5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoic acid | 180868-14-8

• 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: 5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoic acid
• 英文别名: (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoic acid；(2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid；(2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxypenta-2,4-dienoic acid
• CAS: 180868-14-8
• 化学式: C₁₄H₁₁Cl₂NO₃
• 分子量: 312.152
• InChiKey: OSXMSDOICUEYPY-CHMMKSCTSA-N

物化性质

• 熔点：
  249-250 °C
• 沸点：
  572.3±50.0 °C(Predicted)
• 密度：
  1.481±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  62.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoic acid 在 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 生成 (2Z,4Z)-5-(5,6-Dichloro-1H-indol-2-yl)2-methoxy-N-(1,2,2,6,6-pentamethyl piperidin-4-yl)-2,4-pentadienamide
  参考文献：
  名称：

  (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide, a novel, potent and selective inhibitor of the osteoclast V-ATPase

  摘要：

  Optimisation of a novel series of osteoclast ATPase inhibitors led to (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-( 1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide (1) that was the most potent compound in an in vitro osteoclast ATPase assay and in human bone resorption assays. Two of the possible geometric isomers have also been prepared and shown to be significantly less potent than 1. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(98)00660-x
• 作为产物：
  描述：

  4,5-二氯-2-硝基甲苯 在 manganese(IV) oxide 、 sodium hydroxide 、 lithium aluminium tetrahydride 、 potassium ethoxide 、 铁粉 、 sodium hydride 、 二异丁基氢化铝 、 溶剂黄146 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 正己烷 、 乙酸乙酯 为溶剂， 反应 151.5h， 生成 5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoic acid
  参考文献：
  名称：

  5-(5,6-Dichloro-2-indolyl)-2-methoxy-2,4-pentadienamides:  Novel and Selective Inhibitors of the Vacuolar H⁺-ATPase of Osteoclasts with Bone Antiresorptive Activity

  摘要：

  The vacuolar H+-ATPase (V-ATPase) located on the ruffled border of the osteoclast, is a proton pump which is responsible for secreting the massive amounts of protons that are required for the bone resorption process. With the aim to identify new agents which are able to prevent the excessive bone resorption associated with osteoporosis, we have designed a novel class of potent and selective inhibitors of the osteoclast proton pump, starting from the structure of the specific V-ATPase inhibitor bafilomycin A(1). Compounds 3a-d potently inhibited the V-ATPase in chicken osteoclast membranes (IC50 = 60-180 nM) and were able to prevent bone resorption by human osteoclasts in vitro at low-nanomolar concentrations. Notably, the EC50 of compound 3c in this assay was 45-fold lower than the concentration required for half-maximal inhibition of the V-ATPase from human kidney cortex. These results support the validity of the osteoclast proton pump as a useful molecular target to produce novel inhibitors of bone resorption, potentially useful as antiosteporotic agents.

  DOI：

  10.1021/jm9800144

文献信息

• Towards the synthesis of osteoclast inhibitor SB-242784
  作者：Jose J. Conde、Michael McGuire、Michael Wallace

  DOI：10.1016/s0040-4039(03)00544-6

  日期：2003.4

  Osteoclast inhibitor SB-242784 (1) was prepared from pivotal indol intermediate 4. A ‘Stille’ cross coupling of organotin 2c with bromo acrylate 11 afforded diene 12 which was also obtained via a reduction–isomerization process of enyne 16. Bromoamide 3 was prepared from the corresponding acid 7 which was readily obtained from bromopyruvic acid.

  破骨细胞抑制剂SB-242784（1）是由关键的吲哚中间体4制备的。有机锡2c与溴化丙烯酸酯11的“ Stille”交叉偶联提供了二烯12，它也是通过烯炔16的还原异构化过程获得的。溴酰胺3是由相应的酸制备7将其容易地从溴丙酮酸获得。
• New biophysical probes for structure–activity analyses of vacuolar-H⁺-ATPase enzymes
  作者：Neil Dixon、Tibor Pali、Stephen Ball、Michael A. Harrison、Derek Marsh、John B. C. Findlay、Terence P. Kee

  DOI：10.1039/b311401e

  日期：——

  New EPR spin labelled and photoactivatable molecules have been designed to probe specifically the vacuolar-H+-ATPase.

  设计了新的 EPR 自旋标记和光激活分子，以专门探测液泡-H+-ATP 酶。
• [EN] INDOLE DERIVATIVES USEFUL IN THE TREATMENT OF OSTEOPOROSIS<br/>[FR] DERIVES INDOLE UTILES DANS LE TRAITEMENT DE L'OSTEOPOROSE
  申请人：SMITHKLINE BEECHAM S.P.A.

  公开号：WO1996021644A1

  公开（公告）日：1996-07-18

  (EN) A compound of formula (I) or a salt thereof, or a solvate thereof, wherein either: (i) Ra represents a group R5 which is hydrogen, alkyl or optionally substituted aryl and Rb represents a moiety of formula (a); wherein X represents a hydroxy or an alkoxy group wherein the alkyl group may be substituted or unsubstituted or X represents a group NRsRt wherein Rs and Rt each independently represent hydrogen, alkyl, substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group, or Rs and Rt together may form a heterocyclic group; R1 represents an alkyl or a substituted or unsubstituted aryl group; and R2, R3 and R4 each independently represent hydrogen, alkyl, aryl or substituted aryl or (ii) Ra represents a moiety of the above defined formula (a) and Rb represents the above defined R5; R6 and R7 each independently represents hydrogen, hydroxy, amino, alkoxy, optionally substituted aryloxy, optionally substituted benzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl, or R6 and R7 together represent methylenedioxy, carbonyldioxy or carbonyldiamino; and R8 represents hydrogen, hydroxy, alkanoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl or aminosulphonyl; a process for the preparation of such a compound, a pharmaceutical composition comprising such a compound and the use of such a compound in medicine.(FR) Composé de la formule (I), ou un sel ou solvate de celui-ci, dans laquelle soit: (i) Ra représente un groupe R5, lequel représente hydrogène, alkyle ou aryle éventuellement substitué, et Rb représente une fraction de la formule (a) dans laquelle X représente un groupe hydroxy ou alcoxy dans lequel le groupe alkyle peut être substitué ou non, ou bien X représente un groupe NRsRt dans lequel Rs et Rt représentent chacun indépendamment hydrogène, alkyle, alkyle substitué, alcényle éventuellement substitué, aryle éventuellement substitué, arylalkyle éventuellement substitué, un groupe hétérocyclique éventuellement substitué ou un groupe hétérocyclylalkyle éventuellement substitué, ou bien Rs et Tt ensemble peuvent former un groupe hétérocyclique; R1 représente un groupe alkyle ou un groupe aryle substitué ou non; et R2, R3 et R4 représentent chacun indépendamment hydrogène, alkyle, aryle ou aryle substitué; soit (ii) Ra représente une fraction possédant la formule (a) définie ci-dessus et Rb représente R5 ci-dessus défini; R6 et R7 représentent chacun indépendamment hydrogène, hydroxy, amino, alcoxy, aryloxy éventuellement substitué, benzyloxy éventuellement substitué, alkylamino, dialkylamino, halo, trifluorométhyle, trifluorométhoxy, nitro, alkyle, carboxy, carbalcoxy, carbamoyle, alkylcarbamoyle, ou bien R6 et R7 représentent ensemble méthylènedioxy, carbonyldioxy ou carbonyldiamino; et R8 représente hydrogène, hydroxy, alcanoyle, alkyle, aminoalkyle, hydroxyalkyle, carboxyalkyle, carbalcoxyalkyle, carbamoyle ou aminosulfonyle. On décrit également un procédé de préparation d'un tel composé, une composition pharmaceutique comprenant celui-ci ainsi que l'utilisation de ce composé en médecine.

  化合物的式子（I）或其盐或溶剂化物，其中：（i）Ra代表羟基、烷基或者选配取代芳基的氢，Rb代表公式（a）的部分；其中X代表羟基或者烷氧基，其中烷基可以取代或未取代，或者X代表NRsRt的群，其中Rs和Rt各自独立地代表氢、烷基、取代烷基、选配取代烯基、选配取代芳基、选配取代芳基烷基、选配取代杂环基或者选配取代杂环基烷基，或者Rs和Rt一起形成一个杂环基；R1代表烷基或者选配取代芳基；R2、R3和R4各自独立地代表氢、烷基、芳基或者选配取代芳基；或者（ii）Ra代表上述定义的公式（a）的部分，Rb代表上述定义的R5；R6和R7各自独立地代表氢、羟基、氨基、烷氧基、选配取代芳氧基、选配取代苄氧基、烷基氨基、二烷基氨基、卤素、三氟甲基、三氟甲氧基、硝基、烷基、羧基、羧基烷氧基、氨基甲酰基、烷基氨基甲酰基，或者R6和R7一起表示甲亚氧基、羰基二亚氧基或者羰基二氨基；R8代表氢、羟基、烷酰基、烷基、氨基烷基、羟基烷基、羧基烷基、羧基烷氧基、氨基甲酰基或者氨基磺酰基；一种制备这样的化合物的方法，一种包含这样的化合物的药物组合物以及这样的化合物在医学上的用途。
• Indole derivatives for the treatment of osteoporosis
  申请人：Smith Kline Beecham SpA

  公开号：US20020173659A1

  公开（公告）日：2002-11-21

  A compound of formula (I): 1 or a salt thereof, or a solvate thereof, wherein Ra represents a group R 5 which is hydrogen, alkyl or optionally substituted aryl and Rb represents a moiety of formula (a): 2 wherein X represents a hydroxy or an alkoxy group wherein the alkyl group may be substituted or unsubstituted or X represents a group NR s R t wherein R s and R t each independently represent hydrogen, alkyl, substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group, or R s and R t together with the nitrogen to which they are attached form a heterocyclic group; RI represents an alkyl or a substituted or unsubstituted aryl group; and R 2 , R 3 and R 4 each independently represent hydrogen, alkyl, aryl or substituted aryl R 6 and R 7 each independently represents hydrogen, hydroxy, amino, alkoxy, optionally substituted aryloxy, optionally substituted benzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl, or R 6 and R 7 together represent methylenedioxy, carbonyldioxy or carbonyldiamino; and R 8 represents hydrogen, hydroxy, alkanoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl or aminosulphonyl; a process for preparing such a compound, a pharmaceutical composition containing such a compound and the use of such a compound in medicine

  式（I）的化合物：1或其盐，或其溶剂化物，其中Ra代表一个R5基团，该基团是氢，烷基或可选取代芳基，Rb代表式（a）的一个基团：2其中X代表羟基或烷氧基，其中烷基可能是取代或未取代的，或者X代表羰基-NRsRt，其中Rs和Rt各自独立地代表氢，烷基，取代烷基，可选取代烯基，可选取代芳基，可选取代芳基烷基，可选取代杂环基或可选取代杂环基烷基，或Rs和Rt与它们所连接的氮一起形成杂环基；RI代表烷基或取代或未取代的芳基基团；R2、R3和R4各自独立地代表氢，烷基，芳基或取代芳基；R6和R7各自独立地代表氢，羟基，氨基，烷氧基，可选取代芳氧基，可选取代苯甲氧基，烷基氨基，二烷基氨基，卤素，三氟甲基，三氟甲氧基，硝基，烷基，羧基，羰基氧基，氨基甲酰基，烷基氨甲酰基，或R6和R7一起代表亚甲二氧基，羰基二氧基或羰基二氨基；以及R8代表氢，羟基，烷酰基，烷基，氨基烷基，羟基烷基，羧基烷基，羰基氧基烷基，氨甲酰基或氨基磺酰基；一种制备这样的化合物的方法，包含这样的化合物的制药组合物以及这样的化合物在医学上的用途。
• Synthesis of photoactivable inhibitors of osteoclast vacuolar ATPase
  作者：Barbara Biasotti、Sabrina Dallavalle、Lucio Merlini、Carlo Farina、Stefania Gagliardi、Carlo Parini、Pietro Belfiore

  DOI：10.1016/s0968-0896(03)00106-8

  日期：2003.5

  Amides of (2Z,4E)-5-[(5,6-dichloroindol-2-yl)]-2-methoxy-N-[3-[4-[3-(carboxymethoxy)phenyl)] piperazin-1-yl]propyl]-2,4-pentadienamide (1) and of 5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoic acid (2) are strong inhibitors of the vacuolar ATPase located on the plasma membrane of osteoclasts. In order to understand which V-ATPase subunit is involved in the interaction with these novel inhibitors, analogues containing a photoactivable group and an iodine atom were designed. A series of alcohols or amines containing the photoactivable trifluoroaziridinophenyl or benzophenone moiety and an iodine atom were linked to the above acids via an ester or amide group. These compounds could be thereafter used as a radioactive photoprobe to label the protein. Whereas the compounds containing the photoactivable groups maintained good inhibitory activity, the introduction of the bulky iodine atom was generally detrimental, decreasing potency significantly. Better results were obtained by linking. 3-(4-amino-piperidinomethyl)-3'-iodobenzophenone to 3-ethoxy-4-(2-(5,6-dichlorobenzimidazolyl))benzoic acid to give the corresponding amide 27, that inhibited vacuolar ATP-ase with a IC50 = 140 nM. The feasibility of introducing a radioactive 1211 atom,was ascertained by exchanging the iodine with a tributylstannyl group, that was again substituted by iodine. (C) 2003 Elsevier Science Ltd. All rights reserved.