N-[bis(cyclopropyl)methyl]-N-propylamine

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: N-[bis(cyclopropyl)methyl]-N-propylamine
• 英文别名: N-(dicyclopropylmethyl)propan-1-amine
• 化学式: C₁₀H₁₉N
• 分子量: 153.268
• InChiKey: ACNDTVMMCDRRNJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  11
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  12
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  N-[bis(cyclopropyl)methyl]-N-propylamine 在 肼 作用下， 以 乙醇 、 丙酮 为溶剂， 反应 6.0h， 生成 3-(2-dichlorophenyl)-5-(N-propyl-N-[bis(cyclopropyl)methyl]amino)-1H-[1,2,4]triazole
  参考文献：
  名称：

  Rational Design, Synthesis, and Structure−Activity Relationships of Aryltriazoles as Novel Corticotropin-Releasing Factor-1 Receptor Antagonists

  摘要：

  Following the discovery of the very high binding affinity of 4-anilinopyrimidines against corticotropin-releasing factor receptor-1 (CRF1) (e.g., 1, K-i = 2 nM), a new series of triazoles bearing different groups has been synthesized and evaluated. The compounds were prepared by cyclizations of N-acyl-S-methylisothioureas with alkylhydrazines or by cyclizations with hydrazine followed by alkylation. While members of this series showed potent binding affinity against CRF1 receptor, there were important differences between the different regio- (7 and 12) and stereoisomeric aryltriazoles where the R-1 or R-2 side chain in 7 has an asymmetric center. In terms of overall potency, aryltriazole analogues such as 7r bearing an N-(alpha-branched benzyl)-N-propylamino side chain were the most potent, followed by analogues such as 7a, with an N-bis(cyclopropyl)methyl-N-propylamino side chain, and analogues such as 7m, with an N-(alpha-branched aliphatic)-N-propylamino side chain. While the N-propyl group was crucial for high potency, we hypothesized that the terminal methyl mimicked the 5-methyl of pyrazolo[1,5-alpha]pyrimidines 3 and 4. Correlation of the low-energy conformers of compounds of type 3 and 7 generated by computational analyses was very good. The size and shape of the N-alkyl group dramatically changed the potency of the triazoles, which is in contrast to the SAR seen for bicyclic CRF1 antagonists. In general, the S-enantiomer was much more potent than the corresponding R-isomer. Furthermore, to a limited extent in the aryltriazole series the substituent on the 5-phenyl ring changed the potency up to 9-fold. (S)-1-Methyl-3-[N-(4-fluorophenylpentyl)-N-propyl]amino-5-(2-methoxy-4-dichlorophenyl)-1H-[1,2,4]triazole [(S)-7r] showed very potent binding affinity (K-i = 2.7 nM) to CRF1 receptors with an IC50 of 49 nM in a cAMP inhibition assay.

  DOI：

  10.1021/jm049339c

文献信息

• CRF receptor antagonists and methods relating thereto
  申请人：Neurocrine Biosciences, Inc.

  公开号：US05795905A1

  公开（公告）日：1998-08-18

  CRF receptor antagonists are disclosed. Such receptor antagonists are thiadiazole-, pyrimidine-, triazine-, and triazole-containing compounds substituted with both a C3-C14 monocyclic or fused, homoaryl or heteroaryl group and a substituted amine group. The CFR receptor antagonists have utility in the treatment of a variety of disorders, including disorders associated with the hypersecretion of CRF.

  CRF受体拮抗剂已被披露。这些受体拮抗剂是噻二唑、嘧啶、三嗪和三唑含有化合物，其被取代的部分包括C3-C14的单环或融合、同源芳基或杂环基团和取代胺基团。CRF受体拮抗剂在治疗各种疾病中具有用途，包括与CRF过度分泌相关的疾病。
• [EN] AMINO-SUBSTITUTED THIADIAZOLES, PYRIMIDINES, TRIAZINES OR TRIAZOLES USEFUL AS CTF RECEPTOR ANTAGONISTS<br/>[FR] THIADIAZOLES, PYRIMIDINES, TRIAZINES OU TRIAZOLES AMINO-SUBSTITUES UTILES COMME ANTAGONISTES DU RECEPTEUR DU FACTEUR DE LIBERATION DE CORTICOTROPINE
  申请人：NEUROCRINE BIOSCIENCES, INC.

  公开号：WO1996039400A1

  公开（公告）日：1996-12-12

  (EN) Compounds having formulae (I) to (VI) wherein X is a substituted (hetero)aryl group and R1-R6 are various possible substituents, are corticotropin-releasing factor (CRF) receptor antagonists.(FR) L'invention concerne des composés de formules (I) à (VI) où X est un groupe (hétéro)aryle substitué et R1-R6 sont des substituants éventuels divers. Ces composés sont des antagonistes du récepteur du facteur de libération de corticotropine.

  化合物的化学式为(I)到(VI)，其中X是取代的(杂)芳基团，R1-R6是不同的可能的取代基，是促肾上腺皮质激素释放因子（CRF）受体拮抗剂。
• 1-Alkyl-3-amino-5-aryl-1H-[1,2,4]triazoles: novel synthesis via cyclization of N-Acyl-S-methylisothioureas with alkylhydrazines and their potent corticotropin-Releasing factor-1 (CRF1) receptor antagonist activities
  作者：Chen Chen、Raymond Dagnino、Charles Q. Huang、James R. McCarthy、Dimitri E. Grigoriadis

  DOI：10.1016/s0960-894x(01)00657-6

  日期：2001.12

  Cyclizations of alkythydrazines with N-acyl-S-methylisothioureas, readily synthesized from acyl chlorides, sodium thioisocyanate. dialkylamines then methyl iodide in a one-pot reaction, gave 1-alkyl-3-dialkylamino-5-phenyltriazoles 7 as major products. The regioisomers were assigned through the use of NOE NMR experiments. While bearing a,N-bis(cyclopropyl)methyl-N-propylamino group, this series of compounds shows very good binding affinity on the human CRF1 receptor. Among them, 1-methyl-3-[N-bis(cyclopropyl)methyl-N-propylamino]-5-(2,4-dichlorophenyl)-1H-[1,2,4]triazole 7a had the best binding affinity for the CRF1 receptor (K-i = 9 nM). (C) 2001 Elsevier Science Ltd. All rights reserved.
• Design, synthesis, and SAR of 2-dialkylamino-4-arylpyrimidines as potent and selective corticotropin-releasing factor 1 (CRF 1 ) receptor antagonists
  作者：Charles Q Huang、Dimitri E Grigoriadis、Zhengyu Liu、James R McCarthy、John Ramphal、Thomas Webb、Jeffrey P Whitten、Michael Y Xie、Chen Chen

  DOI：10.1016/j.bmcl.2004.02.053

  日期：2004.5

  A series of 2-dialkylamino-4-phenylpyrimidines (7) was designed and synthesized as CRF1 antagonists. SAR studies of this series resulted in the discovery of potent and selective antagonists 7b and 7n bearing a 4-(2,4,6-trisubstituted-phenyl) ring and a bulky 2-(N-bis(cyclopropane)methyl-N-propyl) amino group. (C) 2004 Elsevier Ltd. All rights reserved.
• AMINO-SUBSTITUTED THIADIAZOLES, PYRIMIDINES, TRIAZINES OR TRIAZOLES USEFUL AS CTF RECEPTOR ANTAGONISTS
  申请人：NEUROCRINE BIOSCIENCES, INC.

  公开号：EP0846108A1

  公开（公告）日：1998-06-10