N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]-pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid | 135503-67-2

• 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
• 英文名称: N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]-pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid
• 英文别名: N-[[5-[2-[2-Amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-thien-2-yl]carbonyl]-L-glutamic Acid；2-[[5-[2-(2-amino-4-oxo-4a,5,6,7-tetrahydro-3H-pyrido[2,3-d]pyrimidin-6-yl)ethyl]thiophene-2-carbonyl]amino]pentanedioic acid；(2S)-2-[[5-[2-(2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pyrido[2,3-d]pyrimidin-6-yl)ethyl]thiophene-2-carbonyl]amino]pentanedioic acid
• CAS: 135503-67-2
• 化学式: C₁₉H₂₃N₅O₆S
• 分子量: 449.488
• InChiKey: GQCXGHHHNACOGE-ACGXKRRESA-N

物化性质

• 密度：
  1.68±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  211
• 氢给体数：
  6
• 氢受体数：
  9

制备方法与用途

生物活性

LY 254155 是一种抗叶酸剂，能够抑制 hGARFT 及与 mFBP 结合，其 Ki 值分别为 2.1±0.2 nM 和 1.7±0.1 nM。

靶点

• Ki: 2.1±0.2 (hGARFT), 1.7±0.1 nM (mFBP)

体外研究

LY 254155 抑制重组人单功能丙氨酸核糖核酸甲酰转移酶（hGARFT）并与其膜叶酸结合蛋白（mFBP）结合。

体内研究

LY 254155 对多种小鼠和人类异种移植实体瘤表现出活性。在 C3H 小鼠中，LY 254155 (5, 10, 20 和 40 mg/kg) 抑制了 C3H 癌肿生长，分别导致肿瘤生长抑制率为 49%, 71%, 90% 和 94%。

反应信息

• 作为产物：
  描述：

  dimethyl N-[5-(2-{2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)thien-2-ylcarbonyl]-L-glutamate 、 sodium hydroxide 生成 N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]-pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid
  参考文献：
  名称：

  SHIH, CHUAN;TAYLOR, EDWARD C.

  摘要：

  DOI：

文献信息

• N-(5,6,7,8-tetrahydropyrido(2,3-D)pyrimidin-6-yl-alkanoyl)-glutamic acid derivatives
  申请人：THE TRUSTEES OF PRINCETON UNIVERSITY

  公开号：EP0343801A2

  公开（公告）日：1989-11-29

  A compound selected from the group consisting of a glutamic acid derivative of the formula: in which: R¹ is -OH or -NH₂; R² is hydrogen or a carboxy protecting group; R³ is a carbon-carbon bond, alkylene of 1 to 4 car­bon atoms, cyclohexylene, or R⁴ is hydrogen or an amino protecting group; Q is -S- or -O-; R⁵ is hydrogen, chloro or fluoro; and the configuration about the carbon atom designated * is S; and the pharmaceutically acceptable salts thereof. Also disclosed is a method of combatting neoplastic growth in a mammal and a pharmaceutical composition for combatting neoplastic growth in a mammal making use of the above compound.

  本发明涉及一种从以下组合中选择的化合物：其中：R¹为-OH或-NH₂；R²为氢或羧基保护基；R³为碳-碳键，1到4个碳原子的烷基，环己烷基，或R⁴为氢或氨基保护基；Q为-S-或-O-；R⁵为氢，氯或氟；并且指定的碳原子*的构型为S；以及其药学上可接受的盐。本发明还公开了一种在哺乳动物中对抗肿瘤生长的方法和一种制备上述化合物的药物组合物，用于对抗哺乳动物中的肿瘤生长。
• N-(5,6,7,8-tetrahydropyrido]2,3-d]pyrimidin-6-ylethl-thineyl-and
  申请人：The Trustees of Princeton University

  公开号：US04882334A1

  公开（公告）日：1989-11-21

  N-(Thienylcarbonyl)glutamic acid and N-(furylcarbonyl)glutamic acid derivatives in which the thienyl or furyl group is substituted with the 2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylethyl or 2,4-diamino-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-ylethyl group are antineoplastic agents. Typical embodiments are N-[5-(2-2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}e thyl)thien-2-ylcarbonyl]-L-glutamic acid and N-[5-(2-2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl}e thyl)fur-2-ylcarbony]-L-glutamic acid.

  N-(噻吩基甲酰)谷氨酸和N-(呋喃基甲酰)谷氨酸衍生物，其中噻吩基或呋喃基被2-氨基-4-羟基-5,6,7,8-四氢吡咯并[2,3-d]嘧啶-6-乙基或2,4-二氨基-5,6,7,8-四氢吡咯并[2,3-d]-嘧啶-6-乙基基团取代，是抗肿瘤剂。典型的实施例是N-[5-(2-2-氨基-4-羟基-5,6,7,8-四氢吡咯并[2,3-d]嘧啶-6-基}乙基)噻吩-2-基甲酰]-L-谷氨酸和N-[5-(2-2-氨基-4-羟基-5,6,7,8-四氢吡咯并[2,3-d]嘧啶-6-基}乙基)呋喃-2-基甲酰]-L-谷氨酸。
• Pharmaceutical compositions containing anti-fas antibody
  申请人：SANKYO COMPANY, LIMITED

  公开号：US20020103212A1

  公开（公告）日：2002-08-01

  A pharmaceutical composition containing an anti-human Fas antibody having apoptosis inducing activity and a compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity, as active ingredients for the prophylaxis and/or treatment of an autoimmune disease or rheumatoid arthritis. According to the present invention, the amount of the anti-Fas antibody to be used can be reduced and thereby the possibility that a patient may become tolerant to anti-Fas antibody as a result of the production of antibodies against the anti-Fas antibody in the patient's body or the like can be decreased, and thus is provided a pharmaceutical composition which can be used for a long time.

  一种药物组合物，含有一种具有诱导细胞凋亡活性的抗人 Fas 抗体和一种具有叶酸拮抗剂活性或二氢叶酸还原酶抑制活性的化合物作为活性成分，用于预防和/或治疗自身免疫性疾病或类风湿性关节炎。根据本发明，可以减少抗 Fas 抗体的用量，从而降低患者因体内产生抗 Fas 抗体的抗体等而对 Fas 抗体产生耐受性的可能性，因此提供了一种可以长期使用的药物组合物。
• US4882334A
  申请人：——

  公开号：US4882334A

  公开（公告）日：1989-11-21
• US6426417B1
  申请人：——

  公开号：US6426417B1

  公开（公告）日：2002-07-30