4(S)-(1-methylethyl)-3-[1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl]-2-oxazolidinone | 160447-11-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: 4(S)-(1-methylethyl)-3-[1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl]-2-oxazolidinone
• 英文别名: 4(S)-(1-Methylethyl)-3-{1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl}-2-oxazolidinone；4(S)-(1-Methylethyl)-3-{1-oxo-3-[1-(triphenylmethyl)-1 H-imidazol-4-yl]propyl}-2-oxazolidinone；(4S)-4-propan-2-yl-3-[3-(1-tritylimidazol-4-yl)propanoyl]-1,3-oxazolidin-2-one
• CAS: 160447-11-0
• 化学式: C₃₁H₃₁N₃O₃
• 分子量: 493.605
• InChiKey: CSXVDKQLTVXNKH-MUUNZHRXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  64.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4(S)-(1-methylethyl)-3-[1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl]-2-oxazolidinone 在 四氧化锇 lithium hydroxide 、 NMMO*H₂O 、 双氧水 、 sodium hexamethyldisilazane 、 三氟乙酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 10.0h， 生成 5(RS)-[1(RS)-hydroxy-2-phenylethyl]-3(R)-[[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]dihydrofuran-2(3H)-one
  参考文献：
  名称：

  Novel small renin inhibitors containing 4,5- or 3,5-dihydroxy-2-substituted-6-phenylhexanamide replacements at the P2P3 sites

  摘要：

  Renin inhibitors containing a 4,5- or a 3,5-dihydroxy-2-substituted-6-phenylhexanamide fragment at the P-2- P-3 Sites have been prepared and evaluated. The four possible diastereomeric diols of the two series of inhibitors were synthesized to determine the optimal configuration of the carbinol centers for these replacements. The most potent inhibitors of each series, 1a and 2c have a molecular weight of only 503 and IC50 values of 23 and 20 nM in a human plasma renin assay at pH 6.0. Their very low aqueous solubility limited their further evaluation. The efficacy of these P-2-P-3 replacements is a result of their ability to maintain the important hydrogen-bonds with the enzyme. Due to conformational differences with the dipeptide, adjustment at the P-2 Side chain was required. These 4,5- and 3,5-dihydroxyhexanamide segments could be seen as novel N-terminal dipeptide replacements. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(98)80011-4
• 作为产物：
  描述：

  1-(三苯基甲基)-1H-咪唑-4-丙酸 在 正丁基锂 、 三乙胺 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 2.83h， 生成 4(S)-(1-methylethyl)-3-[1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl]-2-oxazolidinone
  参考文献：
  名称：

  Novel small renin inhibitors containing 4,5- or 3,5-dihydroxy-2-substituted-6-phenylhexanamide replacements at the P2P3 sites

  摘要：

  Renin inhibitors containing a 4,5- or a 3,5-dihydroxy-2-substituted-6-phenylhexanamide fragment at the P-2- P-3 Sites have been prepared and evaluated. The four possible diastereomeric diols of the two series of inhibitors were synthesized to determine the optimal configuration of the carbinol centers for these replacements. The most potent inhibitors of each series, 1a and 2c have a molecular weight of only 503 and IC50 values of 23 and 20 nM in a human plasma renin assay at pH 6.0. Their very low aqueous solubility limited their further evaluation. The efficacy of these P-2-P-3 replacements is a result of their ability to maintain the important hydrogen-bonds with the enzyme. Due to conformational differences with the dipeptide, adjustment at the P-2 Side chain was required. These 4,5- and 3,5-dihydroxyhexanamide segments could be seen as novel N-terminal dipeptide replacements. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(98)80011-4

文献信息

• Renin inhibiting N-(2-amino-2-oxoethyl)butanediamide derivatives
  申请人：Bio-Mega/Boehringer Ingelheim Research Inc.

  公开号：US05541163A1

  公开（公告）日：1996-07-30

  Disclosed herein are compounds of the formula: A--N(R.sup.1)C(O)CH.sub.2 CHR.sup.2 C(O)--B wherein A is R.sup.3 R.sup.4 NC(O)CH.sub.2 wherein, for example, R.sup.3 is hydrogen or alkyl and R.sup.4 is hydrogen, alkyl or a substituted alkyl such as 2-(2-pyridinyl)ethyl, or R.sup.3 and R.sup.4 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or thiomorpholino; R.sup.1 is, for example, benzyl, alkyl or a substituted alkyl such as cyclohexylmethyl; R.sup.2 is, for example, alkyl, cycloalkylmethyl, 1H-imidazol-4-ylmethyl, 4-thiazolylmethyl or (2-amino-4-thiazolyl)methyl; and B is a renin substrate transition state analog, for example, [1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino. The compounds inhibit renin activity and are indicated for the treatment of hypertension and congestive heart failure.

  本文所披露的化合物的公式为：A-N（R1）C（O）CH2CHR2C（O）-B，其中A是R3R4NC（O）CH2，例如，R3是氢或烷基，R4是氢，烷基或取代烷基，例如2-（2-吡啶基）乙基，或者R3和R4与它们所连接的氮原子形成吡咯烷基，哌嗪基，吗啉基或硫代吗啉基; R1是苯甲基，烷基或取代烷基，例如环己基甲基; R2是烷基，环烷基甲基，1H-咪唑-4-基甲基，4-噻唑基甲基或（2-氨基-4-噻唑基）甲基; B是肾素底物过渡态类似物，例如，[1（S）-（环己基甲基）-2（R），3（S）-二羟基-5-甲基己基]氨基。这些化合物抑制肾素活性，适用于治疗高血压和充血性心力衰竭。
• Method of using renin inhibiting N-(2-amino-2-oxoethyl) butanediamide
  申请人：Boehringer Ingelheim (Canada), Ltd.

  公开号：US05693619A1

  公开（公告）日：1997-12-02

  Disclosed herein is a method of using compounds of the formula: A-N(R.sup.1)C(O)CH.sub.2 CHR.sup.2 C(O)-B wherein A is R.sup.3 R.sup.4 NC(O)CH.sub.2 when, for example, R.sup.3 is hydrogen or alkyl and R.sup.4 is hydrogen, alkyl or a substituted alkyl such as 2-(2-pyridinyl)ethyl, or R.sup.3 and R.sup.4 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or thiomorpholino; R.sup.1 is, for example, benzyl, alkyl or a substituted alkyl such as cyclohexylmethyl; R.sup.2 is, for example, alkyl, cycloalkylmethyl, 1H-imidazol-4-ylmethyl, 4-thiazolyl-methyl or (2-amino-4-thiazolyl)methyl; and B is a renin substrate transition state analog, for example, \x9b1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl!amino for the treatment of congestive heart failure.

  本文揭示了一种使用化合物的方法，该化合物的结构式为：A-N(R.sup.1)C(O)CH.sub.2 CHR.sup.2 C(O)-B，其中A为R.sup.3 R.sup.4 NC(O)CH.sub.2，例如，当R.sup.3为氢或烷基，R.sup.4为氢、烷基或取代烷基，如2-(2-吡啶基)乙基，或者R.sup.3和R.sup.4与它们所连接的氮原子形成吡咯烷基、哌嗪烷基、吗啉基或硫代吗啉基；R.sup.1为苯甲基、烷基或取代烷基，如环己基甲基；R.sup.2为烷基、环烷基甲基、1H-咪唑-4-基甲基、4-噻唑基-甲基或(2-氨基-4-噻唑基)甲基；B为肾素底物转化态类似物，例如，\x9b1(S)-(环己基甲基)-2(R),3(S)-二羟基-5-甲基己基!氨基，用于治疗充血性心力衰竭。
• N-(Hydroxyethyl)butanediamide derivatives as renin inhibitors
  申请人：BIO-MEGA/BOEHRINGER INGELHEIM RESEARCH INC.

  公开号：EP0589446A1

  公开（公告）日：1994-03-30

  Disclosed herein are compounds of the formula:         A-N(R¹)C(O)CH₂CHR²C(O)-B wherein A is an oxygen-bearing radical selected from the group consisting of: (a) HO-CH(R³)CH₂ wherein R³ is, for example, hydrogen, lower alkyl, lower cycloalkyl, phenyl or an unsubstituted five- or six-membered heterocyclic ring containing one or two heteroatoms selected from the group of N, O or S; (b) HO-CH₂CH(R⁴) wherein R⁴ is, for example, lower alkyl or phenyl(lower)alkyl; and (c) HO-CR⁵(R⁶)CH₂ wherein each of R⁵ and R⁶ is lower alkyl; or R⁵ and R⁶ together with the carbon atom to which they are attached form a 1,1-(lower cycloalkanediyl), 1,1-(4-hydroxycyclohexanediyl) or 1,1-(4-oxocyclohexanediyl); (d) (lower alkoxy)CR5A(R6A)CH₂ wherein each of R5A and R6A is lower alkyl; or R5A and R6A together with the carbon atom to which they are attached form a 1,1-(lower cycloalkanediyl); and (e) (lower alkyl)C(O)CH₂; R¹ is, for example, benzyl, alkyl, a substituted alkyl such as cyclohexylmethyl, or R⁷R⁸NC(O)CH₂ wherein R⁷ and R⁸ are alkyl such as methyl or ethyl; R² is, for example, alkyl, cycloalkylmethyl, 1H-imidazol-4-ylmethyl, 4-thiazolylmethyl or (2-amino-4-thiazolyl)methyl; and B is a renin substrate transition state mimic, for example, [1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino. The compounds inhibit renin activity and are indicated for the treatment of hypertension and congestive heart failure.

  这里公开的是式中的化合物： A-N(R¹)C(O)CH₂CHR²C(O)-B 其中 A 是选自以下组别的含氧自由基(a) HO-CH(R³)CH₂ 其中 R³ 例如是氢、低级烷基、低级环烷基、苯基或含有选自 N、O 或 S 组的一个或两个杂原子的未取代的五元或六元杂环； (b) HO-CH₂CH(R⁴) 其中 R⁴ 例如是低级烷基或苯基（低级）烷基；(c) HO-CR⁵(R⁶)CH₂，其中 R⁵ 和 R⁶ 均为低级烷基；或 R⁵ 和 R⁶ 与它们所连接的碳原子一起形成 1,1-(低级环烷二基)、1,1-(4-羟基环己烷二基)或 1,1-(4-氧代环己烷二基)；(d) (低级烷氧基)CR5A(R6A)CH₂，其中 R5A 和 R6A 各为低级烷基；或 R5A 和 R6A 与它们所连接的碳原子一起形成 1,1-(低级环烷二基)；(e) (低级烷基)C(O)CH₂；R¹例如是苄基、烷基、取代的烷基如环己基甲基，或 R⁷R⁸NC(O)CH₂，其中 R⁷ 和 R⁸ 是烷基如甲基或乙基；R² 是例如烷基、环烷基甲基、1H-咪唑-4-基甲基、4-噻唑基甲基或（2-氨基-4-噻唑基）甲基；以及 B 是肾素底物过渡态模拟物，例如[1(S)-(环己基甲基)-2(R),3(S)-二羟基-5-甲基己基]氨基。这些化合物可抑制肾素活性，适用于治疗高血压和充血性心力衰竭。
• Renin Inhibiting N-(2-Amino-2-oxoethyl)Butanediamide Derivatives
  申请人：BIO-MEGA/BOEHRINGER INGELHEIM RESEARCH INC.

  公开号：EP0589445A1

  公开（公告）日：1994-03-30

  Disclosed herein are compounds of the formula:         A-N(R¹)C(O)CH₂CHR²C(O)-B wherein A is R³R⁴NC(O)CH₂ wherein, for example, R³ is hydrogen or alkyl and R⁴ is hydrogen, alkyl or a substituted alkyl such as 2-(2-pyridinyl)ethyl, or R³ and R⁴ together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or thiomorpholino; R¹ is, for example, benzyl, alkyl or a substituted alkyl such as cyclohexylmethyl; R² is, for example, alkyl, cycloalkylmethyl, 1H-imidazol-4-ylmethyl, 4-thiazolylmethyl or (2-amino-4-thiazolyl)methyl; and B is a renin substrate transition state analog, for example, [1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino. The compounds inhibit renin activity and are indicated for the treatment of hypertension and congestive heart failure.

  这里公开的是式中的化合物： A-N(R¹)C(O)CH₂CHR²C(O)-B 其中 A 是 R³R⁴NC(O)CH₂，例如，R³是氢或烷基，R⁴是氢、烷基或取代的烷基，如 2-(2-吡啶基)乙基，或 R³ 和 R⁴ 与它们所连接的氮原子一起形成吡咯烷基、哌啶基、吗啉基或硫代吗啉基；R¹例如是苄基、烷基或取代的烷基，如环己基甲基；R²例如是烷基、环烷基甲基、1H-咪唑-4-基甲基、4-噻唑基甲基或（2-氨基-4-噻唑基）甲基；B是肾素底物过渡态类似物，例如[1(S)-(环己基甲基)-2(R),3(S)-二羟基-5-甲基己基]氨基。这些化合物可抑制肾素活性，适用于治疗高血压和充血性心力衰竭。
• Discovery of non-peptidic P 2 –P 3 butanediamide renin inhibitors with high oral efficacy
  作者：Bruno Simoneau、Pierre Lavallée、Paul C. Anderson、Murray Bailey、Gary Bantle、Sylvie Berthiaume、Catherine Chabot、Gulrez Fazal、Ted Halmos、William W. Ogilvie、Marc-André Poupart、Bounkham Thavonekham、Zhili Xin、Diane Thibeault、Gordon Bolger、Maret Panzenbeck、Raymond Winquist、Grace L. Jung

  DOI：10.1016/s0968-0896(98)00265-x

  日期：1999.3

  A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P-2 and P-3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3 mg/kg. These potent renin inhibitors are characterized by oral bioavailabilities of 40 and 89% in the cynomolgus monkey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-development. (C) 1999 Elsevier Science Ltd. All rights reserved.