ethyl 2-[1-[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-[[(E)-N'-nitrocarbamimidoyl]amino]pentanoyl]piperidin-4-yl]acetate | 154938-59-7

• 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-[1-[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-[[(E)-N'-nitrocarbamimidoyl]amino]pentanoyl]piperidin-4-yl]acetate
• CAS: 154938-59-7
• 化学式: C₂₀H₃₆N₆O₇
• 分子量: 472.542
• InChiKey: OBIPGCRGXYIADQ-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  33
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  181
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  ethyl 2-[1-[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-[[(E)-N'-nitrocarbamimidoyl]amino]pentanoyl]piperidin-4-yl]acetate 在 palladium on activated charcoal 盐酸 、 氢气 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、100.0 kPa 条件下， 反应 97.5h， 生成 {1-[5-guanidino-2(S)-(3(RS)-methyl-1,2,3,4-tetrahydroquinolin-8-ylsulfonylamino)pentanoyl]piperidin-4-yl}acetic acid ethyl ester
  参考文献：
  名称：

  Design and Synthesis of Thrombin Inhibitors:  Analogues of MD-805 with Reduced Stereogenicity and Improved Potency

  摘要：

  Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibit;ors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3,3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, PB-FEP, and P1-arginine (45g) had a K-i of 6 nM (MD-805 K-i = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.

  DOI：

  10.1021/jm9811209
• 作为产物：
  描述：

  N^α-t-butoxycarbonyl-N^ω-nitro-L-arginine 在 N-甲基吗啉 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.75h， 生成 ethyl 2-[1-[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-[[(E)-N'-nitrocarbamimidoyl]amino]pentanoyl]piperidin-4-yl]acetate
  参考文献：
  名称：

  Design and Synthesis of Thrombin Inhibitors:  Analogues of MD-805 with Reduced Stereogenicity and Improved Potency

  摘要：

  Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibit;ors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3,3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, PB-FEP, and P1-arginine (45g) had a K-i of 6 nM (MD-805 K-i = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.

  DOI：

  10.1021/jm9811209

文献信息

• Peptide derivatives corresponding to the carboxy terminal sequence of
  申请人：Novartis Corporation

  公开号：US05686564A1

  公开（公告）日：1997-11-11

  Novel compounds of the formula I ##STR1## in which R.sup.1 and R.sup.2 are hydrogen, C.sub.1 -C.sub.4 alkyl or are linked to form C.sub.3 -C.sub.7 cycloalkyl and R.sup.3, R.sup.4 and R.sup.5 are the same or different and are hydrogen, C.sub.1 -C.sub.4 alkyl, hydroxy, OR.sup.6, SR.sup.6, halogen, NR.sup.7 R.sup.8, NO.sub.2, CN, CONR.sup.7 R.sup.8 or CO.sub.2 R.sup.9 wherein R.sup.6 is C.sub.1 -C.sub.4 alkyl or C.sub.7 -C.sub.10 aralkyl and R.sup.7, R.sup.8 and R.sup.9 are the same or different and are hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.7 -C.sub.10 aralkyl or R.sup.7 and R.sup.8 together with the nitrogen atom to which they are bound form 5 or 6 membered azacycloalkyl or oxazacycloalkyl; Arg is arginine \x9bNH--CH(CH.sub.2 CH.sub.2 CH.sub.2 NH--C(.dbd.NH)--NH.sub.2)--CO!; X is methine CH or nitrogen; n is an integer from 0 to 7; L is a peptide linker, and H is the carboxy terminal end of hirudin, and salts thereof, are provided. The novel compounds are useful for the medical treatment or prevention of thrombosis or diseases caused by thrombosis or can be used for the determination of thrombin in blood as diagnostic reagents.

  提供公式I的新化合物，其中R.sup.1和R.sup.2为氢、C.sub.1-C.sub.4烷基或连接形成C.sub.3-C.sub.7环烷基，R.sup.3、R.sup.4和R.sup.5相同或不同，为氢、C.sub.1-C.sub.4烷基、羟基、OR.sup.6、SR.sup.6、卤素、NR.sup.7R.sup.8、NO.sub.2、CN、CONR.sup.7R.sup.8或CO.sub.2R.sup.9，其中R.sup.6为C.sub.1-C.sub.4烷基或C.sub.7-C.sub.10芳基烷基，R.sup.7、R.sup.8和R.sup.9相同或不同，为氢、C.sub.1-C.sub.4烷基或C.sub.7-C.sub.10芳基烷基，或R.sup.7和R.sup.8与它们所结合的氮原子形成5或6元杂环烷基或氧杂杂环烷基；Arg为精氨酸\x9bNH--CH(CH.sub.2CH.sub.2CH.sub.2NH--C(.dbd.NH)--NH.sub.2)--CO!；X为甲基(CH)或氮；n为0到7的整数；L为肽链连接物，H为酵素抑制剂蛛蛤素的羧基末端，以及其盐。这些新化合物可用于医疗治疗或预防血栓形成或由血栓形成引起的疾病，也可用作血液中凝血酶的诊断试剂。
• PEPTIDE DERIVATIVES CORRESPONDING TO THE CARBOXY TERMINAL SEQUENCE OF HIRUDIN
  申请人：Novartis AG

  公开号：EP0637318B1

  公开（公告）日：1998-04-01
• Design and Synthesis of Thrombin Inhibitors:  Analogues of MD-805 with Reduced Stereogenicity and Improved Potency
  作者：Derek Brundish、Alice Bull、Vera Donovan、Joseph D. Fullerton、Sheila M. Garman、Judy F. Hayler、Diana Janus、Peter D. Kane、Mark McDonnell、Garrick P. Smith、Robert Wakeford、Clive V. Walker、Graham Howarth、William Hoyle、Mark C. Allen、John Ambler、Keith Butler、Mark D. Talbot

  DOI：10.1021/jm9811209

  日期：1999.11.1

  Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibit;ors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3,3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, PB-FEP, and P1-arginine (45g) had a K-i of 6 nM (MD-805 K-i = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.