2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide

• 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: 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide
• 英文别名: 2-(2-hydroxyacetylaminopyridin-4-ylmethylthio)-N-(4-trifluoromethoxyphenyl)pyridine-3-carboxamide；2-[[2-[(2-hydroxyacetyl)amino]pyridin-4-yl]methylsulfanyl]-N-[4-(trifluoromethoxy)phenyl]pyridine-3-carboxamide
• 化学式: C₂₁H₁₇F₃N₄O₄S
• 分子量: 478.452
• InChiKey: KLTZDJNSSCMNAO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  139
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide 在 氯化亚砜 作用下， 以 二氯甲烷 为溶剂， 生成 2-(2-chloroacetylaminopyridin-4-ylmethylthio)-N-(4-trifluoromethoxyphenyl)pyridine-3-carboxamide
  参考文献：
  名称：

  Pyridylmethylthio derivatives as VEGF inhibitors: Part 2

  摘要：

  Optimization of compounds 5 and 6 led to the discovery of VEGF inhibitor 10g which reduced CYP inhibition. It was highly active in vitro (VEGF induced HUVEC proliferation assay) and showed efficacies in three disease models in vivo (cancer, RA, and AMD). (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.12.071
• 作为产物：
  描述：

  2-巯基烟酸 在 水 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 31.75h， 生成 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide
  参考文献：
  名称：

  Pyridylmethylthio derivatives as VEGF inhibitors: Part 2

  摘要：

  Optimization of compounds 5 and 6 led to the discovery of VEGF inhibitor 10g which reduced CYP inhibition. It was highly active in vitro (VEGF induced HUVEC proliferation assay) and showed efficacies in three disease models in vivo (cancer, RA, and AMD). (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.12.071

文献信息

• 2-[[[2-[(HYDROXYACETYL)AMINO]-4-PYRIDINYL]METHYL]THIO]-N-[4-(TRIFLUOROMETHOXY)PHENYL]-3-PYRIDINECARBOXAMIDE BENZENESULFONATE, CRYSTAL OF SAME, CRYSTAL POLYMORPH THEREOF, AND METHODS FOR PRODUCTION THEREOF
  申请人：Niwa Masashi

  公开号：US20120116088A1

  公开（公告）日：2012-05-10

  In the course of developing 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide (compound A), there are the multiple problems: 1) compound A or its salt is difficult to be recrystallized, the storage stability largely differs depending on the kind of the salt, and it is very difficult to obtain a salt of compound A having excellent storage stability; 2) in a crystallization process of compound A, it is very difficult to control a crystal polymorph, and 3) compound A (free body) causes mineral deposition in the stomach when it is orally administered repeatedly. For solving these problems, we made examination focusing on the kind of the salt and, as a result, found that 1) benzenesulfonate of compound A does not decompose by light, humidity and other factors in a 1-week preliminary stability test (severe test), and has no problem in its storage stability, 2) a method of selectively producing two kinds of crystal forms of benzenesulfonate of compound A, and that 3) no mineral deposition in the stomach is observed even after a 4-week repeated oral administration.

  在开发2-[[[2-[(羟乙酰)氨基]-4-吡啶基]甲基]硫基]-N-[4-(三氟甲氧基)苯基]-3-吡啶羧酰胺（化合物A）的过程中，出现了多个问题：1）化合物A或其盐很难重结晶，储存稳定性在盐的种类上有很大差异，很难获得具有良好储存稳定性的化合物A盐；2）在化合物A的结晶过程中，很难控制晶体多态性；3）化合物A（游离体）在口服重复给药时会在胃中产生矿物质沉积。为了解决这些问题，我们着重考虑了盐的种类，并发现：1）化合物A的苯磺酸盐在1周的初步稳定性测试（严格测试）中不会受到光线、湿度和其他因素的分解，并且其储存稳定性没有问题；2）一种选择性地产生苯磺酸盐的两种晶体形式的方法；3）即使在4周的口服重复给药后，胃中也没有观察到矿物质沉积。
• Novel cyclic compound having 4-pyridylalkylthio group having substituted or unsubstituted amino group introduced therein
  申请人：Honda Takahiro

  公开号：US20070149574A1

  公开（公告）日：2007-06-28

  A novel cyclic compound having a 4-pyridylalkylthio group having an (un)substituted amino group introduced therein or a salt thereof. They are useful as a medicine. The cyclic compound is a compound represented by the following formula (1), which is useful for the treatment of diseases in which angiogenesis participates. In the following formula (1), ring A represents a benzene ring or a 5- or 6-membered aromatic heterocycle optionally fused with a cycloalkane ring; B represents alkylene; R 1 and R 2 each represents H, (substituted) aryl, (substituted) heterocyclic group, etc.; R 3 and R 4 each represents H, (substituted) alkyl, (substituted) cycloalkyl, -Z-R 5 , etc.; R 5 represents (substituted) alkyl, (substituted) aryl, (substituted) heterocyclic group, etc.; X and Y each represents H, etc.; Z represents —CO—, —COO—, —CONR 6 —, —SO 2 —, etc.; R 6 represents H, etc.; p is 0, 1, or 2; and q is 0 or 1.

  一种具有4-吡啶基烷基硫基团的新型环状化合物，其中引入了（未）取代氨基或其盐。它们可用作药物。环状化合物是由以下式（1）表示的化合物，可用于治疗参与血管生成的疾病。在下式（1）中，环A表示苯环或5-或6-成员芳香杂环，可选择地与环烷环融合；B表示烷基；R1和R2各表示H，（取代）芳基，（取代）杂环基等；R3和R4各表示H，（取代）烷基，（取代）环烷基，-Z-R5等；R5表示（取代）烷基，（取代）芳基，（取代）杂环基等；X和Y各表示H等；Z表示-CO-，-COO-，-CONR6-，-SO2-等；R6表示H等；p为0、1或2；q为0或1。
• 2-[[[2-[(HYDROXYACETYL)AMINO]-4-PYRIDINYL]METHYL]THIO]-N-[4-(TRIFLUOROMETHOXY)PHENYL]-3-PYRIDINECARBOXAMIDE BENZENE- SULFONATE, CRYSTALS OF SAME, POLYMORPHS THEREOF, AND PROCESSES FOR PRODUCTION THEREOF
  申请人：Santen Pharmaceutical Co., Ltd

  公开号：EP2455368A1

  公开（公告）日：2012-05-23

  In the course of developing 2-[[[2 - [(hydroxyacetyl) amino]- 4 -pyridinyl] methyl] thio]- N -[4 -(trifluoromethoxy) phenyl]- 3 -pyridinecarboxamide(compound A), there are the multiple problems: 1) compound A or its salt is difficult to be recrystallized, the storage stability largely differs depending on the kind of the salt, and it is very difficult to obtain a salt of compound A having excellent storage stability; 2) in a crystallization process of compound A, it is very difficult to control a crystal polymorph, and 3) compound A (free body) causes mineral deposition in the stomach when it is orally administered repeatedly. For solving these problems, we made examination focusing on the kind of the salt and, as a result, found that 1) benzenesulfonate of compound A does not decompose by light, humidity and other factors in a 1-week preliminary stability test (severe test), and has no problem in its storage stability, 2) a method of selectively producing two kinds of crystal forms of benzenesulfonate of compound A, and that 3) no mineral deposition in the stomach is observed even after a 4-week repeated oral administration.

  在开发 2-[[[2-[(羟基乙酰)氨基]-4-吡啶基]甲基]硫]-N-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺（化合物 A）的过程中，存在多种问题：1）化合物 A 或其盐很难重结晶，盐的种类不同，贮存稳定性也有很大差异，很难获得贮存稳定性极佳的化合物 A 盐；2）在化合物 A 的结晶过程中，很难控制晶体的多态性；3）反复口服化合物 A（游离体）会导致矿物质在胃内沉积。为了解决这些问题，我们对盐的种类进行了研究，结果发现：1）化合物 A 的苯磺酸盐在为期 1 周的初步稳定性试验（严酷试验）中不受光照、湿度和其他因素的影响而分解，在贮存稳定性方面也没有问题；2）一种选择性生产化合物 A 的苯磺酸盐的两种晶体形态的方法；3）即使反复口服 4 周，也不会观察到胃中有矿物质沉积。
• POLYETHYLENE GLYCOL-CONTAINING COMPOSITION
  申请人：Santen Pharmaceutical Co., Ltd

  公开号：EP3047850A1

  公开（公告）日：2016-07-27

  The present invention relates to a pharmaceutical composition comprising a compound represented by the formula (1) or a salt thereof and polyethylene glycol.

  本发明涉及一种药物组合物，由式（1）代表的化合物或其盐和聚乙二醇组成。
• INJECTABLE AGENT AND DEPOT FORMATION METHOD
  申请人：Santen Pharmaceutical Co., Ltd

  公开号：EP3088003A1

  公开（公告）日：2016-11-02

  The purpose of the present invention is to provide a novel injectable agent having an excellent medicinal agent sustained release property. The injectable agent according to the present invention comprises a medicinal agent, trehalose and gellan gum. It is preferred that the contents of the medicinal agent, trehalose and gellan gum are 0.0001 to 50.00% (w/v), 0.1 to 50.0% (w/v) and 0.01 to 3.00% (w/v), respectively, relative to the total volume of the injectable agent. It is also preferred that the injectable agent can form a depot upon exposure to a phosphate buffer solution or a body fluid (tear fluid, vitreous fluid, etc.).

  本发明的目的是提供一种新型注射剂，它具有优异的药剂缓释性能。根据本发明，注射剂由药剂、树海糖和结冷胶组成。相对于注射剂的总体积，药剂、树海胶和结冷胶的含量最好分别为 0.0001 至 50.00%（重量/体积）、0.1 至 50.0%（重量/体积）和 0.01 至 3.00%（重量/体积）。此外，注射剂在接触磷酸盐缓冲溶液或体液（泪液、玻璃体液等）后能形成沉积物也是优选的。