12-methyl-15-(2-(pyrrolidin-1-yl)ethoxy)-7,25-dioxa-12,19,21,24-tetraazatetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene | 937271-09-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 12-methyl-15-(2-(pyrrolidin-1-yl)ethoxy)-7,25-dioxa-12,19,21,24-tetraazatetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene
• 英文别名: (9E)-12-methyl-15-(2-pyrrolidin-1-ylethoxy)-7,26-dioxa-12,19,21,24-tetrazatetracyclo[18.3.1.12,5.114,18]hexacosa-1(24),2,4,9,14,16,18(25),20,22-nonaene
• CAS: 937271-09-5
• 化学式: C₂₇H₃₃N₅O₃
• 分子量: 475.591
• InChiKey: RVBGHTGHDLQSCG-SNAWJCMRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  35
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  75.9
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  allylmethyl-[2-(2-chloroethoxy)-5-nitrobenzyl]amine 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 盐酸 、 tin(II) chloride dihdyrate 、 水 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 正丁醇 为溶剂， 反应 37.0h， 生成 12-methyl-15-(2-(pyrrolidin-1-yl)ethoxy)-7,25-dioxa-12,19,21,24-tetraazatetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene
  参考文献：
  名称：

  Discovery of the Macrocycle (9E)-15-(2-(Pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a Potent Inhibitor of Janus Kinase 2/Fms-LikeTyrosine Kinase-3 (JAK2/FLT3) for the Treatment of Rheumatoid Arthritis

  摘要：

  Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 141 was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 141 as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 141 (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.

  DOI：

  10.1021/jm201454n

文献信息

• HETEROALKYL LINKED PYRIMIDINE DERIVATIVES
  申请人：Blanchard Stephanie

  公开号：US20120142680A1

  公开（公告）日：2012-06-07

  The present invention relates to pyrimidine compounds that are useful as anti-proliferative agents. More particularly, the present invention relates to heteroalkyl linked and substituted pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative disorders including tumours and cancers as well as other conditions or disorders associated with kinases.

  本发明涉及嘧啶化合物，其可用作抗增殖剂。更具体地，本发明涉及杂原子烷基连接和取代的嘧啶化合物，其制备方法，含有这些化合物的药物组合物以及这些化合物在治疗增殖性疾病方面的用途。这些化合物可能作为药物用于治疗包括肿瘤和癌症在内的多种增殖性疾病，以及与激酶相关的其他情况或疾病。
• US8143255B2
  申请人：——

  公开号：US8143255B2

  公开（公告）日：2012-03-27
• US9133214B2
  申请人：——

  公开号：US9133214B2

  公开（公告）日：2015-09-15
• [EN] HETEROALKYL LINKED PYRIMIDINE DERIVATIVES<br/>[FR] DERIVES DE PYRIMIDINE A LIAISON HETEROALKYLE
  申请人：S BIO PTE LTD

  公开号：WO2007058628A1

  公开（公告）日：2007-05-24

  [EN] The present invention relates to pyrimidine compounds that are useful as anti-proliferative agents. More particularly, the present invention relates to heteroalkyl linked and substituted pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative disorders including tumours and cancers as well as other conditions or disorders associated with kinases.
  [FR] L'invention concerne des composés de pyrimidine utiles comme agents antiprolifératifs. Plus particulièrement, l'invention concerne des composés de pyrimidine à liaison hétéroalkyle et substitués, des procédés de préparation, des compositions pharmaceutiques contenant ces composés et l'utilisation de ceux-ci dans le traitement de troubles prolifératifs. Ces composés, utilisés comme médicaments, sont destinés à traiter des troubles prolifératifs tels que des tumeurs et des cancers ainsi que d'autres troubles ou états pathologiques liés ou associés aux kinases.
• Discovery of the Macrocycle (9<i>E</i>)-15-(2-(Pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a Potent Inhibitor of Janus Kinase 2/Fms-LikeTyrosine Kinase-3 (JAK2/FLT3) for the Treatment of Rheumatoid Arthritis
  作者：Anthony D. William、Angeline C.-H. Lee、Anders Poulsen、Kee Chuan Goh、Babita Madan、Stefan Hart、Evelyn Tan、Haishan Wang、Harish Nagaraj、Dizhong Chen、Chai Ping Lee、Eric T. Sun、Ramesh Jayaraman、Mohammad Khalid Pasha、Kantharaj Ethirajulu、Jeanette M. Wood、Brian W. Dymock

  DOI：10.1021/jm201454n

  日期：2012.3.22

  Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 141 was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 141 as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 141 (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.