N,N'-bis(2-pyridinylmethyl)-N'-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1,4-benzenedimethanamine | 1221898-33-4

• 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: N,N'-bis(2-pyridinylmethyl)-N'-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1,4-benzenedimethanamine
• 英文别名: N-(2-pyridylmethyl)-N-[[4-[(2-pyridylmethylamino)methyl]phenyl]methyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine；N-(pyridin-2-ylmethyl)-N-[[4-[(pyridin-2-ylmethylamino)methyl]phenyl]methyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine
• CAS: 1221898-33-4
• 化学式: C₂₈H₂₉N₅
• 分子量: 435.572
• InChiKey: XNMCPWWXMKHHPR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  53.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N,N'-bis(2-pyridinylmethyl)-N'-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1,4-benzenedimethanamine 在 氢溴酸 、 溶剂黄146 作用下， 以76%的产率得到AMD 8775
  参考文献：
  名称：

  Discovery of Novel Small Molecule Orally Bioavailable C−X−C Chemokine Receptor 4 Antagonists That Are Potent Inhibitors of T-Tropic (X4) HIV-1 Replication

  摘要：

  The redesign of azamacrocyclic CXCR4 chemokine receptor antagonists resulted in the discovery of novel, small molecule, orally bioavailable compounds that retained T-tropic (CXCR4 using, X4) anti-HIV-1 activity. A structure activity relationship (SA R) was determined on the basis of the inhibition of replication of X4 HIV-1 NL4.3 in MT-4 cells. As a result of lead optimization, we identified (S)-N'-((1H-benzo[d]imidazol-2-Amethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (AMD070) 2 as a potent and selective antagonist of CXCR4 with an IC(50) value of 13 nM in a CXCR4 (125)I-SDF inhibition binding assay. Compound 2 inhibited the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC(50) of 2 and 26 nM, respectively, while remaining noncytotoxic to cells at concentrations exceeding 23 mu M. The pharmacokinetics of 2 was evaluated in rat and dog, and good oral bioavailability was observed in both species. This compound represents the first small molecule orally bioavailable CXCR4 antagonist that was developed for the treatment of HIV-1 infection.

  DOI：

  10.1021/jm100073m
• 作为产物：
  描述：

  在 potassium carbonate 、 苯硫酚 、 水 作用下， 以 乙腈 、 二氯甲烷 为溶剂， 以74%的产率得到N,N'-bis(2-pyridinylmethyl)-N'-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1,4-benzenedimethanamine
  参考文献：
  名称：

  Discovery of Novel Small Molecule Orally Bioavailable C−X−C Chemokine Receptor 4 Antagonists That Are Potent Inhibitors of T-Tropic (X4) HIV-1 Replication

  摘要：

  The redesign of azamacrocyclic CXCR4 chemokine receptor antagonists resulted in the discovery of novel, small molecule, orally bioavailable compounds that retained T-tropic (CXCR4 using, X4) anti-HIV-1 activity. A structure activity relationship (SA R) was determined on the basis of the inhibition of replication of X4 HIV-1 NL4.3 in MT-4 cells. As a result of lead optimization, we identified (S)-N'-((1H-benzo[d]imidazol-2-Amethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (AMD070) 2 as a potent and selective antagonist of CXCR4 with an IC(50) value of 13 nM in a CXCR4 (125)I-SDF inhibition binding assay. Compound 2 inhibited the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC(50) of 2 and 26 nM, respectively, while remaining noncytotoxic to cells at concentrations exceeding 23 mu M. The pharmacokinetics of 2 was evaluated in rat and dog, and good oral bioavailability was observed in both species. This compound represents the first small molecule orally bioavailable CXCR4 antagonist that was developed for the treatment of HIV-1 infection.

  DOI：

  10.1021/jm100073m

文献信息

• Chemokine receptor binding heterocyclic compounds
  申请人：——

  公开号：US20040235823A1

  公开（公告）日：2004-11-25

  This invention relates to a novel class of heterocyclic compounds that bind chemokine receptors, inhibiting the binding of their natural ligands thereby. These compounds result in protective effects against infection by HIV through binding to chemokine receptors, including CXCR4 and CCR5, thus inhibiting the subsequent binding by these chemokines. The present invention provides a compound of Formula I 1 wherein, W is a nitrogen atom and Y is absent or, W is a carbon atom and Y=H; R 1 to R 7 may be the same or different and are independently selected from hydrogen or straight, branched or cyclic C 1-6 alkyl; R 8 is a substituted heterocyclic group or a substituted aromatic group Ar is an aromatic or heteroaromatic ring each optionally substituted at single or multiple, non-linking positions with electron-donating or withdrawing groups; n and n′ are independently, 0-2; X is a group of the formula: 2 Wherein, Ring A is an optionally substituted, saturated or unsaturated 5 or 6-membered ring, and P is an optionally substituted carbon atom, an optionally substituted nitrogen atom, sulfur or oxygen atom. Ring B is an optionally substituted 5 to 7-membered ring. Ring A and Ring B in the above formula can be connected to the group W from any position via the group V, wherein V is a chemical bond, a (CH 2 ) n″ group (where n″=0-2) or a C═O group. Z is, (1) a hydrogen atom, (2) an optionally substituted C 1-6 alkyl group, (3) a C 0-6 alkyl group substituted with an optionally substituted aromatic or heterocyclic group, (4) an optionally substituted C 0-6 alkylamino or C 3-7 cycloalkylamino group, (5) an optionally substituted carbonyl group or sulfonyl. These compounds further include any pharmaceutically acceptable acid addition salts and metal complexes thereof and any stereoisomeric forms and mixtures of stereoisomeric forms thereof.

  本发明涉及一类新型杂环化合物，其能够结合趋化因子受体，抑制其自然配体的结合。这些化合物通过结合趋化因子受体，包括CXCR4和CCR5，从而抑制这些趋化因子的后续结合，从而产生对HIV感染的保护作用。本发明提供了一种I1式化合物，其中，W是氮原子，Y不存在或W是碳原子且Y=H；R1至R7可以相同也可以不同，且独立地选择氢或直链、支链或环状C1-6烷基；R8是取代的杂环基或取代的芳香基；Ar是芳香或杂芳环，可以在单个或多个非连接位置上选择电子给体或电子受体基团进行取代；n和n'独立地为0-2；X是以下式的基团：式中，环A是可选择取代的饱和或不饱和5或6元环，P是可选择取代的碳原子、可选择取代的氮原子、硫或氧原子。环B是可选择取代的5至7元环。上述式中的环A和环B可以通过基团V从任何位置连接到基团W，其中V是化学键、(CH2)n''基团(n''=0-2)或C═O基团。Z是(1)氢原子，(2)可选择取代的C1-6烷基，(3)取代的C0-6烷基，取代的芳香或杂环基，(4)可选择取代的C0-6烷基氨基或C3-7环烷基氨基基团，(5)可选择取代的羰基或磺酰基。这些化合物还包括任何药学上可接受的酸加成盐和金属配合物以及其任何立体异构体和立体异构体混合物。
• CHEMOKINE RECEPTOR BINDING HETEROCYCLIC COMPOUNDS
  申请人：BRIDGER Gary J.

  公开号：US20100105915A1

  公开（公告）日：2010-04-29

  Heterocyclic compounds that bind chemokine receptors and inhibit the binding of their natural ligands are disclosed. The invention compounds are protective against infection by HIV and exert effects characteristic of antagonists to the CXCR4 receptor.

  本发明涉及一种能够结合趋化因子受体并抑制其天然配体结合的杂环化合物。这些化合物对HIV感染具有保护作用，并具有CXCR4受体拮抗剂的特征作用。
• CHEMOKINE RECPETOR BINDING HETEROCYCLIC COMPOUNDS
  申请人：ANORMED INC.

  公开号：EP1163238A1

  公开（公告）日：2001-12-19
• US6750348B1
  申请人：——

  公开号：US6750348B1

  公开（公告）日：2004-06-15
• US7183273B2
  申请人：——

  公开号：US7183273B2

  公开（公告）日：2007-02-27