(+/-)-1,4,9,9a-teyrahydro-2-oxa-3a-azacyclopentanaphthalen-3-one | 233272-47-4

• 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: (+/-)-1,4,9,9a-teyrahydro-2-oxa-3a-azacyclopentanaphthalen-3-one
• 英文别名: 3H-Oxazolo[3,4-b]isoquinolin-3-one, 1,5,10,10a-tetrahydro-；1,5,10,10a-tetrahydro-[1,3]oxazolo[3,4-b]isoquinolin-3-one
• CAS: 233272-47-4
• 化学式: C₁₁H₁₁NO₂
• 分子量: 189.214
• InChiKey: PQFFRQRPJFUMFO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (+/-)-1,4,9,9a-teyrahydro-2-oxa-3a-azacyclopentanaphthalen-3-one 在 盐酸 、 氯磺酸 、 氢氧化钾 、 sodium acetate 、 肼 作用下， 以 四氢呋喃 、 乙醇 、 氯仿 为溶剂， 反应 49.0h， 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：

  1,2,3,4-四氢异喹啉-3-羧酸 在 sodium hydroxide 、 硼烷四氢呋喃络合物 、 三氟化硼乙醚 作用下， 以 四氢呋喃 为溶剂， 反应 6.0h， 生成 (+/-)-1,4,9,9a-teyrahydro-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

• CHIRAL TETRADENTATE LIGAND, METHOD FOR PRODUCING SAME AND TRANSITION METAL COMPLEX OF SAID CHIRAL TETRADENTATE LIGAND
  申请人：TAKASAGO INTERNATIONAL CORPORATION

  公开号：US20200369700A1

  公开（公告）日：2020-11-26

  The present invention relates to a compound represented by the formula (1 A ). G represents a group selected from the group consisting of a monovalent group represented by the formula (G P ) and a monovalent group represented by the formula (G S ). R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 each independently represent a hydrogen atom or a group selected from the group consisting of an alkyl group, an alkenyl group, an aryl group, an aralkyl group, an alkoxy group, a halogeno group, and a halogeno alkyl group.

  本发明涉及一种由式（1A）表示的化合物。G代表从单价基团（GP）表示的基团和从单价基团（GS）表示的基团中选择的基团。R4、R5、R6、R7、R8、R9、R10、R11和R12各自独立地表示氢原子或从烷基、烯基、芳基、芳基烷基、烷氧基、卤素基和卤素烷基组成的基团中选择的基团。
• 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.

表征谱图