α-[(benzyloxy)carbamoyl]hydrocinnamic acid | 67681-99-6

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: α-[(benzyloxy)carbamoyl]hydrocinnamic acid
• 英文别名: 2-Benzyl-N-benzyloxy-malonamic acid；2-benzyl-3-oxo-3-(phenylmethoxyamino)propanoic acid
• CAS: 67681-99-6
• 化学式: C₁₇H₁₇NO₄
• 分子量: 299.326
• InChiKey: BVBOLQPFUQBJIV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  α-[(benzyloxy)carbamoyl]hydrocinnamic acid 在 palladium on activated charcoal 氢气 、 1-环已基-2-吗啉乙基碳二亚胺对甲苯磺酸盐 、 1-羟基苯并三唑 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 3.0h， 生成 N-[2-(N-hydroxy carbamoyl) 3-phenyl propanoyl]-glycine isoamylamide
  参考文献：
  名称：

  New bidentates as full inhibitors of enkephalin-degrading enzymes: synthesis and analgesic properties

  摘要：

  New compounds were designed to fully inhibit the in vitro metabolism of enkephalins, ensured by three different metallopeptidases. For this purpose, bidentate ligands as hydroxamate and N-hydroxy-N-formylamino groups were selected as highly potent metal coordinating agents and introduced on Phe-Gly and Phe-Ala related structures. Compounds corresponding to the general formula HC(O)N(OH)CH2CH(CH2Ph)CONHCH2COOH (compound 7) and HN(OH)C(O)CH2CH(CH2Ph)CONHCH(R)COOH (compound 11, R = H; compound 13, R = CH3) behave as full inhibitors of the three enzymes, with IC50's in the nanomolar range for enkephalinase, from 0.3 microM to 1 nM for dipeptidylaminopeptidase, and in the micromolar range for a biologically relevant aminopeptidase. Two diastereoisomers of the most active inhibitor 13 were separated by HPLC and their stereochemistry was assigned by 1H NMR spectroscopy. Both isomers were efficient as enkephalinase blockers, but only the RS isomer, designated kelatorphan, was able to strongly inhibit aminopeptidase and dipeptidylaminopeptidase. Intracerebroventricular injection in mice of these mixed inhibitors, especially kelatorphan, led to naloxone reversible analgesic responses (hot-plate test) that were slightly better than those produced by a mixture of thiorphan and bestatin, two potent inhibitors of enkephalinase and aminopeptidase, respectively. Kelatorphan was also more efficient in potentiating the analgesia induced by a subanalgesic dose of Met-enkephalin. All these results support a physiological role in pain transmission for enkephalinase and a probably synaptic aminopeptidase M.

  DOI：

  10.1021/jm00147a007
• 作为产物：
  描述：

  2-苄基丙二酸乙酯 在 sodium hydroxide 、 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 氯仿 为溶剂， 反应 4.0h， 生成 α-[(benzyloxy)carbamoyl]hydrocinnamic acid
  参考文献：
  名称：

  New bidentates as full inhibitors of enkephalin-degrading enzymes: synthesis and analgesic properties

  摘要：

  New compounds were designed to fully inhibit the in vitro metabolism of enkephalins, ensured by three different metallopeptidases. For this purpose, bidentate ligands as hydroxamate and N-hydroxy-N-formylamino groups were selected as highly potent metal coordinating agents and introduced on Phe-Gly and Phe-Ala related structures. Compounds corresponding to the general formula HC(O)N(OH)CH2CH(CH2Ph)CONHCH2COOH (compound 7) and HN(OH)C(O)CH2CH(CH2Ph)CONHCH(R)COOH (compound 11, R = H; compound 13, R = CH3) behave as full inhibitors of the three enzymes, with IC50's in the nanomolar range for enkephalinase, from 0.3 microM to 1 nM for dipeptidylaminopeptidase, and in the micromolar range for a biologically relevant aminopeptidase. Two diastereoisomers of the most active inhibitor 13 were separated by HPLC and their stereochemistry was assigned by 1H NMR spectroscopy. Both isomers were efficient as enkephalinase blockers, but only the RS isomer, designated kelatorphan, was able to strongly inhibit aminopeptidase and dipeptidylaminopeptidase. Intracerebroventricular injection in mice of these mixed inhibitors, especially kelatorphan, led to naloxone reversible analgesic responses (hot-plate test) that were slightly better than those produced by a mixture of thiorphan and bestatin, two potent inhibitors of enkephalinase and aminopeptidase, respectively. Kelatorphan was also more efficient in potentiating the analgesia induced by a subanalgesic dose of Met-enkephalin. All these results support a physiological role in pain transmission for enkephalinase and a probably synaptic aminopeptidase M.

  DOI：

  10.1021/jm00147a007

文献信息

• Dual-acting antihypertensive agents
  申请人：Allegretti Paul

  公开号：US20080269305A1

  公开（公告）日：2008-10-30

  The invention is directed to compounds having the formula: wherein: Ar, r, Y, Z, Q, W, X, and R 5-7 are as defined in the specification, and pharmaceutically acceptable salts thereof. These compounds have AT 1 receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

  该发明涉及具有以下公式的化合物：其中：Ar、r、Y、Z、Q、W、X和R5-7如规范中定义，并且其药学上可接受的盐。这些化合物具有AT1受体拮抗活性和神经肽酶抑制活性。该发明还涉及包含这些化合物的药物组合物；使用这些化合物的方法；以及制备这些化合物的过程和中间体。
• Renin inhibiting compounds
  申请人：Hoffmann-La Roche Inc.

  公开号：US05250517A1

  公开（公告）日：1993-10-05

  Compounds which are amino acid derivatives and have the formula ##STR1## in which R.sup.1 is hydrogen or methyl, R.sup.2 is ethyl, propyl or imidazol-4-yl, R.sup.3 is isobutyl, cyclohexylmethyl or benzyl, and A is defined as herein are useful as renin inhibitors.

  衍生自氨基酸的化合物具有公式 ##STR1## 其中 R.sup.1 是氢或甲基，R.sup.2 是乙基，丙基或咪唑-4-基，R.sup.3 是异丁基，环己基甲基或苄基，A 的定义如本文所述，可用作肾素抑制剂。
• Dual-acting Imidazole antihypertensive agents
  申请人：Allegretti Paul

  公开号：US20090023228A1

  公开（公告）日：2009-01-22

  The invention is directed to compounds having the formula: wherein: Ar, r, R 2-3 , X, and R 5.7 are as defined in the specification, and pharmaceutically acceptable salts thereof. These compounds have AT 1 receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

  本发明涉及具有以下结构式的化合物：其中：Ar、r、R2-3、X和R5.7如规范中所定义，并且其药学上可接受的盐。这些化合物具有AT1受体拮抗活性和神经肽酶抑制活性。本发明还涉及包含这些化合物的制药组合物；使用这些化合物的方法；以及制备这些化合物的过程和中间体。
• Dual-acting imidazole antihypertensive agents
  申请人：Theravance, Inc.

  公开号：US08158659B2

  公开（公告）日：2012-04-17

  The invention is directed to compounds having the formula: wherein: Ar, r, R2-3, X, and R5-7 are as defined in the specification, and pharmaceutically acceptable salts thereof. These compounds have AT1 receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

  本发明涉及具有以下式子的化合物：其中：Ar、r、R2-3、X和R5-7的定义如规范所述，以及其药学上可接受的盐。这些化合物具有AT1受体拮抗活性和肽酶抑制活性。本发明还涉及包含这些化合物的制药组合物；使用这些化合物的方法；以及制备这些化合物的过程和中间体。
• DUAL-ACTING ANTIHYPERTENSIVE AGENTS
  申请人：Allegretti Paul

  公开号：US20110281925A1

  公开（公告）日：2011-11-17

  The invention is directed to compounds having the formula: wherein: Ar, r, Y, Z, Q, W, X, and R 5-7 are as defined in the specification, and pharmaceutically acceptable salts thereof. These compounds have AT 1 receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

  该发明涉及具有以下式子的化合物：其中：Ar、r、Y、Z、Q、W、X和R5-7如规范中所定义，并且其药学上可接受的盐。这些化合物具有AT1受体拮抗活性和酶解酶抑制活性。该发明还涉及包含这些化合物的制药组合物；使用这些化合物的方法；以及制备这些化合物的过程和中间体。