(2-[1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione) | 145945-21-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: (2-[1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione)
• 英文别名: (R,S)-2-(1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione；N-hydroxymethylthalidomide；CPS11；2-(1-(Hydroxymethyl)-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione；2-[1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl]isoindole-1,3-dione
• CAS: 145945-21-7
• 化学式: C₁₄H₁₂N₂O₅
• 分子量: 288.26
• InChiKey: LZHQPJSJEITGHB-UHFFFAOYSA-N

物化性质

• 沸点：
  561.5±45.0 °C(Predicted)
• 密度：
  1.555±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  95
• 氢给体数：
  1
• 氢受体数：
  5

制备方法与用途

CPS-11（N-(羟甲基)沙利度胺）是一种类似于沙利度胺的化合物，也是一种有效的抗癌剂。它通过提高活性氧水平来抑制NF-κB、激活NFAT，并减少细胞因子表达。与多发性骨髓瘤细胞系相比，CPS-11表现出更广泛的活性谱和更高的效力[1][2][3]。

反应信息

• 作为反应物：
  描述：

  (2-[1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione) 在 氯化亚砜 、 potassium iodide 作用下， 以 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 7.0h， 生成 2-(1-iodomethyl-2,6-dioxo-piperidine-3-yl)-1,3-dihydro-2H-isoindole-1,3-dione
  参考文献：
  名称：

  Synthesis and immunological activity of water-soluble Thalidomide prodrugs

  摘要：

  A series of new water-soluble thalidomide prodrugs was prepared. All compounds were derivatized on the nitrogen of the glutarimide ring. Esters of natural amino acids and succinic acid derivatives have been introduced by reaction with the hydroxymethyl thalidomide 2. Nicotinic acid derivatives were prepared from halomethyl derivatives. Additionally, a methoxy methyl derivative and a carboxymethyl derivative were prepared directly from thalidomide. Most compounds showed a very large increase in water solubility compared to thalidomide itself (0.012 mg/mL). The amorphous hydrochlorides of the N-methylalanine ester 8, valine ester 9, and glycylglycine ester 10, respectively, were the most soluble compounds showing solubility greater than 300 mg/mL, which equals an increase greater than 15,000-fold. The lipophilicity of the prodrugs has been determined by their HPLC capacity factors k '. The stability of selected compounds was determined. The hydrolysis rates follow pseudo-first order kinetics. In order to assess the immunological activity, the prodrugs were tested using tumor necrosis factor-alpha and interleukin-2 inhibition assays. Selected compounds were additionally investigated on their abililty to inhibit the local Shwartzman reaction, an assay to determine the Vascular permeability. The prodrugs retained high effectiveness in the inhibition of TNF-alpha release. Our results indicated that the more stable prodrugs exhibited higher activity in the immunological assays. Some compounds showed higher activity than thalidomide itself, suggesting a high affine binding to the pharmacophore. In conclusion, the prodrugs exhibited high water solubility and high activity and might therefore be used in therapeutic applications. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00342-4
• 作为产物：
  描述：

  沙利度胺 在 聚合甲醛 作用下， 以 水 为溶剂， 以74%的产率得到(2-[1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione)
  参考文献：
  名称：

  Efforts toward elucidating Thalidomide’s molecular target: an expedient synthesis of the first Thalidomide biotin analogue

  摘要：

  在这里，我们描述了第一种沙利度胺-生物素类似物的合成，以启动对沙利度胺未知分子作用机制的研究。我们采用Huisgen 1,3-双极环加成或“点击”合成方法，描述了生物素连接体的结合。

  DOI：

  10.1039/c0ob00060d

文献信息

• Synthesis and Immunosuppressive Activity of New Mycophenolic Acid Derivatives
  作者：Karina Barbieri、Lucas Ercolin、Thierry Louat、Marisa Polesi、Chung Chin、Iracilda Zeppone、Jean Santos

  DOI：10.2174/1573406412666161207121226

  日期：2017.1.30

  diseases. Mycophenolic acid (MPA) and its derivatives are currently one of the most prescribed immunosuppressive drugs; however, metabolic drawbacks and variable interand intrapatient responses limit their use. Objective: In order to find out new safe and effective immunosuppressive compounds, we report here the synthesis and pharmacological evaluation of hybrid MPA derivatives containing the thalidomide/

  背景：免疫抑制药物被广泛用于预防和治疗同种异体移植排斥反应和自身免疫性疾病。霉酚酸（MPA）及其衍生物目前是处方最广泛的免疫抑制药物之一。但是，新陈代谢的缺陷和患者之间以及患者内部反应的差异限制了它们的使用。 目的：为了发现新的安全有效的免疫抑制化合物，我们在此报告含有沙利度胺/邻苯二甲酰亚胺亚基的杂化MPA衍生物的合成和药理学评价。 结果：与母体药物MPA和沙利度胺相比，所有化合物3a-d均具有增强的降低促炎细胞因子水平的能力。混合淋巴细胞反应试验已证明化合物3d-（E）-（3-（1,3-二氧代异吲哚啉-2-基）-2,6-二氧代哌啶-1-基）甲基-6-（4-羟基-6 -甲氧基-7-甲基-3-氧代-1,3-二氢异苯并呋喃-5-基）-4-甲基己基-4-烯酸酯-与MPA相比具有更好的活性。另外，化合物3d对Jurkat细胞的细胞毒性比MPA少，并且没有表现出体内遗传毒性作用。 结论：所有这些数
• Analogs of thalidomide as potential angiogenesis inhibitors
  申请人：——

  公开号：US20040077685A1

  公开（公告）日：2004-04-22

  A number of thalidomide metabolites having superior anti-angiogenic properties have now been isolated and identified In addition, thalidomide analogs that mimic the effects of the isolated and identified active thalidomide metabolites, and variations of such thalidomide analogs, have been developed. Such thalidomide analog compounds show enhanced potency in the inhibition of undesirable angiogenesis without the undesirable effects of administration of thalidomide.

  现在已经分离和鉴定出了多种具有优越的抗血管生成作用的沙利度胺代谢产物。此外，已经开发出了模仿这些活性沙利度胺代谢产物效果的沙利度胺类似物和这些沙利度胺类似物的变体。这些沙利度胺类似物化合物在抑制不良血管生成方面显示出增强的效力，而没有沙利度胺的不良影响。
• Acylated n-hydroxy methyl thalidomide prodrugs with immunomodulator action
  申请人：Gruenenthal GmbH

  公开号：US06417197B1

  公开（公告）日：2002-07-09

  Thalidomide prodrugs of the formula I: in which R is —CHR1—NHR2 or —(CH2)nCOOH; R1 is H or C1-4 alkyl; R2 is H, C1-3 alkyl, C(O)—CH2—NHR3 or an amino-protective group, R3 is H or an amino-protective group, and n is an integer from 2 to 4, in the form of their free bases or of salts with physiologically acceptable acids, as well as a process for preparation of such prodrugs and the use of such prodrugs as an active drug substance.

  化合物I的沙利度胺前药：其中R是—CHR1—NHR2或—(CH2)nCOOH；R1是H或C1-4烷基；R2是H、C1-3烷基、C(O)—CH2—NHR3或氨基保护基，R3是H或氨基保护基，n为2到4的整数，以其自由碱或与生理可接受酸盐的形式存在，以及制备这种前药的方法和将这种前药用作活性药物物质的用途。
• WATER-SOLUBLE THALIDOMIDE DERIVATIVES
  申请人：ZHANG Hesheng

  公开号：US20100240651A1

  公开（公告）日：2010-09-23

  A compound of formula (I), wherein R 1 represents H, or a C 1-4 alkyl group; R 2 represents H, a C 1-4 alkyl group, C(O)CHR 4 NR 5 R 6 , or C(O)W; or R 1 and R 2 taken together represent 1,3-propylene; R 3 represents H, a C 1-4 alkyl group, C(O)CHR 4 NR 5 R 6 , or C(O)W; or R 2 and R 3 taken together represent 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, CH 2 OCH 2 , CH 2 SCH 2 or CH 2 NR 7 CH 2 , wherein R 7 represents H or a C 1-4 alkyl group; and when one of R 2 and R 3 represents H, or a C 1-4 alkyl group, the other one does not represent H; and R 8 represents H, or a C 1-4 alkyl group.

  化合物的化学式为（I），其中R1代表H或C1-4烷基；R2代表H，C1-4烷基，C（O）CHR4NR5R6或C（O）W；或R1和R2一起代表1,3-丙二基；R3代表H，C1-4烷基，C（O）CHR4NR5R6或C（O）W；或R2和R3一起代表1,3-丙二基，1,4-丁二基，1,5-戊二基，1,6-己二基，CH2OCH2，CH2SCH2或CH2NR7CH2，其中R7代表H或C1-4烷基；当R2和R3中的一个代表H或C1-4烷基时，另一个不代表H；R8代表H或C1-4烷基。
• Water-soluble thalidomine derivatives
  申请人：Zhang Hesheng

  公开号：US20060094730A1

  公开（公告）日：2006-05-04

  Thalidomide derivative (I) and their bases or salts are new: where R represents CHR 1 NR 2 R 3 , CHR 1 NR 4 C(O)CHR 5 NR 2 R 3 , W or CHR 5 NR 4 C(O)W, where R 1 , R 4 and R 5 represent independently each other H, C 1-4 alkyl, R 2 is a C 1-4 alkyl, R 3 is a C 1-4 alkyl, or R 2 and R 3 together represents 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, W represents 4-, 5-, 6-, 7-, or 8-mumbered, saturated or unsaturated heterocycle. The invention also relates to processes of production thereof and the use of thereof as an active pharmaceutical ingredient.

  沙利度胺衍生物(I)及其碱或盐是新的： 其中 R 代表 CHR 1 NR 2 R 3 , CHR 1 NR 4 C(O)CHR 5 NR 2 R 3 , W 或 CHR 5 NR 4 C(O)W，其中 R 1 , R 4 和 R 5 各自独立地代表 H、C 1-4 烷基、R 2 是 C 1-4 烷基，R 3 是 C 1-4 烷基，或 R 2 和 R 3 共同代表 1,3-丙烯、1,4-丁烯、1,5-戊烯、1,6-己烯，W 代表 4-、5-、6-、7-或 8-位饱和或不饱和杂环。本发明还涉及其生产工艺及其作为活性药物成分的用途。