3-(1-{[(2-methoxy-4-methylphenyl)sulfonyl]carbamoyl}-1-(3,4-methylenedioxyphenyl)methyl)-1-methyl-1H-indole-6-carboxylic acid | 199589-50-9

• 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: 3-(1-{[(2-methoxy-4-methylphenyl)sulfonyl]carbamoyl}-1-(3,4-methylenedioxyphenyl)methyl)-1-methyl-1H-indole-6-carboxylic acid
• 英文别名: 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid；3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolecarboxylic acid；3-[1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl]-1-methylindole-6-carboxylic acid
• CAS: 199589-50-9
• 化学式: C₂₇H₂₄N₂O₈S
• 分子量: 536.562
• InChiKey: RXNZJEAMURXNLG-UHFFFAOYSA-N

物化性质

• 熔点：
  199 °C
• 密度：
  1.45±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  38
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  142
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-(1-{[(2-methoxy-4-methylphenyl)sulfonyl]carbamoyl}-1-(3,4-methylenedioxyphenyl)methyl)-1-methyl-1H-indole-6-carboxylic acid 在 盐酸 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 正己烷 、 水 、 乙酸乙酯 为溶剂， 反应 2.25h， 生成 3-((1S)-1-(1,3-benzodioxol-5-yl)-2-{[(2-methoxy-4-methylphenyl)sulfonyl]amino}-2-oxoethyl)-1-methyl-1H-indole-6-carboxylic acid
  参考文献：
  名称：

  An Efficient and Scalable Synthesis of the Endothelin Antagonists UK-350,926 and UK-349,862 Using a Dynamic Resolution Process

  摘要：

  The development and scale-up of a potential manufacturing route to the endothelin antagonists UK-350,926 1 and UK-349,862 2 are described. A key synthetic challenge in designing an efficient route to these molecules was the optical lability of the stereogenic centre during the construction of the acylsulfonamide functionality. In the discovery synthesis of UK-350,926 the chiral centre was introduced by classical resolution and the acylsulfonamide functionality synthesized by construction of the N-sulfonyl bond. An alternative more efficient process route was developed involving the preparation of racemic UK-350,926 and final step dynamic resolution with (S)-(-)-1-phenylethylamine as the key step. The process route prepared the acylsulfonamide by construction of the N-carbonyl bond, eliminates a cryogenic reaction and a hazardous intermediate from the synthesis, improves the overall process yield, and allows access to both endothelin antagonists from common intermediates without the need for purification by chromatography. Full experimental details of the new five-step process to prepare UK-349,862 from commercially available starting materials are given for the first time.

  DOI：

  10.1021/op050102f
• 作为产物：
  描述：

  2-甲氧基-4-甲基苯磺酰氯 在 2-溴吡啶-1-氧化物 、 1,10-菲罗啉 、 copper(ll) sulfate pentahydrate 、 [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold bis(trifluoromethanesulfonyl)imidate 、 10 wt% Pd(OH)2 on carbon 、 水 、 氢气 、 potassium carbonate 、 三乙胺 作用下， 以 甲苯 为溶剂， 反应 18.0h， 生成 3-(1-{[(2-methoxy-4-methylphenyl)sulfonyl]carbamoyl}-1-(3,4-methylenedioxyphenyl)methyl)-1-methyl-1H-indole-6-carboxylic acid
  参考文献：
  名称：

  在水中生成金卡宾：吲哚和苯胺有效分子间捕获α-氧代金卡宾类化合物

  摘要：

  在水介质中已经实现了通过金催化的炔烃氧化产生的金卡宾中间体与吲哚和苯胺的有效分子间反应。重要的是，这首次揭示了水可以显着抑制不希望的过氧化，从而为使用外部亲核试剂的金催化的分子间炔烃氧化中的过氧化问题提供了一种通用且实用的解决方案。该策略已成功应用于辉瑞手性内皮素拮抗剂UK-350,926的正式合成。

  DOI：

  10.1039/c4sc00983e

文献信息

• Indole derivatives useful in therapy
  申请人：Pfizer Inc.

  公开号：US06211223B1

  公开（公告）日：2001-04-03

  The invention provides S-(+)-3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid, which is substantially free from its (R)-(−)-enantiomer, and pharmaceutically acceptable derivatives thereof. The compounds are useful in the treatment of inter alia acute renal failure, restenosis and pulmonary hypertension.

  这项发明提供了S-（+）-3- 1-（1,3-苯并二氧杂环戊-5-基）-2-[(2-甲氧基-4-甲基苯基)磺酰氨]-2-氧乙基}-1-甲基-1H-吲哚-6-羧酸，该化合物基本上不含其（R）-（-）-对映体，以及其药学上可接受的衍生物。这些化合物在治疗急性肾衰竭、再狭窄和肺动脉高压等方面是有用的。
• [EN] INDOLE DERIVATIVE USEFUL AS ENDOTHELIN RECEPTOR ANTAGONIST<br/>[FR] DERIVE INDOLIQUE UTILE COMME ANTAGONISTE DE RECEPTEUR D'ENDOTHELINE
  申请人：PFIZER LIMITED

  公开号：WO1999020623A1

  公开（公告）日：1999-04-29

  (EN) The invention provides S-(+)-3- 1-(1,3-benzodioxol -5-yl)-2-[ (2-methoxy-4- methylphenyl)sulfonylamino] -2-oxoethyl }-1-methyl -1$i(H)-indole- 6-carboxylic acid, represented by formula (a), which is substantially free from its (R)-(-)-enantiomer, and pharmaceutically acceptable derivatives thereof. The compound is useful in the treatment of $i(inter alia) acute renal failure, restenosis and pulmonary hypertension.(FR) L'invention concerne un acide S-(+)-3- 1,3-benzodioxol -5-yl)-2-[ (2-méthoxy-4- méthylphényl)sulfonylamino] -2-oxoéthyl }-1-méthyl -1$i(H)-indole- 6 carboxylique représenté par la formule (a) qui est sensiblement exempt de son (R)-(-)-énantiomère et ses dérivés pharmaceutiquement acceptables. Les composés sont utiles dans le traitement notamment d'insuffisance rénale aiguë, de resténose et d'hypertension pulmonaire.

  该发明提供了由式(a)表示的S-(+)-3- 1-(1,3-苯并二氧杂环-5-基)-2-[ (2-甲氧基-4-甲基苯基)磺酰胺]-2-氧代乙基 }-1-甲基-1$i(H)-吲哚-6-羧酸，其基本上不含其(R)-(-)-对映体及其药学可接受的衍生物。该化合物在治疗急性肾功能衰竭、再狭窄和肺动脉高压等方面具有用途。
• Indole derivatives useful as endothelin receptor antagonists
  申请人：——

  公开号：US20010014677A1

  公开（公告）日：2001-08-16

  1 Compounds of formula (I), and their pharmaceutically acceptable derivatives, wherein R 1 and R 2 are optional substituents and independently represent C 1-6 alkyl, C 2-6 alkenyl, optionally substituted by CO 2 H or CO 2 (C 1-6 alkyl), C 2-6 alkynyl, halogen, C 1-3 perfluoroalkyl, (CH 2 ) m Ar 1 , (CH 2 ) m Het 1 , (CH 2 ) m CONR 7 R 8 , (CH 2 ) m CO 2 R 8 , O(CH 2 ) q CO 2 R 8 , (CH 2 ) m COR 8 , (CH 2 ) m OR 8 , O(CH 2 ) p OR 8 , (CH 2 ) m NR 7 R 8 , CO 2 (CH 2 ) q NR 7 R 8 , (CH 2 ) m CN, S(O) n NR 8 , SO 2 NR 7 R 8 , CONH(CH 2 ) m Ar 1 or CONH(CH 2 ) m Het 1 ; R 3 represents H, C 1-6 alkyl, (CH 2 ) p NR 9 R 10 , SO 2 R 10 , SO 2 NR 9 R 10 , (CH 2 ) m CO 2 R 10 , C 2-6 alkenyl, C 2-6 alkynyl (CH 2 ) m CONR 9 R 10 , (CH 2 ) m CO 2 R 10 , (CH 2 ) p CN, (CH 2 ) p R 10 or (CH 2 ) p OR 10 ; R 4 represents H or C 1-6 alkyl; R 5 represents H or OH; R 6 represents phenyl optionally fused to a heterocyclic ring, the group as a whole being optionally substituted; R 7-10 are fully defined herein and may independently represent Ar 2 or Het 2 ; Z represents CO 2 H, CONH(tetrazol-5-yl), CONHSO 2 O(C 1-4 alkyl), CO 2 Ar 3 , CO 2 (C 1-6 alkyl), tetrazol-5-yl, CONHSO 2 Ar 3 , CONHSO 2 (CH 2 ) q Ar 3 or CONHSO 2 (C 1-4 alkyl); Ar 1-3 independently represent phenyl, naphthyl, or an aromatic heterocycle, which groups are optionally fused and optionally substituted; and Het 1 and Het 2 independently represent a non-aromatic heterocycle which is optionally substituted; are useful in the treatment of restenosis, renal failure and pulmonary hypertension.

  式（I）的化合物及其药学上可接受的衍生物，其中R1和R2是可选的取代基，且独立地表示C1-6烷基，C2-6烯基，可选地被CO2H或CO2（C1-6烷基）取代的C2-6炔基，卤素，C1-3全氟烷基，（CH2）mAr1，（CH2）mHet1，（CH2）mCONR7R8，（CH2）mCO2R8，O（CH2）qCO2R8，（CH2）mCOR8，（CH2）mOR8，O（CH2）pOR8，（CH2）mNR7R8，CO2（CH2）qNR7R8，（CH2）mCN，S（O）nNR8，SO2NR7R8，CONH（CH2）mAr1或CONH（CH2）mHet1；R3表示H，C1-6烷基，（CH2）pNR9R10，SO2R10，SO2NR9R10，（CH2）mCO2R10，C2-6烯基，C2-6炔基，（CH2）mCONR9R10，（CH2）mCO2R10，（CH2）pCN，（CH2）pR10或（CH2）pOR10；R4表示H或C1-6烷基；R5表示H或OH；R6表示苯环，可选地融合到杂环上，整个基团可选地被取代；R7-10在此完全定义，可以独立地表示Ar2或Het2；Z表示CO2H，CONH（四唑-5-基），CONHSO2O（C1-4烷基），CO2Ar3，CO2（C1-6烷基），四唑-5-基，CONHSO2Ar3，CONHSO2（CH2）qAr3或CONHSO2（C1-4烷基）；Ar1-3独立地表示苯环，萘环或芳香杂环，这些基团可以可选地融合和可选地被取代；Het1和Het2独立地表示可选地被取代的非芳香杂环；在治疗再狭窄，肾衰竭和肺动脉高压方面有用。
• The design and synthesis of a novel series of indole derived selective ETA antagonists
  作者：David J Rawson、Kevin N Dack、Roger P Dickinson、Kim James

  DOI：10.1016/s0960-894x(01)00660-6

  日期：2002.1

  Conformational constraint has been used as the key design element in the identification of a series of potent and selective ETA antagonists. The most potent antagonist, 32, (ETA IC50 = 0.55 nM) is 722-fold selective over the ETB receptor, as measured by binding experiments. (C) 2002 Elsevier Science Ltd. All rights reserved.
• INDOLE DERIVATIVES USEFUL AS ENDOTHELIN RECEPTOR ANTAGONISTS
  申请人：PFIZER INC.

  公开号：EP0901470B1

  公开（公告）日：2004-03-31