2-(4-hydroxy-2,2-dimethylbutyl)-1H-isoindole-1,3(2H)-dione | 749256-46-0

• 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-(4-hydroxy-2,2-dimethylbutyl)-1H-isoindole-1,3(2H)-dione
• 英文别名: 2-(4-hydroxy-2,2-dimethylbutyl)isoindoline-1,3-dione；2-(4-hydroxy-2,2-dimethylbutyl)isoindole-1,3-dione
• CAS: 749256-46-0
• 化学式: C₁₄H₁₇NO₃
• mdl: MFCD32717129
• 分子量: 247.294
• InChiKey: RCXQCPXEDUALDR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.428
• 拓扑面积：
  57.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(4-hydroxy-2,2-dimethylbutyl)-1H-isoindole-1,3(2H)-dione 在 三氧化硫吡啶 、 三乙酰氧基硼氢化钠 、 溶剂黄146 、 三乙胺 作用下， 以 二氯甲烷 、 二甲基亚砜 、 1,2-二氯乙烷 为溶剂， 反应 15.0h， 生成
  参考文献：
  名称：

  Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties

  摘要：

  CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by >= 48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4(+) tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4(+) immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4 metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4+ leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR44(+) cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off target liabilities. Herein, we report a series of novel tetrahydroisoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented.

  DOI：

  10.1021/acs.jmedchem.7b01420
• 作为产物：
  描述：

  2,2-二甲基丁烷-1,4-二醇 在 咪唑 、 盐酸 、 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 39.0h， 生成 2-(4-hydroxy-2,2-dimethylbutyl)-1H-isoindole-1,3(2H)-dione
  参考文献：
  名称：

  Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties

  摘要：

  CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by >= 48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4(+) tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4(+) immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4 metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4+ leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR44(+) cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off target liabilities. Herein, we report a series of novel tetrahydroisoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented.

  DOI：

  10.1021/acs.jmedchem.7b01420

文献信息

• CYCLOPROPANECARBOXYLIC ACID DERIVATIVE
  申请人：Nagata Tsutomu

  公开号：US20130012532A1

  公开（公告）日：2013-01-10

  A compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof, wherein R 1 represents a C1 to C6 alkyl group which may be substituted by one to three groups selected from substituent group A, or the like (substituent group A: a hydroxy group, a halogeno group, a cyano group, a nitro group, an amino group, a carboxy group, a C1 to C3 alkyl group, etc.); R 2 , R 3 , and R 8 each independently represent a hydrogen atom or a C1 to C3 alkyl group; R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 each independently represent a hydrogen atom or the like; and R 11 represents a hydrogen atom or the like, has TAFIa enzyme inhibitory activity and is useful as a therapeutic drug for myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, or the like.

  以下是由下列通式（I）表示的化合物或其药学上可接受的盐，其中R1代表C1至C6烷基，该烷基可以被选自取代基A的一个至三个基团取代（取代基A：羟基、卤素基、氰基、硝基、氨基、羧基、C1至C3烷基等）；R2、R3和R8各自独立地代表氢原子或C1至C3烷基；R4、R5、R6、R7、R9和R10各自独立地代表氢原子或类似物；而R11代表氢原子或类似物。该化合物具有TAFIa酶抑制活性，可用作治疗心肌梗塞、心绞痛、急性冠状动脉综合征、脑梗死、深静脉血栓、肺栓塞等疾病的治疗药物。
• Imidazole acetic acid TAFIa inhibitors: SAR studies centered around the basic P 1 ′ group
  作者：Philippe G Nantermet、James C Barrow、Stacey R Lindsley、MaryBeth Young、Shi-Shan Mao、Steven Carroll、Carolyn Bailey、Michele Bosserman、Dennis Colussi、Daniel R McMasters、Joseph P Vacca、Harold G Selnick

  DOI：10.1016/j.bmcl.2004.02.033

  日期：2004.5

  Structural modifications of the aminopyridine P'(1), group of imidazole acetic acid based TAFla inhibitors led to the discovery of the aminocyclopentyl analog 28, a 1 nM TAFla inhibitor with CLT50 functional activity of 14 nM but without selectivity against CPB. While not as active, aminobutyl derivative 27 provided an improved 6.7-fold selectivity for TAFla versus CPB. (C) 2004 Elsevier Ltd. All rights reserved.
• US8946443B2
  申请人：——

  公开号：US8946443B2

  公开（公告）日：2015-02-03
• US9662310B2
  申请人：——

  公开号：US9662310B2

  公开（公告）日：2017-05-30
• Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties
  作者：Eric J. Miller、Edgars Jecs、Valarie M. Truax、Brooke M. Katzman、Yesim A. Tahirovic、Robert J. Wilson、Katie M. Kuo、Michelle B. Kim、Huy H. Nguyen、Manohar T. Saindane、Huanyu Zhao、Tao Wang、Chi S. Sum、Mary E. Cvijic、Gretchen M. Schroeder、Lawrence J. Wilson、Dennis C. Liotta

  DOI：10.1021/acs.jmedchem.7b01420

  日期：2018.2.8

  CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by >= 48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4(+) tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4(+) immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4 metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4+ leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR44(+) cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off target liabilities. Herein, we report a series of novel tetrahydroisoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented.