ethyl 4-hydroxy-4H-2,3-dihydro-4-benzothiopyran-4-carboximidate | 74187-65-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 硫铬烷
• 英文名称: ethyl 4-hydroxy-4H-2,3-dihydro-4-benzothiopyran-4-carboximidate
• 英文别名: Ethyl 4-hydroxy-2,3-dihydrothiochromene-4-carboximidate
• CAS: 74187-65-8
• 化学式: C₁₂H₁₅NO₂S
• 分子量: 237.323
• InChiKey: YSACVGAFJSBKOX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  78.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 4-hydroxy-4H-2,3-dihydro-4-benzothiopyran-4-carboximidate 在 palladium on activated charcoal 2,6-二叔丁基-4-甲基苯酚 、 硫酸 、 叠氮磷酸二苯酯 、 2-甲基苯磺酸 、 potassium trimethylsilonate 、 氢气 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 甲苯 为溶剂， 25.0~150.0 ℃ 、351.64 kPa 条件下， 反应 376.0h， 生成 methyl (6aS-cis)-(6,6a,7,8,9,10-hexahydro-10a-dibenzothiopyran-10a-yl)carbamate
  参考文献：
  名称：

  Synthesis and pharmacological evaluation of 4a-phenanthrenamine derivatives acting at the phencyclidine binding site of the N-methyl-D-aspartate receptor complex

  摘要：

  A novel series of octahydrophenanthrenamines and their heterocyclic analogues have been synthesized as potential noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor complex. The compounds were evaluated for their affinity at the phencyclidine (PCP) binding site by determining their ability to displace [H-3]TCP from crude rat brain synaptic membranes. A wide range of affinities were observed, with the most potent analogs possessing IC50's equivalent to that of the reference agent MK-801 (3,dizocilpine). NMDA antagonist activity was demonstrated by prevention of glutamate-induced accumulation of [Ca-45(2+)] in cultured rat cortical neurons. Selected compounds were also studied in vivo to determine their ability to prevent the lethal effects of systemically injected NMDA in the mouse. In general, the SAR of the phenanthrenamine series may be summarized as follows: (a) for the amino group at C4a, NHMe > NH2 > NHEt much-greater-than NC5H10; (b) for the B-ring substitution, X = CH2 > S > 0; (c) unsaturation of the C ring decreases receptor affinity; (d) cis-ring fusion between the B and C rings is desirable; (e) 6-hydroxy or 6-methoxy substitution of the phenanthrenamine system identified an additional hydrogen bonding interaction that substantially increased receptor affinity; (f) spiro analogues (such as 55, IC50 = 3400 nM), which altered the point of attachment of the C ring, caused a substantial reduction in PCP-site affinity. Molecules from this series were useful for refining a pharmacophore model consistent with previous models of the PCP site. In this model, the (R)-(+)-phenanthrenamine 13 superimposes closely onto MK-801 (3), and the angular 4a-amino group is believed to hydrogen bond with a putative receptor site atom. In the phenanthrenamine and thiaphenanthrenamine series, the (R)-(+)-enantiomers (9, 13, and 44) are more potent by approximately 5-10-fold than their corresponding (S)-(-)-enantiomers with respect to their affinity for the PCP site, their ability to prevent accumulation of [Ca-45(2+)] in cultured neuronal cells, and their protection against the lethal effects of NMDA in mice. In general, there was no separation between the dose that prevented NMDA lethality and the dose that produced ataxia in mice, except in the case of the thiaphenanthrenamines 41 and 43. We have not yet obtained evidence that this small separation in activity offers a therapeutic advantage in the treatment of cerebral ischemia or other neurodegenerative disorders.

  DOI：

  10.1021/jm00066a007
• 作为产物：
  描述：

  硫代色满-4-酮 在 盐酸 、 zinc(II) iodide 作用下， 以 二氯甲烷 为溶剂， 反应 44.0h， 生成 ethyl 4-hydroxy-4H-2,3-dihydro-4-benzothiopyran-4-carboximidate
  参考文献：
  名称：

  Synthesis and pharmacological evaluation of 4a-phenanthrenamine derivatives acting at the phencyclidine binding site of the N-methyl-D-aspartate receptor complex

  摘要：

  A novel series of octahydrophenanthrenamines and their heterocyclic analogues have been synthesized as potential noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor complex. The compounds were evaluated for their affinity at the phencyclidine (PCP) binding site by determining their ability to displace [H-3]TCP from crude rat brain synaptic membranes. A wide range of affinities were observed, with the most potent analogs possessing IC50's equivalent to that of the reference agent MK-801 (3,dizocilpine). NMDA antagonist activity was demonstrated by prevention of glutamate-induced accumulation of [Ca-45(2+)] in cultured rat cortical neurons. Selected compounds were also studied in vivo to determine their ability to prevent the lethal effects of systemically injected NMDA in the mouse. In general, the SAR of the phenanthrenamine series may be summarized as follows: (a) for the amino group at C4a, NHMe > NH2 > NHEt much-greater-than NC5H10; (b) for the B-ring substitution, X = CH2 > S > 0; (c) unsaturation of the C ring decreases receptor affinity; (d) cis-ring fusion between the B and C rings is desirable; (e) 6-hydroxy or 6-methoxy substitution of the phenanthrenamine system identified an additional hydrogen bonding interaction that substantially increased receptor affinity; (f) spiro analogues (such as 55, IC50 = 3400 nM), which altered the point of attachment of the C ring, caused a substantial reduction in PCP-site affinity. Molecules from this series were useful for refining a pharmacophore model consistent with previous models of the PCP site. In this model, the (R)-(+)-phenanthrenamine 13 superimposes closely onto MK-801 (3), and the angular 4a-amino group is believed to hydrogen bond with a putative receptor site atom. In the phenanthrenamine and thiaphenanthrenamine series, the (R)-(+)-enantiomers (9, 13, and 44) are more potent by approximately 5-10-fold than their corresponding (S)-(-)-enantiomers with respect to their affinity for the PCP site, their ability to prevent accumulation of [Ca-45(2+)] in cultured neuronal cells, and their protection against the lethal effects of NMDA in mice. In general, there was no separation between the dose that prevented NMDA lethality and the dose that produced ataxia in mice, except in the case of the thiaphenanthrenamines 41 and 43. We have not yet obtained evidence that this small separation in activity offers a therapeutic advantage in the treatment of cerebral ischemia or other neurodegenerative disorders.

  DOI：

  10.1021/jm00066a007

文献信息

• Spiro oxazolidinedione aldose reductase inhibitors
  作者：Rodney C. Schnur、Reinhard Sarges、Michael J. Peterson

  DOI：10.1021/jm00354a012

  日期：1982.12

  Spiro oxazolidinediones (2) derived from five- and six-membered ring aralkyl ketones are potent aldose reductase inhibitors in vitro and in vivo. Their novel and general synthesis has been devised with alpha-hydroxyimidates (5) and 4-alkoxy-2-oxo-3-oxazolines (6) as key intermediates, since traditional synthetic routes through alpha-hydroxy amides (8) usually led to alpha, beta-unsaturated amides (9)

  衍生自五元和六元环芳烷基酮的螺恶唑烷二酮（2）是体外和体内有效的醛糖还原酶抑制剂。他们设计了新颖且通用的合成方法，因为α-羟基亚氨酸盐（5）和4-烷氧基-2-氧代-3-恶唑啉（6）是关键中间体，因为传统的合成途径通常是通过α-羟基酰胺（8）生成α ，β-不饱和酰胺（9）。用辛可尼定拆分得到旋光的螺恶唑烷二酮。最佳生物活性存在于（4S）-6-氯螺[4H-2,3-二氢苯并吡喃-4,5'-恶唑烷] -2'，4'-二酮（21）及其6,8-二氯同类物（23）中。
• SCHNUR, R. C.;SARGES, R.;PETERSON, M. J., J. MED. CHEM., 1982, 25, N 12, 1451-1454
  作者：SCHNUR, R. C.、SARGES, R.、PETERSON, M. J.

  DOI：——

  日期：——
• US4200642A
  申请人：——

  公开号：US4200642A

  公开（公告）日：1980-04-29
• US4267342A
  申请人：——

  公开号：US4267342A

  公开（公告）日：1981-05-12
• US4305877A
  申请人：——

  公开号：US4305877A

  公开（公告）日：1981-12-15