tert-butyl 5-(2-ethoxy-2-oxoethyl)-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate | 1060979-19-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: tert-butyl 5-(2-ethoxy-2-oxoethyl)-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
• 英文别名: tert-Butyl 5-(2-ethoxy-2-oxoethyl)-8-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate；tert-butyl 5-(2-ethoxy-2-oxoethyl)-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2-carboxylate
• CAS: 1060979-19-2
• 化学式: C₂₁H₂₈N₂O₄
• mdl: MFCD26744268
• 分子量: 372.464
• InChiKey: AVWVZKLLUORSEY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  60.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl 5-(2-ethoxy-2-oxoethyl)-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate 在 盐酸 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 4.0h， 生成 ethyl 2-(2-benzoyl-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetate
  参考文献：
  名称：

  Identification of 2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic Acid (Setipiprant/ACT-129968), a Potent, Selective, and Orally Bioavailable Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) Antagonist

  摘要：

  Herein we describe the discovery of the novel CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 28 (setipiprant/ACT-129968), a clinical development candidate for the treatment of asthma and seasonal allergic rhinitis. A lead optimization program was started based on the discovery of the recently disclosed CRTh2 antagonist 2-(2-benzoyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 5. An already favorable and druglike profile could be assessed for lead compound 5. Therefore, the lead optimization program mainly focused on the improvement in potency and oral bioavailability. Data of newly synthesized analogs were collected from in vitro pharmacological, physicochemical, in vitro ADME, and in vivo pharmacokinetic studies in the rat and the dog. The data were then analyzed using a traffic light selection tool as a visualization device in order to evaluate and prioritize candidates displaying a balanced overall profile. This data-driven process and the excellent results of the PK study in the rat (F = 44%) and the dog (F = 55%) facilitated the identification of 28 as a potent (IC50 = 6 nM), selective, and orally available CRTh2 antagonist.

  DOI：

  10.1021/jm400122f
• 作为产物：
  描述：

  8-甲基-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚 在 caesium carbonate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 tert-butyl 5-(2-ethoxy-2-oxoethyl)-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
  参考文献：
  名称：

  Identification of 2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic Acid (Setipiprant/ACT-129968), a Potent, Selective, and Orally Bioavailable Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) Antagonist

  摘要：

  Herein we describe the discovery of the novel CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 28 (setipiprant/ACT-129968), a clinical development candidate for the treatment of asthma and seasonal allergic rhinitis. A lead optimization program was started based on the discovery of the recently disclosed CRTh2 antagonist 2-(2-benzoyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 5. An already favorable and druglike profile could be assessed for lead compound 5. Therefore, the lead optimization program mainly focused on the improvement in potency and oral bioavailability. Data of newly synthesized analogs were collected from in vitro pharmacological, physicochemical, in vitro ADME, and in vivo pharmacokinetic studies in the rat and the dog. The data were then analyzed using a traffic light selection tool as a visualization device in order to evaluate and prioritize candidates displaying a balanced overall profile. This data-driven process and the excellent results of the PK study in the rat (F = 44%) and the dog (F = 55%) facilitated the identification of 28 as a potent (IC50 = 6 nM), selective, and orally available CRTh2 antagonist.

  DOI：

  10.1021/jm400122f

文献信息

• [EN] SUBSTITUTED 2,3,4,5-TETRAHYDRO-1H-PYRIDO[4,3-B]INDOLES, METHODS FOR THE PRODUCTION AND THE USE THEREOF<br/>[FR] 2,3,4,5-TÉTRAHYDRO-1H-PYRIDO[4,3-B]INDOLES SUBSTITUÉS AINSI QUE PROCÉDÉS DE LEUR FABRICATION ET LEUR UTILISATION
  申请人：ALLA CHEM LLC

  公开号：WO2008115098A2

  公开（公告）日：2008-09-25

  [EN] The invention relates to novel substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles, to the pharmaceutically acceptable salts and/or hydrates thereof, to methods for the production and the use thereof in the form of biologically active substances, to novel pharmaceutical compositions and medicinal agents which are based thereon, exhibit antihistamine activity and contain, in the form of an active substance, substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles and the pharmaceutically acceptable salts and/or hydrates thereof and to the to methods for the production and the use thereof. The novel substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles and the pharmaceutically acceptable salts and/or hydrates thereof correspond to general formula 1.1, 1.2 or 1.3, wherein, in the compounds of 1.1, R¹ is an amino group substituent selected from hydrogen or optionally substituted C₁-C₅ alkyl; R² is a hydrogen atom or C₁-C₄ alkyl; R³
  [FR] L'invention concerne de nouveaux 2,3,4,5-tétrahydro-1H-pyrido[4,3-b]indoles substitués, leurs hydrates et/ou sels pharmaceutiquement acceptables, des procédés de fabrication et d'utilisation correspondants en qualité de substances biologiquement actives, de nouveaux agents médicaux et compositions pharmaceutiques basés sur ceux-ci, qui manifestent une activité antihistaminique et contiennent comme substance active des 2,3,4,5-tétrahydro-1H-pyrido[4,3-b]indoles substitués ainsi que leurs hydrates et/ou sels pharmaceutiquement acceptables, de même que des procédés de leur fabrication et utilisation. Les nouveaux 2,3,4,5-tétrahydro-1H-pyrido[4,3-b]indoles substitués ainsi que leurs hydrates et/ou sels pharmaceutiquement acceptables correspondent aux formules générales 1.1, 1.2 ou 1.3. Dans ces formules, dans les composés de 1.1, R1 est un substituant du groupe aminé sélectionné parmi l'hydrogène ou l'alkyle C(1)-C(5) éventuellement substitué; R(2) est un atome d'hydrogène ou alkyle C(1)-C(4); R(3)(i) un ou plusieurs substituants similaires ou différents sélectionnés parmi l'hydrogène, l'halogène, l'alkyle C(1)-C(3) ou CF(3); n=0 ou 1-3; dans les composés de 1.2, R(1) est un substituant du groupe aminé sélectionné parmi l'hydrogène ou l'alkyle C(1)-C(5) éventuellement substitué; R(3)(i) un ou plusieurs substituants similaires ou différents sélectionnés parmi l'hydrogène, l'halogène, l'alkyle C(1)-C(3) ou CF(3) et Ar(1) est aryle ou hétérocyclyle contenant au moins un substituant carboxylique et/ou alkyloxycarbonyle ou R(3)(i) est un substituant carboxylique et/ou alkyloxycarbonyle, and Ar(1) est un aryle ou hétérocyclyle éventuellement substitué; dans les composés de 1.3, R(2) est un atome d'hydrogène ou un alkyle C(1)-C(4); R(3)(i) un ou plusieurs substituants similaires ou différents sélectionnés parmi l'hydrogène, l'halogène, l'alkyle C(1)-C(3) ou CF(3) et Ar(2) est un aryle ou hétérocyclyle éventuellement substitué; k=0 ou 1-4; m=1 ou 2.
• Identification of 2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1<i>H</i>-pyrido[4,3-<i>b</i>]indol-5(2<i>H</i>)-yl)acetic Acid (Setipiprant/ACT-129968), a Potent, Selective, and Orally Bioavailable Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) Antagonist
  作者：Heinz Fretz、Anja Valdenaire、Julien Pothier、Kurt Hilpert、Carmela Gnerre、Oliver Peter、Xavier Leroy、Markus A. Riederer

  DOI：10.1021/jm400122f

  日期：2013.6.27

  Herein we describe the discovery of the novel CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 28 (setipiprant/ACT-129968), a clinical development candidate for the treatment of asthma and seasonal allergic rhinitis. A lead optimization program was started based on the discovery of the recently disclosed CRTh2 antagonist 2-(2-benzoyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 5. An already favorable and druglike profile could be assessed for lead compound 5. Therefore, the lead optimization program mainly focused on the improvement in potency and oral bioavailability. Data of newly synthesized analogs were collected from in vitro pharmacological, physicochemical, in vitro ADME, and in vivo pharmacokinetic studies in the rat and the dog. The data were then analyzed using a traffic light selection tool as a visualization device in order to evaluate and prioritize candidates displaying a balanced overall profile. This data-driven process and the excellent results of the PK study in the rat (F = 44%) and the dog (F = 55%) facilitated the identification of 28 as a potent (IC50 = 6 nM), selective, and orally available CRTh2 antagonist.