(1S,3′R,4′S,5′S,6′R)-5-chloro-3′,4′,5′,6′-tetrahydro-6,6′-bis(hydroxymethyl)-spiro[2-benzofuran-1(3H),2′-[2H]pyran]-3′,4′,5′-triol | 1005142-63-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异香豆素
• 英文名称: (1S,3′R,4′S,5′S,6′R)-5-chloro-3′,4′,5′,6′-tetrahydro-6,6′-bis(hydroxymethyl)-spiro[2-benzofuran-1(3H),2′-[2H]pyran]-3′,4′,5′-triol
• 英文别名: (1S,3'R,4'S,5'R,6'R)-5-chloro-3',4',5',6'-tetrahydro-6,6'-bis(hydroxymethyl)-spiro[isobenzofuran-1(3H),2'-[2H]pyran]-3',4',5'-triol；(1S,3'R,4'S,5'S,6'R)-5-chloro-3',4',5',6'-tetrahydro-6,6'-bis(hydroxymethyl)-spiro[isobenzofuran-1(3H),2'-[2H]pyran]-3',4',5'-triol；(3S,3'R,4'S,5'S,6'R)-6-chloro-5,6'-bis(hydroxymethyl)spiro[1H-2-benzofuran-3,2'-oxane]-3',4',5'-triol
• CAS: 1005142-63-1
• 化学式: C₁₄H₁₇ClO₇
• 分子量: 332.738
• InChiKey: QZEHKIVDSUCWAI-RGDJUOJXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  120
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1S,3′R,4′S,5′S,6′R)-5-chloro-3′,4′,5′,6′-tetrahydro-6,6′-bis(hydroxymethyl)-spiro[2-benzofuran-1(3H),2′-[2H]pyran]-3′,4′,5′-triol 在 二氯二茂钛 、 三甲基氯硅烷 、 四丁基溴化铵 、 sodium carbonate 作用下， 以 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 生成 (1S,3′R,4′S,5′S,6′R)-3′,4′,5′-tri(acetoxy)-6′-acetoxymethyl-5-chloro-6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydrospiro-[isobenzofuran-1(3H),2′-[2H]pyran]
  参考文献：
  名称：

  Discovery of Tofogliflozin, a Novel C-Arylglucoside with an O-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

  摘要：

  Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.

  DOI：

  10.1021/jm300884k
• 作为产物：
  描述：

  2-溴-5-氯对二甲苯 在 N-溴代丁二酰亚胺(NBS) 、 正丁基锂 、 偶氮二异丁腈 、 4-甲基苯磺酸吡啶 、 potassium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 正己烷 、 二氯甲烷 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.74h， 生成 (1S,3′R,4′S,5′S,6′R)-5-chloro-3′,4′,5′,6′-tetrahydro-6,6′-bis(hydroxymethyl)-spiro[2-benzofuran-1(3H),2′-[2H]pyran]-3′,4′,5′-triol
  参考文献：
  名称：

  SUBSTITUTED SPIROKETAL DERIVATIVES AND USE THEREOF AS THERAPEUTIC DRUG FOR DIABETES

  摘要：

  本发明提供了一种由式（II）表示的化合物：其中R1是氯原子、氟原子、甲基基团或乙炔基；Ar是由以下式（a）、式（b）、式（c）或式（d）表示的基团：其中R2是可以用一个或多个卤素原子取代的C1-6烷基基团、可以用一个或多个卤素原子取代的C1-6烷氧基团、C1-3烷基硫基团、卤素原子、C1-3烷基羰基团或可以用—OR4取代的C2-5炔基团；R3是氢原子或C1-3烷基基团；R4是氢原子或C1-3烷基基团；前提是当R1是氟原子、甲基基团或乙炔基时，Ar是由式（a）表示的基团，当R1是甲基基团时，R2是甲氧基团、乙氧基团、异丙基团、丙基团、三氟甲基团、三氟甲氧基团、2-氟乙基基团或1-丙炔基团；以及包括该化合物的药学上可接受的盐或溶剂，以及包括药物代理、药物组合物等的制药剂。

  公开号：

  US20110275703A1

文献信息

• SUBSTITUTED SPIROKETAL DERIVATIVES AND USE THEREOF AS THERAPEUTIC DRUG FOR DIABETES
  申请人：Sato Tsutomu

  公开号：US20110275703A1

  公开（公告）日：2011-11-10

  The present invention provides a compound represented by Formula (II): wherein R 1 is a chlorine atom, a fluorine atom, a methyl group or an ethynyl group; Ar is a group represented by the following Formula (a), Formula (b), Formula (c) or Formula (d): wherein R 2 is a C 1-6 alkyl group which may be substituted with one or more halogen atoms, a C 1-6 alkoxy group which may be substituted with one or more halogen atoms, a C 1-3 alkylthio group, a halogen atom, a C 1-3 alkylcarbonyl group or a C 2-5 alkynyl group which may be substituted with —OR 4 ; R 3 is a hydrogen atom or a C 1-3 alkyl group; R 4 is a hydrogen atom or a C 1-3 alkyl group; provided that Ar is a group represented by Formula (a) when R 1 is a fluorine atom, methyl group or an ethynyl group, and that R 2 is methoxy group, an ethoxy group, an isopropyl group, a propyl group, a trifluoromethyl group, a trifluoromethoxy group, 2-fluoroethyl group or 1-propynyl group when R 1 is a methyl group or a pharmaceutically acceptable salt or a solvate thereof and a pharmaceutical agent, a pharmaceutical composition and so on comprising the compound.

  本发明提供了一种由式（II）表示的化合物：其中R1是氯原子、氟原子、甲基基团或乙炔基；Ar是由以下式（a）、式（b）、式（c）或式（d）表示的基团：其中R2是可以用一个或多个卤素原子取代的C1-6烷基基团、可以用一个或多个卤素原子取代的C1-6烷氧基团、C1-3烷基硫基团、卤素原子、C1-3烷基羰基团或可以用—OR4取代的C2-5炔基团；R3是氢原子或C1-3烷基基团；R4是氢原子或C1-3烷基基团；前提是当R1是氟原子、甲基基团或乙炔基时，Ar是由式（a）表示的基团，当R1是甲基基团时，R2是甲氧基团、乙氧基团、异丙基团、丙基团、三氟甲基团、三氟甲氧基团、2-氟乙基基团或1-丙炔基团；以及包括该化合物的药学上可接受的盐或溶剂，以及包括药物代理、药物组合物等的制药剂。
• SUBSTITUTED SPIROKETAL DERIVATIVE AND USE THEREOF AS DRUG FOR TREATING DIABETES
  申请人：CHUGAI SEIYAKU KABUSHIKI KAISHA

  公开号：EP2048153A1

  公开（公告）日：2009-04-15

  The present invention provides a compound represented by Formula (II): wherein R1 is a chlorine atom, a fluorine atom, a methyl group or an ethynyl group; Ar is a group represented by the following Formula (a), Formula (b), Formula (c) or Formula (d): wherein R2 is a C1-6 alkyl group which may be substituted with one or more halogen atoms, a C1-6 alkoxy group which may be substituted with one or more halogen atoms, a C1-3 alkylthio group, a halogen atom, a C1-3 alkylcarbonyl group or a C2-5 alkynyl group which may be substituted with -OR4; R3 is a hydrogen atom or a C1-3 alkyl group; R4 is a hydrogen atom or a C1-3 alkyl group; provided that Ar is a group represented by Formula (a) when R1 is a fluorine atom, methyl group or an ethynyl group, and that R2 is methoxy group, an ethoxy group, an isopropyl group, a propyl group, a trifluoromethyl group, a trifluoromethoxy group, 2-fluoroethyl group or 1-propynyl group when R1 is a methyl group or a pharmaceutically acceptable salt or a solvate thereof and a pharmaceutical agent, a pharmaceutical composition and so on comprising the compound.

  本发明提供了一种由式 (II) 表示的化合物： 其中 R1 是氯原子、氟原子、甲基或乙炔基； Ar 是由下式(a)、式(b)、式(c)或式(d)代表的基团： 其中 R2 是可被一个或多个卤素原子取代的 C1-6 烷基、可被一个或多个卤素原子取代的 C1-6 烷氧基、C1-3 烷硫基、卤素原子、C1-3 烷羰基或可被-OR4 取代的 C2-5 烷炔基； R3 是氢原子或 C1-3 烷基； R4 是氢原子或 C1-3 烷基； 当 R1 为氟原子、甲基或乙炔基时，Ar 为式(a)所代表的基团，且 当 R1 为甲基时，R2 为甲氧基、乙氧基、异丙基、丙基、三氟甲基、三氟甲氧基、2-氟乙基或 1-丙炔基，或其药学上可接受的盐或溶液，以及包含该化合物的药剂、药物组合物等。
• EP2048153
  申请人：——

  公开号：——

  公开（公告）日：——
• Discovery of Tofogliflozin, a Novel <i>C</i>-Arylglucoside with an <i>O</i>-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes
  作者：Yoshihito Ohtake、Tsutomu Sato、Takamitsu Kobayashi、Masahiro Nishimoto、Naoki Taka、Koji Takano、Keisuke Yamamoto、Masayuki Ohmori、Marina Yamaguchi、Kyoko Takami、Sang-Yong Yeu、Koo-Hyeon Ahn、Hiroharu Matsuoka、Kazumi Morikawa、Masayuki Suzuki、Hitoshi Hagita、Kazuharu Ozawa、Koji Yamaguchi、Motohiro Kato、Sachiya Ikeda

  DOI：10.1021/jm300884k

  日期：2012.9.13

  Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.