2-(2-chloro-4-nitrophenyl)isoindoline-1,3-dione | 19348-51-7

• 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-(2-chloro-4-nitrophenyl)isoindoline-1,3-dione
• 英文别名: N-(2-chloro-4-nitro-phenyl)-phthalimide；4-N-phthalimido-5-chloro-nitrobenzene；N-(2-chloro-4-nitrophenyl)phthalimide；2-(2-chloro-4-nitrophenyl)isoindole-1,3-dione
• CAS: 19348-51-7
• 化学式: C₁₄H₇ClN₂O₄
• 分子量: 302.674
• InChiKey: KVULZZSSIWWTIV-UHFFFAOYSA-N

物化性质

• 熔点：
  181-183 °C(Solv: ethanol (64-17-5))
• 沸点：
  503.8±60.0 °C(Predicted)
• 密度：
  1.588±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  83.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(2-chloro-4-nitrophenyl)isoindoline-1,3-dione 在 盐酸 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 tin(ll) chloride 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 生成
  参考文献：
  名称：

  Chemical Modulation of Mutant mGlu₁ Receptors Derived from Deleterious GRM1 Mutations Found in Schizophrenics

  摘要：

  Schizophrenia is a complex and highly heterogeneous psychiatric disorder whose precise etiology remains elusive. While genome-wide association studies (GWAS) have identified risk genes, they have failed to determine if rare coding single nucleotide polymorphisms (nsSNPs) contribute in schizophrenia. Recently, two independent studies identified 12 rare, deleterious nsSNPS in the GRM1 gene, which encodes the metabotropic glutamate receptor subtype 1 (mGlu(1)), in schizophrenic patients. Here, we generated stable cell lines expressing the mGlu(1) mutant receptors and assessed their pharmacology. Using both the endogenous agonist glutamate and the synthetic agonist DHPG, we found that several of the mutant mGlu(1) receptors displayed a loss of function that was not due to a loss in plasma membrane expression. Due to a lack of mGlu(1) positive allosteric modulators (PAM) tool compounds active at human mGlu(1), we optimized a known mGlu4 PAM/mGlu(1) NAM chemotype into a series of potent and selective mGlu(1) PAMs by virtue of a double "molecular switch". Employing mGlu(1) PAMs from multiple chemotypes, we demonstrate that the mutant receptors can be potentiated by small molecules and in some cases efficacy restored to that comparable to wild type mGlu(1) receptors, suggesting deficits in patients with schizophrenia due to these mutations may be amenable to intervention with an mGlu(1) PAM. However, in wild type animals, mGlu(1) negative allosteric modulators (NAMs) are efficacious in classic models predictive of antipsychotic activity, whereas we show that mGlu(1) PAMs have no effect to slight potentiation in these models. These data further highlight the heterogeneity of schizophrenia and the critical role of patient selection strategies in psychiatric clinical trials to match genotype with therapeutic mechanism.

  DOI：

  10.1021/cb500560h
• 作为产物：
  描述：

  、 potassium phtalimide 以 甲苯 为溶剂， 反应 24.0h， 以99%的产率得到2-(2-chloro-4-nitrophenyl)isoindoline-1,3-dione
  参考文献：
  名称：

  与芳基（TMP）碘化甲苯磺酸酯的酰亚胺芳基化反应。

  摘要：

  在这里，我们描述了N-芳基邻苯二甲酰亚胺的合成，该方法是通过邻苯二甲酰亚胺钾与不对称芳基甲苯磺酸甲苯磺酸盐的无金属偶联而实现的。来自碘鎓部分的芳基转移在电子控制下发生，富电子的三甲氧基苯基作为有效的假配体。N-芳基邻苯二甲酰亚胺的收率中等至较高，并且偶联反应与电子不足和空间受限的芳基相容。

  DOI：

  10.3762/bjoc.14.90

文献信息

• Lead optimization of the VU0486321 series of mGlu 1 PAMs. Part 2: SAR of alternative 3-methyl heterocycles and progress towards an in vivo tool
  作者：Pedro M. Garcia-Barrantes、Hyekyung P. Cho、Adam M. Metts、Anna L. Blobaum、Colleen M. Niswender、P. Jeffrey Conn、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2015.12.104

  日期：2016.2

  This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu1 PAMs (EC50s ∼5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest Fu) and CNS penetration

  这封信描述了VU0486321系列mGlu 1阳性变构调节剂（PAM）的进一步前导优化，这是由将功能GRM1的丧失与精神分裂症联系起来的最新遗传数据驱动的。陡峭和饱满的SAR困扰着该系列，但最终有效的mGlu 1 PAM（EC 50 s〜5 nM）产生了良好的DMPK特性（低内在清除率，干净的CYP曲线，适度的F u）和CNS渗透率（K p s 0.25–0.97），以及相对于mGlu 4和mGlu 5高达450倍以上的选择性。
• Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy
  作者：Rocco D. Gogliotti、Darren W. Engers、Pedro M. Garcia-Barrantes、Joseph D. Panarese、Patrick R. Gentry、Anna L. Blobaum、Ryan D. Morrison、J. Scott Daniels、Analisa D. Thompson、Carrie K. Jones、P. Jeffrey Conn、Colleen M. Niswender、Craig W. Lindsley、Corey R. Hopkins

  DOI：10.1016/j.bmcl.2016.04.041

  日期：2016.6

  This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50=95nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp=1.3), rat CLp=4

  这封信描述了衍生自mGlu4 PAM的甲基吡啶酰胺的家族的进一步化学优化，其中我们确定了甲基吡啶弹头的3-氨基取代基，从而增强了效能，中枢神经系统的穿透力和体内功效。通过此优化活动，VU0477886成为了一种有效的（EC50 = 95nM，89％Glu Max）mGlu4 PAM，具有有吸引力的DMPK分布（大脑：血浆Kp = 1.3），大鼠CLp = 4.0mL / min / kg，t1 / 2 = 3.7h）和在我们标准的临床前帕金森氏病模型氟哌啶醇诱发的僵直症（HIC）中的强大功效。
• Synthesis and Anticonvulsant and Neurotoxic Properties of Substituted <i>N</i>-Phenyl Derivatives of the Phthalimide Pharmacophore
  作者：Joseph Vamecq、Pierre Bac、Christine Herrenknecht、Pierre Maurois、Philippe Delcourt、James P. Stables

  DOI：10.1021/jm990068t

  日期：2000.4.6

  A series of compounds including 4-amino (1), 3-amino (2), 4-nitro (3), 2-methyl-3-amino (4), 2-methyl-3-nitro (5), 2-methyl-4-amino (6), 2-methyl-4-nitro (7), 2-methyl-5-amino (8), 2-methyl-5-nitro (9), 2-methyl-6-amino (10), 2-methyl-6-nitro (11), 2,6-dimethyl (12), 2-methyl-3-carboxy (13), 2-methoxycarbonyl (14), 2-methyl-4-methoxy (15), 2,4-dimethoxy (16), 2-chloro-4-amino (17), and 2-chloro-4-nitro (18) N-phenyl substituents of phthalimide were evaluated along with N-[3-methyl-(2-pyridinyl)]phthalimide (19), N-(3-amino-2-methylphenyl)succinimide (20), and phenytoin for anticonvulsant and neurotoxic properties. Initial screening in the intraperitoneal tip) maximal electroshock-induced seizure (MES) test and the subcutaneous pentylenetetrazol-induced seizure (scPtz) test in mice led to the selection of 1, 2, 4, 10, 12, 17, and 19 for oral MES evaluation in rats. The resultant ED(50) values for 4, 10, 17, and phenytoin were 8.0, 28.3, 5.7 and 29.8 mg/kg, respectively. In the batrachotoxin affinity assay, IC(50) values for 17 and phenytoin were 0.15 and 0.93 mu M, respectively, and in the recently validated magnesium deficiency-dependent audiogenic seizure test, ED(50) values of 5.2 and 23 mg/kg were obtained for 17 and phenytoin, respectively. Electrophysiology studies on compound 17 point out its ability to (i) potentiate GABA-evoked current responses with a failure to directly activate the GABAA receptor and (ii) to affect, at 100 mu M excitatory non NMDA, but not NMDA, receptors with a 25% block of kainate-evoked response. Electrophysiology measurements on voltage-gated sodium channels in N1E-115 neuroblastoma cells confirm voltage-dependent block of these channels by compound 17. In view of its interaction with multiple ion channels, one would predict that compound 17 might be active in a wide range of seizure models.
• PLATELET ADP RECEPTOR INHIBITORS
  申请人：Portola Pharmaceuticals, Inc.

  公开号：EP2314593B1

  公开（公告）日：2016-05-04
• Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu₁), Based on an <i>N</i>-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu₁ Receptors Found in Schizophrenics
  作者：Pedro M. Garcia-Barrantes、Hyekyung P. Cho、Colleen M. Niswender、Frank W. Byers、Charles W. Locuson、Anna L. Blobaum、Zixiu Xiang、Jerri M. Rook、P. Jeffrey Conn、Craig W. Lindsley

  DOI：10.1021/acs.jmedchem.5b00727

  日期：2015.10.22

  The therapeutic potential of selective mGlu(1) activation is vastly unexplored relative to the other group I mGlu receptor, mGlu(5); therefore, our lab has focused considerable effort toward developing mGlu(1) positive allosteric modulators (PAMs) suitable as in vivo proof of concept tool compounds. Optimization of a series of mGlu(1) PAMs based on an N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide scaffold provided 17e, a potent (mGlu(1) EC50 = 31.8 nM) and highly CNS penetrant (brain to plasma ratio (K-p) of 1.02) mGlu(1) PAM tool compound, that potentiated not only wild-type human mGlu(1) but also mutant mGlu(1) receptors derived from deleterious GRM1 mutations found in schizophrenic patients. Moreover, both electrophysiological and in vivo studies indicate the mGlu(1) ago-PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGlu(5) ago-PAMs/PANIs and maintain temporal activity suggesting a broader therapeutic window.