methyl 3-isopropoxy-5,6,7,8-tetrahydro-4H-isoxazolo<4,5-c>azepine-5-carboxylate | 123732-47-8

• 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-isopropoxy-5,6,7,8-tetrahydro-4H-isoxazolo<4,5-c>azepine-5-carboxylate
• 英文别名: Methyl 3-Isopropoxy-5,6,7,8-tetrahydro-4H-isoxazolo[ 4,5-c]azepin-5-carboxylate；methyl 3-propan-2-yloxy-4,6,7,8-tetrahydro-[1,2]oxazolo[4,5-c]azepine-5-carboxylate
• CAS: 123732-47-8
• 化学式: C₁₂H₁₈N₂O₄
• 分子量: 254.286
• InChiKey: ZVUJXDFIMYLVGW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  64.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl 3-isopropoxy-5,6,7,8-tetrahydro-4H-isoxazolo<4,5-c>azepine-5-carboxylate 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 24.0h， 生成 3-Isopropoxy-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepine
  参考文献：
  名称：

  Annulated Heterocyclic Bioisosteres of Norarecoline. Synthesis and Molecular Pharmacology at Five Recombinant Human Muscarinic Acetylcholine Receptors

  摘要：

  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.

  DOI：

  10.1021/jm00012a019
• 作为产物：
  描述：

  2-溴丙烷 、 methyl 3-hydroxy-5,6,7,8-tetrahydro-4H-isoxazolo<4,5-c>azepine-5-carboxylate 在 potassium carbonate 作用下， 生成 methyl 3-isopropoxy-5,6,7,8-tetrahydro-4H-isoxazolo<4,5-c>azepine-5-carboxylate
  参考文献：
  名称：

  Annulated Heterocyclic Bioisosteres of Norarecoline. Synthesis and Molecular Pharmacology at Five Recombinant Human Muscarinic Acetylcholine Receptors

  摘要：

  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.

  DOI：

  10.1021/jm00012a019

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。
• US4960769A
  申请人：——

  公开号：US4960769A

  公开（公告）日：1990-10-02
• 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.