(1R,4E,3aR,7aR)-4-bromomethylene-1-[(1R)-2-formyl-1-methylethyl]-7a-methylperhydroindene | 173388-41-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1R,4E,3aR,7aR)-4-bromomethylene-1-[(1R)-2-formyl-1-methylethyl]-7a-methylperhydroindene
• 英文别名: (3R)-3-[(1R,3aR,4E,7aR)-4-(bromomethylidene)-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-1-yl]butanal
• CAS: 173388-41-5
• 化学式: C₁₅H₂₃BrO
• 分子量: 299.251
• InChiKey: JUWUUJXTSHABMD-SLKDKXDFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  17.1
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  (1R,4E,3aR,7aR)-4-bromomethylene-1-[(1R)-2-formyl-1-methylethyl]-7a-methylperhydroindene 在 吡啶 、 chromium chloride 、 lithium aluminium tetrahydride 、 二异丁基氢化铝 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 为溶剂， 反应 23.0h， 生成 [(3R,4R,6R)-6-[(1R,3aR,4E,7aR)-4-(bromomethylidene)-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-1-yl]-4-hydroxy-2-methylidene-3-phenylheptyl] 2,2-dimethylpropanoate
  参考文献：
  名称：

  Synthesis and 2a-Modification of 24-Phenylvitamin D3 Lactones: Effects on VDR Antagonistic Activity

  摘要：

  DOI：

  10.3987/com-05-s(t)32
• 作为产物：
  描述：

  (S)-2-[(1R,3aR,7aR)-octahydro-7a-methyl-4-oxo-4H-inden-1-yl]propyl 4-methylbenzenesulfonate 在 sodium hexamethyldisilazane 、 二异丁基氢化铝 作用下， 以 四氢呋喃 、 二氯甲烷 、 二甲基亚砜 、 甲苯 为溶剂， 反应 6.0h， 生成 (1R,4E,3aR,7aR)-4-bromomethylene-1-[(1R)-2-formyl-1-methylethyl]-7a-methylperhydroindene
  参考文献：
  名称：

  Remarkable effect of 2α-modification on the VDR antagonistic activity of 1α-hydroxyvitamin D₃-26,23-lactones

  摘要：

  新型2α-甲基、2Îα-(3-羟基丙基)和2Îα-(3-羟基丙氧基)取代的25-脱氢-1Îα-羟基维生素D3-26,23-内酯衍生物通过Reformatsky型烯丙基化和钯催化的烯烃化环化过程被高效合成，并对其生物活性进行了评估。向维生素D3-26,23-内酯的2Îα位引入功能团显著提高了它们对维生素D受体(VDR)的拮抗活性。

  DOI：

  10.1039/b311107e

文献信息

• Further Synthetic and Biological Studies on Vitamin D Hormone Antagonists Based on C24-Alkylation and C2α-Functionalization of 25-Dehydro-1α-hydroxyvitamin D₃-26,23-lactones
  作者：Nozomi Saito、Toshihiro Matsunaga、Hiroshi Saito、Miyuki Anzai、Kazuya Takenouchi、Daishiro Miura、Jun-ichi Namekawa、Seiichi Ishizuka、Atsushi Kittaka

  DOI：10.1021/jm060797q

  日期：2006.11.30

  on process, and the 23,24-trans lactone derivatives were derived from these via inversion of the C23 stereochemistry. The biological evaluation revealed that both binding affinity for chick vitamin D hormone receptor and antagonistic activity (inhibition of vitamin D hormone induced HL-60 cell differentiation) were affected by the orientation and chain-length of the primary alkyl group on the lactone

  高效合成和生物学评估80种新型25-脱氢-1α-羟基维生素D3-26,23S-内酯2（TEI-9647）及其23R差向异构体（3），其中内酯环通过引入描述了在C24位的C1至C4伯烷基（5组4个非对映异构体），以及它们的C2α-甲基，3-羟丙基和3-羟基丙氧基取代的衍生物。维生素D3的三烯结构是通过A环前体烯炔的钯催化烯基环化和侧链上具有C24烷基化内酯部分的CD环对应的溴烯烃而构建的。具有23,24-顺式内酯的CD环前体是通过使用铬介导的顺-选择性烯丙基化-内酯化工艺制备的，然后将23,24-顺式内酯 通过反式的C23立体化学从中衍生出24反式内酯衍生物。生物学评估表明，对鸡维生素D激素受体的结合亲和力和拮抗活性（抑制维生素D激素诱导的HL-60细胞分化）均受内酯环上伯烷基的取向和链长的影响。此外，C24烷基化的维生素D3内酯的C2alpha官能化大大增强了它们的生物学活性。最有效的化合
• Synthesis of 24,24-Ethanovitamin D₃ Lactones Using Ruthenium-Catalyzed Intermolecular Enyne Metathesis: Potent Vitamin D Receptor Antagonists
  作者：Atsushi Kittaka、Nozomi Saito、Manami Masuda、Hiroshi Saito、Kazuya Takenouchi、Seiichi Ishizuka、Jun-ichi Namekawa、Midori Takimoto-Kamimura

  DOI：10.1055/s-2005-872075

  日期：——

  Novel vitamin D receptor antagonists, 24,24-ethanovitamin D3-26,23-lactones 6 and 7 and their 2α-functionalized analogues 6a-c and 7a-c were synthesized and their biological activities were evaluated. The triene structure of vitamin D3 was constructed using Pd-catalyzed alkenylative cyclization of A-ring precursor enynes 12 and 12a-c with the CD-ring bromo-olefin counterpart having 24,24-ethano-α-methylene-γ-lactone on the side chain (21 or 22). The CD-ring precursors 21 and 22 were efficiently synthesized via Ru-catalyzed intermolecular enyne metathesis of 15 with ethylene to give dienone 17 followed by cyclopropanation. The VDR antagonistic activity of the newly designed vitamin D3 lactones 6 and 7 increased to 2.8 times that of TEI-9647 (2) in a HL-60 cell differentiation evaluating system. Moreover, introduction of three substituents, that is, a methyl (6a and 7a), a 3-hydroxypropyl (6b and 7b), or a 3-hydroxypropoxyl group (6c and 7c) into the C2α position of 6 and 7, resulted in marked enhancement, up to 19 times, of the antagonistic activity toward VDR.

  合成了新型维生素 D 受体拮抗剂 24,24-乙酰维生素 D3-26,23-内酯 6 和 7 及其 2δ-官能化类似物 6a-c 和 7a-c，并评估了它们的生物活性。维生素 D3 的三烯结构是通过钯催化 A 环前体烯炔烷 12 和 12a-c 与侧链上具有 24,24-乙hano-δ-亚甲基δ-δ-内酯的 CD 环溴烯烃对应物（21 或 22）发生烯基环化反应而构建的。CD 环前体 21 和 22 是通过 Ru 催化 15 与乙烯的分子间烯炔偏析生成二烯酮 17，然后进行环丙烷化反应而高效合成的。在 HL-60 细胞分化评价体系中，新设计的维生素 D3 内酯 6 和 7 的 VDR 拮抗活性是 TEI-9647 (2) 的 2.8 倍。此外，在 6 和 7 的 C2δ 位上引入三个取代基，即甲基（6a 和 7a）、3-羟基丙基（6b 和 7b）或 3-羟基丙氧基（6c 和 7c），可显著增强对 VDR 的拮抗活性，最高可达 19 倍。
• VITAMIN D3 LACTAM DERIVATIVE
  申请人：Nakamura Yuko

  公开号：US20110207944A1

  公开（公告）日：2011-08-25

  Compound represented by formula (1) or a pharmaceutically acceptable solvate thereof, useful for treating or preventing Paget's disease of bone, hypercalcaemia, osteoporosis or asthma. (1) R 1 represents a C 1 -C 6 alkyl group or C 7 -C 15 aralkyl group (the aromatic ring of which can be substituted by a C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, a hydroxyl group, a halogenatom or a trifluoromethyl group), R 2 represents a C 1 -C 6 alkyl group, and R 3 represents a C 1 -C 6 alkyl or alkoxy group, which can be substituted with a hydroxyl group.

  由以下化学式（1）表示的化合物或其药用可接受的溶剂盐，用于治疗或预防骨的帕吉特病、高钙血症、骨质疏松症或哮喘。其中，R1代表C1-C6烷基或C7-C15芳基烷基（其芳香环可以被C1-C6烷基、C1-C6甲氧基、一个羟基、一个卤原子或三氟甲基取代），R2代表C1-C6烷基，R3代表C1-C6烷基或烷氧基，可以被一个羟基取代。
• VITAMIN D3 LACTONE DERIVATIVE
  申请人：Teijin Pharma Limited

  公开号：EP1589009B1

  公开（公告）日：2014-10-08
• 24,24-Dimethylvitamin D3-26,23-lactones and their 2α-functionalized analogues as highly potent VDR antagonists
  作者：Nozomi Saito、Manami Masuda、Toshihiro Matsunaga、Hiroshi Saito、Miyuki Anzai、Kazuya Takenouchi、Daishiro Miura、Seiichi Ishizuka、Midori Takimoto-Kamimura、Atsushi Kittaka

  DOI：10.1016/j.tet.2004.05.113

  日期：2004.8

  Novel vitamin D receptor (VDR) antagonists, 24,24-dimethyl-1alpha-hydroxyvitamin D-3-26,23-lactones (8 and 9) and their C2alpha functionalized analogues (8a-c and 9a-c) were efficiently synthesized and their biological activities were evaluated. The construction of vitamin D-3 triene skeleton was achieved by palladium-catalyzed alkenylative cyclization of A-ring precursor enyne (22 and 22a-c) with CD-ring bromoolefin having a 24,24-dimethyl-alpha-methylene-gamma-lactone unit on the side chain (13 and 14). The CD-ring precursors 13 and 14 were prepared by using chromium-mediated allylation of the aldehyde 10 derived from vitamin D-2. On the other hand, the A-ring enyne having 2alpha-(3-hydroxypropyl) group (22b) was newly synthesized from epoxide 15 using regio- and stereoselective alkylation methodology. The potency of the antagonistic activity of the newly designed analogues (8 and 9) increased up to 12 times that of TEI-9647 (2). Furthermore, introduction of the three motifs, that is, a methyl (8a and 9a), an omega-hydroxypropyl (8b and 9b) or an omega-hydroxypropoxyl group (8c and 9c) into the C2alpha position of 8 and 9, respectively, resulted in remarkable enhancement, up to 89 times, of the antagonistic activity on VDR. (C) 2004 Elsevier Ltd. All rights reserved.