二甲基[3,3-双(4-氟苯基)-2-(1-甲基-1H-四唑-5-基)-2-丙烯-1-基]膦酸酯 | 118845-72-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 二甲基[3,3-双(4-氟苯基)-2-(1-甲基-1H-四唑-5-基)-2-丙烯-1-基]膦酸酯
• 英文名称: dimethyl <3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propen-1-yl>phosphonate
• 英文别名: [3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenyl]-phosphonic acid,dimethyl ester；Dimethyl [3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propen-1-yl] phosphonate；dimethyl [3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propen-1-yl]phosphonate；5-[3-dimethoxyphosphoryl-1,1-bis(4-fluorophenyl)prop-1-en-2-yl]-1-methyltetrazole
• CAS: 118845-72-0
• 化学式: C₁₉H₁₉F₂N₄O₃P
• 分子量: 420.355
• InChiKey: BXSPGKAQPJLFFF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  79.1
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  二甲基[3,3-双(4-氟苯基)-2-(1-甲基-1H-四唑-5-基)-2-丙烯-1-基]膦酸酯 在 盐酸 、 sodium hydroxide 、 正丁基锂 、 1-环已基-2-吗啉乙基碳二亚胺对甲苯磺酸盐 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 36.75h， 生成 BMY-21950
  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：

  1,1-双(4-氟苯基)-2-(1-甲基-1H-四唑-5-基)丙醇 在 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 对甲苯磺酸 作用下， 以 四氯化碳 、 甲苯 为溶剂， 反应 2.08h， 生成 二甲基[3,3-双(4-氟苯基)-2-(1-甲基-1H-四唑-5-基)-2-丙烯-1-基]膦酸酯
  参考文献：
  名称：

  HMG-CoA还原酶的有效，组织选择性合成抑制剂。

  摘要：

  DOI：

  10.1021/jm00129a004

文献信息

• Intermediates for the preparation of antihypercholesterolemic tetrazole
  申请人：Bristol-Myers Company

  公开号：US04898949A1

  公开（公告）日：1990-02-06

  This invention provides novel tetrazole intermediates of the formula ##STR1## wherein R.sup.1 and R.sup.4 each are independently hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or trifluoromethyl; R.sup.2,R.sup.3,R.sup.5 and R.sup.6 each are independently hydrogen, halogen, C.sub.1-4 alkyl or C.sub.1-4 alkoxy; B is hydrogen, C.sub.1-4 alkoxycarbonyl, CH.sub.2 Y or CH.sub.2 Z; Y is hydrogen, hydroxyl or X; Z is ##STR2## X is bromo, chloro or iodo; R.sup.10 is C.sub.1-4 alkyl; and R.sup.11 is phenyl which is unsubstituted or substituted by one or two C.sub.1-4 alkyl or chloro substituents. and processes thereof which are useful for the preparation of antihypercholesterolemic agents.

  这项发明提供了新型的四唑中间体，其化学式为##STR1##其中R.sup.1和R.sup.4分别独立地是氢、卤素、C.sub.1-4烷基、C.sub.1-4烷氧基或三氟甲基；R.sup.2、R.sup.3、R.sup.5和R.sup.6分别独立地是氢、卤素、C.sub.1-4烷基或C.sub.1-4烷氧基；B是氢、C.sub.1-4烷氧羰基、CH.sub.2 Y或CH.sub.2 Z；Y是氢、羟基或X；Z是##STR2##X是溴、氯或碘；R.sup.10是C.sub.1-4烷基；R.sup.11是苯基，未取代或取代一个或两个C.sub.1-4烷基或氯代基。以及用于制备抗高胆固醇药物的相关方法。
• Antihypercholesterolemic tetrazole compounds
  申请人：Bristol-Meyers Company

  公开号：US04897490A1

  公开（公告）日：1990-01-30

  Compounds of the formula ##STR1## wherein R.sup.1 and R.sup.4 each are independently hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, or trifluoromethyl; R.sup.2, R.sup.3, R.sup.5 and R.sup.6 each are independently hydrogen, halogen C.sub.1-4 alkyl or C.sub.1-4 alkoxy; tet is ##STR2## n is an integer of from 0 to 2, inclusive; A is ##STR3## R.sup.7 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy(lower) alkyl or (2-methoxyethoxy)methyl; X is --OH or .dbd.O; and R.sup.8 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.

  式为##STR1##的化合物，其中R.sup.1和R.sup.4分别独立地是氢、卤素、C.sub.1-4烷基、C.sub.1-4氧烷基或三氟甲基；R.sup.2、R.sup.3、R.sup.5和R.sup.6分别独立地是氢、卤素、C.sub.1-4烷基或C.sub.1-4氧烷基；tet为##STR2##；n是0到2之间的整数；A为##STR3##；R.sup.7为氢、C.sub.1-4烷基、C.sub.1-4氧烷基(较低)烷基或(2-甲氧基乙氧基)甲基；X为--OH或.dbd.O；R.sup.8为氢、可水解酯基团或阳离子，以形成一种无毒的药用可接受盐，这些化合物是新型抗高胆固醇药物，可抑制胆固醇生物合成。揭示了它们的中间体和制备方法。
• Intermediates and process for the preparation of
  申请人：Bristol-Myers Company

  公开号：US04939265A1

  公开（公告）日：1990-07-03

  This invention provides novel tetrazole intermediates of the formula ##STR1## wherein R.sup.1 and R.sup.4 each are independently hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or trifluoromethyl; R.sup.2, R.sup.3, R.sup.5 and R.sup.6 each are independently hydrogen, halogen, C.sub.1-4 alkyl or C.sub.1-4 alkoxy; B is hydrogen, C.sub.1-4 alkoxycarbonyl, CH.sub.2 Y or CH.sub.2 Z; Y is hydrogen, hydroxyl or X; Z is ##STR2## X is bromo, chloro or iodo; R.sup.10 is C.sub.1-4 alkyl; and R.sup.11 is phenyl which is unsubstituted or substituted by one or two C.sub.1-4 alkyl or chloro substituents. and processes thereof which are useful for the preparation of antihypercholesterolemic agents.

  这项发明提供了新型四唑中间体的公式##STR1##其中R.sup.1和R.sup.4各自独立地是氢，卤素，C.sub.1-4烷基，C.sub.1-4烷氧基或三氟甲基; R.sup.2，R.sup.3，R.sup.5和R.sup.6各自独立地是氢，卤素，C.sub.1-4烷基或C.sub.1-4烷氧基; B是氢，C.sub.1-4烷氧羰基，CH.sub.2 Y或CH.sub.2 Z; Y是氢，羟基或X; Z是##STR2##X是溴，氯或碘; R.sup.10是C.sub.1-4烷基; R.sup.11是苯基，未取代或取代一个或两个C.sub.1-4烷基或氯取代基。以及其制备抗高胆固醇药物的方法。
• Tetrazole compounds
  申请人：Bristol-Myers Company

  公开号：US05068346A1

  公开（公告）日：1991-11-26

  Compounds of the formula ##STR1## wherein R.sup.1 and R.sup.4 each are independently hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, or trifluoromethyl; R.sup.2, R.sup.3,R.sup.5 and R.sup.6 each are independently hydrogen, halogen C.sub.1-4 alkyl or C.sub.1-4 alkoxy; tet is ##STR2## n is an integer of from 0 to 2, inclusive; A is ##STR3## R.sup.7 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy(lower) alkyl or (2-methoxyethoxy)methyl; X is --OH or .dbd.O; and R.sup.8 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.

  该化合物的公式为##STR1##其中R.sup.1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；R.sup.2、R.sup.3、R.sup.5和R.sup.6各自独立地为氢、卤素、C.sub.1-4烷基或C.sub.1-4烷氧基；tet为##STR2##n为0至2的整数；A为##STR3##R.sup.7为氢、C.sub.1-4烷基、C.sub.1-4烷氧基(较低)烷基或(2-甲氧基乙氧基)甲基；X为--OH或.dbd.O；R.sup.8为氢、可水解酯基或阳离子，以形成一种无毒的药用可接受盐，是新型的抑制胆固醇生物合成的降胆固醇药物。公开了其中间体和制备方法。
• A potent, tissue-selective, synthetic inhibitor of HMG-CoA reductase
  作者：N. Balasubramanian、P. J. Brown、J. D. Catt、W. T. Han、R. A. Parker、S. Y. Sit、J. J. Wright

  DOI：10.1021/jm00129a004

  日期：1989.9