tert-butyl 3-[3-fluoro-4-{(3S)-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(4-methoxybenzenesulfonyl)amino}propionate | 334618-41-6

• 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: tert-butyl 3-[3-fluoro-4-{(3S)-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(4-methoxybenzenesulfonyl)amino}propionate
• 英文别名: tert-butyl (2S)-3-[[3-fluoro-4-[(3S)-3-(pyrimidin-2-ylamino)piperidin-1-yl]benzoyl]amino]-2-[(4-methoxyphenyl)sulfonylamino]propanoate
• CAS: 334618-41-6
• 化学式: C₃₀H₃₇FN₆O₆S
• 分子量: 628.725
• InChiKey: ZRXOZGHQSDIWHM-OFVILXPXSA-N

物化性质

• 密度：
  1.310±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  44
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  160
• 氢给体数：
  3
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  tert-butyl 3-[3-fluoro-4-{(3S)-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(4-methoxybenzenesulfonyl)amino}propionate 、 三氟乙酸 以 二氯甲烷 为溶剂， 反应 5.0h， 生成
  参考文献：
  名称：

  Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part III: Synthesis of potent antagonists with αvβ3/αIIbβ3 dual activity and improved water solubility

  摘要：

  In order to optimize our novel integrin alpha(v)beta(3)/alpha(IIb)beta(3) dual antagonists, spatial screening at the N-terminus was performed. The alpha(v)beta(3) antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against alpha(IIb)beta(3) was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against alpha(v)beta(3), and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the alpha(v)beta(3) receptor were performed to confirm the SAR findings. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.10.055
• 作为产物：
  描述：

  L-鸟氨酸盐酸盐 在 palladium on activated charcoal sodium hydroxide 、 lithium aluminium tetrahydride 、 氯化亚砜 、 氢气 、 碳酸氢钠 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， -78.0~120.0 ℃ 、101.33 kPa 条件下， 反应 78.0h， 生成 tert-butyl 3-[3-fluoro-4-{(3S)-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(4-methoxybenzenesulfonyl)amino}propionate
  参考文献：
  名称：

  Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part III: Synthesis of potent antagonists with αvβ3/αIIbβ3 dual activity and improved water solubility

  摘要：

  In order to optimize our novel integrin alpha(v)beta(3)/alpha(IIb)beta(3) dual antagonists, spatial screening at the N-terminus was performed. The alpha(v)beta(3) antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against alpha(IIb)beta(3) was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against alpha(v)beta(3), and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the alpha(v)beta(3) receptor were performed to confirm the SAR findings. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.10.055

文献信息

• 3-AMINOPIPERIDINE DERIVATIVES AS INTEGRIN $g(a)v$g(b)3 ANTAGONISTS
  申请人：Meiji Seika Kaisha, Ltd.

  公开号：EP1227083A1

  公开（公告）日：2002-07-31

  An object of the present invention is to provide novel derivatives having integrin αvβ3 antagonistic activity wherein a basic atomic group has been attached to the 3-position of a piperidine ring either directly or through various atomic groups. The derivatives according to the present invention are compounds represented by formula (I) or pharmaceutically acceptable salts or solvates thereof, which are useful for the treatment or prevention of cardiovascular diseases, angiogenesis-related diseases, cerebrovascular diseases, cancers and metastasis thereof, immunological diseases, osteopathy and other diseases: wherein A represents an optionally substituted heterocyclic group containing at least one nitrogen atom, a bicylic group or the like; D represents a bond, >NR4, >CR5R6, O, S, or -NR4-CR5R6-; Z represents CH or N; R7 and R8 represent hydroxyl, alkyl or the like; Q represents >C=O or the like; R9 represents hydrogen, alkyl or the like; J represents a bond or alkylene; R10 represents optionally substituted hydroxyl, amino or the like; R11 represents hydrogen, alkyl or the like; m is 0 to 5; n is 0 to 4; p is 3 or 4; and q is 0 to 3.

  本发明的目的是提供具有整合素αvβ3拮抗活性的新型衍生物，其中碱性原子团直接或通过各种原子团连接到哌啶环的3位。根据本发明的衍生物是式 (I) 所代表的化合物或其药学上可接受的盐或溶液，可用于治疗或预防心血管疾病、血管生成相关疾病、脑血管疾病、癌症及其转移、免疫疾病、骨病和其他疾病： 其中，A 代表含有至少一个氮原子的任选取代杂环基团、双环基团或类似基团；D 代表键、>NR4、>CR5R6、O、S 或 -NR4-CR5R6-；Z 代表 CH 或 N；R7 和 R8 代表羟基、烷基或类似基团；Q 代表 >C=O 或类似物；R9 代表氢、烷基或类似物；J 代表键或亚烷基；R10 代表任选取代的羟基、氨基或类似物；R11 代表氢、烷基或类似物；m 为 0 至 5；n 为 0 至 4；p 为 3 或 4；q 为 0 至 3。
• Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part III: Synthesis of potent antagonists with αvβ3/αIIbβ3 dual activity and improved water solubility
  作者：Minoru Ishikawa、Yukiko Hiraiwa、Dai Kubota、Masaki Tsushima、Takashi Watanabe、Shoichi Murakami、Shokichi Ouchi、Keiichi Ajito

  DOI：10.1016/j.bmc.2005.10.055

  日期：2006.4

  In order to optimize our novel integrin alpha(v)beta(3)/alpha(IIb)beta(3) dual antagonists, spatial screening at the N-terminus was performed. The alpha(v)beta(3) antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against alpha(IIb)beta(3) was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against alpha(v)beta(3), and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the alpha(v)beta(3) receptor were performed to confirm the SAR findings. (c) 2005 Elsevier Ltd. All rights reserved.