trans-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one | 118918-05-1

• 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: trans-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one
• 英文别名: trans-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one；trans-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]tetrahydro-4-hydroxy-2H-pyran-2-one；(4R,6S)-6-[(1E)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one
• CAS: 118918-05-1
• 化学式: C₂₃H₂₀F₂N₄O₃
• 分子量: 438.434
• InChiKey: VIMMECPCYZXUCI-MMKWGKFASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  90.1
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  trans-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one 在 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 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：

  匹伐他汀杂质76 在 盐酸 、 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 、 正己烷 、 二氯甲烷 为溶剂， 反应 36.75h， 生成 trans-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one
  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 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 for antihypercholesterolemic tetrazole compounds
  申请人：Bristol-Myers Company

  公开号：US04824959A1

  公开（公告）日：1989-04-25

  This invention provides novel intermediates of the formula ##STR1## in substantially the cis or cis-(4R,6S) form wherein R.sup.9 and R.sup.10 each are C.sub.1-4 alkyl or R.sup.9 and R.sup.10, taken together with the carbon atom to which they are attached, is cyclopentyl, cyclohexyl or cycloheptyl; and R.sup.12 is hydrogen, C.sub.1-4 alkyl or a metal cation and processes thereof which are useful for the preparation of antihypercholesterolemic agents.

  本发明提供了新的中间体的公式##STR1##，其基本上是顺式或顺式-(4R,6S)形式，其中R.sup.9和R.sup.10各自为C.sub.1-4烷基或R.sup.9和R.sup.10连同它们所附着的碳原子，为环戊基，环己基或环庚基; 而R.sup.12是氢，C.sub.1-4烷基或金属阳离子，以及其制备抗高胆固醇药物的过程。
• 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。
• Preparation of antihypercholesterolemic tetrazole compounds
  申请人：Bristol-Myers Company

  公开号：US04898950A1

  公开（公告）日：1990-02-06

  This invention provides novel intermediates of the formula ##STR1## in substantially the cis or cis-(4R,6S) form wherein R.sup.9 and R.sup.10 each are C.sub.1-4 alkyl or R.sup.9 and R.sup.10, taken together with the carbon atom to which they are attached, is cyclopentyl, cyclohexyl or cycloheptyl; and R.sup.12 is hydrogen, C.sub.1-4 alkyl or a metal cation and processes thereof which are useful for the preparation of antihypercholesterolemic agents.

  本发明提供了公式##STR1##的新型中间体，其在基本上为顺式或顺式-(4R,6S)形式，其中R.sup.9和R.sup.10分别为C.sub.1-4烷基或R.sup.9和R.sup.10与它们附着的碳原子一起是环戊基、环己基或环庚基；而R.sup.12为氢、C.sub.1-4烷基或金属阳离子，以及其制备具有抗高胆固醇作用的药物的过程。
• Use of ACE inhibitors for lowering serum cholesterol
  申请人：E.R. SQUIBB & SONS, INC.

  公开号：EP0508665A2

  公开（公告）日：1992-10-14

  A method is provided for lowering serum cholesterol and thereby inhibiting fatty streak lesions of atherosclerosis by administering to a patient a phosphorus-containing ACE inhibitor, such as fosinopril or ceronapril, alone or in combination with a cholesterol lowering drug, such as pravastatin.

  提供了一种降低血清胆固醇从而抑制动脉粥样硬化脂肪条纹病变的方法，该方法是给患者单独使用或与降低胆固醇的药物（如普伐他汀）联合使用含磷 ACE 抑制剂，如福辛普利或塞洛那普利。