(2-(4'-methoxybenzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid amide)

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (2-(4'-methoxybenzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid amide)
• 英文别名: 2-(4'-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid amide；2-(4-methoxybenzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid amide；2-(4-methoxyphenylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide；2-(4-methoxybenzenesulfonyl)-2,3,4,9-tetrahydro-1H-b-carboxylic acid amide；S002-333；2-[4-methoxybenzenesulfonyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid amide；2-[4-Methoxybenzenesulfonyl]-1,2,3,4,-tetrahydro-9h-pyrido[3,4-b]indole-3-carboxylic acid amide；2-(4-methoxyphenyl)sulfonyl-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxamide
• 化学式: C₁₉H₁₉N₃O₄S
• 分子量: 385.444
• InChiKey: KBVPHVCPUVDXOQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2-(4'-methoxybenzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid amide) 在 chiralcel OD-RH (15/4.6 mm, 5 mm) (ChiralTechnologies Europe, France) 作用下， 以 乙腈 为溶剂， 生成 (S)-(2-(4'-methoxybenzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid amide) 、 (R)-(2-(4'-methoxybenzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid amide)
  参考文献：
  名称：

  Pharmacokinetics, dose proportionality and permeability of S002-333 and its enantiomers, a potent antithrombotic agent, in rabbits

  摘要：

  1. S002-333 [(2-(4'-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido (3,4-b) indole-3-carboxylic acid amide)] is a novel and potent antithrombotic active agent. The present work investigates the pharmacokinetics, bioavailability, dose proportionality and permeability of the racemate, S002-333 in male New Zealand White (NZW) rabbits.2. Rabbits were administered single intravenous (i.v.) (2 mg/kg) and three oral doses of 10, 20 and 40 mg/kg of S002-333, respectively, at different occasions to evaluate dose proportionality. Serial blood samples were collected and analyzed by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Since S002-333 is a racemate consisting of S004-1032 (R) and S007-1558 (S), same samples were analyzed using a chiralcel column so as to evaluate the respective enantiomers.3. The peak plasma concentration, after oral administration, occurred at similar to 10 h post-dose. The clearance (CL) and volume of distribution (V-d) after i.v. dose were found to be 3.05 +/- 0.09 l/h/kg and 6.73 +/- 1.16 l/kg, respectively. The absolute oral bioavailability of S002-333 was 16.32%, whereas it was 6.62 and 5.90% for R-and S-enantiomers, respectively. The absolute bioavailability of 10, 20 and 40 mg/kg doses were found to be 27.91, 14.39 and 16.91%, respectively. The PAMPA (parallel artificial membrane permeability assay) assay shows that S002-333 has a low-passive permeability at gastric and intestinal environment.4. In conclusion, S002-333 has low-passive permeability, low CL and large V-d. The R-enantiomer has a "slightly'' greater bioavailability than the S-enantiomer.

  DOI：

  10.3109/00498254.2015.1034224
• 作为产物：
  描述：

  DL-色氨酸 在 氯化亚砜 、 氨 、 三乙胺 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， -10.0~37.0 ℃ 、4.0 MPa 条件下， 反应 18.0h， 生成 (2-(4'-methoxybenzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid amide)
  参考文献：
  名称：

  新型糖蛋白VI拮抗剂作为抗血栓药：2,3-二取代的四氢吡啶并（3,4- b）吲哚的合成，生物学评估和分子模型研究

  摘要：

  靶向GPVI的小分子抑制剂的开发具有广阔的治疗作用，因为它们可抑制动脉血栓形成并具有有限的出血风险。在显示体内抗血栓形成活性的化合物中，活性最高的化合物6b（小鼠体内的ED 50 = 28.36μmol/ kg po）显示出对胶原蛋白（IC 50 = 6.7μM），CRP-XL（IC 50 = 53.5μM）的抑制作用，与氯沙坦（LOS）（胶原蛋白，IC 50 = 10.4μM; CRP-XL，IC 50 = 158μM; CVX，IC 50 = 11μM）相比，惊厥毒素（CVX）（IC 50 = 5.7μM ）介导的血小板凝集任何其对映异构体S（6c）（胶原蛋白，IC50 = 25.3μM；CRP-XL，IC 50 = 181.4μM；CVX，IC 50 = 9μM）和R（6d）（胶原，IC 50 = 126.3μM; CRP-XL，IC 50 > 500μM; CVX，IC 50 = 86

  DOI：

  10.1021/acs.jmedchem.6b01360

文献信息

• 2-Alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esters/amides useful as antithrombotic agents
  申请人：Gaur Stuti

  公开号：US20060142322A1

  公开（公告）日：2006-06-29

  The present invention relates to antithrombotic compounds 2-alkyl aryl sulphonyl-1,2,3,4,-tetrahydro-9H-pyrido(3,4-b)indole-3-carboxylic acid esters/amides, pharmaceutically acceptable salts and compositions thereof to be used in the treatment of intravascular thrombosis such as myocardial ischemia and stroke. The compound has the following general structure wherein R represents methyl ester or amide and R 1 represents alkyl, aryl and heteroaryl moiety.

  本发明涉及抗血栓化合物2-烷基芳基磺酰基-1,2,3,4-四氢-9H-吡啶并(3,4-b)吲哚-3-羧酸酯/酰胺，其药学上可接受的盐和组合物，用于治疗血管内血栓形成，如心肌缺血和中风。该化合物具有以下一般结构，其中R代表甲酯或酰胺，R1代表烷基、芳基和杂环芳基基团。
• 2-ALKYL/ARYL SULPHONYL-1,2,3,4-TETRAHYDRO-9H-PYRIDO (3,4-B) INDOLE-3-CARBOXYLIC ACID ESTERS/AMIDES USEFUL AS ANTITHROMBOTIC AGENTS
  申请人：Gaur Stuti

  公开号：US20070287723A1

  公开（公告）日：2007-12-13

  The present invention relates to antithrombotic compounds 2-alkyl aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid esters/amides, pharmaceutically acceptable salts and compositions thereof to be used in the treatment of intravascular thrombosis such as myocardial ischemia and stroke. The compound has the following general structure wherein R represents methyl ester or amide and R 1 represents alkyl, aryl and heteroaryl moiety.

  本发明涉及抗血栓化合物2-烷基芳基磺酰基-1,2,3,4-四氢-9H-吡啶[3,4-b]吲哚-3-羧酸酯/酰胺，其制备的药学上可接受的盐及其组合物，用于治疗血管内血栓形成，如心肌缺血和中风。该化合物具有以下一般结构式，其中R代表甲酯或酰胺，R1代表烷基、芳基和杂环芳基基团。
• WO2006/70385
  申请人：——

  公开号：——

  公开（公告）日：——
• <i>In vitro</i>metabolism of a novel antithrombotic compound, S002-333, and its enantiomers: quantitative cytochrome P450 phenotyping, metabolic profiling and enzyme kinetic studies
  作者：Amrita Saxena、Girish K. Jain、Hefazat H. Siddiqui、Shom S. Bhunia、Anil K. Saxena、Jiaur R. Gayen

  DOI：10.3109/00498254.2013.831958

  日期：2014.4

  1. S002-333, (2-(40'-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido (3,4-b) indole-3-carboxylic acid amide) is a novel potent antithrombotic molecule currently under development phase. It is the racemic mixture of two enantiomers, namely S004-1032 (R-form) and S007-1558 (S-form).2. The contribution of five major isoenzymes, namely CYP2B6, 2C9, 2C19, 2D6 and 3A4 was quantified using recombinant P450s in the phase-I metabolism through relative activity factor approach. CYP2C19 was found to be the major contributor for S002-333 and S007-1558, while CYP3A4 showed greater involvement in S004-1032 metabolism. Chemical inhibition and immunoinhibition studies reconfirmed the results in human liver microsomes (HLM).3. Four major phase-I metabolites of S002-333; M-1 and M-3 (oxidative), M-2 (O-demethylated) and M-4 (dehydrogenated) were characterized in HLM. These metabolites constituted 11.2, 11.3 and 21.5% of the parent in comparison with the net phase-I metabolism of 29.9, 31.4 and 38.3% of S002-333, S004-1032 and S007-1558, respectively.4. Among CYP2C9, 2C19 and 3A4, the relative contribution of CYP2C9 was found to be maximum during M-1 through M-4 formation. Enzyme kinetic analysis for detected metabolites indicated that M-1 to M-3 followed classical hyperbolic kinetics, whereas M-4 showed evidence of autoactivation. In conclusion, the results suggest prominent role of CYP2C9, 2C19 and 3A4 isoforms for enantioselective disposition of S002-333 in vitro.
• US7601838B2
  申请人：——

  公开号：US7601838B2

  公开（公告）日：2009-10-13