4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1'H-[2,2'-biinden]-2-yl)methyl)benzoic acid | 1380445-03-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚和异茚
• 英文名称: 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1'H-[2,2'-biinden]-2-yl)methyl)benzoic acid
• 英文别名: 4-(((1'S,2'S)-1'-HYdroxy-1',3'-dihydro-1H,2'H-[2,2'-biinden]-2'-yl)methyl)benzoic acid；4-[[(1S,2S)-1-hydroxy-2-(1H-inden-2-yl)-1,3-dihydroinden-2-yl]methyl]benzoic acid
• CAS: 1380445-03-3
• 化学式: C₂₆H₂₂O₃
• 分子量: 382.459
• InChiKey: COXZEKKBJOWBAG-RSXGOPAZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  57.5
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1'H-[2,2'-biinden]-2-yl)methyl)benzoic acid 在 吡啶 、 二碳酸二叔丁酯 、 碳酸氢铵 作用下， 以 二甲基亚砜 为溶剂， 反应 1.08h， 以57%的产率得到4-{[(1'S,2'S)-1'-hydroxy-1',3'-dihydro-1H,2'H-2,2'-biinden-2'-yl]methyl}benzamide
  参考文献：
  名称：

  [EN] INDANE DIMERS FOR USE IN THE TREATMENT OF AUTOIMMUNE INFLAMMATORY DISEASE
  [FR] DIMÈRES D'INDANE POUVANT ÊTRE UTILISÉS DANS LE TRAITEMENT DES MALADIES INFLAMMATOIRES AUTO-IMMUNES

  摘要：

  用于自身免疫性炎症性疾病，尤其是治疗炎症性肠病的化合物具有以下结构式：其中R从氢、羟基、可选择的取代烷基、可选择的取代芳基、烷氧基、芳氧基、硫醇和可选择的取代氨基中的一个或多个中选择，R1从氢、乙酰基、可选择的取代烷基、可选择的取代芳基以及从亮氨酸、缬氨酸、异亮氨酸和甘氨酸中选择的氨基酸中的一个或多个中选择。

  公开号：

  WO2013014660A1
• 作为产物：
  描述：

  1-trimethylsilyloxy-3H-indene 在 sodium tetrahydroborate 、 三氟甲磺酸三甲基硅酯 、 potassium tert-butylate 、 水 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 叔丁醇 为溶剂， 反应 30.0h， 生成 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1'H-[2,2'-biinden]-2-yl)methyl)benzoic acid
  参考文献：
  名称：

  6-(Methylamino)hexane-1,2,3,4,5-pentanol 4-(((1S,2S)-1-Hydroxy-2,3-dihydro-1H,1′H-[2,2-biinden]-2-yl)methyl)benzoate (PH46A): A Novel Small Molecule With Efficacy In Murine Models Of Colitis

  摘要：

  The indane skeleton is found naturally and in several therapeutic molecules in medicinal chemistry. During our work on the anti-inflammatory activity of naturally occurring and synthetic indanes, we have synthesized a novel indane scaffold that has been optimized for both anti-inflammatory activity and bioavailability. We have evaluated our lead molecule, PH46A, in in vivo models of inflammatory bowel disease (MD), an area of considerable unmet clinical need; current therapies are often unable to control the course of the disease. The compound significantly reduced histological damage and serum amyloid A (SAA) levels in IL-10(-/-) colitis mice, was efficacious in the 5% dextran sulfate sodium (DSS) colitis model, and compared favorably with prednisolone in this model and supports its potential use to treat acute exacerbations of the disease. Further, the graded response to the compound may also lend itself to be used at a lower dose to maintain periods of remission.

  DOI：

  10.1021/jm300390f

文献信息

• [EN] INDENE DERIVATIVES FOR USE IN THE TREATMENT OF INFLAMMATORY BOWEL DISEASE<br/>[FR] DÉRIVÉS D'INDÈNE POUVANT ÊTRE UTILISÉS DANS LE TRAITEMENT DES MALADIES INFLAMMATOIRES DE L'INTESTIN
  申请人：VENANTIUS LTD

  公开号：WO2013014659A1

  公开（公告）日：2013-01-31

  Described are compounds of the structural formula (I): Also provided are pharmacologically acceptable isomers and salts of the compound of (I). The compounds are useful in the treatment of inflammatory bowel disease.

  描述了结构式（I）的化合物。还提供了化合物（I）的药理学上可接受的异构体和盐。这些化合物对治疗炎症性肠病有用。
• Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent
  作者：Graham R. Cumming、Tao Zhang、Gaia Scalabrino、Neil Frankish、Helen Sheridan

  DOI：10.1021/acs.oprd.7b00258

  日期：2017.12.15

  group as a potential therapeutic agent for the treatment of inflammatory and autoimmune diseases. The initial synthetic route to PH46A gave a low overall yield, due in large part to the generation of undesired diastereoisomer 5 and the unwanted enantiomer (R,R)-8 during the synthesis. The aim of this work was to carry out a comprehensive investigation into the stereoselective synthesis of PH46A. Significant

  PH46A属于1，2-茚满二聚体，是我们的研究小组开发的，可作为治疗炎症和自身免疫性疾病的潜在治疗剂。最初合成PH46A的途径总产率较低，这在很大程度上是由于合成过程中产生了非所需的非对映异构体5和不需要的对映异构体（R，R）-8。这项工作的目的是对PH46A的立体选择性合成进行全面的研究。酮还原步骤取得了重大进展，与使用先前方法获得的不利比例相比，使用三异丁基铝[TiBA，Al（iBu）3]对目标非对映异构体（rac）-6的选择性高。这使得能够在GMP环境中进行PH46A的多千克级合成。进一步，
• (1<i>S</i>)-1-Phenylethanaminium 4-{[(1<i>S</i>,2<i>S</i>)-1-hydroxy-2,3-dihydro-1<i>H</i>,1′<i>H</i>-[2,2′-biinden]-2-yl]methyl}benzoate
  作者：Christopher S. Frampton、Tao Zhang、Gaia A. Scalabrino、Neil Frankish、Helen Sheridan

  DOI：10.1107/s0108270112031265

  日期：2012.8.15

  The title molecular salt, C₈H₁₂N⁺·C₂₆H₂₁O₃⁻, contains a dimeric indane pharmacophore that demonstrates potent anti-inflammatory activity. The indane group of the anion exhibits some disorder about the α-C atom, which appears common to many structures containing this group. A model to account for the slight disorder was attempted, but this was deemed unsuccessful because applying bond-length constraints to all the bonds about the α-C atom led to instability in the refinement. The absolute configuration was determined crystallographically asS,S,Sby anomalous dispersion methods with reference to both the Flack parameter and Bayesian statistics on Bijvoet differences. The configuration was also determined by ana prioriknowledge of the absolute configuration of the (1S)-1-phenylethanaminium counter-ion. The molecules pack in the crystal structure to form an infinite two-dimensional hydrogen-bond network in the (100) plane of the unit cell.

  标题分子盐 C8H12N+-C26H21O3- 包含一个二聚茚满药效团，具有很强的抗炎活性。阴离子中的茚满基团在 α-C 原子上表现出一些紊乱，这似乎是许多含有该基团的结构所共有的。我们曾尝试建立一个模型来解释这种轻微的无序，但由于对有关 α-C 原子的所有键都施加键长限制会导致细化结果不稳定，因此这个模型被认为是不成功的。绝对构型通过晶体学方法确定为 S,S,S，采用的是反常色散方法，同时参考了 Flack 参数和 Bijvoet 差异的贝叶斯统计。构型也是根据 (1S)-1 苯乙胺反离子的绝对构型的先验知识确定的。分子在晶体结构中堆积，在单位晶胞的 (100) 平面上形成一个无限的二维氢键网络。
• INDANE DIMERS FOR USE IN THE TREATMENT OF AUTOIMMUNE INFLAMMATORY DISEASE
  申请人：Venantius Limited

  公开号：US20150141506A1

  公开（公告）日：2015-05-21

  Compounds particularly for use in an autoimmune inflammatory disease and especially the treatment of inflammatory bowel disease have the absolute stereochemistry and formula: In some cases R 1 is leucine and R is selected from: OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , NH 2 , NHCH 2 CH 2 OH, NHCH 3 , N(CH 3 ) 2 , NH(4-OH-3-benzoic acid).

  这段话的意思是：化合物特别是用于自身免疫性炎症性疾病，特别是治疗炎症性肠病的绝对立体化学和公式为：在某些情况下，R1为亮氨酸，R选择自：OH，OCH3，OCH2CH3，OCH2CH2CH3，NH2，NHCH2CH2OH，NHCH3，N（CH3）2，NH（4-OH-3-苯甲酸）中选。
• COMPOUNDS FOR USE IN THE TREATMENT OF IMMUNE RELATED INFLAMMATORY DISEASE
  申请人：Frankish Neil

  公开号：US20140107194A1

  公开（公告）日：2014-04-17

  Compounds particularly for use in an autoimmune inflammatory disease and especially the treatment of inflammatory bowel disease have the formula: wherein R is selected from one or more of the same or different of hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted aryl, alkoxy, aryloxy, thiol, and optionally substituted amino, and wherein R 1 is selected from one or more of the same or different of hydrogen, acetyl, optionally substituted alkyl, optionally substituted aryl, and an amino acid selected from leucine, valine, isoleucine, and glycine.

  该化合物特别用于自身免疫性炎症性疾病，尤其是治疗炎症性肠病，其化学式为：其中R选择来自氢、羟基、可选取代烷基、可选取代芳基、烷氧基、芳氧基、硫醇和可选取代氨基中的一个或多个，R1选择来自氢、乙酰基、可选取代烷基、可选取代芳基以及从亮氨酸、缬氨酸、异亮氨酸和甘氨酸中选择的氨基酸中的一个或多个。