(+/-)-6-methylsulfonyl-1,4,9,9a-tetrahydro-2-oxa-3a-azacyclopentanaphthalen-3-one | 233272-52-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: (+/-)-6-methylsulfonyl-1,4,9,9a-tetrahydro-2-oxa-3a-azacyclopentanaphthalen-3-one
• 英文别名: 7-Methylsulfonyl-1,5,10,10a-tetrahydro-[1,3]oxazolo[3,4-b]isoquinolin-3-one
• CAS: 233272-52-1
• 化学式: C₁₂H₁₃NO₄S
• 分子量: 267.306
• InChiKey: CEQHFNACOXOVJK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  72.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (+/-)-6-methylsulfonyl-1,4,9,9a-tetrahydro-2-oxa-3a-azacyclopentanaphthalen-3-one 在 盐酸 、 氢氧化钾 作用下， 生成 (+/-)-7-methylsulfonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride
  参考文献：
  名称：

  3,7-Disubstituted-1,2,3,4-tetrahydroisoquinolines Display Remarkable Potency and Selectivity as Inhibitors of Phenylethanolamine N-Methyltransferase versus the α₂-Adrenoceptor^1a

  摘要：

  3-Hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (4) is a more selective inhibitor (PNMT K-i = 1.1 mu M, alpha(2) K-i = 6.6 mu M, selectivity (alpha(2) K-i/PNMT K-i) = 6.0) of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), with respect to its az-adrenoceptor affinity, than is 3-methyl-1,2,3,4-tetrahydroisoquinoline (2; PNMT K-i = 2.1 mu M, alpha 2 K-i = 0.76 mu M, selectivity = 0.36) or 1,2,3,4-tetrahydroisoquinoline (1, THIQ; PNMT K-i = 9.7 mu M, alpha 2 K-i = 0.35 mu M, selectivity = 0.036). Evaluation of the O-methyl ether derivative of 4 suggested that the 3-hydroxymethyl substituent might be involved in a hydrogen-bond donor-type of interaction at a sterically compact region in the PNMT active site. The directionality of the steric bulk tolerance at both the PNMT active site and the alpha(2)-adrenoceptor appears to be the same. Since the presence of a hydrophilic electron-withdrawing substituent (such as NO2, SO2CH3, or SO2NH2) at the 7-position of THIQ reduced the binding affinity toward the alpha(2)-adrenoceptor, we investigated the combination of both a hydrophilic electron-withdrawing 7-substituent and a S-alkyl substituent on a THIQ nucleus. A synergistic effect in increasing the PNMT-inhibitory potency of the THIQ nucleus and reducing the affinity toward the alpha(2)-adrenoceptor was observed with this 3,7-disubstitution. Remarkably, 7-aminosulfonyl-3-hydroxymethyl-THIQ (12; PNMT K-i = 0.34 mu M, alpha 2 K-i = 1400 mu M, selectivity = 4100) displayed a 23-680-fold enhanced selectivity over the parent compounds 27 (SK&F 29661; PNMT K-i = 0.55 mu M, alpha 2 K-i = 100 mu M, selectivity = 180) and 4 (selectivity = 6.0) and is thus the most selective PNMT inhibitor yet reported.

  DOI：

  10.1021/jm9807252
• 作为产物：
  描述：

  3-羟甲基-1,2,3,4-四氢异喹啉 在 氯磺酸 、 sodium acetate 、 肼 作用下， 以 四氢呋喃 、 乙醇 、 氯仿 为溶剂， 反应 39.0h， 生成 (+/-)-6-methylsulfonyl-1,4,9,9a-tetrahydro-2-oxa-3a-azacyclopentanaphthalen-3-one
  参考文献：
  名称：

  3,7-Disubstituted-1,2,3,4-tetrahydroisoquinolines Display Remarkable Potency and Selectivity as Inhibitors of Phenylethanolamine N-Methyltransferase versus the α₂-Adrenoceptor^1a

  摘要：

  3-Hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (4) is a more selective inhibitor (PNMT K-i = 1.1 mu M, alpha(2) K-i = 6.6 mu M, selectivity (alpha(2) K-i/PNMT K-i) = 6.0) of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), with respect to its az-adrenoceptor affinity, than is 3-methyl-1,2,3,4-tetrahydroisoquinoline (2; PNMT K-i = 2.1 mu M, alpha 2 K-i = 0.76 mu M, selectivity = 0.36) or 1,2,3,4-tetrahydroisoquinoline (1, THIQ; PNMT K-i = 9.7 mu M, alpha 2 K-i = 0.35 mu M, selectivity = 0.036). Evaluation of the O-methyl ether derivative of 4 suggested that the 3-hydroxymethyl substituent might be involved in a hydrogen-bond donor-type of interaction at a sterically compact region in the PNMT active site. The directionality of the steric bulk tolerance at both the PNMT active site and the alpha(2)-adrenoceptor appears to be the same. Since the presence of a hydrophilic electron-withdrawing substituent (such as NO2, SO2CH3, or SO2NH2) at the 7-position of THIQ reduced the binding affinity toward the alpha(2)-adrenoceptor, we investigated the combination of both a hydrophilic electron-withdrawing 7-substituent and a S-alkyl substituent on a THIQ nucleus. A synergistic effect in increasing the PNMT-inhibitory potency of the THIQ nucleus and reducing the affinity toward the alpha(2)-adrenoceptor was observed with this 3,7-disubstitution. Remarkably, 7-aminosulfonyl-3-hydroxymethyl-THIQ (12; PNMT K-i = 0.34 mu M, alpha 2 K-i = 1400 mu M, selectivity = 4100) displayed a 23-680-fold enhanced selectivity over the parent compounds 27 (SK&F 29661; PNMT K-i = 0.55 mu M, alpha 2 K-i = 100 mu M, selectivity = 180) and 4 (selectivity = 6.0) and is thus the most selective PNMT inhibitor yet reported.

  DOI：

  10.1021/jm9807252

文献信息

• 3,7-Disubstituted-1,2,3,4-tetrahydroisoquinolines Display Remarkable Potency and Selectivity as Inhibitors of Phenylethanolamine <i>N-</i>Methyltransferase versus the α₂-Adrenoceptor^1a
  作者：Gary L. Grunewald、Vilas H. Dahanukar、Bee Teoh、Kevin R. Criscione

  DOI：10.1021/jm9807252

  日期：1999.6.1

  3-Hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (4) is a more selective inhibitor (PNMT K-i = 1.1 mu M, alpha(2) K-i = 6.6 mu M, selectivity (alpha(2) K-i/PNMT K-i) = 6.0) of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), with respect to its az-adrenoceptor affinity, than is 3-methyl-1,2,3,4-tetrahydroisoquinoline (2; PNMT K-i = 2.1 mu M, alpha 2 K-i = 0.76 mu M, selectivity = 0.36) or 1,2,3,4-tetrahydroisoquinoline (1, THIQ; PNMT K-i = 9.7 mu M, alpha 2 K-i = 0.35 mu M, selectivity = 0.036). Evaluation of the O-methyl ether derivative of 4 suggested that the 3-hydroxymethyl substituent might be involved in a hydrogen-bond donor-type of interaction at a sterically compact region in the PNMT active site. The directionality of the steric bulk tolerance at both the PNMT active site and the alpha(2)-adrenoceptor appears to be the same. Since the presence of a hydrophilic electron-withdrawing substituent (such as NO2, SO2CH3, or SO2NH2) at the 7-position of THIQ reduced the binding affinity toward the alpha(2)-adrenoceptor, we investigated the combination of both a hydrophilic electron-withdrawing 7-substituent and a S-alkyl substituent on a THIQ nucleus. A synergistic effect in increasing the PNMT-inhibitory potency of the THIQ nucleus and reducing the affinity toward the alpha(2)-adrenoceptor was observed with this 3,7-disubstitution. Remarkably, 7-aminosulfonyl-3-hydroxymethyl-THIQ (12; PNMT K-i = 0.34 mu M, alpha 2 K-i = 1400 mu M, selectivity = 4100) displayed a 23-680-fold enhanced selectivity over the parent compounds 27 (SK&F 29661; PNMT K-i = 0.55 mu M, alpha 2 K-i = 100 mu M, selectivity = 180) and 4 (selectivity = 6.0) and is thus the most selective PNMT inhibitor yet reported.