[(R)-5-Bromo-4-(4-chloro-benzyl)-7-fluoro-1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl]-acetic acid methyl ester | 571170-89-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: [(R)-5-Bromo-4-(4-chloro-benzyl)-7-fluoro-1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl]-acetic acid methyl ester
• CAS: 571170-89-3
• 化学式: C₂₁H₁₈BrClFNO₂
• 分子量: 450.735
• InChiKey: JMCPMBAVZXZZKG-CYBMUJFWSA-N

物化性质

• 沸点：
  554.0±50.0 °C(Predicted)
• 密度：
  1.52±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.84
• 重原子数：
  27.0
• 可旋转键数：
  4.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  31.23
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  [(R)-5-Bromo-4-(4-chloro-benzyl)-7-fluoro-1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl]-acetic acid methyl ester 在 sodium hydroxide 、 copper(l) iodide 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 甲醇 为溶剂， 反应 6.0h， 生成 拉罗皮兰
  参考文献：
  名称：

  Discovery of a Potent and Selective Prostaglandin D₂ Receptor Antagonist, [(3R)-4-(4-Chloro- benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic Acid (MK-0524)

  摘要：

  The discovery of the potent and selective prostaglandin D-2 (PGD(2)) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13)is presented. Initial lead antagonists 6and 7were found to be potent and selective DP antagonists (DP K-i = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (C-max = 1100 mu M for 6and 3900 mu M for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6and 7with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist 13.

  DOI：

  10.1021/jm0603668
• 作为产物：
  描述：

  7-氟-5-溴-1,2,3,4-四氢乙酯 在 吡啶 、 盐酸 、 sodium hydroxide 、 (S)-(-)-1-(1-naphthyl)ethylamine salt 、 sodium hydride 、 溶剂黄146 、 pyridinium hydrobromide perbromide 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 [(R)-5-Bromo-4-(4-chloro-benzyl)-7-fluoro-1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl]-acetic acid methyl ester
  参考文献：
  名称：

  Discovery of a Potent and Selective Prostaglandin D₂ Receptor Antagonist, [(3R)-4-(4-Chloro- benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic Acid (MK-0524)

  摘要：

  The discovery of the potent and selective prostaglandin D-2 (PGD(2)) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13)is presented. Initial lead antagonists 6and 7were found to be potent and selective DP antagonists (DP K-i = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (C-max = 1100 mu M for 6and 3900 mu M for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6and 7with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist 13.

  DOI：

  10.1021/jm0603668

文献信息

• Method of Treating Pathological Blushing
  申请人：Tobert A. Jonathan

  公开号：US20070299122A1

  公开（公告）日：2007-12-27

  A method of treating pathological blushing is disclosed wherein the patient is administered a DP receptor antagonist. Compositions containing DP antagonists are also included.

  揭示了一种治疗病理性面红的方法，其中患者接受DP受体拮抗剂。还包括含有DP拮抗剂的组合物。
• Practical [14C]-synthesis of molecules containing an acetic acid moiety: application to [14C]-labeled DP1 antagonists
  作者：Carl Berthelette、Zhaoyin Wang

  DOI：10.1002/jlcr.1146

  日期：——

  provided the carbon-14 labeled acid 1. Compound 2 was obtained from the same alcohol intermediate 4 and two diastereomeric compounds 6 and 7 were easily prepared from compound 2. Carbon-14 synthesis of compounds 1, 2, 6 and 7 were achieved in good yields, high radiochemical purity (>99%) and with high specific activity (45 mCi/mmol). Copyright © 2006 John Wiley & Sons, Ltd.

  报告了四种有效和选择性 DP1 拮抗剂的有效碳 14 标记。合成顺序从α-羟基化、酯的还原开始，然后是氧化二醇裂解和醛还原。将所得醇 4 转化为甲磺酸酯，然后用 [14C]-氰化钠进行亲核取代以产生腈，其在碱性水解后提供碳 14 标记的酸 1。化合物 2 由相同的醇中间体 4 和由化合物 2 轻松制备了两种非对映异构化合物 6 和 7。 化合物 1、2、6 和 7 的碳 14 合成收率高、放射化学纯度高 (>99%) 且比活性高 (45 mCi/mmol) ）。版权所有 © 2006 John Wiley & Sons, Ltd.
• Fluoro substituted cycloalkanoindoles, compositions containing such compounds and methods of treatment
  申请人：Merck Frosst Canada & Co.

  公开号：US07317036B2

  公开（公告）日：2008-01-08

  Fluoro substituted cycloalkanoindole derivatives are antagonists of prostaglandins, and as such are useful for the treatment of prostaglandin mediated diseases.

  氟代环烷基吲哚衍生物是前列腺素拮抗剂，因此对于治疗前列腺素介导的疾病是有用的。
• 7,8-cyclopropataxanes
  申请人：Bristol-Myers Squibb Company

  公开号：US05254580A1

  公开（公告）日：1993-10-19

  An antitumor compound of formula I ##STR1## in which R.sup.1 is --COR.sup.z in which R.sup.z is t-butyloxy, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, or phenyl, optionally substituted with one to three same or different C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or --CF.sub.3 groups; R.sup.2 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, or a radical of the formula --W--R.sup.x in which W is a bond, C.sub.2-6 alkenediyl, or --(CH.sub.2).sub.t --, in which t is one to six; and R.sup.x is naphthyl, furyl, thienyl or phenyl, and furthermore R.sup.x can be optionally substituted with one to three same or different C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or --CF.sub.3 groups; R.sup.3 is OCOR, --OCOOR, H, or OH; R.sup.4 is hydrogen; or R.sup.3 and R.sup.4 jointly form a carbonyl group; and R is C.sub.1-6 alkyl. Also provided by this invention are pharmaceutical formulations (compositions) and a method of treating mammalian tumors with a compound of formula I.

  公式I的抗肿瘤化合物如下：##STR1## 其中R.sup.1是--COR.sup.z，其中R.sup.z是t-丁氧基，C.sub.1-6烷基，C.sub.2-6烯基，C.sub.2-6炔基，C.sub.3-6环烷基或苯基，可选地被一个到三个相同或不同的C.sub.1-6烷基，C.sub.1-6烷氧基，卤素或--CF.sub.3基取代；R.sup.2是C.sub.1-6烷基，C.sub.2-6烯基，C.sub.2-6炔基，C.sub.3-6环烷基或公式--W--R.sup.x的基团，其中W是键，C.sub.2-6烯二基或--(CH.sub.2).sub.t --，其中t是一到六；而R.sup.x是萘基，呋喃基，噻吩基或苯基，此外，R.sup.x可选地被一个到三个相同或不同的C.sub.1-6烷基，C.sub.1-6烷氧基，卤素或--CF.sub.3基取代；R.sup.3是OCOR，--OCOOR，H或OH；R.sup.4是氢；或R.sup.3和R.sup.4共同形成一个羰基；而R是C.sub.1-6烷基。此发明还提供了公式I化合物的药物配方（组合物）和治疗哺乳动物肿瘤的方法。
• WO2006/57922
  申请人：——

  公开号：——

  公开（公告）日：——