cis-1,9,10,10a-tetrahydro-4a(4H)-phenanthrenecarboxylic acid | 132451-56-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: cis-1,9,10,10a-tetrahydro-4a(4H)-phenanthrenecarboxylic acid
• 英文别名: (+/-)-(10acH)-1.9.10.10a-tetrahydro-4H-phenanthrene-carboxylic acid-(4ar)；(+/-)-(10acH)-1.9.10.10a-Tetrahydro-4H-phenanthren-carbonsaeure-(4ar)；(4aR,10aR)-4,9,10,10a-tetrahydro-1H-phenanthrene-4a-carboxylic acid
• CAS: 132451-56-0；149495-90-9；149495-92-1
• 化学式: C₁₅H₁₆O₂
• 分子量: 228.291
• InChiKey: VPIKHFWERATWBS-SWLSCSKDSA-N

物化性质

• 沸点：
  379.1±42.0 °C(Predicted)
• 密度：
  1.210±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  cis-1,9,10,10a-tetrahydro-4a(4H)-phenanthrenecarboxylic acid 生成 (4aS-cis)-1,9,10,10a-tetrahydro-4a(4H)-phenanthrene carboxylic acid
  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：

  alkaline earth salt of/the/ methylsulfuric acid 在 sodium ethanolate 作用下， 生成 cis-1,9,10,10a-tetrahydro-4a(4H)-phenanthrenecarboxylic acid
  参考文献：
  名称：

  The Synthesis of Phenanthrene and Hydrophenanthrene Derivatives. V. The Addition of Dienes to Cyclic α,β-Unsaturated Esters

  摘要：

  DOI：

  10.1021/ja01302a069

文献信息

• Polycyclic amines useful as cerebrovascular agents
  申请人：Warner-Lambert Company

  公开号：US05180736A1

  公开（公告）日：1993-01-19

  A novel series of polycyclic amines, derivatives, methods of making the compounds, novel intermediates, compositions containing them, and methods for using them in the treatment and prevention of cerebrovascular disorders are disclosed.

  本发明揭示了一系列新型多环胺、衍生物、制备这些化合物的方法、新型中间体、包含它们的组合物以及在治疗和预防脑血管疾病中使用它们的方法。
• Tetracyclic amines having pharmaceutical activity
  申请人：Warner-Lambert Company

  公开号：US05141934A1

  公开（公告）日：1992-08-25

  The present invention relates to novel tetracyclic amines and derivatives thereof useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The compounds of the present invention are useful in the treatment of neurodegenerative disorders including cerebrovascular disorders.

  本发明涉及新型四环胺及其衍生物，可用作药物，以及其生产方法、包括这些化合物和药用可接受载体的制药组合物，以及药用治疗方法。本发明的化合物可用于治疗包括脑血管疾病在内的神经退行性疾病。
• Synthesis and pharmacological evaluation of 4a-phenanthrenamine derivatives acting at the phencyclidine binding site of the N-methyl-D-aspartate receptor complex
  作者：Christopher F. Bigge、Thomas C. Malone、Sheryl J. Hays、Graham Johnson、Perry M. Novak、Leonard J. Lescosky、Daniel M. Retz、Daniel F. Ortwine、Albert W. Probert

  DOI：10.1021/jm00066a007

  日期：1993.7

  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.
• The Synthesis of Phenanthrene and Hydrophenanthrene Derivatives. V. The Addition of Dienes to Cyclic α,β-Unsaturated Esters
  作者：L. F. Fieser、H. L. Holmes

  DOI：10.1021/ja01302a069

  日期：1936.11