4-(2-chloroethoxy)-3-((allyloxy)methyl)benzenamine | 1312603-46-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 4-(2-chloroethoxy)-3-((allyloxy)methyl)benzenamine
• 英文别名: 3-allyloxymethyl-4-(2-chloroethoxy)phenylamine；3-[(Allyloxy)methyl]-4-(2-chloroethoxy)aniline；4-(2-chloroethoxy)-3-(prop-2-enoxymethyl)aniline
• CAS: 1312603-46-5
• 化学式: C₁₂H₁₆ClNO₂
• 分子量: 241.718
• InChiKey: VYSMZKMFYRHJDD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  16
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  44.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-(2-chloroethoxy)-3-((allyloxy)methyl)benzenamine 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 盐酸 作用下， 以 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 、 正丁醇 为溶剂， 反应 9.5h， 生成 pacritinib
  参考文献：
  名称：

  Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma

  摘要：

  Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (ME). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for ME and lymphoma.

  DOI：

  10.1021/jm200326p
• 作为产物：
  描述：

  2-(2-氯乙氧基)-5-硝基苯甲醛 在 sodium tetrahydroborate 、 四丁基硫酸氢铵 、 铁粉 、 氯化铵 、 potassium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 16.0h， 生成 4-(2-chloroethoxy)-3-((allyloxy)methyl)benzenamine
  参考文献：
  名称：

  Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma

  摘要：

  Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (ME). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for ME and lymphoma.

  DOI：

  10.1021/jm200326p

文献信息

• HETEROALKYL LINKED PYRIMIDINE DERIVATIVES
  申请人：Blanchard Stephanie

  公开号：US20090258886A1

  公开（公告）日：2009-10-15

  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.

  本发明涉及用作抗增殖剂的嘧啶化合物。更具体地说，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，含有这些化合物的制药组合物以及在治疗增殖性疾病中使用这些化合物的用途。这些化合物可能作为药物对许多增殖性疾病，包括肿瘤和癌症以及与激酶相关的其他疾病或疾病的治疗有用。
• WO2007058627A1
  申请人：——

  公开号：——

  公开（公告）日：——
• J. Med. Chem. 2011, 54, 4638-4658
  作者：

  DOI：——

  日期：——
• Design and Synthesis of Janus Kinase 2 (JAK2) and Histone Deacetlyase (HDAC) Bispecific Inhibitors Based on Pacritinib and Evidence of Dual Pathway Inhibition in Hematological Cell Lines
  作者：Eugene Guorong Yang、Nurulhuda Mustafa、Eng Chong Tan、Anders Poulsen、Pondy Murugappan Ramanujulu、Wee Joo Chng、Jeffrey J. Y. Yen、Brian W. Dymock

  DOI：10.1021/acs.jmedchem.6b00157

  日期：2016.9.22

  Blockage of more than one oncoptotein or pathway is now a standard approach in modem cancer therapy. Multiple inhibition is typically achieved with two or more drugs. Herein, we describe a pharmacophore Merging strategy combining the JAK2/FLT3 inhibitor pacritnib with the pan-HDAC inhibitor, vorinostat, to create bispecific single molecules with both JAK and HDAC targeted inhibition. A preferred ether hydroxamate, 51, inhibits JAK2 and HDAC6 with low nanomolar potency, is <100 nM potent against HDACs 2 and potent against HDACs 1, 8, and 11, and >50-, fold selective for JAK2 in a panel of 97 kinases. Broad cellular antiproliferative potency is supported by demonstration of JAK-STAT and HDAC pathway blockade in several hematological cell lines, inhibition of colony formation in HEL cells, and analysis of apoptosis. This study provides new tool compounds for further exploration of dual JAK-HDAC pathway inhibiton achieved with a single molecule.
• Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma
  作者：Anthony D. William、Angeline C.-H. Lee、Stéphanie Blanchard、Anders Poulsen、Ee Ling Teo、Harish Nagaraj、Evelyn Tan、Dizhong Chen、Meredith Williams、Eric T. Sun、Kee Chuan Goh、Wai Chung Ong、Siok Kun Goh、Stefan Hart、Ramesh Jayaraman、Mohammed Khalid Pasha、Kantharaj Ethirajulu、Jeanette M. Wood、Brian W. Dymock

  DOI：10.1021/jm200326p

  日期：2011.7.14

  Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (ME). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for ME and lymphoma.