3-(2-(2,3:4,6-di-O-isopropylidene-α-D-mannopyranosyloxy)phenyl)benzoic acid | 171905-77-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-(2-(2,3:4,6-di-O-isopropylidene-α-D-mannopyranosyloxy)phenyl)benzoic acid
• 英文别名: 3-[2-[[(1R,2S,6S,7R,9R)-4,4,12,12-tetramethyl-3,5,8,11,13-pentaoxatricyclo[7.4.0.02,6]tridecan-7-yl]oxy]phenyl]benzoic acid
• CAS: 171905-77-4
• 化学式: C₂₅H₂₈O₈
• 分子量: 456.493
• InChiKey: BGSJTYBBKQJDOL-RBRWEJTLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  92.7
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-(2-(2,3:4,6-di-O-isopropylidene-α-D-mannopyranosyloxy)phenyl)benzoic acid 在 盐酸 、 sodium hydroxide 、 N-羟基丁二酰亚胺 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 生成 (2S)-2-[[3-[2-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]benzoyl]amino]butanedioic acid
  参考文献：
  名称：

  Rational Design and Synthesis of Small Molecule, Non-oligosaccharide Selectin Inhibitors: (.alpha.-D-Mannopyranosyloxy)biphenyl-Substituted Carboxylic Acids

  摘要：

  The calcium dependent E-selectin/sialyl Lewis(x) (sLe(x)) interaction plays a key role in inflammation where it mediates the rolling of leukocytes prior to firm adhesion and extravasation from the vasculature. A model of E-selectin/sLe(x) binding, along with previously reported structure-activity relationships of sLe(x)-related oligosaccharide, was used in the rational design of non-oligosaccharide inhibitors of this pivotal interaction. A palladium-mediated biaryl-coupling (Suzuki) reaction was used as the key step to prepare a number of substituted biphenyls which were assayed for their ability to inhibit the binding of E-, P-, and L-selectin-IgG fusion proteins to sLe(x) expressed on the surface of HL60 cells. Some of the compounds developed had greater in vitro potency than the parent sLe(x) tetrasaccharide and are currently being evaluated in in vivo models of inflammation to select a candidate for clinical development.

  DOI：

  10.1021/jm00026a004
• 作为产物：
  描述：

  2-羟基-[1,1-联苯]-3-羧酸甲酯 在 lithium hydroxide 、 三氟化硼乙醚 、 对甲苯磺酸 、 丙酮 作用下， 以 1,2-二氯乙烷 、 乙腈 为溶剂， 反应 0.75h， 生成 3-(2-(2,3:4,6-di-O-isopropylidene-α-D-mannopyranosyloxy)phenyl)benzoic acid
  参考文献：
  名称：

  Rational Design and Synthesis of Small Molecule, Non-oligosaccharide Selectin Inhibitors: (.alpha.-D-Mannopyranosyloxy)biphenyl-Substituted Carboxylic Acids

  摘要：

  The calcium dependent E-selectin/sialyl Lewis(x) (sLe(x)) interaction plays a key role in inflammation where it mediates the rolling of leukocytes prior to firm adhesion and extravasation from the vasculature. A model of E-selectin/sLe(x) binding, along with previously reported structure-activity relationships of sLe(x)-related oligosaccharide, was used in the rational design of non-oligosaccharide inhibitors of this pivotal interaction. A palladium-mediated biaryl-coupling (Suzuki) reaction was used as the key step to prepare a number of substituted biphenyls which were assayed for their ability to inhibit the binding of E-, P-, and L-selectin-IgG fusion proteins to sLe(x) expressed on the surface of HL60 cells. Some of the compounds developed had greater in vitro potency than the parent sLe(x) tetrasaccharide and are currently being evaluated in in vivo models of inflammation to select a candidate for clinical development.

  DOI：

  10.1021/jm00026a004

文献信息

• Binding of E-selectin or P-selectin to sialyl Lewis.sup.x or
  申请人：Texas Biotechnology Corporation

  公开号：US05444050A1

  公开（公告）日：1995-08-22

  This invention relates to compounds that inhibit the binding of E-selectin and/or P-selectin to sialyl-Lewis.sup.x or sialyl-Lewis.sup.a presented on a cell surface having the general structure ##STR1## wherein X is selected from the group consisting of --(CH.sub.2).sub.n CO.sub.2 H, --O(CH.sub.2).sub.m CO.sub.2 H, --(CH.sub.2).sub.n O(CH.sub.2).sub.m CO.sub.2 H, --CONH(CH.sub.2).sub.m CO.sub.2 H, --CH(OZ)(CO.sub.2 H), --CH(Z)(CO.sub.2 H), --(CH.sub.2).sub.n SO.sub.3 H, --(CH.sub.2).sub.n PO.sub.3 D.sub.1 D.sub.2, --NH(CH.sub.2).sub.m CO.sub.2 H, --CONH(CHR.sub.6)CO.sub.2 H, (1-H-tetrazolyl-5-alkyl-), and --OH; R.sub.1 and R.sub.2 are independently selected from the group consisting of hydrogen, alkyl, halogen, --OZ, --NO.sub.2, --NH.sub.2 and --NHZ; R.sub.3 is selected from the group consisting of hydrogen, halogen, alkyl, --OZ and --NHZ; R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxyl, hydroxyl-O-sulfate and --OZ; R.sub.5 is selected from the group consisting of hydroxyl, --CN, --N.sub.3, --NH.sub.2, --NHNH.sub.2, --NE.sub.1 E.sub.2, --NHE.sub.1, --NHCO(CH.sub.2).sub.n CO.sub.2 H, --S(CH.sub.2).sub.m CO.sub.2 H and --NHCHNHNH.sub.2 ; R.sub.6 is selected from the group consisting of hydrogen, alkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkyl carboxylic acid and alkyl carboxamide; wherein n is 0 to 6, m is 1 to 6, p is 0 to 6, b is 0 to 2, Z is alkyl, aryl or aralkyl, D.sub.1 and D.sub.2 are independantly hydrogen or alkyl, E.sub.1 is alkyl or --(CH.sub.2).sub.8 CO.sub.2 H, and E.sub.2 is alkyl, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. This invention also relates to methods of inhibiting the binding of E-selectin and/or P-selectin to sialyl-Lewis.sup.x or sialyl-Lewis.sup.a presented on a cell surface using said compounds and to pharmaceutically active compositions comprising compounds that inhibit the binding of E-selectin to sialyl-Lewis.sup.x and to methods of treatment of septic shock, ARDS, Crohn's disease, chronic inflammatory diseases, such as psoriasis and rheumatoid arthritis, and reperfusion injuries that occur following heart attacks, strokes and organ transplants.

  这项发明涉及抑制E-选择素和/或P-选择素与细胞表面上呈现的唾液酸-Lewis.sup.x或唾液酸-Lewis.sup.a结合的化合物，其具有以下一般结构##STR1##其中X从--(CH.sub.2).sub.n CO.sub.2 H，--O(CH.sub.2).sub.m CO.sub.2 H，--(CH.sub.2).sub.n O(CH.sub.2).sub.m CO.sub.2 H，--CONH(CH.sub.2).sub.m CO.sub.2 H，--CH(OZ)(CO.sub.2 H)，--CH(Z)(CO.sub.2 H)，--(CH.sub.2).sub.n SO.sub.3 H，--(CH.sub.2).sub.n PO.sub.3 D.sub.1 D.sub.2，--NH(CH.sub.2).sub.m CO.sub.2 H，--CONH(CHR.sub.6)CO.sub.2 H，(1-H-四唑基-5-烷基-)和--OH中选择；R.sub.1和R.sub.2分别从氢，烷基，卤素，--OZ，--NO.sub.2，--NH.sub.2和--NHZ组中选择；R.sub.3从氢，卤素，烷基，--OZ和--NHZ组中选择；R.sub.4从氢，卤素，烷基，羟基，羟基-O-硫酸酯和--OZ组中选择；R.sub.5从羟基，--CN，--N.sub.3，--NH.sub.2，--NHNH.sub.2，--NE.sub.1 E.sub.2，--NHE.sub.1，--NHCO(CH.sub.2).sub.n CO.sub.2 H，--S(CH.sub.2).sub.m CO.sub.2 H和--NHCHNHNH.sub.2组中选择；R.sub.6从氢，烷基，芳基烷基，羟基烷基，氨基烷基，烷基羧酸和烷基羧酰胺组中选择；其中n为0至6，m为1至6，p为0至6，b为0至2，Z为烷基，芳基或芳基烷基，D.sub.1和D.sub.2独立地为氢或烷基，E.sub.1为烷基或--(CH.sub.2).sub.8 CO.sub.2 H，E.sub.2为烷基，以及其药学上可接受的盐，酯，酰胺和前药。这项发明还涉及使用所述化合物抑制E-选择素和/或P-选择素与细胞表面上呈现的唾液酸-Lewis.sup.x或唾液酸-Lewis.sup.a结合的方法，以及包含抑制E-选择素与唾液酸-Lewis.sup.x结合的化合物的药用活性组合物，以及用于治疗败血症休克，ARDS，克罗恩病，银屑病和类风湿性关节炎等慢性炎症性疾病以及心脏病发作，中风和器官移植后发生的再灌注损伤的治疗方法。
• TRICYCLIC COMPOUNDS HAVING SPIRO UNION
  申请人：MOCHIDA PHARMACEUTICAL CO., LTD.

  公开号：EP1191028B1

  公开（公告）日：2004-11-03
• BINDING OF E-SELECTIN, P-SELECTIN OR L-SELECTIN TO SIALYL-LEWISx OR SIALYL-LEWISa
  申请人：TEXAS BIOTECHNOLOGY CORPORATION

  公开号：EP0758243B1

  公开（公告）日：2003-03-12
• US5444050A
  申请人：——

  公开号：US5444050A

  公开（公告）日：1995-08-22
• Rational Design and Synthesis of Small Molecule, Non-oligosaccharide Selectin Inhibitors: (.alpha.-D-Mannopyranosyloxy)biphenyl-Substituted Carboxylic Acids
  作者：Timothy P. Kogan、Brian Dupre、Karin M. Keller、Ian L. Scott、Huong Bui、Robert V. Market、Pamela J. Beck、Jennifer A. Voytus、B. Mitch Revelle、Delores Scott

  DOI：10.1021/jm00026a004

  日期：1995.12

  The calcium dependent E-selectin/sialyl Lewis(x) (sLe(x)) interaction plays a key role in inflammation where it mediates the rolling of leukocytes prior to firm adhesion and extravasation from the vasculature. A model of E-selectin/sLe(x) binding, along with previously reported structure-activity relationships of sLe(x)-related oligosaccharide, was used in the rational design of non-oligosaccharide inhibitors of this pivotal interaction. A palladium-mediated biaryl-coupling (Suzuki) reaction was used as the key step to prepare a number of substituted biphenyls which were assayed for their ability to inhibit the binding of E-, P-, and L-selectin-IgG fusion proteins to sLe(x) expressed on the surface of HL60 cells. Some of the compounds developed had greater in vitro potency than the parent sLe(x) tetrasaccharide and are currently being evaluated in in vivo models of inflammation to select a candidate for clinical development.