5,6-dimethoxy-2-((1-(3-methylbenzyl)piperidin-4-yl)methyl)-2,3-dihydro-1H-inden-1-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 5,6-dimethoxy-2-((1-(3-methylbenzyl)piperidin-4-yl)methyl)-2,3-dihydro-1H-inden-1-one
• 英文别名: 1-(3-methylbenzyl)-4-<(5,6-dimethoxy-1-oxoindan-2-yl)methyl>piperidine；5,6-Dimethoxy-2-[1-(3-methyl-benzyl)-piperidin-4-ylmethyl]-indan-1-one; hydrochloride；5,6-dimethoxy-2-[[1-[(3-methylphenyl)methyl]piperidin-4-yl]methyl]-2,3-dihydroinden-1-one
• 化学式: C₂₅H₃₁NO₃
• 分子量: 393.526
• InChiKey: QBOHSSFTEGRUFM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3-甲基苄溴 、 5,6-二甲氧基-2-(4-哌啶基)亚甲基-1-茚酮 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 8.0h， 以83%的产率得到5,6-dimethoxy-2-((1-(3-methylbenzyl)piperidin-4-yl)methyl)-2,3-dihydro-1H-inden-1-one
  参考文献：
  名称：

  合理修饰多奈哌齐作为多功能乙酰胆碱酯酶抑制剂以治疗阿尔茨海默氏病

  摘要：

  设计，合成和评估了一系列新型多奈哌齐衍生物，作为多功能乙酰胆碱酯酶（AChE）抑制剂，用于治疗阿尔茨海默氏病（AD）。筛选结果表明，大多数化合物均表现出对AChE的有效抑制作用，IC 50值在纳摩尔范围内。此外，这些衍生物显示良好的抗氧化，A β相互作用，血脑屏障渗透（PAMPA-BBB +）和ADMET性质（在硅片）。其中，图5c显示了优秀的抑制乙酰胆碱酯酶（IC 50：85纳米的eeAChE，73纳米的HACHE），金属螯合，并在自感应，HACHE诱导和Cu抑制作用2+诱导的阿β 1-42聚合（18.5％，72.4％和46.3％，在20  μ M）。动力学分析和分子建模研究表明5c可以同时与AChE的催化活性位点（CAS）和外围阴离子位点（PAS）结合。更重要的是，5C表现出对一个显著的神经保护效力β 1-42诱导PC12细胞损伤。此外，逐步被动回避测试显示5c可以显着逆转东pol碱所

  DOI：

  10.1016/j.ejmech.2016.07.052

文献信息

• Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine Hydrochloride and Related Compounds
  作者：Hachiro Sugimoto、Youichi Iimura、Yoshiharu Yamanishi、Kiyomi Yamatsu

  DOI：10.1021/jm00024a009

  日期：1995.11

  (anti-AChE) inhibitors such as 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine (1), we reported that its rigid analogue, 1-benzyl-4-(2-isoindolin-2-ylethyl)piperidine (5), had more potent activity. We have extended the structure-activity relationship (SAR) study for the rigid analogue and found that the 2-isoindoline moiety in compound 5 can be replaced with a indanone moiety (8) without a major loss

  在发现了一系列新的抗乙酰胆碱酯酶（抗AChE）抑制剂如1-苄基-4- [2-（N-苯甲酰氨基）乙基]哌啶（1）之后，我们报道了其刚性类似物1-苄基-4-（2-异吲哚啉-2-基乙基）哌啶（5）具有更强的活性。我们扩展了对刚性类似物的结构-活性关系（SAR）研究，发现化合物5中的2-异吲哚啉部分可被茚满酮部分（8）取代，而效力没有重大损失。在茚满酮衍生物中，发现1-苄基-4-[（5,6-二甲氧基-1-氧代茚满-2-基）甲基]哌啶（13e）（E2020）（IC50 = 5.7 nM）是最丰富的衍生物之一。有效的抗AChE抑制剂。化合物13e对AChE的选择性亲和力比对丁酰胆碱酯酶大1250倍。体内研究表明，在5 mg / kg（po）的剂量下13e具有比毒扁豆碱更长的作用持续时间，并且在大鼠大脑皮层中乙酰胆碱含量显着增加。我们报告的合成，SAR和拟议的假设绑定网站的13e（E2020）。
• Sigma receptor binding agent containing indanone derivative
  申请人：Iimura Yoichi

  公开号：US20090137629A1

  公开（公告）日：2009-05-28

  A method for treatment of a mental disorder containing the step of administering a therapeutically effective amount of a sigma receptor binding agent containing an indanone compound represented by the following formula (I), a pharmacologically acceptable salt thereof or a hydrate of them. The variables of formula (I) are recited in the present specification.

  一种治疗精神障碍的方法，包括以下步骤：给予治疗有效量的sigma受体结合剂，该结合剂包含以下式子（I）所表示的indanone化合物，其药理学上可接受的盐或水合物。式子（I）的变量在本说明书中已列出。
• SIGMA RECEPTOR BINDER CONTAINING INDANONE DERIVATIVE
  申请人：Eisai Co., Ltd.

  公开号：EP1468684A1

  公开（公告）日：2004-10-20

  The present invention provides an indanone derivative and an excellent sigma receptor binding agent comprising an indanone derivative. More specifically, it provides a sigma receptor binding agent comprising an indanone derivative represented by the following formula, a pharmacologically acceptable salt thereof or a hydrate of them. In the formula (I), R1, R2, R3 and R4 are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, nitrile group, a C1-6 alkyl group which may be substituted, a cycloalkyl group having three to eight carbon atoms which may be substituted, a C1-6 alkoxy group which may be substituted, a cycloalkoxy group having three to eight carbon atoms which may be substituted, an acyl group having one to six carbon atoms which may be substituted, a C1-6 alkoxycarbonyl group which may be substituted, a C1-6 alkylaminocarbonyloxy group which may be substituted, a di(C1-6 alkyl)aminocarbonyloxy group which may be substituted, nitro group, an amino group which may be substituted, an amido group which may be substituted, mercapto group or a thio-C1-6 alkoxy group which may be substituted, and further R1 with R2, R2 with R3, or R3 with R4 may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; the partial structure: represents a group represented by >CH-CH2-, >C=CH- or >C(-R7)-CH2-; m represents an integer of 0 or 1 to 5; and R5 represents hydrogen atom, a C1-6 alkyl group which may be substituted, a C2-6 alkenyl group which may be substituted, a C2-6 alkynyl group which may be substituted, a cycloalkyl group having three to eight carbon atoms which may be substituted, a 2,2-(alkylenedioxy)ethyl group or a group represented by the formula: (wherein the ring C represents benzene ring, an aliphatic ring or a heterocyclic ring; R6s are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, nitrile group, a C1-6 alkyl group which may be substituted, a C2-6 alkenyl group which may be substituted, a C2-6 alkynyl group which may be substituted, a cycloalkyl group having three to eight carbon atoms which may be substituted, a C1-6 alkoxy group which may be substituted, a C1-6 alkoxyalkoxy group which may be substituted, an aryloxy group which may be substituted or an aralkyloxy group which may be substituted, and further two of R6s may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; R7 represents a halogen atom, hydroxyl group, a C1-6 alkyl group which may be substituted, a C1-6 alkoxy group, nitrile group, a halogeno-C1-6 alkyl group, a hydroxyl-C1-6 alkyl group, a cyano-C1-6 alkyl group, an amino-C1-6 alkyl group, nitro group, azide group, an amino group which may be substituted, a carbamoyl group which may be substituted, a carboxyl group which may be substituted, mercapto group or a thio-C1-6 alkoxy group; and n represents an integer of 1 to 5), provided that 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine, a pharmacologically acceptable salt thereof or a hydrate of them are excluded.

  本发明提供了一种茚满酮衍生物和一种包含茚满酮衍生物的优良σ受体结合剂。更具体地说，本发明提供了一种σ受体结合剂，它由下式所代表的茚酮衍生物、其药理学上可接受的盐或它们的水合物组成。 在式 (I) 中，R1、R2、R3 和 R4 彼此相同或不同，各自代表氢原子、卤素原子、羟基、腈基、可被取代的 C1-6 烷基、具有三至八个碳原子且可被取代的环烷基、可被取代的 C1-6 烷氧基、具有三至八个碳原子且可被取代的环烷氧基、具有一至六个碳原子且可被取代的酰基、可被取代的 C1-6 烷氧基羰基、可被取代的 C1-6 烷基氨基羰氧基、可被取代的二（C1-6 烷基）氨基羰氧基、硝基、可被取代的氨基、可被取代的酰胺基、巯基或可被取代的硫代-C1-6 烷氧基，此外，R1 与 R2、R2 与 R3 或 R3 与 R4 可共同形成脂肪环、芳香环、杂环或烷基二氧基环；部分结构： 代表由 >CH-CH2-、>C=CH- 或 >C(-R7)-CH2-代表的基团；m 代表 0 或 1 至 5 的整数；R5 代表氢原子、可被取代的 C1-6 烷基、可被取代的 C2-6 烯基、可被取代的 C2-6 烷基、可被取代的具有 3 至 8 个碳原子的环烷基、2,2-(烷基二氧基)乙基或由式...代表的基团： (其中环 C 代表苯环、脂肪环或杂环；R6s 彼此相同或不同，各自代表氢原子、卤素原子、羟基、腈基、可被取代的 C1-6 烷基、可被取代的 C2-6 烯基、可被取代的 C2-6 烷基、具有三至八个碳原子的可被取代的环烷基、可被取代的 C1-6 烷氧基、可被取代的 C1-6 烷氧基、可被取代的芳氧基或可被取代的芳烷氧基，另外两个 R6 可共同形成脂肪环、芳香环、杂环或烷二氧基环；R7 代表卤素原子、羟基、可被取代的 C1-6 烷基、C1-6 烷氧基、腈基、卤素-C1-6 烷基、羟基-C1-6 烷基、氰基-C1-6 烷基、氨基-C1-6 烷基、硝基、叠氮基、可被取代的氨基、可被取代的氨基甲酰基、可被取代的羧基、巯基或硫代-C1-6 烷氧基；和 n 代表 1 至 5 的整数），但不包括 1-苄基-4-[(5,6-二甲氧基-1-茚酮)-2-基]甲基哌啶、其药理学上可接受的盐或它们的水合物。
• Sigma receptor binder containing indanone derivative
  申请人：Iimura Yoichi

  公开号：US20050107432A1

  公开（公告）日：2005-05-19

  The present invention provides an indanone derivative and an excellent sigma receptor binding agent comprising an indanone derivative. More specifically, it provides a sigma receptor binding agent comprising an indanone derivative represented by the following formula, a pharmacologically acceptable salt thereof or a hydrate of them. In the formula (I), R 1 , R 2 , R 3 and R 4 are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, nitrile group, a C 1-6 alkyl group which may be substituted, a cycloalkyl group having three to eight carbon atoms which may be substituted, a C 1-6 alkoxy group which may be substituted, a cycloalkoxy group having three to eight carbon atoms which may be substituted, an acyl group having one to six carbon atoms which may be substituted, a C 1-6 alkoxycarbonyl group which may be substituted, a C 1-6 alkylaminocarbonyloxy group which may be substituted, a di(C 1-6 alkyl)aminocarbonyloxy group which may be substituted, nitro group, an amino group which may be substituted, an amido group which may be substituted, mercapto group or a thio-C 1-6 alkoxy group which may be substituted, and further R 1 with R 2 , R 2 with R 3 , or R 3 with R 4 may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; the partial structure: represents a group represented by >CH—CH 2 —, >C═CH— or >C(—R 7 )—CH 2 —; m represents an integer of 0 or 1 to 5; and R 5 represents hydrogen atom, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a cycloalkyl group having three to eight carbon atoms which may be substituted, a 2,2-(alkylenedioxy)ethyl group or a group represented by the formula: (wherein the ring C represents benzene ring, an aliphatic ring or a heterocyclic ring; R 6 s are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, nitrile group, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a cycloalkyl group having three to eight carbon atoms which may be substituted, a C 1-6 alkoxy group which may be substituted, a C 1-6 alkoxyalkoxy group which may be substituted, an aryloxy group which may be substituted or an aralkyloxy group which may be substituted, and further two of R 6 s may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; R 7 represents a halogen atom, hydroxyl group, a C 1-6 alkyl group which may be substituted, a C 1-6 alkoxy group, nitrile group, a halogeno-C 1-6 alkyl group, a hydroxyl-C 1-6 alkyl group, a cyano-C 1-6 alkyl group, an amino-C 1-6 alkyl group, nitro group, azide group, an amino group which may be substituted, a carbamoyl group which may be substituted, a carboxyl group which may be substituted, mercapto group or a thio-C 1-6 alkoxy group; and n represents an integer of 1 to 5), provided that 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine, a pharmacologically acceptable salt thereof or a hydrate of them are excluded.

  本发明提供了一种茚满酮衍生物和一种包含茚满酮衍生物的优良σ受体结合剂。更具体地说，本发明提供了一种σ受体结合剂，它包含下式所代表的茚满酮衍生物、其药理学上可接受的盐或它们的水合物。 在式 (I) 中，R 1 , R 2 , R 3 和 R 4 相同或不同，且各自代表氢原子、卤素原子、羟基、腈基、C 1-6 烷基（可被取代）、具有三至八个碳原子的环烷基（可被取代）、C 1-6 1-6 可被取代的 C 1-6 烷氧基、具有三至八个碳原子且可被取代的环烷氧基、具有一至六个碳原子且可被取代的酰基、C 1-6 1-6 烷氧基羰基（可被取代）、C 1-6 烷基氨基羰氧基（可被取代）、二（C 1-6 1-6 烷基）氨基羰氧基（可被取代）、硝基、氨基（可被取代）、酰胺基（可被取代）、巯基或硫代-C 1-6 1-6 烷氧基（可被取代），以及进一步的 R 1 与 R 2 , R 2 与 R 3 或 R 3 与 R 4 可共同形成脂肪族环、芳香族环、杂环或烷基二氧基环； 部分结构： 代表一个由 >CH-CH 2 -、>C═CH- 或 >C(-R 7 ) -CH 2 -代表 0 或 1 至 5 的整数；以及 R 5 代表氢原子、C 1-6 烷基（可被取代）、C 2-6 可被取代的 C 2-6 烷基 2-6 可被取代的 C 2-6 烷基、可被取代的 C 2-6 烯基、可被取代的 C 2-6 炔基、具有 3 至 8 个碳原子的可被取代的环烷基、2,2-(亚烷基二氧基)乙基或由以下式子表示的基团： (其中环 C 代表苯环、脂肪族环或杂环； R 6 相同或不同，且各自代表氢原子、卤素原子、羟基、腈基、C 1-6 烷基（可被取代）、C 2-6 烯基（可被取代）、C 2-6 可被取代的 C 2-6 烷基、可被取代的 C 2-6 烯基、可被取代的 C 2-6 炔基、具有三至八个碳原子的环烷基、可被取代的 C 1-6 烷氧基（可被取代）、C 1-6 可被取代的 C 1-6 烷氧基、可被取代的 C 1-6 烷氧基、可被取代的芳氧基或可被取代的芳烷氧基，以及 R 6 中的两个可共同形成脂肪环、芳香环、杂环或烷基二氧基环； R 7 7 代表卤素原子、羟基、C 1-6 烷基（可被取代）、C 1-6 烷氧基、腈基、卤素-C 1-6 烷基、羟基-C 1-6 烷基、氰基-C 1-6 烷基、氨基-C 1-6 烷基、硝基、叠氮基、可被取代的氨基、可被取代的氨基甲酰基、可被取代的羧基、巯基或硫代-C 1-6 1-6 烷氧基；以及 n 代表 1 至 5 的整数），但不包括 1-苄基-4-[(5,6-二甲氧基-1-茚酮)-2-基]甲基哌啶、其药理学上可接受的盐或它们的水合物。
• Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer's disease
  作者：Zhi-Min Wang、Pei Cai、Qiao-Hong Liu、Ding-Qiao Xu、Xue-Lian Yang、Jia-Jia Wu、Ling-Yi Kong、Xiao-Bing Wang

  DOI：10.1016/j.ejmech.2016.07.052

  日期：2016.11

  A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Aβ interaction, blood-brain

  设计，合成和评估了一系列新型多奈哌齐衍生物，作为多功能乙酰胆碱酯酶（AChE）抑制剂，用于治疗阿尔茨海默氏病（AD）。筛选结果表明，大多数化合物均表现出对AChE的有效抑制作用，IC 50值在纳摩尔范围内。此外，这些衍生物显示良好的抗氧化，A β相互作用，血脑屏障渗透（PAMPA-BBB +）和ADMET性质（在硅片）。其中，图5c显示了优秀的抑制乙酰胆碱酯酶（IC 50：85纳米的eeAChE，73纳米的HACHE），金属螯合，并在自感应，HACHE诱导和Cu抑制作用2+诱导的阿β 1-42聚合（18.5％，72.4％和46.3％，在20  μ M）。动力学分析和分子建模研究表明5c可以同时与AChE的催化活性位点（CAS）和外围阴离子位点（PAS）结合。更重要的是，5C表现出对一个显著的神经保护效力β 1-42诱导PC12细胞损伤。此外，逐步被动回避测试显示5c可以显着逆转东pol碱所