Diphenyl amino(4-amidinophenyl)methane-phosphonate dihydrochloride

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: Diphenyl amino(4-amidinophenyl)methane-phosphonate dihydrochloride
• 英文别名: 4-[Amino(diphenoxyphosphoryl)methyl]benzenecarboximidamide;hydrochloride
• 化学式: C₂₀H₂₀N₃O₃P*2ClH
• 分子量: 454.293
• InChiKey: ANALENBXRRHJBV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  111
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  Diphenyl amino(4-amidinophenyl)methane-phosphonate dihydrochloride 在 palladium on activated charcoal 盐酸 、 TEA 、 氢气 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.25h， 生成
  参考文献：
  名称：

  Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase

  摘要：

  Thirty-six new amino acid and peptidyl diphenyl phosphonate esters were synthesized and evaluated to identify potent and selective inhibitors for four trypsin-like proteases: lymphocyte granzymes A and K, human mast cell tryptase, and pancreatic trypsin. Among five Cbz derivatives of Lys and Arg homologues, Z-(4-AmPhe)(P)(OPh)(2) is the mast potent inhibitor for granzyme A, and Z-Lys(P)(OPh)(2) is the best inhibitor for granzyme K, mast tryptase, and trypsin. The amidino P1 residue D,L-(4-AmPhGly)(P)(OPh)(2) was utilized in a series of compounds with several different N-protecting groups and systematic substitutions at P2 in Cbz-AA derivatives and at P3 in Cbz-AA-Ala derivatives. Generally, these phosphonates inhibit granzyme A and trypsin more potently than granzyme K and tryptase. The P2 Thr and Ala dipeptide phosphonates, Cbz-AA-(4-AmPhGly)(P)(OPh)(2), are the most potent inhibitors for granzyme A, and Cbz-Thr-(4-AmPhGly)(P)(OPh)(2) (k(obs)/[I] = 2220 M-1 s(-1)) was quite specific with much lower inhibition rates for granzyme K and trypsin (k(obs)/[I] = 3 and 97 M-1 s(-1), respectively) and no inhibition with tryptase. The most effective inhibitor of granzyme A was Ph-SO2-Gly-Pro-(4-AmPhGly)(P)(OPh)(2) with a second-order rate constant of 3650 M-1 s(-1). The most potent inhibitor for granzyme K was 3,3-diphenylpropanoyl-Pro-(4-AmPhGly)(P)(OPh)(2) with a k(obs)/[I] = 1830 M-1 s(-1) all other phosphonates inhibited granzyme K weakly (k(obs)[I] < 60 M-1 s(-1)). Human mast cell tryptase was inhibited slowly by these phosphonates with Cbz-Lys(P)(OPh)(2) as the best inhibitor (k(obs)/[I] = 89 M-1 s(-1)). The overall results suggest that scaffolds of Phe-Thr-(4-AmPhe) and Phe-Pro-Lys will be useful to create selective phosphonate inhibitors for granzymes A and K, respectively, and that P4 substituents offer opportunities to further enhance selectivity and reactivity.

  DOI：

  10.1021/jm970543s
• 作为产物：
  描述：

  diphenyl [N-(benzyloxycarbonyl)amino(4-cyanophenyl)methyl]phosphonate 在 palladium on activated charcoal 盐酸 、 氨 、 氢气 作用下， 以 甲醇 、 氯仿 为溶剂， 反应 32.0h， 生成 Diphenyl amino(4-amidinophenyl)methane-phosphonate dihydrochloride
  参考文献：
  名称：

  新型含am的肽基膦酸酯作为血液不可逆抑制剂和相关丝氨酸蛋白酶。

  摘要：

  合成了一系列含有4-ami基苯基的新的肽基（α-氨基烷基）膦酸二苯酯，并作为凝血酶和其他胰蛋白酶样酶的不可逆抑制剂进行了测试。这些膦酸酯不可逆地抑制了几种凝血酶和胰蛋白酶。Boc-D-Phe-Pro-（4-AmPhGly）P（OPh）2是该系列中最佳的人类凝血酶抑制剂，其ak（obs）/ [I]值为11,000 M-1 s-1，并且可以抑制凝血酶比其他测试酶高出5倍以上。Z-（4-AmPhGly）P（OPh）2是血浆激肽释放酶的最佳抑制剂，其ak（obs）/ [I]值为18,000 M-1 s-1。通常，（4-AmPhGly）P（OPh）2衍生物比相应的（4-AmPhe）P（OPh）2衍生物是凝血酶和胰蛋白酶的更好抑制剂，后者含有一个额外的CH2，可将a基苯基与肽骨架分开。mid基膦酸酯不抑制乙酰胆碱酯酶，并且在中性缓冲液中化学稳定。另外，被抑制的胰蛋白酶衍生物在除去过量的抑制剂并在pH 7

  DOI：

  10.1021/jm00028a004

文献信息

• Proline phosphonate derivatives
  申请人：Georgia Tech Research Corp.

  公开号：US05543396A1

  公开（公告）日：1996-08-06

  Peptidyl derivatives of diesters of .alpha.-aminoalkylphosphonic acids, particularly those with proline or related structures, their use in inhibiting serine proteases with chymotrypsin-like, trypsin-like, elastase-like, and dipeptidyl peptidase IV specificity and their roles as anti-inflammatory agents, anticoagulants, and anti-tumor agents.

  α-氨基磷酸酯的肽衍生物，尤其是那些具有脯氨酸或相关结构的肽衍生物，在抑制具有类似于胰蛋白酶、胰蛋白酶、弹性蛋白酶和二肽肽酶IV特异性的丝氨酸蛋白酶方面的用途，以及它们作为抗炎药物、抗凝血剂和抗肿瘤药物的作用。
• US5543396A
  申请人：——

  公开号：US5543396A

  公开（公告）日：1996-08-06
• US5686419A
  申请人：——

  公开号：US5686419A

  公开（公告）日：1997-11-11
• [EN] PROLINE PHOSPHONATE DERIVATIVES<br/>[FR] DERIVES DE LA PROLINE PHOSPHONATE
  申请人：GEORGIA TECH RESEARCH CORPORATION

  公开号：WO1995029691A1

  公开（公告）日：1995-11-09

  (EN) Peptidyl derivatives of diesters of $g(a)-aminoalkylphosphonic acids, particularly those with proline or related structures, their use in inhibiting serine proteases with chymotrypsin-like, trypsin-like, elastase-like, and dipeptidyl peptidase IV specificity and their roles as anti-inflammatory agents, anticoagulants, anti-tumor agents, and anti-AIDS agents.(FR) L'invention traite de dérivés peptidyle de diesters d'acides $g(a)-aminoalkylphosphoniques, en particulier, ceux présentant une structure proline ou apparentée. L'invention concerne également leur utilisation pour inhiber des sérine protéases avec une spécificité apparentée à la chymotrypsine, à la trypsine, à l'élastase, et propre à la dipeptidyle peptidase IV et leur rôle comme agents anti-inflammatoires, anti-coagulants, anti-tumoraux et anti-SIDA.