4-(piperazin-1-yl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine | 1438879-93-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-(piperazin-1-yl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine
• 英文别名: 4-Piperazin-1-yl-2-pyridin-4-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine；4-piperazin-1-yl-2-pyridin-4-yl-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidine
• CAS: 1438879-93-6
• 化学式: C₁₉H₂₁N₅S
• 分子量: 351.475
• InChiKey: VVENTSJOKWJQFG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  82.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-(piperazin-1-yl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine 在 盐酸 作用下， 以 乙醚 、 二氯甲烷 、 水 为溶剂， 反应 1.0h， 以99%的产率得到
  参考文献：
  名称：

  Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidines as atypical protein kinase C inhibitors to control retinal vascular permeability and cytokine-induced edema

  摘要：

  Studies demonstrate that small molecule targeting of atypical protein kinase C (aPKC) may provide an effective means to control vascular permeability, prevent edema, and reduce inflammation providing novel and important alternatives to anti-VEGF therapies for certain blinding eye diseases. Based on a literature tricyclic thieno[2,3-d] pyrimidine lead (1), an ATP-competitive inhibitor of the aPKC iota (iota) and aPKC zeta (zeta) isoforms, we have synthesized a small series of compounds in 1-2 steps from a readily available chloro intermediate. A single pyridine congener was also made using 2D NMR to assign regiochemistry. Within the parent pyrimidine series, a range of potencies was observed against aPKC zeta whereas the pyridine congener was inactive. Selected compounds were also tested for their effect toward VEGF-induced permeability in BREC cells. The most potent of these (7l) was further assayed against the aPKC iota isoform and showed a favorable selectivity profile against a panel of 31 kinases, including kinases from the AGC superfamily, with a focus on PKC isoforms and kinases previously shown to affect permeability. Further testing of 7l in a luciferase assay in HEK293 cells showed an ability to prevent TNF-alpha induced NF kappa B activation while not having any effect on cell survival. Intravitreal administration of 7l to the eye yielded a complete reduction in permeability in a test to determine whether the compound could block VEGF- and TNF alpha-induced permeability across the retinal vasculature in a rat model. The compound in mice displayed good microsomal stability and in plasma moderate exposure (AUC and C-max), low clearance, a long half-life and high oral bioavailability. With IV dosing, higher levels were observed in the brain and eye relative to plasma, with highest levels in the eye by either IV or PO dosing. With a slow oral absorption profile, 7l accumulates in the eye to maintain a high concentration after dosing with higher levels than in plasma. Compound 7l may represent a class of aPKC inhibitors for further investigation.

  DOI：

  10.1016/j.bmc.2020.115480
• 作为产物：
  描述：

  2-氨基-4,5,6,7-四氢苯并噻酚-3-羧酸乙酯 在 盐酸 、 草酰氯 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 21.0h， 生成 4-(piperazin-1-yl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine
  参考文献：
  名称：

  Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidines as atypical protein kinase C inhibitors to control retinal vascular permeability and cytokine-induced edema

  摘要：

  Studies demonstrate that small molecule targeting of atypical protein kinase C (aPKC) may provide an effective means to control vascular permeability, prevent edema, and reduce inflammation providing novel and important alternatives to anti-VEGF therapies for certain blinding eye diseases. Based on a literature tricyclic thieno[2,3-d] pyrimidine lead (1), an ATP-competitive inhibitor of the aPKC iota (iota) and aPKC zeta (zeta) isoforms, we have synthesized a small series of compounds in 1-2 steps from a readily available chloro intermediate. A single pyridine congener was also made using 2D NMR to assign regiochemistry. Within the parent pyrimidine series, a range of potencies was observed against aPKC zeta whereas the pyridine congener was inactive. Selected compounds were also tested for their effect toward VEGF-induced permeability in BREC cells. The most potent of these (7l) was further assayed against the aPKC iota isoform and showed a favorable selectivity profile against a panel of 31 kinases, including kinases from the AGC superfamily, with a focus on PKC isoforms and kinases previously shown to affect permeability. Further testing of 7l in a luciferase assay in HEK293 cells showed an ability to prevent TNF-alpha induced NF kappa B activation while not having any effect on cell survival. Intravitreal administration of 7l to the eye yielded a complete reduction in permeability in a test to determine whether the compound could block VEGF- and TNF alpha-induced permeability across the retinal vasculature in a rat model. The compound in mice displayed good microsomal stability and in plasma moderate exposure (AUC and C-max), low clearance, a long half-life and high oral bioavailability. With IV dosing, higher levels were observed in the brain and eye relative to plasma, with highest levels in the eye by either IV or PO dosing. With a slow oral absorption profile, 7l accumulates in the eye to maintain a high concentration after dosing with higher levels than in plasma. Compound 7l may represent a class of aPKC inhibitors for further investigation.

  DOI：

  10.1016/j.bmc.2020.115480

文献信息

• [EN] THIENOPYRIMIDINE INHIBITORS OF ATYPICAL PROTEIN KINASE C<br/>[FR] INHIBITEURS DE TYPE THIÉNOPYRIMIDINE DE PROTÉINES KINASES C ATYPIQUES
  申请人：CANCER REC TECH LTD

  公开号：WO2013078126A1

  公开（公告）日：2013-05-30

  The present invention provides a compound of formula (I) or a salt thereof, wherein R1, R2, R3, R4, R5, R6, A, G, M, Q and X are as defined herein. A compound of formula (I) and its salts have a PKC inhibitory activity, and may be used to treat proliferative disorders.

  本发明提供了一种式（I）的化合物或其盐，其中R1、R2、R3、R4、R5、R6、A、G、M、Q和X如本文所定义。式（I）的化合物及其盐具有PKC抑制活性，并可用于治疗增生性疾病。
• Thienopyrimidine Inhibitors of Atypical Protein Kinase C
  申请人：Cancer Research Technology Limited

  公开号：US20140323435A1

  公开（公告）日：2014-10-30

  The present application provides a compound of formula (I) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, G, M, Q and X are as defined herein. A compound of formula (I) and its salts have aPKC inhibitory activity, and may be used to treat proliferative disorders.

  本申请提供了公式（I）的化合物或其盐，其中R1、R2、R3、R4、R5、R6、A、G、M、Q和X的定义如本文所述。公式（I）的化合物及其盐具有aPKC抑制活性，可用于治疗增殖性疾病。
• THIENOPYRIMIDINE AS INHIBITORS OF ATYPICAL PROTEIN KINASE C
  申请人：Cancer Research Technology Limited

  公开号：EP3048106A1

  公开（公告）日：2016-07-27

  The present invention provides a compound of formula (I) or a salt thereof, wherein R1, R2, R3, R4, R5, R6, A, G, M, Q and X are as defined herein. The compound of formula (I) and its salts has aPKC inhibitory activity, and may be used to treat proliferative disorders.

  本发明提供了一种式 (I) 的化合物 或其盐，其中 R1、R2、R3、R4、R5、R6、A、G、M、Q 和 X 如本文所定义。式（I）化合物及其盐具有 PKC 抑制活性，可用于治疗增殖性疾病。
• Thienopyrimidine inhibitors of atypical protein kinase C
  申请人：Cancer Research Technology Limited

  公开号：US10183950B2

  公开（公告）日：2019-01-22

  The present application provides a compound of formula (I) or a salt thereof, wherein R1, R2, R3, R4, R5, R6, A, G, M, Q and X are as defined herein. A compound of formula (I) and its salts have aPKC inhibitory activity, and may be used to treat proliferative disorders.

  本申请提供了一种式 (I) 的化合物 或其盐，其中 R1、R2、R3、R4、R5、R6、A、G、M、Q 和 X 如本文所定义。式（I）化合物及其盐具有 PKC 抑制活性，可用于治疗增殖性疾病。
• EP2782917A1
  申请人：——

  公开号：EP2782917A1

  公开（公告）日：2014-10-01