methyl 3-hydroxy-5,6,7,8-tetrahydro-4H-isoxazolo<4,5-c>azepine-5-carboxylate | 65202-70-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吖庚因类
• 英文名称: methyl 3-hydroxy-5,6,7,8-tetrahydro-4H-isoxazolo<4,5-c>azepine-5-carboxylate
• 英文别名: 3-oxo-2,3,4,6,7,8-hexahydro-isoxazolo[4,5-c]azepine-5-carboxylic acid methyl ester；methyl 3-hydroxy-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepin-5-carboxylate；methyl 3-oxo-4,6,7,8-tetrahydro-[1,2]oxazolo[4,5-c]azepine-5-carboxylate
• CAS: 65202-70-2
• 化学式: C₉H₁₂N₂O₄
• 分子量: 212.205
• InChiKey: ZAWNGCPCBZJPHX-UHFFFAOYSA-N

物化性质

• 密度：
  1.37±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 3-hydroxy-5,6,7,8-tetrahydro-4H-isoxazolo<4,5-c>azepine-5-carboxylate 在 盐酸 、 potassium carbonate 作用下， 以 乙酸乙酯 、 丙酮 为溶剂， 反应 24.5h， 生成 2-benzyl-5,6,7,8-tetrahydro-4H-[1,2]oxazolo[4,5-c]azepin-3-one
  参考文献：
  名称：

  N-和O-取代的5,6,7,8-Tetrahydro-4 H -isoxazolo [4,5 - d ] azepin-3-ol类似物的设计，合成和药理学表征：新型5-HT 2A / 5-具有前认知特性的HT 2C受体激动剂

  摘要：

  双环异恶唑的异恶唑-3-一个互变异构体5,6,7,8-四氢-4 H-异恶唑[4,5- d ] azepin-3-ol（THAZ）以前已被证明是弱的GABA A和甘氨酸受体拮抗剂。在本研究中，已经通过一系列N和O取代的THAZ类似物的合成和药理学表征探索了该支架的潜力。发现类似物N -Bn-THAZ（3d）和O -Bn-THAZ（4d）是人5-HT 2A和5-HT 2C的有效激动剂。受体。从对许多其他中枢神经系统靶点进行的详尽药理分析来看，该3d类似物似乎对这两种受体具有选择性。在位置识别Y迷宫模型中3d的施用大大改善了小鼠的认知能力，这种作用可以通过选择性5-HT 2C拮抗剂SB242084的共同施用而完全逆转。总之，作为新型的生物利用的认知增强剂，最有可能通过5-HT 2A和/或5-HT 2C受体介导其作用，异恶唑3d和4d构成了进一步药物化学发展的有趣线索。

  DOI：

  10.1021/jm301656h
• 作为产物：
  描述：

  6-hydroxycarbamoyl-1,4-dioxa-8-aza-spiro[4.6]undecane-8-carboxylic acid methyl ester 、 盐酸 生成 methyl 3-hydroxy-5,6,7,8-tetrahydro-4H-isoxazolo<4,5-c>azepine-5-carboxylate
  参考文献：
  名称：

  KROGSGAARD-LARSEN P., ACTA CHEM. SCAND., 1977, B31, NO

  摘要：

  DOI：

文献信息

• 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]-azepine derivatives
  申请人：H. Lundbeck A/S

  公开号：US04960769A1

  公开（公告）日：1990-10-02

  The present invention relates to novel compounds of the following formula: ##STR1## wherein R.sup.1 is alkyl, alkenyl, alkynyl, branched or unbranched, with 1-6 carbon atoms either unsubstituted or optionally substituted with fluoro, hydroxy or phenyl, in which the phenyl group may be substituted with halogen,trifluoromethyl, lower alkyl, hydroxy or lower alkoxy; R.sup.2 is hydrogen or lower alkyl (1-6 C-atoms); R.sup.3 and R.sup.4 are the same or different, and each represents hydrogen, alkyl (1-6 C-atoms) or cycloalkyl (3-6 C-atoms), or phenyl optionally substituted with halogen, trifluoromethyl, lower alkyl (1-6 C-atoms), hydroxy, or lower alkoxy (1-6 C-atoms) or phenyl-lower alkyl (7-10 C-atoms), in which the phenyl group may be substituted with halogen, trifluoromethyl, lower alkyl(1-6 C-atoms), hydroxy or lower alkoxy (1-6 C-atoms); as well as individual isomers and pharmaceutically acceptable acid addition salts thereof. The invention moreover, relates to methods for the preparation of the compounds of formula I, to novel intermediates, to pharmaceutical compositions containing same and to methods for the treatment of disorders, caused by malfunction of the acetylcholine (AcCh) or muscarinic system, by administering a non-toxic effective amount of a compound of formula I.

  本发明涉及以下式的新化合物：##STR1## 其中R.sup.1是烷基，烯基，炔基，支链或直链，具有1-6个碳原子，可以未取代或可选地取代为氟，羟基或苯基，其中苯基可以用卤素，三氟甲基，较低的烷基，羟基或较低的烷氧基取代; R.sup.2是氢或较低的烷基（1-6个C原子）; R.sup.3和R.sup.4相同或不同，每个代表氢，烷基（1-6个C原子）或环烷基（3-6个C原子），或苯基，可选地用卤素，三氟甲基，较低的烷基（1-6个C原子），羟基或较低的烷氧基（1-6个C原子）或苯基-较低的烷基（7-10个C原子）取代，其中苯基可以用卤素，三氟甲基，较低的烷基（1-6个C原子），羟基或较低的烷氧基（1-6个C原子）取代;以及其各个异构体和药学上可接受的酸加盐。此外，本发明还涉及制备式I化合物的方法，新的中间体，含有该化合物的制药组合物，以及通过给予式I化合物的非毒性有效量治疗由乙酰胆碱（AcCh）或肌动系统功能障碍引起的疾病的方法。
• Annulated Heterocyclic Bioisosteres of Norarecoline. Synthesis and Molecular Pharmacology at Five Recombinant Human Muscarinic Acetylcholine Receptors
  作者：Hans Braeuner-Osborne、Bjarke Ebert、Mark R. Brann、Erik Falch、Povl Krogsgaard-Larsen

  DOI：10.1021/jm00012a019

  日期：1995.6

  A series of O-alkylated analogs of 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepin-3-ol (THAO) were synthesized and characterized as ligands for muscarinic acetylcholine receptors (mAChRs). O-Methyl-THAO (4a), O-ethyl-THAO (4b), O-isopropyl-THAO (4c), and O-propargyl-THAO (4d) were shown to be potent inhibitors of the binding of tritiated quinuclidinyl benzilate (QNB), pirenzepine (PZ), and oxotremorine-M (Oxo-M) to tissue membrane preparations. In the [3H]-Oxo-M binding assay, receptor affinities in the low nanomolar range were measured for 4a (IC50 = 0.010 microM), 4b (IC50 = 0.003 microM), 4c (IC50 = 0.011 microM), and 4d (IC50 = 0.0008 microM). Pharmacological effects (EC50 or Ki values) and intrinsic activities (per cent of maximal carbachol responses) were determined using five recombinant human mAChRs (m1-m5) and the functional assay, receptor selection and amplification technology (R-SAT). Compound 4c antagonized carbachol-induced responses at m1, m3, and m5. With the exception of 4b, which was an antagonist at m5, 4a,b,d showed partial agonism at m1-m5 with very similar subtype selectivity (m2 > m4 > m1 > or = m3 > m5). Agonist index values for 4a-d, which were calculated from [3H]QNB (brain) and [3H]Oxo-M (brain) binding data, were shown to be predictive of pharmacologically determined intrinsic activities at m1-m5, the same rank order of intrinsic activity being observed at all five mAChRs (4a > 4d > 4b > 4c). It is concluded that within this class of high-affinity mAChR (m1-m5) ligands, containing secondary amino groups, minor changes of the bioisosteric ester alkyl groups have marked effects on potency and, in particular, intrinsic activity.
• US4960769A
  申请人：——

  公开号：US4960769A

  公开（公告）日：1990-10-02
• Design, Synthesis, and Pharmacological Characterization of <i>N</i>- and <i>O</i>-Substituted 5,6,7,8-Tetrahydro-4<i>H</i>-isoxazolo[4,5-<i>d</i>]azepin-3-ol Analogues: Novel 5-HT_2A/5-HT_2C Receptor Agonists with Pro-Cognitive Properties
  作者：Anders A. Jensen、Niels Plath、Martin H. F. Pedersen、Vignir Isberg、Jacob Krall、Petrine Wellendorph、Tine B. Stensbøl、David E. Gloriam、Povl Krogsgaard-Larsen、Bente Frølund

  DOI：10.1021/jm301656h

  日期：2013.2.14

  study, the potential in this scaffold has been explored through the synthesis and pharmacological characterization of a series of N- and O-substituted THAZ analogues. The analogues N-Bn-THAZ (3d) and O-Bn-THAZ (4d) were found to be potent agonists of the human 5-HT2A and 5-HT2C receptors. Judging from an elaborate pharmacological profiling at numerous other CNS targets, the 3d analogue appears to be

  双环异恶唑的异恶唑-3-一个互变异构体5,6,7,8-四氢-4 H-异恶唑[4,5- d ] azepin-3-ol（THAZ）以前已被证明是弱的GABA A和甘氨酸受体拮抗剂。在本研究中，已经通过一系列N和O取代的THAZ类似物的合成和药理学表征探索了该支架的潜力。发现类似物N -Bn-THAZ（3d）和O -Bn-THAZ（4d）是人5-HT 2A和5-HT 2C的有效激动剂。受体。从对许多其他中枢神经系统靶点进行的详尽药理分析来看，该3d类似物似乎对这两种受体具有选择性。在位置识别Y迷宫模型中3d的施用大大改善了小鼠的认知能力，这种作用可以通过选择性5-HT 2C拮抗剂SB242084的共同施用而完全逆转。总之，作为新型的生物利用的认知增强剂，最有可能通过5-HT 2A和/或5-HT 2C受体介导其作用，异恶唑3d和4d构成了进一步药物化学发展的有趣线索。
• KROGSGAARD-LARSEN P., ACTA CHEM. SCAND., 1977, B31, NO
  作者：KROGSGAARD-LARSEN P.

  DOI：——

  日期：——