(R)-N¹-((1S,2R,3S)-1-Cyclohexylmethyl-2,3-dihydroxy-5-methyl-hexyl)-N⁴-dimethylcarbamoylmethyl-N⁴-((S)-1-phenyl-ethyl)-2-(1-trityl-1H-imidazol-4-ylmethyl)-succinamide | 160447-15-4

• 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: (R)-N¹-((1S,2R,3S)-1-Cyclohexylmethyl-2,3-dihydroxy-5-methyl-hexyl)-N⁴-dimethylcarbamoylmethyl-N⁴-((S)-1-phenyl-ethyl)-2-(1-trityl-1H-imidazol-4-ylmethyl)-succinamide
• 英文别名: (2R)-N-[(2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy-6-methylheptan-2-yl]-N'-[2-(dimethylamino)-2-oxoethyl]-N'-[(1S)-1-phenylethyl]-2-[(1-tritylimidazol-4-yl)methyl]butanediamide
• CAS: 160447-15-4
• 化学式: C₅₃H₆₇N₅O₅
• 分子量: 854.145
• InChiKey: FCPUCXVWFPSTPO-MOEVUIIRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.8
• 重原子数：
  63
• 可旋转键数：
  20
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  128
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (R)-N¹-((1S,2R,3S)-1-Cyclohexylmethyl-2,3-dihydroxy-5-methyl-hexyl)-N⁴-dimethylcarbamoylmethyl-N⁴-((S)-1-phenyl-ethyl)-2-(1-trityl-1H-imidazol-4-ylmethyl)-succinamide 在 palladium dihydroxide 氢气 作用下， 以 乙醇 、 溶剂黄146 为溶剂， 反应 41.0h， 以48%的产率得到(R)-N¹-((1S,2R,3S)-1-Cyclohexylmethyl-2,3-dihydroxy-5-methyl-hexyl)-N⁴-dimethylcarbamoylmethyl-2-(1H-imidazol-4-ylmethyl)-N⁴-((S)-1-phenyl-ethyl)-succinamide
  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：

  4(S)-(1-methylethyl)-3-[1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl]-2-oxazolidinone 在 palladium on activated charcoal lithium hydroxide 、 氢气 、 双氧水 、 sodium hexamethyldisilazane 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， -78.0~25.0 ℃ 、101.33 kPa 条件下， 反应 10.25h， 生成 (R)-N¹-((1S,2R,3S)-1-Cyclohexylmethyl-2,3-dihydroxy-5-methyl-hexyl)-N⁴-dimethylcarbamoylmethyl-N⁴-((S)-1-phenyl-ethyl)-2-(1-trityl-1H-imidazol-4-ylmethyl)-succinamide
  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：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。
• [EN] N-(HYDROXYETHYL)BUTANEDIAMIDE DERIVATIVES AS RENIN INHIBITORS<br/>[FR] DERIVES DE N-(HYDROXYETHYL)BUTANEDIAMINE INHIBITEURS DE LA RENINE
  申请人：BIO-MEGA/BOEHRINGER INGELHEIM RESEARCH INC.

  公开号：WO1994007845A1

  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 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 hereroatoms 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, 1$i(H)-imidazol-4-ylmethyl, 4-thiazolylmethyl or (2-amino-4-thiazolyl)methyl; and B is a renin substrate transition state mimic, for example, [1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino. The compounds inhibit renin activity and are indicated for the treatment of hypertension and congestive heart failure.(FR) L'invention concerne des composés de la formule: A-N(R1)C(O)CH2CHR2C(O)-B. Dans cette formule, A représente un radical portant un oxygène, choisi dans le groupe constitué par (a) HO-CH(R3)CH2, où R3 représente, par exemple, un hydrogène, un alkyle inférieur, un cycloalkyle inférieur, un phényle ou un noyau hétérocyclique non substitué à cinq ou à six éléments renfermant un ou deux hétéroatomes choisis dans le groupe constitué par N, O et S; (b) HO-CH2CH(R4) où R4 représente, par exemple, un alkyle inférieur ou un phénylalkyle inférieur; et (c) HO-CR5(R6)CH2, où R5 et R6 chacun représentent un alkyle inférieur; ou R5 et R6 forment ensemble avec l'atome de carbone auquel ils sont liés un 1,1-(cycloalcanediyle inférieur), un 1,1-(4-hydroxycyclohexanediyle) ou un 1,1-(4-oxocyclohexanediyle); (d) (alcoxy inférieur)CR5A(R6A)CH2, où R5A et R6A représentent chacun un alkyle inférieur; ou R5A et R6A forment ensemble avec l'atome de carbone auquel ils sont liés un 1,1-(cycloalcanediyle inférieur); et (e) représente un (alkyle inférieur)C(O)CH2; R1 représente, par exemple, un benzyle, un alkyle, un alkyle substitué tel que le cycloyhexylméthyle ou R7R8NC(O)CH2 où R7 et R8 représentent alkyle tel que méthyle ou éthyle; R2 représente, par exemple, un alkyle, un cycloalkylméthyle, un 1$i(H)-imidazol-4-ylméthyle, un 4-thiazolylméthyle ou un (2-amino-4-thiazolyl)méthyle. Enfin, B représente un groupe simulant un état de transition du substrat de la rénine, par exemple un [1(S)-(cyclohexylméthyl)-2(R),3(S)-dihydroxy-5-méthylhexyl]amino. Ces composés inhibent l'activité de la rénine et ils sont recommandés dans le traitement de l'hypertension ou de l'insuffisance cardiaque.
• [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.