methyl 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonyl-amino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylate | 199589-43-0

• 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: methyl 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonyl-amino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylate
• 英文别名: methyl 3-(1-{[(2-methoxy-4-methylphenyl)sulfonyl]carbamoyl}-1-(3,4-methylenedioxyphenyl)methyl)-1-methyl-1H-indole-6-carboxylate；3-{1-(1,3-Benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-(methoxycarbonyl)-1-methyl-1H-indole；methyl 3-[1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl]-1-methylindole-6-carboxylate
• CAS: 199589-43-0
• 化学式: C₂₈H₂₆N₂O₈S
• 分子量: 550.589
• InChiKey: BLQXCKYYXZJCLS-UHFFFAOYSA-N

物化性质

• 熔点：
  184-185 °C
• 密度：
  1.40±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  39
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  131
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonyl-amino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylate 在 sodium tetrahydroborate 、 马钱子碱 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 丙酮 为溶剂， 反应 1.58h， 生成 (S)-(+)-2-(6-hydroxymethyl-1-methyl-1H-indol-3-yl)-N-[(2-methoxy-4-methylphenyl)sulfonyl]-2-(3,4-methylenedioxyphenyl)acetamide
  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-(1,3-benzodioxol-5-yl)-2-bromoacetic acid 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 生成 methyl 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonyl-amino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylate
  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

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。
• Indole derivatives useful as endothelin receptor antagonists
  申请人：Pfizer Inc.

  公开号：US06017945A1

  公开（公告）日：2000-01-25

  Compounds of formula (I), and their pharmaceutically acceptable derivatives, wherein R.sup.1 and R.sup.2 are optional substituents and independently represent C.sub.1-6 alkyl, C.sub.2-6 alkenyl [optionally substituted by CO.sub.2 H or CO.sub.2 (C.sub.1-6 alkyl)], C.sub.2-6 alkynyl, halogen, C.sub.1-3 perfluoroalkyl, (CH.sub.2).sub.m Ar.sup.1, (CH.sub.2).sub.m Het.sup.1, (CH.sub.2).sub.m CONR.sup.7 R.sup.8, (CH.sub.2).sub.m CO.sub.2 R.sup.8, O(CH.sub.2).sub.q CO.sub.2 R.sup.8, (CH.sub.2).sub.m COR.sup.8, (CH.sub.2).sub.m OR.sup.8, O(CH.sub.2).sub.p OR.sup.8, (CH.sub.2).sub.m NR.sup.7 R.sup.8, CO.sub.2 (CH.sub.2).sub.q NR.sup.7 R.sup.8, (CH.sub.2).sub.m CN, S(O).sub.n R.sup.8, SO.sub.2 NR.sup.7 R.sup.8, CONH(CH.sub.2).sub.m Ar.sup.1 or CONH(CH.sub.2).sub.m Het.sup.1 ; R.sup.3 represents H, C.sub.1-6, alkyl, (CH.sub.2).sub.p NR.sup.9 R.sup.10, SO.sub.2 R.sup.10, SO.sub.2 NR.sup.9 R.sup.10, (CH.sub.2).sub.m COR.sup.10, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.m CONR.sup.9 R.sup.10, (CH.sub.2).sub.m CO.sub.2 R.sup.10, (CH.sub.2).sub.p CN, (CH.sub.2).sub.p R.sup.10 or (CH.sub.2).sub.p OR.sup.10 ; R.sup.4 represents H or C.sub.1-6 alkyl; R.sup.5 represents H or OH; R.sup.6 represents phenyl optionally fused to a heterocyclic ring, the group as a whole being optionally substituted; R.sup.7-10 are fully defined herein and may independently represent Ar.sup.2 or Het.sup.2 ; Z represents CO.sub.2 H, CONH(tetrazol-5-yl), CONHSO.sub.2 O(C.sub.1-4 alkyl), CO.sub.2 Ar.sup.3, CO.sub.2 (C.sub.1-6 alkyl), tetrazol-5-yl, CONHSO.sub.2 Ar.sup.3, CONHSO.sub.2 (CH.sub.2).sub.q Ar.sup.3 or CONHSO.sub.2 (C.sub.1-6 alkyl); Ar.sup.1-3 independently represent phenyl, naphthyl, or an aromatic heterocycle, which groups are optionally fused and optionally substituted; and Het.sup.1 and Het.sup.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)的化合物及其药用可接受的衍生物，其中R.sup.1和R.sup.2是可选取代基团，独立表示C.sub.1-6烷基，C.sub.2-6烯基[可选择性地被CO.sub.2 H或CO.sub.2(C.sub.1-6烷基)取代]，C.sub.2-6炔基，卤素，C.sub.1-3全氟烷基，(CH.sub.2).sub.m Ar.sup.1，(CH.sub.2).sub.m Het.sup.1，(CH.sub.2).sub.m CONR.sup.7 R.sup.8，(CH.sub.2).sub.m CO.sub.2 R.sup.8，O(CH.sub.2).sub.q CO.sub.2 R.sup.8，(CH.sub.2).sub.m COR.sup.8，(CH.sub.2).sub.m OR.sup.8，O(CH.sub.2).sub.p OR.sup.8，(CH.sub.2).sub.m NR.sup.7 R.sup.8，CO.sub.2(CH.sub.2).sub.q NR.sup.7 R.sup.8，(CH.sub.2).sub.m CN，S(O).sub.n R.sup.8，SO.sub.2 NR.sup.7 R.sup.8，CONH(CH.sub.2).sub.m Ar.sup.1或CONH(CH.sub.2).sub.m Het.sup.1；R.sup.3表示H，C.sub.1-6烷基，(CH.sub.2).sub.p NR.sup.9 R.sup.10，SO.sub.2 R.sup.10，SO.sub.2 NR.sup.9 R.sup.10，(CH.sub.2).sub.m COR.sup.10，C.sub.2-6烯基，C.sub.2-6炔基，(CH.sub.2).sub.m CONR.sup.9 R.sup.10，(CH.sub.2).sub.m CO.sub.2 R.sup.10，(CH.sub.2).sub.p CN，(CH.sub.2).sub.p R.sup.10或(CH.sub.2).sub.p OR.sup.10；R.sup.4表示H或C.sub.1-6烷基；R.sup.5表示H或OH；R.sup.6表示苯基，可选地融合到杂环环，整体可选取代；R.sup.7-10在此完全定义，可独立表示Ar.sup.2或Het.sup.2；Z表示CO.sub.2 H，CONH(tetrazol-5-yl)，CONHSO.sub.2O(C.sub.1-4烷基)，CO.sub.2 Ar.sup.3，CO.sub.2(C.sub.1-6烷基)，tetrazol-5-yl，CONHSO.sub.2 Ar.sup.3，CONHSO.sub.2(CH.sub.2).sub.q Ar.sup.3或CONHSO.sub.2(C.sub.1-6烷基)；Ar.sup.1-3独立表示苯基，萘基或芳香杂环，这些基团可选地融合和可选取代；Het.sup.1和Het.sup.2独立表示可选取代的非芳香杂环；在治疗再狭窄、肾功能衰竭和肺动脉高压方面是有用的。
• [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。
• 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