7,7-bis(4-fluorophenyl)-6-(1-methyl-1H-tetrazol-5-yl)-2,4,6-heptatrienal | 130200-52-1

• 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: 7,7-bis(4-fluorophenyl)-6-(1-methyl-1H-tetrazol-5-yl)-2,4,6-heptatrienal
• 英文别名: (2E,4E)-7,7-bis(4-fluorophenyl)-6-(1-methyltetrazol-5-yl)hepta-2,4,6-trienal
• CAS: 130200-52-1
• 化学式: C₂₁H₁₆F₂N₄O
• 分子量: 378.381
• InChiKey: TUSZZKSGMDECTD-ZUVMSYQZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  60.7
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  乙酰乙酸乙酯 、 5,5-bis(4-fluorophenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal 、 7,7-bis(4-fluorophenyl)-6-(1-methyl-1H-tetrazol-5-yl)-2,4,6-heptatrienal 、 sodium 以58%的产率得到
  参考文献：
  名称：

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

  摘要：

  DOI：
• 作为产物：
  描述：

  1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-propene 在 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 2-硝基丙烷 、 sodium ethanolate 作用下， 以 四氯化碳 、 乙醇 、 苯 为溶剂， 反应 4.5h， 生成 7,7-bis(4-fluorophenyl)-6-(1-methyl-1H-tetrazol-5-yl)-2,4,6-heptatrienal
  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

• 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：——
• US4897490A
  申请人：——

  公开号：US4897490A

  公开（公告）日：1990-01-30
• US5068346A
  申请人：——

  公开号：US5068346A

  公开（公告）日：1991-11-26
• [EN] ANTIHYPERCHOLESTEROLEMIC TETRAZOLE COMPOUNDS
  申请人：BRISTOL-MYERS COMPANY

  公开号：WO1988006584A1

  公开（公告）日：1988-09-07

  (EN) Compounds of formula (I), wherein R1 and R4 each are independently hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, or trifluoromethyl; R2, R3, R5 and R6 each are independently hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy; tet is (II) or (III); n is an integer of from 0 to 2, inclusive; A is (IV) or (V); R7 is hydrogen, C1-4 alkyl, C1-4 alkoxy(lower)alkyl or (2-methoxyethoxy)methyl; X is -OH or =O; and R8 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.(FR) Les composés décrits sont représentés par la formule (I), où R1 et R4 représentent un hydrogène, un halogène, un alkyle de 1 à 4 atomes de carbone, un alkoxyle de 1 à 4 atomes de carbone ou trifluorométhyle; R2, R3, R5, et R6 représentent chacun pris séparément un hydrogène, un halogène, un alkyle de 1 à 4 atomes de carbone ou un alkoxyle de 1 à 4 atomes de carbone, tet représente (II) ou (III); n est égal à un nombre entier entre 0 et 2 inclus; A représente (IV) ou (V); R7 représente un hydrogène, un alkyle de 1 à 4 atomes de carbone, un alkoxy alkyle (inférieur) de 1 à 4 atomes de carbone ou un (2-méthoxyéthoxy)méthyle; X représente -OH ou =O; et R8 représente un hydrogène, un groupe ester hydrolysable ou un cation, de façon à former un sel non toxique pharmaceutiquement acceptable. Lesdits composés constituent de nouveaux agents antihypercholestérolémiques qui inhibent la biosynthèse du cholestérol. Des composés intermédiaires et des procédés servant à leur préparation sont décrits.
• 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.