[4-(2,5-dichloro-4-bromophenoxy)pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)methanone | 1315468-79-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: [4-(2,5-dichloro-4-bromophenoxy)pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)methanone
• 英文别名: [4-(4-Bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone；[4-(4-bromo-2,5-dichlorophenoxy)pyridin-3-yl]-(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)methanone
• CAS: 1315468-79-1
• 化学式: C₂₃H₁₈BrCl₂N₃O₂
• 分子量: 519.225
• InChiKey: GMOJDZOBJJCMDM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  45.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  [4-(2,5-dichloro-4-bromophenoxy)pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)methanone 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 lithium hydrochloride monohydrate 、 水 、 三乙胺 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 1,4-二氧六环 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 20.0~120.0 ℃ 、7.0 MPa 条件下， 反应 24.0h， 生成 {2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-acetic acid methyl ester
  参考文献：
  名称：

  4-PHENOXY-NICOTINAMIDE OR 4-PHENOXY-PYRIMIDINE-5-CARBOXAMIDE COMPOUNDS

  摘要：

  这项发明涉及公式的新型苯基酰胺或吡啶基酰胺衍生物 其中A 1 ，A 2 ，B 1 ，B 2 和R 1 到R 11 如描述和索赔中所定义，并且其药学上可接受的盐。这些化合物是GPBAR1激动剂，可用作治疗诸如2型糖尿病等疾病的药物。

  公开号：

  US20110178089A1
• 作为产物：
  描述：

  4-溴-2,5-二氯苯酚 在 tetrakis(actonitrile)copper(I) hexafluorophosphate caesium carbonate 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 邻二甲苯 、 N,N-二甲基甲酰胺 为溶剂， 反应 33.0h， 生成 [4-(2,5-dichloro-4-bromophenoxy)pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)methanone
  参考文献：
  名称：

  [EN] 4-PHENOXY-NICOTINAMIDE OR 4-PHENOXY-PYRIMIDINE-5-CARBOXAMIDE COMPOUNDS
  [FR] COMPOSÉS DE 4-PHÉNOXYNICOTINAMIDE OU DE 4-PHÉNOXY-PYRIMIDINE-5-CARBOXAMIDE

  摘要：

  这项发明涉及公式（I）中的新型苯基酰胺或吡啶基酰胺衍生物，其中A1、A2、B1、B2和R1至R11如描述和索赔中所定义，并且其药学上可接受的盐。这些化合物是GPBAR1激动剂，可用作治疗疾病如2型糖尿病的药物。

  公开号：

  WO2011089099A1

文献信息

• OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition
  作者：Shan-yao Ma、Meng-meng Ning、Qing-an Zou、Ying Feng、Yang-liang Ye、Jian-hua Shen、Ying Leng

  DOI：10.1038/aps.2016.27

  日期：2016.10

  TGR5 agonists stimulate intestinal glucagon-like peptide-1 (GLP-1) release, but systemic exposure causes unwanted side effects, such as gallbladder filling. In the present study, linagliptin, a DPP-4 inhibitor with a large molecular weight and polarity, and MN6, a previously described TGR5 agonist, were linked to produce OL3, a novel low-absorbed TGR5 agonist with reduced side-effects and dual function in lowering blood glucose by activation of TGR5 and inhibition of DPP-4. TGR5 activation was assayed in HEK293 cells stably expressing human or mouse TGR5 and a CRE-driven luciferase gene. DPP-4 inhibition was assessed based on the rate of hydrolysis of a surrogate substrate. GLP-1 secretion was measured in human enteroendocrine NCI-H716 cells. OL3 permeability was tested in Caco-2 cells. Acute glucose-lowering effects of OL3 were evaluated in ICR and diabetic ob/ob mice. OL3 activated human and mouse TGR5 with an EC50 of 86.24 and 17.36 nmol/L, respectively, and stimulated GLP-1 secretion in human enteroendocrine NCI-H716 cells (3–30 μmol/L). OL3 inhibited human and mouse DPP-4 with IC50 values of 18.44 and 69.98 μmol/L, respectively. Low permeability of OL3 was observed in Caco-2 cells. In ICR mice treated orally with OL3 (150 mg/kg), the serum OL3 concentration was 101.10 ng/mL at 1 h, and decreased to 13.38 ng/mL at 5.5 h post dose, confirming the low absorption of OL3 in vivo. In ICR mice and ob/ob mice, oral administration of OL3 significantly lowered the blood glucose levels, which was a synergic effect of activating TGR5 that stimulated GLP-1 secretion in the intestine and inhibiting DPP-4 that cleaved GLP-1 in the plasma. In ICR mice, oral administration of OL3 did not cause gallbladder filling. OL3 is a low-absorbed TGR5 agonist that lowers blood glucose without inducing gallbladder filling. This study presents a new strategy in the development of potent TGR5 agonists in treating type 2 diabetes, which target to the intestine to avoid systemic side effects.

  TGR5激动剂能刺激肠道释放胰高血糖素样肽-1（GLP-1），但全身暴露会引起不必要的副作用，如胆囊充盈。在本研究中，将分子量大、极性强的 DPP-4 抑制剂利拉利汀和之前描述过的 TGR5 激动剂 MN6 联用，生产出一种新型低吸收 TGR5 激动剂 OL3，这种激动剂副作用小，并具有通过激活 TGR5 和抑制 DPP-4 降低血糖的双重功能。在稳定表达人或小鼠 TGR5 和 CRE 驱动荧光素酶基因的 HEK293 细胞中检测 TGR5 的活化情况。根据代底物的水解率评估 DPP-4 抑制作用。在人肠内分泌 NCI-H716 细胞中测量 GLP-1 的分泌。在 Caco-2 细胞中测试了 OL3 的渗透性。在 ICR 和糖尿病 ob/ob 小鼠中评估了 OL3 的急性降糖效果。OL3激活人和小鼠TGR5的EC50分别为86.24和17.36 nmol/L，并刺激人肠内分泌NCI-H716细胞分泌GLP-1（3â30 μ mol/L）。OL3 可抑制人和小鼠 DPP-4，其 IC50 值分别为 18.44 μmol/L 和 69.98 μmol/L 。在 Caco-2 细胞中观察到 OL3 的低渗透性。口服OL3（150毫克/千克）治疗ICR小鼠，1小时后血清中OL3浓度为101.10纳克/毫升，服药后5.5小时降至13.38纳克/毫升，证实OL3在体内的吸收率很低。在ICR小鼠和肥胖/ob小鼠中，口服OL3可显著降低血糖水平，这是激活TGR5刺激肠道分泌GLP-1和抑制DPP-4裂解血浆中GLP-1的协同效应。在ICR小鼠中，口服OL3不会引起胆囊充盈。OL3 是一种低吸收的 TGR5 激动剂，可降低血糖而不会引起胆囊充盈。这项研究为开发治疗 2 型糖尿病的强效 TGR5 激动剂提供了一种新策略，这种激动剂以肠道为靶点，可避免全身副作用。
• 4-phenoxy-nicotinamide or 4-phenoxy-pyrimidine-5-carboxamide compounds
  申请人：Bissantz Caterina

  公开号：US08420647B2

  公开（公告）日：2013-04-16

  This invention relates to novel phenyl amide or pyridyl amide derivatives of the formula wherein A1, A2, B1, B2 and R1 to R11 are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are GPBAR1 agonists and can be used as medicaments for the treatment of diseases such as type II diabetes.

  本发明涉及以下式子的新型苯酰胺或吡啶酰胺衍生物： 其中A1、A2、B1、B2和R1到R11如描述和权利要求中所定义，并且其药学上可接受的盐。这些化合物是GPBAR1激动剂，可用作治疗二型糖尿病等疾病的药物。
• Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists
  作者：Hongliang Duan、Mengmeng Ning、Xiaoyan Chen、Qingan Zou、Liming Zhang、Ying Feng、Lina Zhang、Ying Leng、Jianhua Shen

  DOI：10.1021/jm301071h

  日期：2012.12.13

  4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists are reported. Several 4-phenoxynicotinamide derivatives were found to activate human and mouse TGR5 (hTGR5 and mTGR5) with EC50 values in the low nanomolar range. Compound 23g, with an EC50 value of 0.72 nM on hTGR5 and an EC50 value of 6.2 nM on mTGR5, was selected for further in vivo efficacy studies. This compound exhibited a significant dose-dependent glucagon-like peptide-1 (GLP-1) secretion effect. A single oral dose of 23g (50 mg/kg) significantly reduced blood glucose levels in db/db mice and caused a 49% reduction in the area under the blood glucose curve (AUC)(0-120) (min) following an oral glucose tolerance test (OGTT) in imprinting control region (ICR) mice. However, 23g stimulated gallbladder filling, which might result in side effects to the gallbladder.
• Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes
  作者：Hongliang Duan、Mengmeng Ning、Qingan Zou、Yangliang Ye、Ying Feng、Lina Zhang、Ying Leng、Jianhua Shen

  DOI：10.1021/jm500829b

  日期：2015.4.23

  Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 angstrom(2), and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2.
• US8420647B2
  申请人：——

  公开号：US8420647B2

  公开（公告）日：2013-04-16