7-氟-3,4-二氢-3-氧代-2-喹喔啉羧酸乙酯 | 55496-01-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 7-氟-3,4-二氢-3-氧代-2-喹喔啉羧酸乙酯
• 英文名称: ethyl 3,4-dihydro-7-fluoro-3-oxoquinoxaline-2-carboxylate
• 英文别名: ethyl 7-fluoro-3-oxo-3,4-dihydroquinoxaline-2-carboxylate；7-fluoro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid,ethyl ester；ethyl 7-fluoro-3-oxo-4H-quinoxaline-2-carboxylate
• CAS: 55496-01-0
• 化学式: C₁₁H₉FN₂O₃
• 分子量: 236.202
• InChiKey: GCMGUGKUNDNIMO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  67.8
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• 海关编码：
  2933990090

反应信息

• 作为反应物：
  描述：

  7-氟-3,4-二氢-3-氧代-2-喹喔啉羧酸乙酯 在 硝酸 、 溶剂黄146 、 silver(l) oxide 作用下， 以 甲苯 为溶剂， 反应 4.0h， 生成 ethyl 7-fluoro-3-methoxy-6-nitroquinoxaline-2-carboxylate
  参考文献：
  名称：

  设计，合成和AMPA受体拮抗活性的新型6-硝基-3-氧代喹喔啉-2-羧酸在7位取代苯基。

  摘要：

  我们描述了一系列新型的7-取代的6-硝基-3-氧代喹喔啉-2-羧酸的设计，合成和生物学特性。经过设计，研究结构-活性关系并评估了各种化合物的性能，我们发现7-杂环-6-硝基-3-氧代喹喔啉-2-羧酸含有在7位上通过氨基甲酸酯连接的取代苯基具有良好的丙酸α-氨基-3-羟基-5-甲基异恶唑受体（AMPA-R）拮抗活性。在测试的化合物中，在末端苯基部分具有4-羧基的化合物29p（GRA-293）在体外对AMPA-R表现出高效力和选择性，并且在体内具有良好的神经保护功效。它还显示出良好的水溶性。

  DOI：

  10.1016/j.bmc.2005.05.030
• 作为产物：
  描述：

  4-氟-2-硝基苯胺 在 potassium tert-butylate 、 三溴化磷 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 27.0h， 生成 7-氟-3,4-二氢-3-氧代-2-喹喔啉羧酸乙酯
  参考文献：
  名称：

  设计，合成和AMPA受体拮抗活性的新型6-硝基-3-氧代喹喔啉-2-羧酸在7位取代苯基。

  摘要：

  我们描述了一系列新型的7-取代的6-硝基-3-氧代喹喔啉-2-羧酸的设计，合成和生物学特性。经过设计，研究结构-活性关系并评估了各种化合物的性能，我们发现7-杂环-6-硝基-3-氧代喹喔啉-2-羧酸含有在7位上通过氨基甲酸酯连接的取代苯基具有良好的丙酸α-氨基-3-羟基-5-甲基异恶唑受体（AMPA-R）拮抗活性。在测试的化合物中，在末端苯基部分具有4-羧基的化合物29p（GRA-293）在体外对AMPA-R表现出高效力和选择性，并且在体内具有良好的神经保护功效。它还显示出良好的水溶性。

  DOI：

  10.1016/j.bmc.2005.05.030

文献信息

• 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid derivatives, addition salts thereof, and processes for the preparation of both
  申请人：Kyorin Pharmaceutical Co., Ltd.

  公开号：US06348461B1

  公开（公告）日：2002-02-19

  The present invention provides 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compounds and their addition salts, and processes for preparing them, which have antagonism against excitatory amino acid receptors, in particular, an AMPA receptor. The 6,7-asymmetrically disubstituted quinoxalinecarboxylic acid compounds and their addition salts of the present invention are represented by formula (1) wherein Q, R, R1 and R2 are as described in the specification.

  本发明提供了6,7-不对称二取代喹喔啉羧酸化合物及其加合盐，以及制备它们的方法，这些化合物对兴奋性氨基酸受体，特别是AMPA受体具有拮抗作用。本发明的6,7-不对称二取代喹喔啉羧酸化合物及其加合盐由下式表示（1式），其中Q、R、R1和R2如规范中所述。
• New Quinoxaline Derivatives as Dual Pim-1/2 Kinase Inhibitors: Design, Synthesis and Biological Evaluation
  作者：Bruno Oyallon、Marie Brachet-Botineau、Cédric Logé、Thomas Robert、Stéphane Bach、Sajida Ibrahim、William Raoul、Cécile Croix、Pascal Berthelot、Jean Guillon、Noël Pinaud、Fabrice Gouilleux、Marie-Claude Viaud-Massuard、Caroline Denevault-Sabourin

  DOI：10.3390/molecules26040867

  日期：——

  leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure–activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two

  已在多种血液学（例如多发性骨髓瘤或急性骨髓性白血病（AML））和实体（例如结直肠癌）肿瘤中发现了莫洛尼氏鼠白血病病毒（Pim）-1/2激酶过表达的前病毒整合位点，在癌症进展，转移和耐药中起关键作用，并且与不良预后有关。因此，这些激酶被认为是肿瘤学中令人关注的靶标。我们在此报告了新的喹喔啉衍生物作为双重Pim1 / 2抑制剂的设计，合成，结构-活性关系（SAR）和体外评估。两种铅化合物（5c和5e然后确定）为有效的亚微摩尔Pim-1和Pim-2抑制剂。这些分子还能够抑制两种人类细胞系MV4-11（AML）和HCT-116（结肠直肠癌）的生长，并表达高内源性的Pim-1 / 2激酶。
• Discovery of 2-[(<i>E</i>)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-<i>N</i>-(tetrahydro-2<i>H</i>-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor
  作者：Yoichi Kadoh、Haruko Miyoshi、Takehiko Matsumura、Yoshihito Tanaka、Mitsuya Hongu、Mayumi Kimura、Kei Takedomi、Kenji Omori、Jun Kotera、Takashi Sasaki、Tamaki Kobayashi、Hiroyuki Taniguchi、Yumi Watanabe、Koki Kojima、Toshiaki Sakamoto、Toshiyuki Himiyama、Eiji Kawanishi

  DOI：10.1248/cpb.c17-00783

  日期：——

  Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.

  磷酸二酯酶（PDE）10A是一种双水解酶，能够水解cAMP和cGMP，并且在纹状体中型棘突神经元中高度表达。抑制PDE10A通过调节cAMP和cGMP调控中型棘突神经元（MSN）的活性。MSN的信号控制被认为与精神症状相关。因此，PDE10A抑制剂被期待作为治疗精神疾病（如精神分裂症）的方法。阿伐那非（1）是我们公司发现的一种PDE5抑制剂（用于治疗勃起功能障碍）。我们关注PDE10A与PDE5的同源性，并利用PDE5抑制剂库发现PDE10A抑制剂，找到了系列对PDE10A表现出比PDE5更高效能的化合物。我们转化了这些对PDE10A抑制活性较弱的衍生物，并发现了白藜芦醇作为PDE10A抑制剂。通过进一步转化含氮杂环及其取代基，改善了该化合物的脑部穿透能力。所得到的二甲氨基嘧啶在大鼠条件回避反应（CAR）测试中显示有效，但脑部穿透性并不好。我们对此进行了深入优化，重点关注喹啉环的取代基，合成了3-甲基-7-氟喹啉。由于其强大的PDE10A抑制活性和良好的药代动力学，该化合物在大鼠CAR测试中是最有效的。
• Quinoxaline-2-carboxamidotetrazoles
  申请人：Allen & Hanburys Limited

  公开号：US03997535A1

  公开（公告）日：1976-12-14

  Compounds of the general formula I: ##STR1## and pharmaceutically acceptable salts thereof in which: A represents the group ##STR2## or the group ##STR3## linked to the adjacent benzene ring through the nitrogen atom, in which R.sub.1 represents a hydrogen atom, or an alkyl group which may optionally be substituted by one or more aryl, aryloxy, alkoxy, acyloxy, amino, alkylamino, dialkylamino or hydroxy groups or represents an alkenyl group; R.sub.2 represents a hydrogen atom, a halogen atom or an alkyl group or the group OR.sub.3, where R.sub.3 is a hydrogen atom or an alkyl group which may optionally be substituted by one or more aryl, aryloxy, alkoxy, acyloxy, hydroxy, amino, alkylamino or dialkylamino groups or the group NR.sub.4 R.sub.5 where R.sub.4 and R.sub.5 may be the same or different and have the meanings given for R.sub.1 or R.sub.4 and R.sub.5 together with the nitrogen atom form a 5 or 6 membered heterocyclic ring which may optionally contain additional hetero atoms; R.sub.6 and R.sub.7 which may be the same or different represent a hydrogen atom, or a halogen atom or an alkyl group or the group OR.sub.3 or the group NR.sub.4 R.sub.5 as defined above. These compounds have activity as for the treatment of conditions caused primarily by the combination of an antigen with a reaginic antibody.

  通式I的化合物：##STR1##及其药用可接受的盐，其中：A代表基团##STR2##或基团##STR3##通过氮原子连接到相邻的苯环上，其中R.sub.1代表氢原子，或者一个烷基基团，该基团可以选择性地被一个或多个芳基、芳氧基、烷氧基、酰氧基、氨基、烷基氨基、二烷基氨基或羟基取代，或者代表烯基基团；R.sub.2代表氢原子，卤原子或烷基基团或基团OR.sub.3，其中R.sub.3是氢原子或烷基基团，该基团可以选择性地被一个或多个芳基、芳氧基、烷氧基、酰氧基、羟基、氨基、烷基氨基或二烷基氨基取代，或者基团NR.sub.4 R.sub.5，其中R.sub.4和R.sub.5可以相同也可以不同，并具有R.sub.1或R.sub.4和R.sub.5给定的含义，或者R.sub.4和R.sub.5连同氮原子形成一个可能含有额外杂原子的5或6元杂环的环；R.sub.6和R.sub.7可以相同也可以不同，代表氢原子，或卤原子或烷基基团或基团OR.sub.3或上述定义的基团NR.sub.4 R.sub.5。这些化合物具有治疗主要由抗原与变应原抗体结合引起的病症的活性。
• TRI-SUBSTITUTED PYRIMIDINE COMPOUNDS AND THEIR USE AS PDE10 INHIBITORS
  申请人：Kawanishi Eiji

  公开号：US20110160206A1

  公开（公告）日：2011-06-30

  The present invention provides a tri-substituted pyrimidine compound having an excellent PDE10 inhibitory activity. The present invention relates to a tri-substituted pyrimidine compound represented by the following formula [I 0 ] or a pharmaceutically acceptable salt thereof, a method for preparing the same, and use of said compound for PDE10 inhibitor, and a pharmaceutical composition comprising said compounds as an active ingredient: wherein: either one of X 1 and X 2 is N, and the other of X 1 and X 2 is CH; A is *-CH═CH—, *-C(Alk)=CH—, *-CH 2 —CH 2 — or *-O—CH 2 — (* is a bond with R 1 ); Alk is a lower alkyl group; Ring B is an optionally substituted nitrogen-containing aliphatic heterocyclic group; R 1 is an optionally substituted quinoxalinyl or an optionally substituted quinolyl; Y 0 is mono- or di-substituted amino group, or a pharmaceutically acceptable salt thereof.

  本发明提供了一种具有优异的PDE10抑制活性的三取代嘧啶化合物。本发明涉及一种由以下式[I0]表示的三取代嘧啶化合物或其药学上可接受的盐，以及制备该化合物的方法，以及将所述化合物用作PDE10抑制剂的用途，以及包含所述化合物作为活性成分的药物组合物：其中：X1和X2中的任一者为N，另一者为CH；A为*-CH═CH—，*-C(Alk)=CH—，*-CH2— —或*-O— —（*是与R1形成键）；Alk为较低的烷基基团；环B为可选择地取代的含氮脂肪杂环基团；R1为可选择地取代的喹唑啉基或可选择地取代的喝啉基；Y0为单取代或双取代的氨基团，或其药学上可接受的盐。