(1R)-1-(N-methyl-L-alanyl-L-alanyl-L-alanylamino)-ethylphosphonic acid | 71922-18-4

• 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: (1R)-1-(N-methyl-L-alanyl-L-alanyl-L-alanylamino)-ethylphosphonic acid
• 英文别名: [(1R)-1-[[(2S)-2-[[(2S)-2-[[(2S)-2-(methylamino)propanoyl]amino]propanoyl]amino]propanoyl]amino]ethyl]phosphonic acid
• CAS: 71922-18-4
• 化学式: C₁₂H₂₅N₄O₆P
• 分子量: 352.327
• InChiKey: YUFLVNFSZBNGLI-XSPKLOCKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.5
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  157
• 氢给体数：
  6
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  L-alanyl-L-alanyl-L-1-aminoethylphosphonic acid 在 palladium on activated charcoal 氢气 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 (1R)-1-(N-methyl-L-alanyl-L-alanyl-L-alanylamino)-ethylphosphonic acid
  参考文献：
  名称：

  Synthesis and structure-activity relationships of antibacterial phosphonopeptides incorporating (1-aminoethyl)phosphonic acid and (aminomethyl)phosphonic acid

  摘要：

  Phosphonodipeptides and phosphonooligopeptides based on L- and D-(1-aminoethyl)phosphonic acids L-Ala(P) and D-Ala(P) and (aminomethyl)phosphonic acid Gly(P) at the acid terminus have been synthesized and investigated as antibacterial agents, which owe their activity to the inhibition of bacterial cell-wall biosynthesis. A method for large-scale synthesis of the potent antibacterial agent L-Ala-L-Ala(P) (1, Alafosfalin) is described. Structure-activity relationships in the dipeptide series have been studied by systematic variation of structure 1. L stereochemistry is generally required for both components. Changes in the L-Ala(P) moiety mostly lead to loss of antibacterial activity, but the phosphonate analogues of L-phenylalanine, L-Phe(P), and L-serine, L-Ser(P), give rise to weakly active L-Ala-L-Phe(P) and L-Ala-L-Ser(P). Replacement of L-Ala in 1 by common and rare amino acids can give rise to more potent in vitro antibacterials such as L-Nva-L-Ala(P) (45). Synthetic variation of these more potent dipeptides leads to decreased activity. Phosphonooligopeptides such as (L-Ala)2-L-Ala(P) have a broader in vitro antibacterial spectrum than their phosphonodipeptide precursor, but this is not expressed in vivo, presumably due to rapid metabolism to 1. Stabilized compounds such as Sar-L-Nva-L-Nva-L-Ala(P) (46) have been developed that are more potent in vivo and have a broader in vivo antibacterial spectrum than the parent phosphonodipeptide.

  DOI：

  10.1021/jm00151a005

文献信息

• Acyl derivatives
  申请人：Hoffmann-La Roche Inc.

  公开号：US04250085A1

  公开（公告）日：1981-02-10

  Peptide derivatives provided by the present invention are compounds of the general formula ##STR1## wherein R.sup.1 represents a hydrogen atom or the methyl or hydroxymethyl group or a mono-, di- or trihalomethyl mgroup; R.sup.2 represents the characterizing group of an .alpha.-amino acid of the type normally found in proteins or a lower alkyl or hydroxy- (lower alkyl) group other than the characterising group of an .alpha.-amino acid of the type normally found in proteins; R.sup.3 represents a lower alkyl, lower cycloalkyl, lower alkenyl, aryl or aryl-(lower alkyl) group; R.sup.4 represents a hydrogen atom or a lower alkyl group; n stands for 1,2 or 3; the configuration at the carbon atom designated as (a) is (R) when R.sup.1 represents other than a hydrogen atom and the configuration at the carbon atom designated as (b) is (L) when R.sup.2 represents other than a hydrogen atom, and pharmaceutically acceptable salts thereof. The compounds exhibit activity as antibacterial agents against a range of gram-positive and gram-negative bacteria. Also disclosed are intermediates and a process for the production of the end product.

  本发明提供的肽衍生物是具有一般式##STR1##的化合物，其中R.sup.1代表氢原子或甲基或羟甲基基团或单、二或三卤甲基基团；R.sup.2代表通常在蛋白质中发现的α-氨基酸的特征基团或低烷基或除了通常在蛋白质中发现的α-氨基酸的特征基团以外的羟基-(低烷基)基团；R.sup.3代表低烷基、低环烷基、低烯基、芳基或芳基-(低烷基)基团；R.sup.4代表氢原子或低烷基基团；n代表1、2或3；当R.sup.1代表除氢原子以外的其他基团时，指定为(a)的碳原子处的构型为(R)，当R.sup.2代表除氢原子以外的其他基团时，指定为(b)的碳原子处的构型为(L)，以及其药学上可接受的盐。这些化合物表现出抗一系列革兰氏阳性和革兰氏阴性细菌的活性。还披露了中间体和生产终产品的方法。
• Wirkstoffkombinationen, pharmazeutische Präparate sowie deren Herstellung
  申请人：F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft

  公开号：EP0026409A1

  公开（公告）日：1981-04-08

  Wirkstoffkombinationen mit antibiotischen Eigenschaften, dadurch gekennzeichnet, dass sie ein Peptid-derivat der allgemeinen Formel worin R' Wasserstoff, Methyl, Hydroxymethyl, eine Mono-, Di- oder Trihalogenmethylgruppe ist; R2 einen für eine normalerweise in Proteinen vorkommende a-Aminosäure charakteristischen Rest oder einen Niederalkyl- oder Hydroxyniederalkylrest, der charakterisch ist für eine in Proteinen normalerweise nicht vorkommende α-Aminosäure, darstellt; R3 Niederalkyl, Nieder-cycloalkyl, Nieder-alkenyl, Aryl oder Aryl-niederalkyl ist; R' Wasserstoff oder Niederalkyl bedeutet; n 2 oder 3 bedeutet und die Konfigurationen an den C-Atomen (a) und (b) R (wenn R1 ≠ H) bzw. L sind, oder ein physiologisch verträgliches Salz einer solchen Verbindung und ein Antibiotikum enthalten, deren Verwendung und pharmazeutische Präparate sowie deren Herstellung.

  具有抗生素特性的活性成分组合，其特征在于它们含有通式如下的肽衍生物 其中 R'是氢、甲基、羟甲基、一卤代、二卤代或三卤代甲基； R2 是通常存在于蛋白质中的 a-氨基酸所特有的基团，或通常不存在于蛋白质中的α-氨基酸所特有的低级烷基或羟基-低级烷基； R3 是低级烷基、低级环烷基、低级烯基、芳基或芳基-低级烷基； R' 是氢或低级烷基 n 是 2 或 3；以及 C 原子上的构型 (a) 和 (b) R（当 R1 ≠ H 时）和 L 分别是这样的化合物或生理上可接受的盐和抗生素，它们的用途和药物组合物及其制备。
• US4250085A
  申请人：——

  公开号：US4250085A

  公开（公告）日：1981-02-10
• Synthesis and structure-activity relationships of antibacterial phosphonopeptides incorporating (1-aminoethyl)phosphonic acid and (aminomethyl)phosphonic acid
  作者：Frank R. Atherton、Cedric H. Hassall、Robert W. Lambert

  DOI：10.1021/jm00151a005

  日期：1986.1

  Phosphonodipeptides and phosphonooligopeptides based on L- and D-(1-aminoethyl)phosphonic acids L-Ala(P) and D-Ala(P) and (aminomethyl)phosphonic acid Gly(P) at the acid terminus have been synthesized and investigated as antibacterial agents, which owe their activity to the inhibition of bacterial cell-wall biosynthesis. A method for large-scale synthesis of the potent antibacterial agent L-Ala-L-Ala(P) (1, Alafosfalin) is described. Structure-activity relationships in the dipeptide series have been studied by systematic variation of structure 1. L stereochemistry is generally required for both components. Changes in the L-Ala(P) moiety mostly lead to loss of antibacterial activity, but the phosphonate analogues of L-phenylalanine, L-Phe(P), and L-serine, L-Ser(P), give rise to weakly active L-Ala-L-Phe(P) and L-Ala-L-Ser(P). Replacement of L-Ala in 1 by common and rare amino acids can give rise to more potent in vitro antibacterials such as L-Nva-L-Ala(P) (45). Synthetic variation of these more potent dipeptides leads to decreased activity. Phosphonooligopeptides such as (L-Ala)2-L-Ala(P) have a broader in vitro antibacterial spectrum than their phosphonodipeptide precursor, but this is not expressed in vivo, presumably due to rapid metabolism to 1. Stabilized compounds such as Sar-L-Nva-L-Nva-L-Ala(P) (46) have been developed that are more potent in vivo and have a broader in vivo antibacterial spectrum than the parent phosphonodipeptide.