methyl 3-(4-fluorobenzylidene)-4-oxochroman-7-carboxylate | 1023650-07-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 高异黄酮
• 英文名称: methyl 3-(4-fluorobenzylidene)-4-oxochroman-7-carboxylate
• 英文别名: methyl 3-[(4-fluorophenyl)methylidene]-4-oxochromene-7-carboxylate
• CAS: 1023650-07-8
• 化学式: C₁₈H₁₃FO₄
• 分子量: 312.297
• InChiKey: ITWHOQHAWHVVNL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-chloro-4-hydrazinobenzonitrile hydrochloride 、 methyl 3-(4-fluorobenzylidene)-4-oxochroman-7-carboxylate 以 乙醇 为溶剂， 生成
  参考文献：
  名称：

  Discovery of (3S,3aR)-2-(3-Chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic Acid (PF-3882845), an Orally Efficacious Mineralocorticoid Receptor (MR) Antagonist for Hypertension and Nephropathy

  摘要：

  We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (M R) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.

  DOI：

  10.1021/jm100505n
• 作为产物：
  描述：

  4-氧代苯并二氢吡喃-7-羧酸甲酯 、 对氟苯甲醛 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 以76%的产率得到methyl 3-(4-fluorobenzylidene)-4-oxochroman-7-carboxylate
  参考文献：
  名称：

  Discovery of (3S,3aR)-2-(3-Chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic Acid (PF-3882845), an Orally Efficacious Mineralocorticoid Receptor (MR) Antagonist for Hypertension and Nephropathy

  摘要：

  We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (M R) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.

  DOI：

  10.1021/jm100505n

文献信息

• Pyrazoline Compounds
  申请人：Meyers Marvin J.

  公开号：US20080167294A1

  公开（公告）日：2008-07-10

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I: wherein R 1 , R 2 , R 3A , R 3B , R 4 , R 5 , R 6 , R 7 , R 8 , and X are as defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, and intermediates are also disclosed.

  公开了化合物和药物可接受的盐，其中化合物具有公式I的结构:其中R1，R2，R3A，R3B，R4，R5，R6，R7，R8和X如发明的详细说明中所定义的那样。还公开了相应的药物组合物，治疗方法和中间体。
• PYRAZOLINE COMPOUNDS
  申请人：Meyers Marvin J.

  公开号：US20100280016A1

  公开（公告）日：2010-11-04

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I: wherein R 1 , R 2 , R 3A , R 3B , R 4 , R 5 , R 6 , R 7 , R 8 , and X are as defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, and intermediates are also disclosed.

  本发明披露了具有I式结构的化合物及其药学上可接受的盐，其中化合物的结构如下：其中R1、R2、R3A、R3B、R4、R5、R6、R7、R8和X的定义详见发明的详细说明。本发明还披露了相应的药物组合物、治疗方法和中间体。
• Pyrazoline compounds
  申请人：Pfizer Inc.

  公开号：US07781428B2

  公开（公告）日：2010-08-24

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I: wherein R1, R2, R3A, R3B, R4, R5, R6, R7, R8, and X are as defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, and intermediates are also disclosed.

  本发明揭示了化合物及其药学上可接受的盐，其中化合物具有公式I的结构：其中R1、R2、R3A、R3B、R4、R5、R6、R7、R8和X的定义详见本发明的详细说明。本发明还揭示了相应的药物组合物、治疗方法和中间体。
• Discovery of (3<i>S</i>,3a<i>R</i>)-2-(3-Chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2<i>H</i>-benzo[<i>g</i>]indazole-7-carboxylic Acid (PF-3882845), an Orally Efficacious Mineralocorticoid Receptor (MR) Antagonist for Hypertension and Nephropathy
  作者：Marvin J. Meyers、Graciela B. Arhancet、Susan L. Hockerman、Xiangyang Chen、Scott A. Long、Matthew W. Mahoney、Joseph R. Rico、Danny J. Garland、James. R. Blinn、Joe T. Collins、Shengtian Yang、Horng-Chih Huang、Kevin F. McGee、Jay M. Wendling、Jessica D. Dietz、Maria A. Payne、Bruce L. Homer、Marcia I. Heron、David B. Reitz、Xiao Hu

  DOI：10.1021/jm100505n

  日期：2010.8.26

  We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (M R) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.