(2S)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoic acid | 343850-67-9

• 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: (2S)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoic acid
• 英文别名: N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine
• CAS: 343850-67-9
• 化学式: C₂₄H₂₄ClN₃O₅
• 分子量: 469.925
• InChiKey: XWJUDXXALXRTIE-SFHVURJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  107
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoic acid 在 碳酸氢钠 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine ethyl 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
• 作为产物：
  描述：

  N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine ethyl ester 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 生成 (2S)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoic acid
  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：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。
• [EN] IMPROVED SOLUBILITY FOR TARGET COMPOUNDS<br/>[FR] SOLUBILITÉ AMÉLIORÉE POUR COMPOSÉS CIBLES
  申请人：AUNOVA MEDCHEM LLC

  公开号：WO2017040459A1

  公开（公告）日：2017-03-09

  The present disclosure relates to compounds having an improved solubility thereby increasing their bioavailability, lower dosages, etc. The target compounds, may include but are not limited to, macrophage migration inhibitory factor (MIF) inhibitors, epidermal growth factor receptor (EGRF) inhibitors, kinase inhibitors and prodrugs of alpha4 beta1 and alpha4 beta7 integrin antagonists. An illustrative compound is shown below (Formula I):

  本公开涉及具有改善溶解性以增加其生物利用度、降低剂量等特性的化合物。目标化合物可能包括但不限于巨噬细胞迁移抑制因子（MIF）抑制剂、表皮生长因子受体（EGRF）抑制剂、激酶抑制剂以及α4β1和α4β7整合素拮抗剂的前药。下面显示了一个示例化合物（式I）：
• Isoidide derivatives and methods of making and using same
  申请人：Rutgers, the State University of New Jersey

  公开号：US10815244B2

  公开（公告）日：2020-10-27

  The present disclosure relates to compounds having an improved solubility thereby increasing their bioavailability, lower dosages, etc. The target compounds, may include but are not limited to, macrophage migration inhibitory factor (MIF) inhibitors, epidermal growth factor receptor (EGRF) inhibitors, kinase inhibitors and prodrugs of alpha4 beta1 and alpha4 beta7 integrin antagonists. An illustrative compound is shown below:

  本公开涉及的化合物具有更好的溶解性，从而提高了生物利用度，降低了剂量等。目标化合物可包括但不限于巨噬细胞迁移抑制因子（MIF）抑制剂、表皮生长因子受体（EGRF）抑制剂、激酶抑制剂以及α4 β1和α4 β7整合素拮抗剂的原药。下面是一种说明性化合物：
• 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
• SOLUBILITY FOR TARGET COMPOUNDS
  申请人：Aunova Medchem LLC

  公开号：US20170066778A1

  公开（公告）日：2017-03-09

  The present disclosure relates to compounds having an improved solubility thereby increasing their bioavailability, lower dosages, etc. The target compounds, may include but are not limited to, macrophage migration inhibitory factor (MIF) inhibitors, epidermal growth factor receptor (EGRF) inhibitors, kinase inhibitors and prodrugs of alpha4 beta1 and alpha4 beta7 integrin antagonists. An illustrative compound is shown below: