儿的体重都有所减轻。在骨骼成熟指标中，只有未接受叶酸的一氧化二氮组的骨化胸椎数量减少。未经处理的一氧化二氮组主要骨骼异常的发生率显著增加，是对照组的五倍，而接受叶酸的一氧化二氮组与对照组相比没有显著差异。因此，可以得出结论，叶酸预处理至少可以部分减少一氧化二氮在大鼠中的致畸作用。

The Sprague Dawley rat was used to demonstrate the effect of nitrous oxide, with and without folinic pretreatment, on reproductive indices and fetal development. ... Groups of animals were exposed to 70-75% nitrous oxide on day 9 of pregnancy with or without folinic acid 0.1 mg ip 12 hr before, and immediately before, exposure. Subsequent fetal development was compared with that of various control groups. There were no significant differences in fetal survival, but fetal wt were reduced in both groups exposed to nitrous oxide. Of the indices of skeletal maturity, the number of ossified sternebrae was reduced only in the nitrous oxide group not receiving folinic acid. The incidence of major skeletal abnormalities in the untreated nitrous oxide group was significantly increased to five times that of the control groups, whereas the incidence in the nitrous oxide group receiving folinic acid was not significantly different from control. It is concluded that pretreatment with folinic acid can at least partially reduce the teratogenic effects of nitrous oxide in the rat.

来源:Hazardous Substances Data Bank (HSDB)

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)

吸收、分配和排泄

作用开始时间：口服：20至30分钟。肌肉注射：10至20分钟。静脉注射：小于5分钟。

Onset of action: Oral: 20 to 30 minutes. Intramuscular: 10 to 20 minutes. Intravenous: Less than 5 minutes.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

中等量地穿过血脑屏障；主要集中在大脑和肝脏。

Crosses blood-brain barrier in moderate amounts; largely concentrated in liver.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

消除：肾脏：80-90%。粪便：5-8%。

Elimination: Renal: 80-90%. Fecal: 5-8%.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  folinic acid 生成 5,10-Methenyltetrahydrofolat
  参考文献：
  名称：

  5,10-methylene-tetrahydrofolate as a modulator of a chemotherapeutic

  摘要：

  本发明涉及化合物5,10-亚甲基四氢叶酸(CH.sub.2 FH.sub.4)，以及其溶液产物异构体FH.sub.4，这些化合物的治疗用途以及它们的组合物。CH.sub.2 FH.sub.4和FH.sub.4强烈调节5-氟尿嘧啶的体内抗肿瘤作用。

  公开号：

  US05376658A1
• 作为产物：
  描述：

  leucovorin, calcium salt 在 盐酸 作用下， 以 水 为溶剂， 反应 4.0h， 生成 folinic acid
  参考文献：
  名称：

  [DE] VERFAHREN ZUR HERSTELLUNG VON KRISTALLINER (6RS)-N(5)-FORMYL-5,6,7,8-TETRAHYDROFOLSÄURE
  [EN] METHOD FOR THE PRODUCTION OF CRYSTALLINE (6RS)-N(5)-FORMYL-5,6,7,8-TETRAHYDROFOLIC ACID
  [FR] PROCEDE POUR PRODUIRE DE L'ACIDE (6RS)-N(5)-FORMYL-5,6,7,8-TETRAHYDROFOLIQUE CRISTALLIN

  摘要：

  公开号：

  WO2005080395A3

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。
• [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] CYCLIC PHOSPHATE COMPOUNDS<br/>[FR] COMPOSÉS DE PHOSPHATE CYCLIQUE
  申请人：LIGAND PHARM INC

  公开号：WO2020219464A1

  公开（公告）日：2020-10-29

  Provided herein are cyclic phosphate compounds, their preparation and their uses, such as treating liver diseases or conditions or a disease or condition in which the physiological or pathogenic pathways involve the liver.

  本文提供了环磷酸酯化合物，它们的制备以及它们的用途，例如用于治疗肝脏疾病或病况，或者涉及肝脏的生理或病理途径的疾病或病况。
• CYCLIC ETHER PYRAZOL-4-YL-HETEROCYCLYL-CARBOXAMIDE COMPOUNDS AND METHODS OF USE
  申请人：Genentech, Inc.

  公开号：US20140088117A1

  公开（公告）日：2014-03-27

  Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R 2 is a cyclic ether and X is thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  公式I的环醚吡唑-4-基-杂环基-羧酰胺化合物，包括立体异构体、几何异构体、互变异构体和其药学上可接受的盐，其中R2为环醚，X为噻唑基、吡啶基、吡啶基或嘧啶基，可用于抑制Pim激酶，并用于治疗由Pim激酶介导的癌症等疾病。公开了使用公式I化合物进行体外、体内和体内诊断、预防或治疗哺乳动物细胞中的这类疾病或相关病理条件的方法。