(R)-8-((2-(5-fluoro-1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)octahydropyrazino[2,1-c][1,4]oxazine | 1147421-61-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: (R)-8-((2-(5-fluoro-1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)octahydropyrazino[2,1-c][1,4]oxazine
• 英文别名: (R)-8-[2-(5-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-octahydro-pyrazino[2,1-c][1,4]oxazine；(9aR)-8-[[2-(5-fluoro-1H-indol-4-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine
• CAS: 1147421-61-1
• 化学式: C₂₆H₂₉FN₆O₂S
• 分子量: 508.62
• InChiKey: JSISTYTUHYTCID-QGZVFWFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  36
• 可旋转键数：
  4
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  98
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  (R)-1-BOC-3-羟甲基哌嗪 在 lithium aluminium tetrahydride 、 四(三苯基膦)钯 、 potassium tert-butylate 、 caesium carbonate 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 1,2-二氯乙烷 为溶剂， 反应 16.17h， 生成 (R)-8-((2-(5-fluoro-1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)octahydropyrazino[2,1-c][1,4]oxazine
  参考文献：
  名称：

  Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition

  摘要：

  PI3K delta is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(alpha, beta, delta) and IB (gamma), which catalyze the phosphorylation of PIP2 to PIP3. PI3K delta is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3K delta inhibitors and describe a structural hypothesis for isoform (alpha, beta, gamma) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.

  DOI：

  10.1021/jm3003747

文献信息

• THIENOPYRIMIDINE DERIVATIVES AS P13K INHIBITORS
  申请人：Hancox Timothy Colin

  公开号：US20110021496A1

  公开（公告）日：2011-01-27

  Thienopyrimidines of formula (I) wherein W and R 1 to R 4 are as defined in the claims, and the pharmaceutically acceptable salts thereof are inhibitors of PI3K and are selective for the p110δ isoform, which is a class Ia PI3 kinase, over both other class Ia and class Ib kinases. The compounds may be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.

  公式（I）中，W和R1至R4的定义如索权所述，其药学上可接受的盐是PI3K的抑制剂，并且选择性地作用于p110δ同工酶，该同工酶是一种Ia类PI3激酶，优于其他Ia类和Ib类激酶。这些化合物可用于治疗由PI3激酶引起的异常细胞生长、功能或行为所引起的疾病和障碍，如癌症、免疫障碍、心血管疾病、病毒感染、炎症、代谢/内分泌功能障碍和神经系统障碍。
• THIENOPYRIMIDIENE DERIVATIVES AS PI3K INHIBITORS
  申请人：F. Hoffmann-La Roche AG

  公开号：EP2205610B1

  公开（公告）日：2013-11-20
• US8293735B2
  申请人：——

  公开号：US8293735B2

  公开（公告）日：2012-10-23
• [EN] THIENOPYRIMIDIENE DERIVATIVES AS PI3K INHIBITORS<br/>[FR] DÉRIVÉS DE THIÉNOPYRIMIDIÈNE COMME INHIBITEURS DE PI3K
  申请人：HOFFMANN LA ROCHE

  公开号：WO2009053715A1

  公开（公告）日：2009-04-30

  Thienopyrimidines of formula (I) wherein W and R1 to R4 are as defined in the claims, and the pharmaceutically acceptable salts thereof are inhibitors of PI3K and are selective for the p110δ isoform, which is a class Ia PI3 kinase, over both other class Ia and class Ib kinases. The compounds may be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.
• Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition
  作者：Brian S. Safina、Stewart Baker、Matt Baumgardner、Paul M. Blaney、Bryan K. Chan、Yung-Hsiang Chen、Matthew W. Cartwright、Georgette Castanedo、Christine Chabot、Arnaud J. Cheguillaume、Paul Goldsmith、David M. Goldstein、Bindu Goyal、Timothy Hancox、Raj K. Handa、Pravin S Iyer、Jasmit Kaur、Rama Kondru、Jane R. Kenny、Sussie L. Krintel、Jun Li、John Lesnick、Matthew C. Lucas、Cristina Lewis、Sophie Mukadam、Jeremy Murray、Alan J. Nadin、Jim Nonomiya、Fernando Padilla、Wylie S. Palmer、Jodie Pang、Neil Pegg、Steve Price、Karin Reif、Laurent Salphati、Pascal A. Savy、Eileen M. Seward、Stephen Shuttleworth、Sukhjit Sohal、Zachary K. Sweeney、Suzanne Tay、Parcharee Tivitmahaisoon、Bohdan Waszkowycz、Binqing Wei、Qin Yue、Chenghong Zhang、Daniel P. Sutherlin

  DOI：10.1021/jm3003747

  日期：2012.6.28

  PI3K delta is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(alpha, beta, delta) and IB (gamma), which catalyze the phosphorylation of PIP2 to PIP3. PI3K delta is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3K delta inhibitors and describe a structural hypothesis for isoform (alpha, beta, gamma) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.