2-[(4R,6S)-2,2-dimethyl-6-[(E)-2-phenylethenyl]-1,3-dioxan-4-yl]acetic acid | 118845-88-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-[(4R,6S)-2,2-dimethyl-6-[(E)-2-phenylethenyl]-1,3-dioxan-4-yl]acetic acid
• CAS: 118845-88-8；118918-08-4；123284-03-7；123409-07-4；130273-41-5
• 化学式: C₁₆H₂₀O₄
• 分子量: 276.332
• InChiKey: YWACBBGYAKTLGI-SJXIGLKTSA-N

物化性质

• 沸点：
  435.3±30.0 °C(Predicted)
• 密度：
  1.164±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-[(4R,6S)-2,2-dimethyl-6-[(E)-2-phenylethenyl]-1,3-dioxan-4-yl]acetic acid 在 二甲基硫 、 臭氧 作用下， 以 二氯甲烷 为溶剂， 生成 匹伐他汀杂质76
  参考文献：
  名称：

  Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

  摘要：

  A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.

  DOI：

  10.1021/jm00173a013
• 作为产物：
  描述：

  methyl (3S^*,5R^*)-3,5-isopropylidenedioxy-7-phenyl-6-heptenoate 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 0.75h， 生成 2-[(4R,6S)-2,2-dimethyl-6-[(E)-2-phenylethenyl]-1,3-dioxan-4-yl]acetic acid
  参考文献：
  名称：

  Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

  摘要：

  A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.

  DOI：

  10.1021/jm00173a013

文献信息

• [EN] CONDENSED PYRIDINE TYPE MEVALONOLACTONE INTERMEDIATE AND PROCESS FOR ITS PRODUCTION<br/>[FR] INTERMEDIAIRE CONDENSE DE SYNTHESE DU MEVALONOLACTONE DE TYPE PYRIDINE ET PROCEDE DE FABRICATION DE CET INTERMEDIAIRE
  申请人：NISSAN CHEMICAL INDUSTRIES LTD.

  公开号：WO1995011898A1

  公开（公告）日：1995-05-04

  (EN) The present invention provides a synthetic condensed pyridine type mevalonolactone intermediate of formula (1), wherein Z is (a) or (b), each of R9a and R9b is a hydroxyl-protecting group, and R10 is methyl, ethyl, propyl, isopropyl, tert-butyl, tetrahydropyranyl, allyl, benzyl, triphenylmethyl, trimethylsilyl or tert-butyldimethylsilyl. The intermediate is useful for producing a 7-position substituted (E, 3R, 5S)-3,5-dihydroxy-6-heptenoic acid or its 1,5-lactone or its enantiomer which has an activity as an HMG-CoA reductase inhibitor and which is useful as a hypercholesterolemia therapeutic agent.(FR) L'invention concerne un intermédiaire condensé de synthèse du mévalonolactone de type pyridine, présentant la formule (1) dans laquelle Z représente (a) ou (b), chaque R9a et R9b représente un groupe protecteur hydroxyle, et R10 représente méthyle, éthyle, propyle, isopropyle, tert-butyle, tétrahydropyranyle, allyle, benzyle, triphénylméthyle, triméthylsilyle ou tert-butyldiméthylsilyle. Cet intermédiaire est utile pour produire un acide hepténoïque (E,3R,5S)-3,5-dihydroxy-6 substitué en position 7 ou son 1,5-lactone ou son énantiomère qui présente une activité comme inhibiteur de la HMG-CoA réductase, et peut être utilisé comme agent thérapeutique de l'hypercholestérolémie.

  本发明提供了一种合成的紧凑型吡啶型甲烷酸内酯中间体，其化学式为（1），其中Z为（a）或（b），R9a和R9b均为羟基保护基，R10为甲基、乙基、丙基、异丙基、叔丁基、四氢吡喃基、烯丙基、苄基、三苯基甲基、三甲基硅基或叔丁基二甲基硅基。该中间体可用于生产7位取代的（E，3R，5S）-3,5-二羟基-6-庚烯酸或其1,5-内酯或其对映体，其具有作为HMG-CoA还原酶抑制剂的活性，可用作治疗高胆固醇血症的药物。
• HAN, WILLIAM T.;WRIGHT, JOHN J.
  作者：HAN, WILLIAM T.、WRIGHT, JOHN J.

  DOI：——

  日期：——
• SIT, S. Y.;PARKER, R. A.;MOTOC, I.;HAN, W.;BALASUBRAMANIAN, N.;CATT, J. D+, J. MED. CHEM., 33,(1990) N1, C. 2982-2999
  作者：SIT, S. Y.、PARKER, R. A.、MOTOC, I.、HAN, W.、BALASUBRAMANIAN, N.、CATT, J. D+

  DOI：——

  日期：——
• Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
  作者：S. Y. Sit、R. A. Parker、I. Motoc、W. Han、N. Balasubramanian、J. D. Catt、P. J. Brown、W. E. Harte、M. D. Thompson、J. J. Wright

  DOI：10.1021/jm00173a013

  日期：1990.11

  A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.