N-{4-[(6aR)-3-氨基-1-氧代-1,4,5,6,6A,7-六氢咪唑并[1,5-f]蝶啶-8(9H)-基]苯甲酰基}谷氨酸 | 31690-11-6

• 物质功能分类: 分析化学 - 标准品
• 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
• 中文名称: N-{4-[(6aR)-3-氨基-1-氧代-1,4,5,6,6A,7-六氢咪唑并[1,5-f]蝶啶-8(9H)-基]苯甲酰基}谷氨酸
• 中文别名: 左亚叶酸钙杂质7
• 英文名称: N⁵,N¹⁰-methylenetetrahydrofolate
• 英文别名: (2S)-2-[[4-[(6aR)-3-amino-1-oxo-5,6,6a,7,9,10-hexahydro-2H-imidazo[1,5-f]pteridin-10-ium-8-yl]benzoyl]amino]-5-hydroxy-5-oxopentanoate
• CAS: 31690-11-6
• 化学式: C₂₀H₂₃N₇O₆
• 分子量: 457.446
• InChiKey: QYNUQALWYRSVHF-OLZOCXBDSA-N

物化性质

• 密度：
  1.75±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  190
• 氢给体数：
  6
• 氢受体数：
  10

制备方法与用途

亚叶酸钙是一种叶酸还原型的甲酰化衍生物，为叶酸在体内的活化形式。它能够“解救”过量的叶酸拮抗物引起的毒性反应，并有助于胸腺嘧啶核苷酸、DNA、RNA乃至蛋白质的合成。此外，亚叶酸钙还能刺激白细胞的生长和成熟。

本品可通过竞争性作用限制甲氨蝶呤对正常细胞造成的损害，并能逆转其对骨髓和胃肠黏膜的影响；然而，对于已存在的甲氨蝶呤神经毒性则无明显效果。主要用途是作为叶酸拮抗剂（如甲氨蝶呤、乙胺嘧啶或甲氧苄啶等）的解毒剂。

亚叶酸钙杂质7是在其合成过程中可能产生的杂质之一。

反应信息

• 作为反应物：
  描述：

  N-{4-[(6aR)-3-氨基-1-氧代-1,4,5,6,6A,7-六氢咪唑并[1,5-f]蝶啶-8(9H)-基]苯甲酰基}谷氨酸 在 sodium tetrahydroborate 、 水 作用下， 反应 6.0h， 生成 L-5-甲基四氢叶酸
  参考文献：
  名称：

  L-5-甲基四氢叶酸钙的制备工艺

  摘要：

  本发明涉及一种L‑5‑甲基四氢叶酸钙的制备工艺，采用不对称催化加氢将将叶酸还原为(6S)‑四氢叶酸，叶酸的转化率高、(6S)‑四氢叶酸非对映体过量程度高；通过成盐并结晶，可以容易地富集得到具有极高非对映体过量的(6S)‑四氢叶酸中间体，由此最终制得的L‑5‑甲基四氢叶酸钙的收率和纯度高。本发明的催化加氢工艺在工业应用上十分成熟，操作方便；后续的甲基化和成盐步骤易于实施，在提高了产物收率和纯度的情况下，所述制备工艺具有很高的经济价值和实用价值。

  公开号：

  CN113603691B
• 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 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 N-{4-[(6aR)-3-氨基-1-氧代-1,4,5,6,6A,7-六氢咪唑并[1,5-f]蝶啶-8(9H)-基]苯甲酰基}谷氨酸
  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

文献信息

• SHMT Inhibitors
  申请人：The Trustees of Princeton University

  公开号：US20180072751A1

  公开（公告）日：2018-03-15

  The disclosure provides compounds of Formulae (I)-(IX). The disclosed compounds are capable of inhibiting a mammalian SHMT. Compounds of the disclosure have numerous uses, such as for treatment of cancer or autoimmune disorders.

  本公开提供了式(I)-(IX)的化合物。所述公开的化合物能够抑制哺乳动物的丝氨酸羟甲基转移酶。本公开的化合物有多种用途，例如用于治疗癌症或自身免疫性疾病。
• Stable salts of 5,10-methylenetetrahydrofolic acid
  申请人：Eprova Aktiengesellschaft

  公开号：US05300505A1

  公开（公告）日：1994-04-05

  Salts of 5,10-methylene-(6R)-, (6R,S)-, and (6S)-tetrahydrofolic acid with sulfuric acid or a sulfonic acid are stable in solid form and can be used as a constituent and/or as a starting material for the production of pharmaceutical compositions.

  5,10-亚甲基-(6R)-、(6R,S)-和(6S)-四氢叶酸的硫酸盐或磺酸盐在固态形式下是稳定的，并且可以用作制药组分和/或制药组分的起始材料。
• Methionine restriction for cancer therapy
  申请人：——

  公开号：US20030129262A1

  公开（公告）日：2003-07-10

  The present invention is directed to methods and compositions regarding induction of apoptosis in a cell and treatment of cancer in an individual wherein methionine deprivation of the cell is followed by methionine repletion of the cell. The methionine deprivation of the cell results in G2 arrest in the cell, leading to DNA damage in the cell. Upon readministration of methionine to the cell, the damaged cell exits G2 arrest and enters into apoptosis. In a specific embodiment, a therapeutic effect is elicited by cycling the patient between a methionine-depleted diet and a normal, methionine-replete diet. The present invention also regards chronic methionine deprivation for treatment of cancer in a human, in addition to methods for methionine restriction as adjunctive therapy for other cancer treatment methods.

  本发明涉及诱导细胞凋亡和治疗个体癌症的方法和组成物，其中细胞的蛋氨酸限制随后是细胞的蛋氨酸再补充。细胞的蛋氨酸限制导致细胞的G2阻滞，导致细胞的DNA损伤。在向细胞重新添加蛋氨酸后，受损细胞退出G2阻滞并进入凋亡状态。在一个特定的实施例中，通过让患者在蛋氨酸缺乏饮食和正常的蛋氨酸再补充饮食之间循环，来产生治疗效果。本发明还涉及慢性蛋氨酸限制用于治疗人类癌症，以及作为其他癌症治疗方法的辅助疗法的蛋氨酸限制方法。
• Use of folates for producing a preparation suitable for preventing and treating inflammation and diseases associated with inflammation, especially for influencing the inflammation markers crp and saa
  申请人：Mueller Thomas

  公开号：US20060063768A1

  公开（公告）日：2006-03-23

  This invention relates to the use of folates for producing a pharmaceutical preparation suitable for the prevention and treatment of inflammation and of diseases associated with inflammation, particularly for influencing the inflammation markers C-reactive protein (CRP) and serum amyloid A protein (SAA). The clinical areas of application are all anomalies of the CRP and SM levels. The invention also relates to pharmaceutical preparations for the prevention and treatment of inflammation and of diseases associated with inflammation, particularly for influencing CRP and SM levels, characterised in that as an active ingredient it comprises at least one compound which is selected from the group consisting of pteroic acid monoglutamate (folic acid), dihydrofolic acid, 5-formyltetrahydrofolic acid, 5-methyltetrahydrofolic acid, 5,10-methylenetetrahydrofolic acid, 5,10-methenyl-tetrahydrofolic acid, 10-formyltetrahydrofolic acid or tetrahydrofolic acid, polyglutamates thereof, optical isomers thereof, particularly optically pure natural isomers thereof, and mixtures of optical isomers also, particularly racemic mixtures, as well as pharmaceutically acceptable salts thereof also, together with pharmaceutically acceptable active ingredients and adjuvants.

  本发明涉及使用叶酸制备适用于预防和治疗炎症及与炎症相关的疾病的药物制剂，特别是用于影响炎症标志物C-反应蛋白（CRP）和血清淀粉样蛋白A（SAA）。临床应用领域包括CRP和SM水平的所有异常。本发明还涉及用于预防和治疗炎症及与炎症相关的疾病，特别是用于影响CRP和SM水平的药物制剂，其特征在于其活性成分包括至少一种化合物，所述化合物选自以下组中的一种：叶酸单谷氨酸（叶酸）、二氢叶酸、5-甲基四氢叶酸、5,10-甲烷基四氢叶酸、5,10-甲烯基四氢叶酸、10-甲酰基四氢叶酸或四氢叶酸，其聚谷氨酸，其光学异构体，特别是其光学纯天然异构体，以及其光学异构体的混合物，特别是外消旋混合物，以及其药学上可接受的盐，以及药学上可接受的活性成分和辅料。
• USE OF FOLATES FOR PRODUCING A PREPARATION SUITABLE FOR PREVENTING AND TREATING INFLAMMATION AND DISEASES ASSOCIATED WITH INFLAMMATION, ESPECIALLY FOR INFLUENCING THE INFLAMMATION MARKERS CRP AND SAA
  申请人：MUELLER Thomas

  公开号：US20100179095A1

  公开（公告）日：2010-07-15

  This invention relates to the use of folates for producing a pharmaceutical preparation suitable for the prevention and treatment of inflammation and of diseases associated with inflammation, particularly for influencing the inflammation markers C-reactive protein (CRP) and serum amyloid A protein (SAA). The clinical areas of application are all anomalies of the CRP and SAA levels. The invention also relates to pharmaceutical preparations for the prevention and treatment of inflammation and of diseases associated with inflammation, particularly for influencing CRP and SAA levels, characterised in that as an active ingredient it comprises at least one compound which is selected from the group consisting of pteroic acid monoglutamate (folic acid), dihydrofolic acid, 5-formyltetrahydrofolic acid, 5-methyltetrahydrofolic acid, 5,10-methylenetetrahydrofolic acid, 5,10-methenyl-tetrahydrofolic acid, 10-formyltetrahydrofolic acid or tetrahydrofolic acid, polyglutamates thereof, optical isomers thereof, particularly optically pure natural isomers thereof, and mixtures of optical isomers also, particularly racemic mixtures, as well as pharmaceutically acceptable salts thereof also, together with pharmaceutically acceptable active ingredients and adjuvants.

  本发明涉及使用叶酸制备适用于预防和治疗炎症及与炎症相关疾病的制药制剂，特别是用于影响炎症标志物C-反应蛋白（CRP）和血清淀粉样蛋白A（SAA）。临床应用领域包括所有CRP和SAA水平异常的情况。本发明还涉及用于预防和治疗炎症及与炎症相关疾病的制药制剂，特别是用于影响CRP和SAA水平，其特征在于其活性成分包括至少一种来自以下化合物组的化合物：叶酸单谷氨酸盐（叶酸）、二氢叶酸、5-甲酰四氢叶酸、5-甲基四氢叶酸、5,10-甲烷双氢叶酸、5,10-甲烯双氢叶酸、10-甲酰四氢叶酸或四氢叶酸、其多谷氨酸盐、其光学异构体，特别是其光学纯天然异构体，以及其光学异构体的混合物，特别是外消旋混合物，以及其药学上可接受的盐，以及药学上可接受的活性成分和辅料。