Ethyl 2(R,S)-[[(4-morpholinyl)carbonyl]amino]-3, 3-dimethyl-3-phenylpropionate | 114359-58-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: Ethyl 2(R,S)-[[(4-morpholinyl)carbonyl]amino]-3, 3-dimethyl-3-phenylpropionate
• 英文别名: Ethyl 2(R,S) [[(4-morpholinyl)carbonyl]amino]-3,3-dimethyl-3-phenylpropionate；ethyl 3-methyl-2-(morpholine-4-carbonylamino)-3-phenylbutanoate
• CAS: 114359-58-9
• 化学式: C₁₈H₂₆N₂O₄
• 分子量: 334.415
• InChiKey: ZBZOPAFMJBVEOZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  Ethyl 2(R,S)-[[(4-morpholinyl)carbonyl]amino]-3, 3-dimethyl-3-phenylpropionate 在 sodium hydroxide 、 N,N'-二环己基碳二亚胺 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 (2S,3R,4S)-2-{[(4-morpholinylcarbonyl)-L-β,β-dimethylphenylalanyl-L-histidyl]amino}-1-cyclohexyl-3,4-dihydroxy-6-methylheptane
  参考文献：
  名称：

  Renin inhibitors. Dipeptide analogs of angiotensinogen utilizing a structurally modified phenylalanine residue to impart proteolytic stability

  摘要：

  A series of renin inhibitors have been prepared and evaluated for their susceptibility to cleavage by the serine protease chymotrypsin. The compounds were designed by consideration of the structural requirements in the active-site region of renin and chymotrypsin. By systematic alteration of the P3 phenylalanine residue, compounds with varying degrees of renin inhibitory potency and chymotrypsin susceptibility were obtained. Selected analogues from this group were examined in vivo for both their hypotensive effects and metabolic patterns.

  DOI：

  10.1021/jm00120a006
• 作为产物：
  描述：

  diethyl (α,α-dimethylbenzyl) malonate 在 盐酸 、 氢氧化钾 、 叠氮磷酸二苯酯 、 三乙胺 作用下， 反应 23.5h， 生成 Ethyl 2(R,S)-[[(4-morpholinyl)carbonyl]amino]-3, 3-dimethyl-3-phenylpropionate
  参考文献：
  名称：

  Renin inhibitors. Dipeptide analogs of angiotensinogen utilizing a structurally modified phenylalanine residue to impart proteolytic stability

  摘要：

  A series of renin inhibitors have been prepared and evaluated for their susceptibility to cleavage by the serine protease chymotrypsin. The compounds were designed by consideration of the structural requirements in the active-site region of renin and chymotrypsin. By systematic alteration of the P3 phenylalanine residue, compounds with varying degrees of renin inhibitory potency and chymotrypsin susceptibility were obtained. Selected analogues from this group were examined in vivo for both their hypotensive effects and metabolic patterns.

  DOI：

  10.1021/jm00120a006

文献信息

• Renin-inhibiting functionalized peptidyl aminodiols and - triols
  申请人：ABBOTT LABORATORIES

  公开号：EP0341602A2

  公开（公告）日：1989-11-15

  A renin inhibiting compound of the formula: or a pharmaceutically acceptable salt, ester or prodrug thereof.

  一个公式为的抑制肾素的化合物： 或其药用可接受的盐、酯或前药。
• Angiotensinogen analogs
  申请人：Abbott Laboratories

  公开号：US04857507A1

  公开（公告）日：1989-08-15

  The invention relates to renin inhibiting compounds of the formula ##STR1## wherein A is hydrogen; loweralkyl; arylalkyl; OR.sub.10 or SR.sub.10 wherein R.sub.10 is hydrogen, loweralkyl or aminoalkyl; NR.sub.11 R.sub.12 wherein R.sub.11 and R.sub.12 are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; ##STR2## wherein B is NH, alkylamino, S, O, CH.sub.2 or CHOH and R.sub.13 is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, N-protected aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic) alkyl or a substituted or unsubstituted heterocyclic; W is CO or CHOH and U is CH.sub.2 or NR.sub.2 with the proviso that when W is CHOH then U is CH.sub.2 ; R.sub.1 is loweralkyl, cycloaklylmethyl, benzyl, .alpha.,.alpha.-dimethylbenzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoyl)-methyl, phenethyl, phenoxy, thiophenoxy or anilino; provided if R.sub.1 is phenoxy, thiophenoxy or anilino, B is CH.sub.2 or CHOH or A is hydrogen, R.sub.3 is loweralkyl, vinylloweralkyl, benzyl or heterocyclic ring substituted methyl, R.sub.5 is loweralkyl, cycloalkylmethyl or benzyl; R.sub.2 and R.sub.4 are independently selected from hydrogen and loweralkyl; R.sub.6 is CHOH or CO; R.sub.7 is CH.sub.2, CF.sub.2 or CF with the proviso that when R.sub.6 is CO, R.sub.7 is CF.sub.2 ; R.sub.8 is CH.sub.2, CHR.sub.14 wherein R.sub.14 is lower-alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, or R.sub.7 and R.sub.8 taken together can be ##STR3## with the proviso that when R.sub.7 is CF.sub.2, R.sub.8 is CH.sub.2 ; E is O, S, SO, SO.sub.2, NR.sub.15 wherein R.sub.15 is hydrogen or loweralkyl or NR.sub.16 CO wherein R.sub.16 is hydrogen or loweralkyl; R.sub.9 is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or an N-protected group, or E and R.sub.9 taken together can be N.sub.3, with the proviso that when E is NH, R.sub.9 is an N-protecting group; and pharmaceutically acceptable salts thereof.

  该发明涉及以下结构的肾素抑制化合物##STR1##其中A为氢；较低烷基；芳基烷基；OR.sub.10或SR.sub.10，其中R.sub.10为氢，较低烷基或氨基烷基；NR.sub.11 R.sub.12，其中R.sub.11和R.sub.12分别选择自氢，较低烷基，氨基烷基，氰基烷基和羟基烷基；##STR2##其中B为NH，烷基氨基，S，O，CH.sub.2或CHOH，R.sub.13为较低烷基，环烷基，芳基，芳基烷基，烷氧基，烯基氧基，羟基烷氧基，二羟基烷氧基，芳基烷氧基，芳基烷氧基烷基，氨基，烷基氨基，二烷基氨基，(羟基烷基)(烷基)氨基，(二羟基烷基)(烷基)氨基，氨基烷基，烷氧羰基烷基，羧基烷基，N-保护氨基烷基，烷基氨基烷基，(N-保护)(烷基)氨基烷基，二烷基氨基烷基，(杂环)烷基或取代或未取代的杂环；W为CO或CHOH，U为CH.sub.2或NR.sub.2，但当W为CHOH时，U为CH.sub.2；R.sub.1为较低烷基，环烷基甲基，苄基，.alpha.，.alpha.-二甲基苄基，4-甲氧基苄基，卤代苄基，(1-萘基)甲基，(2-萘基)甲基，(4-咪唑基)-甲基，苯乙基，苯氧基，噻吩氧基或苯胺基；但如果R.sub.1为苯氧基，噻吩氧基或苯胺基，B为CH.sub.2或CHOH或A为氢，R.sub.3为较低烷基，烯基较低烷基，苄基或杂环环取代甲基，R.sub.5为较低烷基，环烷基甲基或苄基；R.sub.2和R.sub.4分别选择自氢和较低烷基；R.sub.6为CHOH或CO；R.sub.7为CH.sub.2，CF.sub.2或CF，但当R.sub.6为CO时，R.sub.7为CF.sub.2；R.sub.8为CH.sub.2，CHR.sub.14，其中R.sub.14为较低烷基，环烷基，环烷基烷基，芳基或芳基烷基，或R.sub.7和R.sub.8一起可以是##STR3##但当R.sub.7为CF.sub.2时，R.sub.8为CH.sub.2；E为O，S，SO，SO.sub.2，NR.sub.15，其中R.sub.15为氢或较低烷基或NR.sub.16 CO，其中R.sub.16为氢或较低烷基；R.sub.9为较低烷基，环烷基，环烷基烷基，芳基，芳基烷基或N-保护基，或E和R.sub.9一起可以是N.sub.3，但当E为NH时，R.sub.9为N-保护基；及其药学上可接受的盐。
• Renin-inhibiting peptidyl heterocycles
  申请人：ABBOTT LABORATORIES

  公开号：EP0307837A3

  公开（公告）日：1991-12-11

  A renin inhibiting compound of the formula: wherein A is a substituent; W is C=O, CHOH or NR₂ wherein R₂ is hydrogen or loweralkyl; U is C=O, CH₂ or NR₂ wherein R₂ is hydrogen or loweralkyl, with the proviso that when W is CHOH then U is CH₂ and with the proviso that U is C=O or CH₂ when W is NR₂; V is CH, C(OH) or C(halogen) with the proviso that V is CH when U is NR₂; R₁ is loweralkyl, cycloalkylalkyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-methoxybenzyl, halobenzyl, 4-hydroxybenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (unsubstituted heterocyclic)methyl, (substituted heterocyclic)methyl, phenethyl, 1-benzyloxyethyl, phenoxy, thiophenoxy or anilino, provided that B is CH₂ or CHOH or A is hydrogen when R₁ is phenoxy, thiophenoxy or anilino; R₃ is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)alkyl, carboxyalkyl, (thioalkoxy)alkyl, azidoalkyl, aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl, (alkoxy)(alkyl)aminoalkyl, (alkoxy)aminoalkyl, benzyl or heterocyclic ring substituted methyl; R₄ is loweralkyl, cycloalkylmethyl or benzyl; R₅ is OH or NH₂; and Z is a substituent.Also disclosed are compositions for and a method of treating hypertension, methods of making the renin inhibiting compounds and intermediates useful in making the renin inhibiting compounds.

  一种抑制肾素的化合物，其结构式为：其中A是取代基；W为C=O、CHOH或NR₂，其中R₂为氢或较低的烷基；U为C=O、CH₂或NR₂，其中R₂为氢或较低的烷基，但当W为CHOH时，U为CH₂，且当U为C=O或CH₂时，W为NR₂；V为CH、C(OH)或C(卤素)，但当U为NR₂时，V为CH；R₁为较低的烷基、环烷基烷基、苄基、(α,α)-二甲基苄基、4-甲氧基苄基、卤代苄基、4-羟基苄基、(1-萘基)甲基、(2-萘基)甲基、(未取代的杂环)甲基、(取代的杂环)甲基、苯乙基、1-苄氧基乙基、苯氧基、硫代苯氧基或苯胺基，但当R₁为苯氧基、硫代苯氧基或苯胺基时，B为CH₂或CHOH或A为氢；R₃为较低的烷基、较低的烯基、((烷氧基)烷氧基)烷基、羧基烷基、(硫代烷氧基)烷基、叠氮基烷基、氨基烷基、(烷基)氨基烷基、二烷基氨基烷基、(烷氧基)(烷基)氨基烷基、(烷氧基)氨基烷基、苄基或取代的杂环环取代的甲基；R₄为较低的烷基、环烷基甲基或苄基；R₅为OH或NH₂；Z为取代基。还披露了用于治疗高血压的组合物、制备抑制肾素化合物的方法以及制备抑制肾素化合物的中间体的方法。
• Peptidylaminodiols
  申请人：Abbott Laboratories

  公开号：US05032577A1

  公开（公告）日：1991-07-16

  A renin inhibiting compound of the formula: ##STR1## wherein A is a substituent; W is C.dbd.O or CHOH; U is CH.sub.2 or NR.sub.2, provided that when W is CHOH then U is CH.sub.2 ; R.sub.1 is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; R.sub.2 is hydrogen or loweralkyl; R.sub.3 is loweralkenyl, [(alkoxy)alkoxy]alkyl, (thioalkoxy)alkyl, lowerakenyl, benzyl or heterocyclic ring substituted methyl; R.sub.4 is loweralkyl, cycloalkylmethyl or benzyl; R.sub.5 is vinyl, formyl, hydroxymethyl or hydrogen; R.sub.7 is hydrogen or loweralkyl; R.sub.8 and R.sub.9 are independently selected from OH and NH.sub.2 ; and R.sub.6 is hydrogen, loweralkyl, vinyl or arylalkyl; provided that when R.sub.5 and R.sub.7 are both hydrogen and R.sub.8 and R.sub.9 are OH, the carbon bearing R.sub.5 is of the "R" configuration and the carbon bearing R.sub.6 is of the "S" configuration, or pharmaceutically acceptable salts or esters thereof. Also disclosed are renin inhibiting compositions, a method of treating hypertension, methods of making the renin inhibiting compounds and intermediates useful in making the renin inhibiting compounds.

  一种肾素抑制化合物的公式为：##STR1## 其中A是取代基；W是C.dbd.O或CHOH；U是CH.sub.2或NR.sub.2，但当W为CHOH时，U为CH.sub.2；R.sub.1是较低的烷基，环烷基甲基，苄基，4-甲氧基苄基，卤苄基，(1-萘基)甲基，(2-萘基)甲基，(4-咪唑基)甲基，(α，α)-二甲基苄基，1-苄氧基乙基，苯乙基，苯氧基，硫代苯氧基或苯胺基；R.sub.2是氢或较低的烷基；R.sub.3是较低烯基，[(烷氧基)烷氧基]烷基，(硫代烷氧基)烷基，较低烯基，苄基或杂环戒指取代的甲基；R.sub.4是较低的烷基，环烷基甲基或苄基；R.sub.5是乙烯基，甲酰基，羟甲基或氢；R.sub.7是氢或较低的烷基；R.sub.8和R.sub.9分别选自OH和NH.sub.2；R.sub.6是氢，较低的烷基，乙烯基或芳基烷基；但当R.sub.5和R.sub.7都是氢且R.sub.8和R.sub.9是OH时，承载R.sub.5的碳为“R”构型，承载R.sub.6的碳为“S”构型，或其药用盐或酯。还公开了肾素抑制组合物，治疗高血压的方法，制备肾素抑制化合物的方法以及制备肾素抑制化合物中有用的中间体。
• Functionalized peptidyl aminodiols and -triols
  申请人：Abbott Laboratories

  公开号：US04977277A1

  公开（公告）日：1990-12-11

  The invention relates to renin inhibiting compounds of the formula ##STR1## wherein A is hydrogen; loweralkyl; arylalkyl; OR.sub.8 or SR.sub.8 wherein R.sub.8 is hydrogen, loweralkyl or aminoalkyl; NR.sub.9 R.sub.10 wherein R.sub.9 and R.sub.10 are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; ##STR2## wherein B is NH, alkylamino, S, O, CH.sub.2 or CHOH and R.sub.11 is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, carboxylic acid-substituted alkyl, alkoxycarbonylalkyl, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (N-protected)-(alkyl)aminoalkyl, (heterocyclic)alkyl or a substituted or unsubstituted heterocyclic; R.sub.1 is loweralkyl, cycloalkylmethyl, benzyl, .alpha.-methylbenzyl, .alpha., .alpha.-dimethylbenzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)-methyl, (2-naphthyl)methyl, (4-imidazoyl)methyl, phenethyl, phenoxy, thiophenoxy or anilino; provided if R.sub.1 is phenoxy, thiophenoxy or anilino, B is CH.sub.2 or CHOH or A is hydrogen; R.sub.3 is loweralkyl, benzyl or heterocyclic ring-substituted methyl; R.sub.4 is lower-alkyl, cycloalkyl- methyl or benzyl; R.sub.2, R.sub.5 and R.sub.6 are independently hydrogen or loweralkyl; X is O, NH or S; R.sub.7 is hydrogen, loweralkyl, alkanoyl, alkylsulfonyl ##STR3## wherein R.sub.12 and R.sub.13 are independently hydrogen or loweralkyl, n is 0-2 and R.sub.14 is substituted or unsubstituted phenyl or heterocyclic; or XR.sub.7 together are loweralkylsulfonyl, N.sub.3 or Cl, and pharmaceutically acceptable salts thereof.

  本发明涉及公式##STR1##的肾素抑制化合物，其中A为氢；低烷基；芳基烷基；OR.sub.8或SR.sub.8，其中R.sub.8为氢，低烷基或氨基烷基；NR.sub.9R.sub.10，其中R.sub.9和R.sub.10独立选择自氢，低烷基，氨基烷基，氰基烷基和羟基烷基；##STR2##其中B为NH，烷基氨基，S，O，CH.sub.2或CHOH，R.sub.11为低烷基，环烷基，芳基，芳基烷基，烷氧基，烯烃氧基，羟基烷氧基，二羟基烷氧基，芳基烷氧基，芳基烷氧基烷基，氨基，烷基氨基，二烷基氨基，（羟基烷基）（烷基）氨基，（二羟基烷基）（烷基）氨基，羧酸取代的烷基，烷氧羰基烷基，氨基烷基，N-保护氨基烷基，烷基氨基烷基，二烷基氨基烷基，（N-保护）-（烷基）氨基烷基，（杂环）烷基或取代或未取代的杂环；R.sub.1为低烷基，环烷基甲基，苯甲基，α-甲基苯甲基，α，α-二甲基苯甲基，4-甲氧基苯甲基，卤代苯甲基，（1-萘基）-甲基，（2-萘基）-甲基，（4-咪唑基）-甲基，苯乙基，苯氧基，噻吩氧基或苯胺基；但如果R.sub.1为苯氧基，噻吩氧基或苯胺基，则B为CH.sub.2或CHOH或A为氢；R.sub.3为低烷基，苯甲基或杂环环取代甲基；R.sub.4为低烷基，环烷基甲基或苯甲基；R.sub.2，R.sub.5和R.sub.6独立地为氢或低烷基；X为O，NH或S；R.sub.7为氢，低烷基，烷酰基，烷基磺酰基##STR3##其中R.sub.12和R.sub.13独立地为氢或低烷基，n为0-2，R.sub.14为取代或未取代的苯基或杂环；或XR.sub.7一起为低烷基磺酰基，N.sub.3或Cl，以及其药学上可接受的盐。