4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester | 343851-09-2

• 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: 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester
• 英文别名: methyl (2S)-2-amino-3-[3-methyl-4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoate
• CAS: 343851-09-2
• 化学式: C₁₈H₂₃N₃O₄
• 分子量: 345.398
• InChiKey: CNZJYGPCYSWRPM-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  92.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester 、 2,6-二氯苯甲酰氯 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 以48%的产率得到N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester
  参考文献：
  名称：

  4-Pyrimidinyl-n-acyl-l phenylalanines

  摘要：

  公式I的化合物被披露，具有作为VCAM-1和表达VLA-4的细胞之间结合抑制剂的活性，因此可用于治疗症状和/或损害与VCAM-1与表达VLA-4的细胞结合相关的疾病。

  公开号：

  US06380387B1
• 作为产物：
  描述：

  3-甲基-4-硝基苄醇 在 盐酸 、 manganese(IV) oxide 、 硫酸 、 palladium 10% on activated carbon 、 palladium on activated charcoal 、 Rh[(COD)-(S,S)-Me-DuPhos]⁽¹⁺⁾*TfO^(1-) 、 氢气 、 三(邻甲基苯基)磷 、 potassium iodide 、 bis(dibenzylideneacetone)-palladium⁽⁰⁾ 、 环己烯 、 sodium nitrite 、 四甲基胍 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 乙酸乙酯 为溶剂， -30.0~50.0 ℃ 、413.7 kPa 条件下， 反应 72.33h， 生成 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester
  参考文献：
  名称：

  Identification of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives and their orally active prodrug esters as dual-acting alpha4–beta1 and alpha4–beta7 receptor antagonists

  摘要：

  N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against alpha 4-integrins. Several derivatives were identified as very potent dual-acting alpha 4-integrin, alpha 4 beta 1 and alpha 4 beta 7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting alpha 4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.12.026

文献信息

• 4-PYRIMIDINYL-N-ACYL-L-PHENYLALANINES
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP1237878B1

  公开（公告）日：2007-03-21
• US6380387B1
  申请人：——

  公开号：US6380387B1

  公开（公告）日：2002-04-30
• [EN] 4-PYRIMIDINYL-N-ACYL-L-PHENYLALANINES<br/>[FR] 4-PYRIMIDINYL-N-ACYL-L-PHENYLALANINES
  申请人：HOFFMANN LA ROCHE

  公开号：WO2001042225A2

  公开（公告）日：2001-06-14

  Coumpounds of Formula (I) are disclosed, wherein R1 to R6 are as defined in specification and which are inhibitors of binding between VCAM-1 and cells expressing VLA-4, and accordingly are useful for treating diseases whose symptoms and or damage are related to the binding of VCAM-1 to cells expressing VLA-4.
• 4-Pyrimidinyl-n-acyl-l phenylalanines
  申请人：Hoffmann-La Roche Inc.

  公开号：US06380387B1

  公开（公告）日：2002-04-30

  Compounds of Formula I are disclosed, having activity as inhibitors of binding between VCAM-1 and cells expressing VLA-4, and accordingly useful for treating diseases whose symptoms and or damage are related to the binding of VCAM-1 to cells expressing VLA-4.

  公式I的化合物被披露，具有作为VCAM-1和表达VLA-4的细胞之间结合抑制剂的活性，因此可用于治疗症状和/或损害与VCAM-1与表达VLA-4的细胞结合相关的疾病。
• Identification of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives and their orally active prodrug esters as dual-acting alpha4–beta1 and alpha4–beta7 receptor antagonists
  作者：Achyutharao Sidduri、Jefferson W. Tilley、Jianping Lou、Nadine Tare、Gary Cavallo、Karl Frank、Anjula Pamidimukkala、Duk Soon Choi、Louise Gerber、Aruna Railkar、Louis Renzetti

  DOI：10.1016/j.bmcl.2012.12.026

  日期：2013.2

  N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against alpha 4-integrins. Several derivatives were identified as very potent dual-acting alpha 4-integrin, alpha 4 beta 1 and alpha 4 beta 7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting alpha 4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates. (C) 2012 Elsevier Ltd. All rights reserved.