2-cyano-3,3-bis(4-fluorophenyl)-2-propenal | 128995-63-1

• 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-cyano-3,3-bis(4-fluorophenyl)-2-propenal
• 英文别名: 3,3-bis(4-fluorophenyl)-2-formylprop-2-enenitrile
• CAS: 128995-63-1
• 化学式: C₁₆H₉F₂NO
• 分子量: 269.25
• InChiKey: YILWFYJIKSGIGO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  40.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-cyano-3,3-bis(4-fluorophenyl)-2-propenal 在 sodium hydroxide 、 sodium tetrahydroborate 、 三乙基硼 作用下， 以 四氢呋喃 、 甲醇 、 苯 为溶剂， 反应 7.5h， 生成 (+/-)-(E)-erythro-8-cyano-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-6,8-nonadienoic 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
• 作为产物：
  描述：

  4,4'-二氟二苯甲酮 在 lithium hydroxide 、 lithium aluminium tetrahydride 、 草酰氯 、 溶剂黄146 、 pyridinium chlorochromate 、 β-丙氨酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 苯 为溶剂， 反应 356.08h， 生成 2-cyano-3,3-bis(4-fluorophenyl)-2-propenal
  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

• Antihypercholesterolemic nitrile compounds
  申请人：Bristol-Myers Company

  公开号：US04927944A1

  公开（公告）日：1990-05-22

  Compounds of the formula ##STR1## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each are independently hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or trifluoromethyl; A is ##STR2## and R.sup.5 is hydrogen, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt, are novel antihypercholesterolemic agents which inhibit cholesterol biosynthesis. Intermediates and processes for their preparation are disclosed.

  式子为##STR1##的化合物，其中R.sup.1、R.sup.2、R.sup.3和R.sup.4各自独立地为氢、卤素、C.sub.1-4烷基、C.sub.1-4烷氧基或三氟甲基；A为##STR2##而R.sup.5为氢、可水解酯基或阳离子，以形成一种非毒性药学上可接受的盐，这些化合物是新的抗高胆固醇血症制剂，可以抑制胆固醇生物合成。还公开了它们的中间体和制备过程。
• 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：——
• US4927944A
  申请人：——

  公开号：US4927944A

  公开（公告）日：1990-05-22
• US4981991A
  申请人：——

  公开号：US4981991A

  公开（公告）日：1991-01-01
• US5028730A
  申请人：——

  公开号：US5028730A

  公开（公告）日：1991-07-02