trans-N-{3-[2-(phenylamino)pyrimidin-5-yl]imidazo[1,2-b]pyridazin-6-yl}cyclohexane-1,4-diamine | 1330594-94-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: trans-N-{3-[2-(phenylamino)pyrimidin-5-yl]imidazo[1,2-b]pyridazin-6-yl}cyclohexane-1,4-diamine
• CAS: 1330594-94-9
• 化学式: C₂₂H₂₄N₈
• 分子量: 400.486
• InChiKey: KUNDZIQYLIUGDW-SAABIXHNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.61
• 重原子数：
  30.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  106.05
• 氢给体数：
  3.0
• 氢受体数：
  8.0

反应信息

• 作为产物：
  描述：

  trans-1,4-Diaminocyclohexane 在 盐酸 、 4-二甲氨基吡啶 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 CyPF-tBu 、 palladium diacetate 、 caesium carbonate 、 三乙胺 、 sodium t-butanolate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N-甲基吡咯烷酮 、 水 为溶剂， 反应 65.5h， 生成 trans-N-{3-[2-(phenylamino)pyrimidin-5-yl]imidazo[1,2-b]pyridazin-6-yl}cyclohexane-1,4-diamine
  参考文献：
  名称：

  Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)

  摘要：

  A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (Pf CDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds with PfCDPK1 enzyme IC50 values less than 10 nM and in vitro P. falciparum antiparasite EC50 values down to 12 nM, although these compounds did not have suitable ADME properties to show in vivo efficacy in a mouse model. Structural modifications designed to address the ADME issues, in particular permeability, were initially accompanied by losses in antiparasite potency, but further optimization allowed a good balance in the compound profile to be achieved. Upon testing in vivo in a murine model of efficacy against malaria, high levels of compound exposure relative to their in vitro activities were achieved, and the modest efficacy that resulted raises questions about the level of effect that is achievable through the targeting of PfCDPK1.

  DOI：

  10.1021/jm500342d

文献信息

• [EN] FUSED HETEROCYCLIC COMPOUNDS FOR USE IN THE TREATMENT OF MALARIA<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES CONDENSÉS POUR UTILISATION DANS LE TRAITEMENT DU PALUDISME
  申请人：MEDICAL RES COUNCIL TECHNOLOGY

  公开号：WO2011101640A1

  公开（公告）日：2011-08-25

  A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein: R1 is -NR3R4 or -OR5; R2 is selected from aryl, heteroaryl, fused aryl- heterocycloalkyl and fused heteroaryl-heterocycloalkyl each of which may be optionally substituted by one or more R8 groups; R3 is H or alkyl; R4 is: (i) cycloalkyl optionally substituted by one or more -NR11R12, -NHCO2R11, -NHCOR11 and -NHSO2R11 groups; or (ii) -(CH2)n-heterocycloalkyl, wherein said heterocycloalkyl is a 4, 5 or 6-membered nitrogen-containing group optionally containing one or more CO groups, wherein said heterocycloalkyl is optionally substituted by one or more one or more (CH2)nR7 groups; (iii) -(CH2)n-heteroaryl, wherein said heteroaryl group is optionally substituted by one or more R7 groups; or (iv) alkyl substituted by one or more -NR11R12groups; or R3 and R4 are linked together with the nitrogen to which they are attached to form a 4, 5 or 6-membered heterocycloalkyl group optionally containing one or two further groups selected from CO, O, N and S, and which is optionally further substituted by one or more R7 groups; R5 is selected from alkyl, -(CH2)n-heteroaryl and -(CH2)n-heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl groups are each optionally substituted by one or more R7 groups; each R11 and R12 is independently H or alkyl; and each n is independently an integer from O to 6; for use in treating or preventing a disorder associated with CDPK. Further aspects relate to the use of said compounds in the treatment of various therapeutic disorders, and more particularly as inhibitors of PfCDPK1.

  发明的第一个方面涉及式(I)的化合物，或其药学上可接受的盐或酯，其中：R1为-NR3R4或-OR5；R2选自芳基、杂环芳基、融合芳基-杂环烷基和融合杂环芳基-杂环烷基，每种基可能被一个或多个R8基取代；R3为H或烷基；R4为：(i) 可选地被一个或多个-NR11R12、-NHCO2R11、-NHCOR11和-NHSO2R11基取代的环烷基；或(ii) -(CH2)n-杂环烷基，其中所述杂环烷基是一个含氮的4、5或6成员环基，可选地含有一个或多个CO基团，其中所述杂环烷基可被一个或多个(CH2)nR7基团取代；(iii) -(CH2)n-杂芳基，其中所述杂芳基可被一个或多个R7基团取代；或(iv) 被一个或多个-NR11R12基团取代的烷基；或R3和R4与它们连接到的氮一起形成一个含有一个或两个进一步选择自CO、O、N和S的4、5或6成员杂环烷基基团，可选地进一步被一个或多个R7基团取代；R5选自烷基、-(CH2)n-杂芳基和-(CH2)n-杂环烷基，其中所述杂芳基和杂环烷基基团可选地被一个或多个R7基团取代；每个R11和R12独立地为H或烷基；每个n独立地为0到6的整数；用于治疗或预防与CDPK相关的疾病。进一步方面涉及所述化合物在治疗各种治疗性疾病中的使用，更特别地作为PfCDPK1的抑制剂。
• Optimization of an Imidazopyridazine Series of Inhibitors of <i>Plasmodium falciparum</i> Calcium-Dependent Protein Kinase 1 (<i>Pf</i>CDPK1)
  作者：Timothy M. Chapman、Simon A. Osborne、Claire Wallace、Kristian Birchall、Nathalie Bouloc、Hayley M. Jones、Keith H. Ansell、Debra L. Taylor、Barbara Clough、Judith L. Green、Anthony A. Holder

  DOI：10.1021/jm500342d

  日期：2014.4.24

  A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (Pf CDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds with PfCDPK1 enzyme IC50 values less than 10 nM and in vitro P. falciparum antiparasite EC50 values down to 12 nM, although these compounds did not have suitable ADME properties to show in vivo efficacy in a mouse model. Structural modifications designed to address the ADME issues, in particular permeability, were initially accompanied by losses in antiparasite potency, but further optimization allowed a good balance in the compound profile to be achieved. Upon testing in vivo in a murine model of efficacy against malaria, high levels of compound exposure relative to their in vitro activities were achieved, and the modest efficacy that resulted raises questions about the level of effect that is achievable through the targeting of PfCDPK1.