胆钙化醇杂质21(维生素D3杂质21) | 156965-15-0

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 胆钙化醇杂质21(维生素D3杂质21)
• 英文名称: ZK 159222
• 英文别名: ZK159222；butyl-(5Z-7E-22E),(1S,3R,24R)-1,3,24-trihydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylate；(1S,3R,24R)-1,3,24-Trihydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylic acid butyl ester；butyl 1-[(E,1R,4R)-4-[(1R,3aS,4E,7aR)-4-[(2Z)-2-[(3S,5R)-3,5-dihydroxy-2-methylidenecyclohexylidene]ethylidene]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-1-yl]-1-hydroxypent-2-enyl]cyclopropane-1-carboxylate
• CAS: 156965-15-0
• 化学式: C₃₂H₄₈O₅
• 分子量: 512.73
• InChiKey: SPARTCPUGRJFRS-PBDCIXLPSA-N

物化性质

• 熔点：
  >62°C (dec.)
• 沸点：
  646.3±55.0 °C(Predicted)
• 密度：
  1.13±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、乙酸乙酯（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  37
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  87
• 氢给体数：
  3
• 氢受体数：
  5

制备方法与用途

生物活性

ZK159222 是 1α,25-(OH)2D3 的类似物，是有效的 1α,25-(OH)2D3 受体 (VDR) 拮抗剂。ZK159222 拮抗作用的机制是由配体诱导的维生素 D 受体与辅助激活剂的相互作用缺乏所介导的。ZK159222 具有部分激动性。

体外研究

ZK159222, displayed the profile of a weak VDR agonists that requires an approximate 7-fold higher concentration than of the natural hormone 1α,25-(OH)2D3 to stabilize VDR-RXR heterodimer complex formation on a DR3-type VDRE. ZK159222 was found to belong to the category of 1α,25-(OH)2D3 analogues that stabilize an additional third functional VDR conformation, which has also been described for some agonistic 20-epi analogues. The remaining reporter gene activity that was obtained by a combined treatment of 10 nM 1α,25-(OH)2D3 with 1 μM ZK159222 is close to the partial agonistic activity of 1 μM ZK159222.

反应信息

• 作为产物：
  描述：

  butyl (22E)-(8S,24R)-de-A,B-8-(tert-butyldimethylsilyl)oxy-26,27-cyclo-24-hydroxy-22-cholestene-25-carboxylate 在 四(三苯基膦)钯 四丙基高钌酸铵 、 4 A molecular sieve 、 四丁基氟化铵 、 sodium hexamethyldisilazane 、 二甲基氯化铝 、 4-甲基苯磺酸吡啶 、 N-甲基吗啉氧化物 、 三乙胺 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 甲苯 为溶剂， 反应 126.08h， 生成 胆钙化醇杂质21(维生素D3杂质21)
  参考文献：
  名称：

  Design and synthesis of potent vitamin D receptor antagonists with A-ring modifications: remarkable effects of 2α-methyl introduction on antagonistic activity

  摘要：

  Novel A-ring analogues of the vitamin D receptor (VDR) antagonist (3a), ZK-159222, and its 24-epimer (3b) were convergently synthesized. Preparation of the CD-ring portions with the side chains of 3a,b, followed by palladium-catalyzed cross-coupling with the A-ring enyne precursors (15a,b), (3S,4S,5R)- and (3S,4S,5S)-bis[(tert-butyldimethylsilyl)oxy]-4-methyloct-1-en-7-yne, afforded the 2alpha-methyl-introduced analogues (4a,b) and their 3-epimers (5a,b). The biological profiles of the hybrid analogues were assessed in terms of affinity for VDR, and antagonistic activity to inhibit HL-60 cell differentiation induced by the natural hormone, 1alpha,25-dihydroxyvitamin D-3. The analogue 4a showed an approximately fivefold higher antagonistic activity compared with 3a. The 2alpha-methyl introduction into 3a increased the receptor affinity, thereby enhancing VDR antagonism. This approach to design potent antagonists based on hybridization of structural motifs in the A-ring and in the side chain may prove to be valuable. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00371-7

文献信息

• Process for the synthesis of vitamin d compounds and intermediates for the synthesis of the compounds
  申请人：Kashiwagi Hirotaka

  公开号：US20070135394A1

  公开（公告）日：2007-06-14

  An object of the present invention is to provide a process for synthesizing a vitamin D compound by simple procedures at lower costs. The present invention provides a process for preparing a vitamin D compound and an intermediate thereof, comprising the step of: (a) mixing a ketone or aldehyde, a Wittig reagent, and a base; or (b) mixing a ketone or aldehyde and a Wittig reagent, and then adding a base to the resulting mixture.

  本发明的一个目的是提供一种通过简单程序以更低成本合成维生素D化合物的方法。本发明提供了一种制备维生素D化合物及其中间体的方法，包括以下步骤：(a)混合酮或醛、威蒂格试剂和碱；或者(b)混合酮或醛和威蒂格试剂，然后向所得混合物中加入碱。
• 25-Carboxylic acid derivatives in the vitamin D series, process for
  申请人：Schering Aktiengesellschaft

  公开号：US05583125A1

  公开（公告）日：1996-12-10

  New 25-carboxylic acid derivatives of general formula I, ##STR1## R.sup.19 and R.sup.19a each mean a hydrogen atom or together form an exocyclic methylene group, R.sup.21 and R.sup.21a independently of one another mean a hydrogen atom, a chlorine or fluorine atom, an alkyl group with 1 to 4 carbon atoms, together a methylene group, together with quaternary carbon atom 20 mean a 3-7 membered, saturated or unsaturated carboxylic ring, Y preferably means a derivatized carboxyl radical, and the other substituents have the meanings indicated in the description as well as process for their production, are described. The new compounds have vitamin D activity as well as proliferation-inhibiting and cell-differentiating effects and are suitable for the production of pharmaceutical agents.

  新的25-羧酸衍生物的通式I，##STR1##其中R.sup.19和R.sup.19a分别表示氢原子或一起形成外环亚甲基基团，R.sup.21和R.sup.21a独立地表示氢原子、氯或氟原子、具有1至4个碳原子的烷基、与第20个季铵碳原子一起形成3-7个成员的饱和或不饱和羧酸环，Y优选表示衍生的羧基基团，其他取代基的含义如描述中所示，以及其制备方法。新的化合物具有维生素D活性以及抑制增殖和细胞分化的效果，并适用于制药剂的生产。
• Use of Vitamin D3 agonist in a mammalian model for atopic diseases and of Vitamin D3 antagonists for the treatment of atopic diseases
  申请人：Association pour la recherche à l'IGBMC (ARI)

  公开号：EP1891944A1

  公开（公告）日：2008-02-27

  The present invention concerns a method for generating a human atopic disease-like phenotype, preferably an atopic dermatitis (AD)-like phenotype in a mammal comprising administrating to said mammal at least one compound selected in the group comprising the physiologically active vitamin D3 (1α,25 (OH)2 D3) and agonistic analogs thereof. The present invention also concerns a method for treating and/or preventing an atopic disease in a patient comprising administrating to said patient an effective amount of at least one vitamin D3 antagonist.

  本发明涉及一种在哺乳动物中产生人类特应性疾病样表型，优选特应性皮炎（AD）样表型的方法，包括向所述哺乳动物施用至少一种选自生理活性维生素D3（1α,25 (OH)2 D3）及其激动类似物的化合物。本发明还涉及一种治疗和/或预防患者特应性疾病的方法，包括向所述患者施用有效量的至少一种维生素 D3 拮抗剂。
• 25-CARBONSÄURE-DERIVATE IN DER VITAMIN D-REIHE, DIESE DERIVATE ENTHALTENDE PHARMAZEUTISCHE PRÄPARATE SOWIE DEREN VERWENDUNG ZUR HERSTELLUNG VON ARZNEIMITTELN
  申请人：SCHERING AKTIENGESELLSCHAFT

  公开号：EP0663902B1

  公开（公告）日：1998-03-11
• USE OF VITAMIN D3 AGONIST MC903 IN A MAMMALIAN MODEL FOR ATOPIC DISEASES
  申请人：Association pour la recherche à l'IGBMC (ARI)

  公开号：EP2046309B1

  公开（公告）日：2010-12-15