N-(3-(7-chloro-1-methyl-2-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide | 839708-52-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(3-(7-chloro-1-methyl-2-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide
• 英文别名: N-[3-(7-chloro-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide
• CAS: 839708-52-0
• 化学式: C₂₂H₁₇ClF₃N₅O₂
• 分子量: 475.857
• InChiKey: UTMCQPQEMULBJK-UHFFFAOYSA-N

物化性质

• 沸点：
  560.7±50.0 °C(Predicted)
• 密度：
  1.459±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  33
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  78.4
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-(3-(7-chloro-1-methyl-2-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 在 氨 作用下， 以 二甲基亚砜 为溶剂， 反应 15.0h， 以28%的产率得到N-(3-(7-amino-1-methyl-2-oxo-1,4-dihydropyrimido[4,5-d]-pyrimidin-3(2H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia

  摘要：

  GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, 10d, 10g, and 11i, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound lli is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, 10k possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML.

  DOI：

  10.1021/acs.jmedchem.8b00882
• 作为产物：
  描述：

  (2-chloro-5-vinylpyrimidin-4-yl)methylamine 在 sodium cyanoborohydride 、 臭氧 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 氯仿 为溶剂， 反应 8.05h， 生成 N-(3-(7-chloro-1-methyl-2-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  WO2006/135824

  摘要：

  公开号：

文献信息

• THERAPEUTIC AGENT OF ACUTE MYELOID LEUKEMIA CONTAINING 1,3,7-TRISUBSTITUTED 3,4-DIHYDROPYRIMIDO[4,5-D]PYRIMIDINE-2(1H)-ONE DERIVATIVES
  申请人：KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY

  公开号：US20180065969A1

  公开（公告）日：2018-03-08

  The present invention provides a therapeutic agent of acute myeloid leukemia containing a 1,3,7-trisubstituted 3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one compound as an active ingredient, which has proliferation inhibitory activity for a human acute myeloid leukemia cell line OCI-AML3 having a NRAS mutant gene while having low inhibitory activity for wild type NRAS and has activity of inhibiting GCK and ACK1 protein kinases at the same time.

  本发明提供了一种急性髓样白血病的治疗剂，含有1,3,7-三取代3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮化合物作为活性成分，对携带NRAS突变基因的人类急性髓样白血病细胞系OCI-AML3具有增殖抑制活性，同时对野生型NRAS的抑制活性较低，并具有同时抑制GCK和ACK1蛋白激酶的活性。
• Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance
  作者：Namkyoung Kim、Injae Shin、Jiwon Lee、Eunhye Jeon、Younghoon Kim、Seongshick Ryu、Eunhye Ju、Wonjeong Cho、Taebo Sim

  DOI：10.3390/ijms22073783

  日期：——

  Melanoma accounts for the majority of skin cancer deaths. About 50% of all melanomas are associated with BRAF mutations. BRAF mutations are classified into three classes with regard to dependency on RAF dimerization and RAS signaling. The most frequently occurring class I BRAF V600 mutations are sensitive to vemurafenib whereas class II and class III mutants, non-V600 BRAF mutants are resistant to vemurafenib. Herein we report six pyrimido[4,5-d]pyrimidin-2-one derivatives possessing highly potent anti-proliferative activities on melanoma cells harboring BRAF class I/II/III mutants. Novel and most potent derivative, SIJ1777, possesses not only two-digit nanomolar potency but also 2 to 14-fold enhanced anti-proliferative activities compared with reference compound, GNF-7 against melanoma cells (SK-MEL-2, SK-MEL-28, A375, WM3670, WM3629). Moreover, SIJ1777 substantially inhibits the activation of MEK, ERK, and AKT and remarkably induces apoptosis and significantly blocks migration, invasion, and anchorage-independent growth of melanoma cells harboring BRAF class I/II/II mutations while both vemurafenib and PLX8394 have little to no effects on melanoma cells expressing BRAF class II/III mutations. Taken together, our six GNF-7 derivatives exhibit highly potent activities against melanoma cells harboring class I/II/III BRAF mutations compared with vemurafenib as well as PLX8394.

  黑色素瘤是皮肤癌死亡的主要原因。约50％的黑色素瘤与BRAF突变相关。BRAF突变根据对RAF二聚化和RAS信号的依赖性分为三类。最常见的I类BRAF V600突变对维姆拉芬尼敏感，而II类和III类突变，即非V600 BRAF突变对维姆拉芬尼具有抗药性。本文报道了六种嘧啶并[4,5-d]嘧啶-2-酮衍生物，具有高度有效的抗黑色素瘤细胞增殖活性，携带BRAF I / II / III突变。新颖而最有效的衍生物SIJ1777不仅具有两位数纳摩尔的有效性，而且与参考化合物GNF-7相比，在黑色素瘤细胞（SK-MEL-2，SK-MEL-28，A375，WM3670，WM3629）上具有2至14倍的增强抗增殖活性。此外，SIJ1777显着抑制MEK，ERK和AKT的活化，并显着诱导细胞凋亡，并显著阻止携带BRAF I / II / III突变的黑色素瘤细胞的迁移，侵袭和无定形生长，而维姆拉芬尼和PLX8394对表达BRAF II / III突变的黑色素瘤细胞几乎没有影响。综上所述，我们的六种GNF-7衍生物与维姆拉芬尼以及PLX8394相比，在携带I / II / III类BRAF突变的黑色素瘤细胞中表现出高效活性。
• Novel Small Molecules Capable of Blocking mtRAS-Signaling Pathway
  作者：Namkyoung Kim、Injae Shin、Younghoon Kim、Eunhye Jeon、Jiwon Lee、Chaeyoung Lee、Yunju Nam、Sumin Lee、Eunhye Ju、Chan Kim、Woolim Son、SeongShick Ryu、Minjoo Ko、Taebo Sim

  DOI：10.3389/fonc.2021.768022

  日期：——

  We herein report novel and potent mtRAS-signaling pathway blockers, SIJ1795 and SIJ1772, possessing 2 to 10-fold increased anti-proliferative activities compared to those of GNF-7 on cancer cells harboring mtRAS as well as on Ba/F3 cells transformed with mtRAS. Both SIJ1795 and SIJ1772 attenuate phosphorylation of RAS downstream molecules (AKT and MEK) and induce apoptosis and G0/G1 cell cycle arrest

  RAS 突变体涉及大约 30% 的人类癌症，由于相对光滑的蛋白质表面和模糊的结合口袋，RAS 突变体被认为是不可成药的靶点。在我们之前的研究中，我们已经证明 GNF-7 是一种多靶向激酶抑制剂，对 NRAS-G12D 转化的 Ba/F3 细胞具有有效的抗增殖活性。基于我们使用 mtRAS 转化的 Ba/F3 细胞的进一步分析，我们发现了一系列嘧啶[4,5-d]pyrimidin-2-one 类似物作为 mtRAS 信号通路阻滞剂。此外，我们的努力扩大了对 mtRAS 癌细胞的评估，这表明这些物质还能够强烈抑制各种携带 KRAS-G12D (AsPC-1)、KRAS-G12V (SW480、DU-145) 的癌细胞的增殖)、KRAS-G12C (H358)、KRAS-G13D (MDA-MB-231)、KRAS-Q61L (HT-29) 和 NRAS-Q61L (OCI-AML3)。我们在此报告了新型且有效的
• Therapeutic agent of acute myeloid leukemia containing 1,3,7-trisubstituted 3,4-dihydropyrimido[4,5-D]pyrimidine-2(1H)-one derivatives
  申请人：KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY

  公开号：US10155767B2

  公开（公告）日：2018-12-18

  The present invention provides a therapeutic agent of acute myeloid leukemia containing a 1,3,7-trisubstituted 3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one compound as an active ingredient, which has proliferation inhibitory activity for a human acute myeloid leukemia cell line OCI-AML3 having a NRAS mutant gene while having low inhibitory activity for wild type NRAS and has activity of inhibiting GCK and ACK1 protein kinases at the same time.

  本发明提供了一种急性髓性白血病治疗剂，其活性成分为1,3,7-三取代的3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮化合物、它对具有 NRAS 突变基因的人类急性髓性白血病细胞系 OCI-AML3 具有增殖抑制活性，而对野生型 NRAS 的抑制活性较低，并同时具有抑制 GCK 和 ACK1 蛋白激酶的活性。
• 二氢嘧啶[4,5-d]嘧啶-2(H)-酮类Nrf2激活剂及其制备方法与用途
  申请人：寒武智元（南京）生物医药科技有限公司

  公开号：CN117384167A

  公开（公告）日：2024-01-12

  本发明公开了一种二氢嘧啶[4,5‑d]嘧啶‑2(H)‑酮类Nrf2激活剂及其制备方法与用途。该类化合物具有如下所示的结构通式：#imgabs0#实验证明该类化合物能够有效地激活Nrf2信号通路产生抗氧化应激作用，从而保护神经细胞，可用于预防和/或治疗神经退行性疾病。