(+/-)-trans-3,4,4a,10b-tetrahydro-9-methoxy-2H,5H-[1]benzothiopyranol[4,3-b]-1,4-oxazine

• 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: (+/-)-trans-3,4,4a,10b-tetrahydro-9-methoxy-2H,5H-[1]benzothiopyranol[4,3-b]-1,4-oxazine
• 英文别名: (4aR,10bS)-9-methoxy-2,3,4,4a,5,10b-hexahydrothiochromeno[4,3-b][1,4]oxazine
• 化学式: C₁₂H₁₅NO₂S
• 分子量: 237.323
• InChiKey: UYHWXSVSBWZEDP-JQWIXIFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (+/-)-trans-3,4,4a,10b-tetrahydro-9-methoxy-2H,5H-[1]benzothiopyranol[4,3-b]-1,4-oxazine 在 potassium tert-butylate 、 水 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.83h， 生成 (+)-(4aS,10bR)-3,4,4a,10b-tetrahydro-9-methoxy-2H,5H-[1]benzothiopyranol[4,3-b]-1,4-oxazine
  参考文献：
  名称：

  Synthesis and Pharmacological Evaluation of Thiopyran Analogues of the Dopamine D₃ Receptor-Selective Agonist (4aR,10bR)-(+)-trans-3,4,4a,10b- Tetrahydro-4-n-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol (PD 128907)

  摘要：

  Benzopyranoxazine (+)-7 (PD 128907) is the most dopamine (DA) D-3 receptor-selective agonist presently known. The only structural feature which distinguishes 7 from the analogous nonselective naphthoxazines is an oxygen atom in the 6-position. To extend this series of tricyclic DA agonists we used a classic bioisoster approach and synthesized thiopyran analogues of 7, which have a sulfur atom in the 6-position. We prepared trans-4-n-propyl-3,4,4a, 10b-tetrahydro-2H,5H-[1]benzothiopyrano[4,3-b]-1,4-oxazin -(9,trans-9-OH-PTBTO), its enantiomers ((+)-9 and (-)-9), the racemic cia-analogue (10), and the racemic trans-sulfoxide (11) and studied the potency and selectivity for DA receptors of these compounds. As with other rigid DA agonists, the highest affinity for DA receptors resided in one of the enantiomers, in this case the (-)enantiomer of 9. On the basis of a single-crystal X-ray analysis of a key intermediate, the absolute configuration of(-)-9 was found to be 4aS, 10bR, which is homochiral with (+)-(4aR-10bR)-7. In contrast to (+)-7 however, (-)-9 displayed no selectivity for any of the DA receptors. In addition, it has affinity for 5HT(1A) receptors. (+/-)-cis-4-n-Propyl-3,4,4a,10b-tetrahydro- [1]benzothiopyrano[4,3-b]-1,4-oxazin-9-ol (10), which was expected to be inactive, displayed affinity and selectivity for the DA D-3 receptor, whereas the sulfoxide 11 displayed some DA D-3 selectivity, but with a lower affinity. Further pharmacological evaluation revealed that (-)-9 is a very potent full agonist at DA D-2 receptors and a partial agonist at DA D-3 receptors. The cia-analogue (+/-)-10 displayed the same profile, but with lower potency. These findings were confirmed in vivo: in reserpinized rats (-)-9 displayed short-acting activation of locomotor activity (DA D-2 agonism) and also lower lip retraction and flat body posture, (5HT(1A) agonism). Compound (+/-)-10 had no effect on locomotor activity. In unilaterally 6-OH-DA lesioned rats, (-)-9 gave short-acting locomotor activation. Furthermore, in microdialysis studies in rat striatum, (-)-9 potently decreased DA release, confirming its activation of presynaptic DA D-2 receptors.

  DOI：

  10.1021/jm0000113
• 作为产物：
  描述：

  (+/-)-trans-3,4,4a,10b-tetrahydro-9-methoxy-2H,5H-[1]benzothiopyranol[4,3-b]-1,4-oxazin-3-one 在 lithium aluminium tetrahydride 作用下， 以 乙醚 为溶剂， 反应 2.0h， 以97%的产率得到(+/-)-trans-3,4,4a,10b-tetrahydro-9-methoxy-2H,5H-[1]benzothiopyranol[4,3-b]-1,4-oxazine
  参考文献：
  名称：

  Synthesis and Pharmacological Evaluation of Thiopyran Analogues of the Dopamine D₃ Receptor-Selective Agonist (4aR,10bR)-(+)-trans-3,4,4a,10b- Tetrahydro-4-n-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol (PD 128907)

  摘要：

  Benzopyranoxazine (+)-7 (PD 128907) is the most dopamine (DA) D-3 receptor-selective agonist presently known. The only structural feature which distinguishes 7 from the analogous nonselective naphthoxazines is an oxygen atom in the 6-position. To extend this series of tricyclic DA agonists we used a classic bioisoster approach and synthesized thiopyran analogues of 7, which have a sulfur atom in the 6-position. We prepared trans-4-n-propyl-3,4,4a, 10b-tetrahydro-2H,5H-[1]benzothiopyrano[4,3-b]-1,4-oxazin -(9,trans-9-OH-PTBTO), its enantiomers ((+)-9 and (-)-9), the racemic cia-analogue (10), and the racemic trans-sulfoxide (11) and studied the potency and selectivity for DA receptors of these compounds. As with other rigid DA agonists, the highest affinity for DA receptors resided in one of the enantiomers, in this case the (-)enantiomer of 9. On the basis of a single-crystal X-ray analysis of a key intermediate, the absolute configuration of(-)-9 was found to be 4aS, 10bR, which is homochiral with (+)-(4aR-10bR)-7. In contrast to (+)-7 however, (-)-9 displayed no selectivity for any of the DA receptors. In addition, it has affinity for 5HT(1A) receptors. (+/-)-cis-4-n-Propyl-3,4,4a,10b-tetrahydro- [1]benzothiopyrano[4,3-b]-1,4-oxazin-9-ol (10), which was expected to be inactive, displayed affinity and selectivity for the DA D-3 receptor, whereas the sulfoxide 11 displayed some DA D-3 selectivity, but with a lower affinity. Further pharmacological evaluation revealed that (-)-9 is a very potent full agonist at DA D-2 receptors and a partial agonist at DA D-3 receptors. The cia-analogue (+/-)-10 displayed the same profile, but with lower potency. These findings were confirmed in vivo: in reserpinized rats (-)-9 displayed short-acting activation of locomotor activity (DA D-2 agonism) and also lower lip retraction and flat body posture, (5HT(1A) agonism). Compound (+/-)-10 had no effect on locomotor activity. In unilaterally 6-OH-DA lesioned rats, (-)-9 gave short-acting locomotor activation. Furthermore, in microdialysis studies in rat striatum, (-)-9 potently decreased DA release, confirming its activation of presynaptic DA D-2 receptors.

  DOI：

  10.1021/jm0000113

文献信息

• Synthesis and Pharmacological Evaluation of Thiopyran Analogues of the Dopamine D₃ Receptor-Selective Agonist (4a<i>R</i>,10b<i>R</i>)-(+)-<i>trans</i>-3,4,4a,10b- Tetrahydro-4-<i>n</i>-propyl-2<i>H</i>,5<i>H</i>-[1]benzopyrano[4,3-<i>b</i>]-1,4-oxazin-9-ol (PD 128907)
  作者：L. Alexander van Vliet、Nienke Rodenhuis、Durk Dijkstra、Håkan Wikström、Thomas A. Pugsley、Kevin A. Serpa、Leonard T. Meltzer、Thomas G. Heffner、Lawrence D. Wise、Mary E. Lajiness、Rita M. Huff、Kjell Svensson、Staffan Sundell、Max Lundmark

  DOI：10.1021/jm0000113

  日期：2000.7.1

  Benzopyranoxazine (+)-7 (PD 128907) is the most dopamine (DA) D-3 receptor-selective agonist presently known. The only structural feature which distinguishes 7 from the analogous nonselective naphthoxazines is an oxygen atom in the 6-position. To extend this series of tricyclic DA agonists we used a classic bioisoster approach and synthesized thiopyran analogues of 7, which have a sulfur atom in the 6-position. We prepared trans-4-n-propyl-3,4,4a, 10b-tetrahydro-2H,5H-[1]benzothiopyrano[4,3-b]-1,4-oxazin -(9,trans-9-OH-PTBTO), its enantiomers ((+)-9 and (-)-9), the racemic cia-analogue (10), and the racemic trans-sulfoxide (11) and studied the potency and selectivity for DA receptors of these compounds. As with other rigid DA agonists, the highest affinity for DA receptors resided in one of the enantiomers, in this case the (-)enantiomer of 9. On the basis of a single-crystal X-ray analysis of a key intermediate, the absolute configuration of(-)-9 was found to be 4aS, 10bR, which is homochiral with (+)-(4aR-10bR)-7. In contrast to (+)-7 however, (-)-9 displayed no selectivity for any of the DA receptors. In addition, it has affinity for 5HT(1A) receptors. (+/-)-cis-4-n-Propyl-3,4,4a,10b-tetrahydro- [1]benzothiopyrano[4,3-b]-1,4-oxazin-9-ol (10), which was expected to be inactive, displayed affinity and selectivity for the DA D-3 receptor, whereas the sulfoxide 11 displayed some DA D-3 selectivity, but with a lower affinity. Further pharmacological evaluation revealed that (-)-9 is a very potent full agonist at DA D-2 receptors and a partial agonist at DA D-3 receptors. The cia-analogue (+/-)-10 displayed the same profile, but with lower potency. These findings were confirmed in vivo: in reserpinized rats (-)-9 displayed short-acting activation of locomotor activity (DA D-2 agonism) and also lower lip retraction and flat body posture, (5HT(1A) agonism). Compound (+/-)-10 had no effect on locomotor activity. In unilaterally 6-OH-DA lesioned rats, (-)-9 gave short-acting locomotor activation. Furthermore, in microdialysis studies in rat striatum, (-)-9 potently decreased DA release, confirming its activation of presynaptic DA D-2 receptors.