methyl 2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate | 450358-64-2

• 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: methyl 2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate
• 英文别名: methyl 3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate；(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)acetic acid methyl ester；methyl (3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate；methyl 2-(3-oxo-1,4-benzoxazin-4-yl)acetate
• CAS: 450358-64-2
• 化学式: C₁₁H₁₁NO₄
• mdl: MFCD04207474
• 分子量: 221.213
• InChiKey: GRKABAHGNIWBSD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.272
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate 在 甲醇 、 sodium hydroxide 、 水 、 盐酸 作用下， 反应 3.5h， 生成 (3-氧代-2,3-二氢-4H-1,4-苯并恶嗪)-4-乙酸
  参考文献：
  名称：

  Carboxylic Acid Compounds and Use Thereof

  摘要：

  提供一种优越的URAT1活性抑制剂，用于治疗与尿酸有关的病理，如高尿酸血症、痛风石、急性痛风性关节炎、慢性痛风性关节炎、痛风性肾病、尿路结石、肾功能障碍、冠心病、缺血性心脏病等。 一种包含下式[1]所表示的化合物或其药学上可接受的盐，或其溶剂化合物的URAT1活性抑制剂作为活性成分： 其中每个符号如规范中定义。

  公开号：

  US20070197512A1
• 作为产物：
  描述：

  2H-1,4-苯并噁嗪-3(4H)-酮 、 溴乙酸甲酯 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.17h， 生成 methyl 2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate
  参考文献：
  名称：

  Carboxylic Acid Compounds and Use Thereof

  摘要：

  提供一种优越的URAT1活性抑制剂，用于治疗与尿酸有关的病理，如高尿酸血症、痛风石、急性痛风性关节炎、慢性痛风性关节炎、痛风性肾病、尿路结石、肾功能障碍、冠心病、缺血性心脏病等。 一种包含下式[1]所表示的化合物或其药学上可接受的盐，或其溶剂化合物的URAT1活性抑制剂作为活性成分： 其中每个符号如规范中定义。

  公开号：

  US20070197512A1

文献信息

• Carboxylic Acid Compounds and Use Thereof
  申请人：Inoue Teruhiko

  公开号：US20070197512A1

  公开（公告）日：2007-08-23

  Provision of a superior URAT1 activity inhibitor effective for the treatment and the like of a pathology involving uric acid, such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urinary lithiasis, renal dysfunction, coronary heart disease, ischemic cardiac diseases and the like. A URAT1 activity inhibitor containing a compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient: wherein each symbol is as defined in the specification.

  提供一种优越的URAT1活性抑制剂，用于治疗与尿酸有关的病理，如高尿酸血症、痛风石、急性痛风性关节炎、慢性痛风性关节炎、痛风性肾病、尿路结石、肾功能障碍、冠心病、缺血性心脏病等。 一种包含下式[1]所表示的化合物或其药学上可接受的盐，或其溶剂化合物的URAT1活性抑制剂作为活性成分： 其中每个符号如规范中定义。
• Photo-cleavable analog of BAPTA for the fast and efficient release of Ca²⁺
  作者：Mariia V. Sutton、Matthew McKinley、Revathy Kulasekharan、Vladimir V. Popik

  DOI：10.1039/c7cc02056b

  日期：——

  A new photocleavable analog of BAPTA chelating ligand has a high affinity towards Ca2+ ions (K = 2.5 × 106 M−1). The use of photolabile 3-(hydroxymethyl)-2-naphthol core in the design of photo-BAPTA allows for the efficient (Φ = 0. 63) and very fast (τ < 12 μs) release of Ca2+ ions upon 300 or 350 nm irradiation.

  BAPTA螯合配体的新的光可裂解类似物对Ca 2+离子具有高亲和力（K = 2.5×10 6 M -1）。在光BAPTA设计中使用对光不稳定的3-（羟甲基）-2-萘酚核可在300或200 ℃时有效（Φ = 0. 63）和非常快（τ <12μs）释放Ca 2+离子。 350 nm照射。
• Synthesis and characterisation of Thio-H, a new excitation and emission ratioable fluorescent Ca2+/Mg2+ indicator with high brightness
  作者：Els Cielen、Agnieszka Stobiecka、Abdellah Tahri、Georges J. Hoornaert、Frans C. De Schryver、Jacques Gallay、Michel Vincent、Noël Boens

  DOI：10.1039/b107042h

  日期：2002.5.22

  A new fluorescent ratiometric indicator for Ca2+ and Mg2+, tricaesium salt of 2-[bis(carboxymethyl)amino]-5-(5-phenylthiophen-2-yl)phenoxy}acetic acid, Thio-H, has been synthesised and evaluated for its cation binding properties via fluorimetric titrations. Thio-H has the interesting property of being both excitation and emission ratioable, expanding the range of possible applications. The in vitro dissociation constant, Kd, measured at 20 °C in 100 mM KCl, pH 7.20 for the Ca2+–Thio-H complex is 45 ± 13 μM; for Mg2+–Thio-H a Kd value of 5.6 ± 0.6 mM is found. The free form of Thio-H has a high fluorescence quantum yield (0.74), which decreases to 0.50 and 0.65 upon binding to Ca2+ and Mg2+, respectively. Measurements under physiological conditions show that increasing the temperature from 20 to 37 °C decreases the affinity of Thio-H for Ca2+. Changing the pH from 7.05 to 7.40 does not affect the Kd value of the Mg2+ complex but it increases somewhat the affinity of the probe for Ca2+. In the presence of 1 mM Mg2+, the Ca2+ affinity of Thio-H decreases (Kd = 126 ± 46 μM at 20 °C, pH 7.05). Time-resolved fluorescence measurements confirm that the inflection point in the fluorimetric titration curve can be correctly assigned to Kd. Since the dissociation constant for the Mg2+–indicator complex falls within the intracellular [Mg2+] domain, while the Kd value for Ca2+ is well above the basal Ca2+ levels, Thio-H has potential applications as a Mg2+ indicator. The low affinity for Ca2+ can be exploited for detecting intracellular Ca2+ levels in the micromolar range, on condition that [Mg2+]i remains practically constant during the measurements. Thio-H provides an excellent addition to the commercial ratiometric low-affinity Ca2+ indicators Mag-fura-2, Mag-fura-5, Mag-indo-1, Fura-FF, and BTC.

  合成了一种新的 Ca2+ 和 Mg2+ 荧光比率指示剂，即 2-[双（羧甲基）氨基]-5-(5-苯基噻吩-2-基)苯氧基}乙酸的三铯盐，Thio-H，并对其进行了评估通过荧光滴定测定其阳离子结合特性。 Thio-H 具有激发和发射可比的有趣特性，扩大了可能的应用范围。 Ca2+-Thio-H 复合物的体外解离常数 Kd（在 20 °C、100 mM KCl、pH 7.20 中测量）为 45 ± 13 μM；对于 Mg2+–Thio-H，Kd 值为 5.6 ± 0.6 mM。游离形式的 Thio-H 具有较高的荧光量子产率 (0.74)，与 Ca2+ 和 Mg2+ 结合后分别降至 0.50 和 0.65。生理条件下的测量表明，将温度从 20 达到 37 °C 会降低 Thio-H 对 Ca2+ 的亲和力。将 pH 从 7.05 更改为 7.40 不会影响 Mg2+ 复合物的 Kd 值，但会在一定程度上增加探针对 Ca2+ 的亲和力。在 1 mM Mg2+ 存在下，Thio-H 的 Ca2+ 亲和力降低（Kd = 126 ± 46 μM（20 °C，pH 7.05）。时间分辨荧光测量证实荧光滴定曲线中的拐点可以正确分配给 Kd。由于 Mg2+ 指示剂复合物的解离常数落在细胞内 [Mg2+] 域内，而 Ca2+ 的 Kd 值远高于基础 Ca2+ 水平，因此 Thio-H 作为 Mg2+ 指示剂具有潜在的应用。可以利用对 Ca2+ 的低亲和力 用于检测微摩尔范围内的细胞内 Ca2+ 水平，条件是 [Mg2+]i 在测量过程中实际上保持恒定。 Thio-H 为商业比率低亲和力 Ca2+ 指示剂 Mag-fura-2、Mag-fura-5、Mag-indo-1、Fura-FF 和 BTC 提供了出色的补充。
• CARBOXYLIC ACID COMPOUND AND USE THEREOF
  申请人：Japan Tobacco, Inc.

  公开号：EP1985297A1

  公开（公告）日：2008-10-29

  Provision of a superior URAT1 activity inhibitor effective for the treatment and the like of a pathology involving uric acid, such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urinary lithiasis, renal dysfunction, coronary heart disease, ischemic cardiac diseases and the like. A URAT1 activity inhibitor containing a compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient: wherein each symbol is as defined in the specification.

  提供一种优异的URAT1活性抑制剂，有效治疗涉及尿酸的病症，如高尿酸血症、痛风性头痛、急性痛风性关节炎、慢性痛风性关节炎、痛风性肾、尿路结石、肾功能障碍、冠心病、缺血性心脏病等。 一种含有下式[1]代表的化合物或其药学上可接受的盐或其溶液作为活性成分的 URAT1 活性抑制剂： 其中各符号如说明书中所定义。
• N-Heteroaryl glycinamides and glycinamines as potent NPY5 antagonists
  作者：Lingyun Wu、Kai Lu、Mahesh Desai、Mathivanan Packiarajan、Amita Joshi、Mohammad R. Marzabadi、Vrej Jubian、Kim Andersen、Gamini Chandrasena、Noel J. Boyle、Mary W. Walker

  DOI：10.1016/j.bmcl.2011.06.078

  日期：2011.9

  Subtype specific ligands are needed to evaluate the therapeutic potential of modulating the brain's neuropeptide Y system. The benzothiazepine glycinamide 1a was identified as an NPY5 antagonist lead. While having acceptable solubility, the compound was found to suffer from high clearance and poor exposure. Optimization efforts are described targeting improvements in potency, microsomal stability, and PK properties. The low microsomal stability and poor PK properties were addressed through the optimization of the sulfonyl urea and replacement of the benzothiazepinone with other N-heteroaryl glycinamides. For example, the analogous benzoxazine glycinamide 2e has improvements in both affinity (human Y5 K-i 4 nM vs 1a 27 nM) and microsomal stability (human CLint 2.5 L/min vs 1a 35 L/min). However the brain penetration (B/P 43/430 nM at 10 mg/kg PO) remained an unresolved issue. Further optimization by decreasing the hydrogen bond donating properties and PSA provided potent and brain penetrant NPY5 antagonists such as 5f (human Y5 K-i 9 nM, B/P 520/840 nM 10 mg/kg PO). (C) 2011 Elsevier Ltd. All rights reserved.