N-(6-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-N'-(4-chlorophenyl)thiourea

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: N-(6-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-N'-(4-chlorophenyl)thiourea
• 英文别名: BPDZ490；R/S-6-bromo-4-(4-chlorophenylaminothiocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran；1-(6-Bromo-2,2-dimethyl-3,4-dihydrochromen-4-yl)-3-(4-chlorophenyl)thiourea
• 化学式: C₁₈H₁₈BrClN₂OS
• 分子量: 425.777
• InChiKey: XGJJLDUNEIOCCW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  65.4
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N-(6-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-N'-(4-chlorophenyl)thiourea 、 碘甲烷 以 丙酮 为溶剂， 以83%的产率得到N-(6-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-N'-(4-chlorophenyl)-S-methylisothiouronium hydroiodide
  参考文献：
  名称：

  New R/S-3,4-dihydro-2,2-dimethyl-2H-1-benzopyrans as KATP channel openers: Modulation of the 4-position

  摘要：

  The present work aimed at exploring a series of diversely 4-arylthiourea-substituted R/S-3,4-dihydro-2,2-dimethyl- 6-halo-2H-1-benzopyrans structurally related to (+/-)-cromakalim. These new compounds were examined in vitro as putative potassium channel openers (PCOs) on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (relaxation of aorta ring) and their activity was compared to that of the reference K-ATP channel activators (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and of previously reported cromakalim analogues. Structure-activity relationships indicated that the most pronounced inhibitory activity on the insulin secretory process was obtained with molecules bearing a strong metaor para-electron-withdrawing group (CN or NO2) on the phenyl ring of the arylthiourea moiety at the 4-position of the benzopyran nucleus (compounds 12-23). Among those, R/S-6-chloro-4-(4-cyanophenylaminothiocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (16) was found to be the most potent benzopyran-type inhibitor of insulin release ever described. Most of these original benzopyran derivatives show increased selectivity for pancreatic versus vascular tissue. Radioisotopic investigations indicated that these new compounds activated pancreatic KATP channels. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.09.041
• 作为产物：
  描述：

  4-氯异硫氰酸苯酯 、 6-溴-3,4-二氢-2,2-二甲基-2H-1-苯并吡喃-4-胺 以 二氯甲烷 为溶剂， 反应 0.5h， 以60%的产率得到N-(6-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-N'-(4-chlorophenyl)thiourea
  参考文献：
  名称：

  新的R / S-3,4-二氢-2,2-二甲基-6-卤代4-（苯基氨基硫代羰基氨基）-2H-1-苯并吡喃酮与（+/-）-cromakalim在结构上相关，可作为组织选择性胰腺β-细胞K（ATP）通道开启剂。

  摘要：

  本工作旨在探索一系列与（+/-）结构相关的R / S-3,4-二氢-2,2-二甲基-6-卤代4-（苯基氨基硫代羰基氨基）-2H-1-苯并吡喃-cromakalim，在4位和6位上有不同取代。这些推定的ATP敏感性钾通道激活剂（K（ATP））的生物学效应在体外在胰腺内分泌组织上（抑制胰岛素释放）和在血管平滑肌组织上（主动脉环松弛）进行了表征。进一步将这些新的二甲基苯并二氢吡喃衍生物的生物活性与（+/-）-cromakalim，（+/-）-吡那地尔，二氮嗪和BPDZ 73的生物活性进行了比较。构效关系表明，通过在C-4苯环上引入间位或对位电子吸收基团（例如氯原子），可以获得胰腺组织增强的效力，而与卤素原子的性质无关苯并吡喃核的6位。大多数原始的二甲基苯并二氢吡喃硫脲在抑制胰岛素释放方面比其“脲”同系物更有效，甚至比二氮嗪更有效。此外，与（+/-）-cromakalim或（+/-）-吡那地尔不同

  DOI：

  10.1016/j.bmc.2008.03.065

文献信息

• [EN] BENZOPYRAN DERIVATIVES, METHOD OF PRODUCTION AND USE THEREOF<br/>[FR] DERIVES DE BENZOPYRANE, PROCEDE DE PRODUCTION ET D'UTILISATION DE CEUX-CI
  申请人：UNIV LIEGE

  公开号：WO2005075463A1

  公开（公告）日：2005-08-18

  The invention relates to novel benzopyran derivatives of formula (I), to their method of production, to composition comprising the derivatives and use thereof. Formula (I) wherein: R1, R2, R3 and R4 are independently hydrogen, halogen, C1-6-alkyl. C3-8­-cycloalkyl, hydroxy, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, nitro, amino, cyano, cyanomethyl, perhalomethyl, C1-6-monoalkyl- or dialkylamino, sulfamoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkylsulfinyl, formyl, C1-6-alkylcarbonylamino, R8arylthio, R8arylsulfinyl, R8arylsulfonyl, C1-6-alkoxycarbonyl, C1-6-alkoxycarbonyl-C1-6-alkyl, carbamoyl, carbamoylmethyl, C1-6-monoalkyl- or dialkylaminocarbonyl, C1-6-monoalkyl- or dialkylaminothiocarbonyl, ureido, C1-6-monoalkyl- or dialkylaminocarbonylamino, thioureido, C1-6-monoalkyl- or dialkylaminothiocarbonylamino, C1-6-monoalkyl- or dialkylaminosulfonyl, carboxy, carboxy-C1-6-alkyl, acyl, R8aryl, R8aryl-C1-6-alkyl, R8aryloxy; R5 and R6 are each independently hydrogen, C1-6-alkyl or, R5 and R6 taken together with the carbon atom to which they are attached form a 3- to 6-membered carbocyclic ring; R7 is 2-, 3- or 4-pyridyl optionally mono- or polysubstituted by R1; R7 is 2- or 3-thienyl optionally mono- or polysubstituted substituted by R1 or R7 is phenyl optionally mono- or polysubstituted by R1 with the exception of or R7 representing C6H5 ; R8 is hydrogen, halogen, C1-6-alkyl, C3-8-cycloalkyl, hydroxy, C1-6-alkoxy, nitro, amino, cyano, cyanomethyl, perhalomethyl; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture or any polymorphic and tautomeric form.

  该发明涉及公式（I）的新型苯并吡喃衍生物，以及它们的生产方法、包含这些衍生物的组合物和它们的用途。公式（I）中：R1、R2、R3和R4独立地为氢、卤素、C1-6-烷基、C3-8-环烷基、羟基、C1-6-烷氧基、C1-6-烷氧基-C1-6-烷基、硝基、氨基、氰基、氰甲基、全卤甲基、C1-6-单烷基或二烷基氨基、磺酰胺基、C1-6-烷基硫基、C1-6-烷基磺酰基、C1-6-烷基亚磺酰基、甲酰基、C1-6-烷基羰胺基、R8芳基硫基、R8芳基亚磺酰基、R8芳基磺酰基、C1-6-烷氧羰基、C1-6-烷氧羰基-C1-6-烷基、氨基甲酰基、氨基甲基、C1-6-单烷基或二烷基氨基甲酰基、C1-6-单烷基或二烷基氨基硫酰基、脲基、C1-6-单烷基或二烷基氨基甲酰胺基、硫脲基、C1-6-单烷基或二烷基氨基硫酰胺基、C1-6-单烷基或二烷基氨基磺酰基、羧基、羧基-C1-6-烷基、酰基、R8芳基、R8芳基-C1-6-烷基、R8芳氧基；R5和R6各自独立地为氢、C1-6-烷基或者R5和R6与它们连接的碳原子一起形成3-至6-成员的碳环；R7为2-、3-或4-吡啶基，可选地通过R1单取代或多取代；R7为2-或3-噻吩基，可选地通过R1单取代或多取代，或者R7为苯基，可选地通过R1单取代或多取代，但不包括R7代表C6H5；R8为氢、卤素、C1-6-烷基、C3-8-环烷基、羟基、C1-6-烷氧基、硝基、氨基、氰基、氰甲基、全卤甲基；或其与药学上可接受的酸或碱形成的盐，或任何光学异构体或光学异构体混合物，包括消旋混合物或任何多形和互变异构体。
• New R/S-3,4-dihydro-2,2-dimethyl-2H-1-benzopyrans as KATP channel openers: Modulation of the 4-position
  作者：Xavier Florence、Sophie Sebille、Pascal de Tullio、Philippe Lebrun、Bernard Pirotte

  DOI：10.1016/j.bmc.2009.09.041

  日期：2009.11

  The present work aimed at exploring a series of diversely 4-arylthiourea-substituted R/S-3,4-dihydro-2,2-dimethyl- 6-halo-2H-1-benzopyrans structurally related to (+/-)-cromakalim. These new compounds were examined in vitro as putative potassium channel openers (PCOs) on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (relaxation of aorta ring) and their activity was compared to that of the reference K-ATP channel activators (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and of previously reported cromakalim analogues. Structure-activity relationships indicated that the most pronounced inhibitory activity on the insulin secretory process was obtained with molecules bearing a strong metaor para-electron-withdrawing group (CN or NO2) on the phenyl ring of the arylthiourea moiety at the 4-position of the benzopyran nucleus (compounds 12-23). Among those, R/S-6-chloro-4-(4-cyanophenylaminothiocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (16) was found to be the most potent benzopyran-type inhibitor of insulin release ever described. Most of these original benzopyran derivatives show increased selectivity for pancreatic versus vascular tissue. Radioisotopic investigations indicated that these new compounds activated pancreatic KATP channels. (C) 2009 Elsevier Ltd. All rights reserved.
• New R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminothiocarbonylamino)-2H-1-benzopyrans structurally related to (±)-cromakalim as tissue-selective pancreatic β-cell KATP channel openers
  作者：Sophie Sebille、Pascal de Tullio、Xavier Florence、Bénédicte Becker、Marie-Hélène Antoine、Catherine Michaux、Johan Wouters、Bernard Pirotte、Philippe Lebrun

  DOI：10.1016/j.bmc.2008.03.065

  日期：2008.5

  the vascular smooth muscle tissue (relaxation of aorta rings). The biological activity of these new dimethylchroman derivatives was further compared to that of (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and BPDZ 73. Structure-activity relationships indicated that an improved potency for the pancreatic tissue was obtained by introducing a meta- or a para-electron-withdrawing group such as a chlorine

  本工作旨在探索一系列与（+/-）结构相关的R / S-3,4-二氢-2,2-二甲基-6-卤代4-（苯基氨基硫代羰基氨基）-2H-1-苯并吡喃-cromakalim，在4位和6位上有不同取代。这些推定的ATP敏感性钾通道激活剂（K（ATP））的生物学效应在体外在胰腺内分泌组织上（抑制胰岛素释放）和在血管平滑肌组织上（主动脉环松弛）进行了表征。进一步将这些新的二甲基苯并二氢吡喃衍生物的生物活性与（+/-）-cromakalim，（+/-）-吡那地尔，二氮嗪和BPDZ 73的生物活性进行了比较。构效关系表明，通过在C-4苯环上引入间位或对位电子吸收基团（例如氯原子），可以获得胰腺组织增强的效力，而与卤素原子的性质无关苯并吡喃核的6位。大多数原始的二甲基苯并二氢吡喃硫脲在抑制胰岛素释放方面比其“脲”同系物更有效，甚至比二氮嗪更有效。此外，与（+/-）-cromakalim或（+/-）-吡那地尔不同