N-<1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl>-2(R)-(cyclopropylmethyl)-4-(1,1-dimethylethoxy)-4-oxobutanamide | 160447-08-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: N-<1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl>-2(R)-(cyclopropylmethyl)-4-(1,1-dimethylethoxy)-4-oxobutanamide
• 英文别名: 3(R)-(cyclopropylmethyl)-4-{[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxobutanoic acid tert-butyl ester；tert-butyl (3R)-4-[[(2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy-6-methylheptan-2-yl]amino]-3-(cyclopropylmethyl)-4-oxobutanoate
• CAS: 160447-08-5
• 化学式: C₂₆H₄₇NO₅
• 分子量: 453.663
• InChiKey: WYSWWCJXIFAGTH-HOUBMWHVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  32
• 可旋转键数：
  14
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.92
• 拓扑面积：
  95.9
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-<1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl>-2(R)-(cyclopropylmethyl)-4-(1,1-dimethylethoxy)-4-oxobutanamide 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 7.0h， 以70%的产率得到N-<<1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl>amino>-3(R)-(cyclopropylmethyl)-4-oxobutanoic acid
  参考文献：
  名称：

  Discovery of non-peptidic P 2 –P 3 butanediamide renin inhibitors with high oral efficacy

  摘要：

  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.

  DOI：

  10.1016/s0968-0896(98)00265-x
• 作为产物：
  描述：

  3-(3-cyclopropyl-1-oxopropyl)-4(S)-(1-methylethyl)-2-oxazolidinone 在 N,N-二甲基丙烯基脲 、 lithium hydroxide 、 双氧水 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 N-<1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl>-2(R)-(cyclopropylmethyl)-4-(1,1-dimethylethoxy)-4-oxobutanamide
  参考文献：
  名称：

  Discovery of non-peptidic P 2 –P 3 butanediamide renin inhibitors with high oral efficacy

  摘要：

  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.

  DOI：

  10.1016/s0968-0896(98)00265-x

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。
• 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。
• US5541163A
  申请人：——

  公开号：US5541163A

  公开（公告）日：1996-07-30
• [EN] RENIN INHIBITING N-(2-AMINO-2-OXOETHYL)BUTANEDIAMIDE DERIVATIVES<br/>[FR] DERIVES DE N-(2-AMINO-2-OXOETHYL)BUTANEDIAMIDE INHIBANT LA RENINE
  申请人：BIO-MEGA/BOEHRINGER INGELHEIM RESEARCH INC.

  公开号：WO1994007846A1

  公开（公告）日：1994-04-14

  (EN) 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, 1$i(H)-imidazol-4-ylmethyl, 4-thiazolylmethyl or (2-amino-4-thiazolyl)methyl; and B is a renin substrate transition state analog, for example, [1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino. The compounds inhibit renin activity and are indicated for the treatment of hypertension and congestive heart failure.(FR) L'invention concerne les composés de la formule: A-N(R1)C(O)CH2CHR2C(O)-B où, par exemple, R3 représente hydrogène ou alkyle et R4 représente hydrogène, alkyle ou alkyle substitué tel que 2-(2-pyridinyl)éthyle, ou R3 et R4 forment ensemble avec l'atome d'azote auquel ils sont liés un groupe pyrrolidino, pipéridino, morpholino ou thiomorpholino. R1 représente, par exemple, benzyle, alkyle, ou alkyle substitué tel que cyclohexylméthyle. R2, par exemple, alkyle, cycloalkylméthyle, 1$i(H)-imidazol-4-ylméthyle, 4-thiazolylméthyle ou (2-amino-4-thiazolyl)méthyle. Enfin B représente un analogue d'un état transitoire du substrat de la rénine, par exemple [1(S)-(cyclohexylméthyl)-2(R),3(S)-dihydroxy-5-méthylhexyl]amino. Ces composés inhibent l'activité de la rénine et ils sont indiqués pour le traitement de l'hypertension et de l'insuffisance cardiaque.
• 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.