(3R,4S)-4-cyclohexyl-3-hydroxy-2-azetidinone | 156742-11-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 英文名称: (3R,4S)-4-cyclohexyl-3-hydroxy-2-azetidinone
• 英文别名: (3R,4S)-3-hydroxy-4-cyclohexyl-2-azetidinone；(3R,4S)-4-cyclohexyl-3-hydroxyazetidin-2-one
• CAS: 156742-11-9
• 化学式: C₉H₁₅NO₂
• 分子量: 169.224
• InChiKey: JHTSLEYVTKBQTI-JGVFFNPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  49.3
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (3R,4S)-4-cyclohexyl-3-hydroxy-2-azetidinone 在 4-二甲氨基吡啶 、 sodium hexamethyldisilazane 、 对甲苯磺酸 、 三乙胺 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 6.5h， 生成 3'-cyclohexyl-3'-dephenyl-2'-(1-ethoxyethyl)-2-(hexahydro)docetaxel
  参考文献：
  名称：

  Synthesis and Structure-Activity Relationships of New Antitumor Taxoids. Effects of Cyclohexyl Substitution at the C-3' and/or C-2 of Taxotere (Docetaxel)

  摘要：

  Synthesis and cytotoxicity of the new analogs (11-13) of docetaxel possessing cyclohexyl groups instead of phenyl groups at the C-3' and/or C-2 benzoate positions are described. The C-2 cyclohexanecarboxylate analog of paclitaxel(15) is also synthesized for comparison. The potency of these new taxoids were examined for their inhibitory activity for microtubule disassembly and also for their cytotoxicity against murine P388 leukemia cell line as well. as doxorubicin-resistant P388 leukemia cell line (P388/Dox). It is found that 3'-dephenyl-3'-cyclohexyldocetaxel (11) (0.72T) and 2-(hexahydro)docetaxel (12) (0.85T) possess strong inhibitory activity for microtubule disassembly equivalent to docetaxel (0.7T), which is more potent than paclitaxel (1.0T). The results clearly indicate that phenyl or an aromatic group at C-3' or C-2 is not a requisite for strong binding to the microtubules. This finding has opened an avenue for development of new nonaromatic analogs of docetaxel and paclitaxel. 3'-Dephenyl-3'-cyclohexyl-2-(hexahydro)docetaxel (13) (2T) turns out to be a substantially weaker inhibitor. The cytotoxicities of 11-13 against P388 are, however, in the same range that is 8-12 times weaker than docetaxel and 4-6 times weaker than paclitaxel, i.e., 13 shows equivalent cytotoxicity to that of 11 or 12 in spite of much lower microtubule disassembly inhibitory activity. The cytotoxicities of these new taxoids against the P388/Dox cell line are only 2-2.5 times lower than that of docetaxel. The potency of 2-(hexahydro)paclitaxel (15) for these assays is much lower than the docetaxel counterpart 12. The significant loss of activity in vivo against B16 melanoma is observed for 11-13, i.e., 11 is only marginal (T/C = 38% at 20 mg/kg/day), and 12 and 13 are inactive (T/C = 76% and 79%, respectively). This could be ascribed to faster metabolism, faster excretion or other bioavailability problems.

  DOI：

  10.1021/jm00042a013
• 作为产物：
  描述：

  (3R,4S)-3-羟基-4-苯基-2-氮杂环丁酮 在 Rh on carbon 氢气 作用下， 以 甲醇 为溶剂， 90.0 ℃ 、5.52 MPa 条件下， 反应 120.0h， 以85%的产率得到(3R,4S)-4-cyclohexyl-3-hydroxy-2-azetidinone
  参考文献：
  名称：

  Synthesis and Structure-Activity Relationships of New Antitumor Taxoids. Effects of Cyclohexyl Substitution at the C-3' and/or C-2 of Taxotere (Docetaxel)

  摘要：

  Synthesis and cytotoxicity of the new analogs (11-13) of docetaxel possessing cyclohexyl groups instead of phenyl groups at the C-3' and/or C-2 benzoate positions are described. The C-2 cyclohexanecarboxylate analog of paclitaxel(15) is also synthesized for comparison. The potency of these new taxoids were examined for their inhibitory activity for microtubule disassembly and also for their cytotoxicity against murine P388 leukemia cell line as well. as doxorubicin-resistant P388 leukemia cell line (P388/Dox). It is found that 3'-dephenyl-3'-cyclohexyldocetaxel (11) (0.72T) and 2-(hexahydro)docetaxel (12) (0.85T) possess strong inhibitory activity for microtubule disassembly equivalent to docetaxel (0.7T), which is more potent than paclitaxel (1.0T). The results clearly indicate that phenyl or an aromatic group at C-3' or C-2 is not a requisite for strong binding to the microtubules. This finding has opened an avenue for development of new nonaromatic analogs of docetaxel and paclitaxel. 3'-Dephenyl-3'-cyclohexyl-2-(hexahydro)docetaxel (13) (2T) turns out to be a substantially weaker inhibitor. The cytotoxicities of 11-13 against P388 are, however, in the same range that is 8-12 times weaker than docetaxel and 4-6 times weaker than paclitaxel, i.e., 13 shows equivalent cytotoxicity to that of 11 or 12 in spite of much lower microtubule disassembly inhibitory activity. The cytotoxicities of these new taxoids against the P388/Dox cell line are only 2-2.5 times lower than that of docetaxel. The potency of 2-(hexahydro)paclitaxel (15) for these assays is much lower than the docetaxel counterpart 12. The significant loss of activity in vivo against B16 melanoma is observed for 11-13, i.e., 11 is only marginal (T/C = 38% at 20 mg/kg/day), and 12 and 13 are inactive (T/C = 76% and 79%, respectively). This could be ascribed to faster metabolism, faster excretion or other bioavailability problems.

  DOI：

  10.1021/jm00042a013

文献信息

• Synthesis and Biological Evaluation of C-3'-Modified Analogs of 9(R)-Dihydrotaxol
  作者：Leping Li、Sheela A. Thomas、Larry L. Klein、Clinton M. Yeung、Clarence J. Maring、David J. Grampovnik、Paul A. Lartey、Jacob J. Plattner

  DOI：10.1021/jm00043a005

  日期：1994.8

  Taxol (1) is considered a most exciting new drug in cancer chemotherapy. The promising antitumor activity of 9(R)-dihydrotaxol (3) encouraged us to further explore the structure-activity relationship of this new member of the taxane family. Studies indicated that the C-13 side chain of taxol is indispensable for antitumor activity and that the natural substitution pattern of a 2'(R)-hydroxy and a 3'(S)-acylamino

  紫杉醇（1）被认为是癌症化疗中最令人兴奋的新药。9（R）-二氢紫杉醇（3）的有希望的抗肿瘤活性鼓励我们进一步探索紫杉烷家族这个新成员的结构-活性关系。研究表明，紫杉醇的C-13侧链对于抗肿瘤活性是必不可少的，并且2'（R）-羟基和3'（S）-酰氨基的天然取代方式可能是最佳的。然而，关于3'-苯环对活性的影响了解的很少。描述了在C-3'位置修饰的3的类似物的合成和生物学评估。这项研究表明3'-苯环不是活性所必需的，并鉴定了几种在体外和体内活性均与紫杉醇相同或更高的化合物。
• Process for the preparation of taxane derivatives and &bgr;-lactam intermediates therefor
  申请人：The State University of New York at Stony Brook

  公开号：US06218553B1

  公开（公告）日：2001-04-17

  Taxol (I) is a complex deterpene which is currently considered the most exciting lead in cancer chemotherapy. Taxol possesses high cytotoxicity and strong antitumor activity against different cancers which have not been effectively treated by existing antitumor drugs. However, taxol has a problem with solubility in aqueous media, which may impose some serious limitation in its use. Taxotére (III) seems to have antitumor activity superior to taxol with better bioavailability. Taxotére has a modified taxol structure with a modified C-13 side chain. This fact strongly indicates that modification on the C-13 side chain would provide a new series of taxol and Taxotére analogues which may have higher potency, better bioavailability and less unwanted toxicity. The present invention provides efficient and practical methods for the syntheses of Taxotére and its analogues through &bgr;-lactam intermediates and their coupling with baccatin III.

  Taxol (I)是一种复杂的二萜类化合物，目前被认为是癌症化疗中最为令人兴奋的前导物。Taxol具有高细胞毒性和强烈的抗肿瘤活性，可对目前未能有效治疗的不同癌症产生作用。然而，taxol在水介质中的溶解度存在问题，这可能会对其使用造成一些严重限制。Taxotére (III)似乎具有优于taxol的抗肿瘤活性，并具有更好的生物利用度。Taxotére具有改性的taxol结构和改性的C-13侧链。这一事实强烈表明，对C-13侧链进行修饰将提供一系列新的taxol和Taxotére类似物，这些类似物可能具有更高的效力、更好的生物利用度和更少的不良毒性。本发明提供了通过β-内酰胺中间体和其与baccatin III的偶联合成Taxotére及其类似物的高效实用方法。
• PROCESS FOR PREPARATION OF TAXANE DERIVATIVES AND BETA-LACTAM INTERMEDIATES THEREFOR
  申请人：THE RESEARCH FOUNDATION OF STATE UNIVERSITY OF NEW YORK

  公开号：EP0681568B1

  公开（公告）日：2006-07-26
• ANTI-TUMOR COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, METHODS FOR PREPARATION THEREOF AND FOR TREATMENT
  申请人：THE RESEARCH FOUNDATION OF STATE UNIVERSITY OF NEW YORK

  公开号：EP0690856A1

  公开（公告）日：1996-01-10
• EP0690856A4
  申请人：——

  公开号：EP0690856A4

  公开（公告）日：1996-02-07