公开(公告)号：EP2676962A1

公开(公告)日：2013-12-25

申请号：EP13172944.4

申请日：2013-06-20

申请人： Universität Ulm ,  Wroclaw University of Technology

发明人： Sienczyk, Marcin ,  Grzywa, Renata ,  Pietrusewicz, Ewa ,  Oleksyszyn, Józef ,  Winiarski, Lukasz ,  Burster, Timo ,  Böhm, Otto

IPC分类号： C07F9/40 ,  C12Q1/37 ,  G01N33/573

CPC分类号： C07F9/405 ,  C12Q1/37 ,  G01N33/573 ,  G01N2333/96433 ,  Y02P20/55

摘要： The subject of the invention relates to 1-aminoalkylphosphonate diaryl esters of formula I, in which Bt represents biotin, W is a hydrocarbon linker chain of 5 to 10 carbon atoms, Y is the amino acid residues in an amount of 0 to 4, R is a substituent corresponding to the side chain of valine, alanine, leucine, phenylalanine, 4-guanidinephenylglycine, or 2-aminobutyric acid (Abu), X is the hydrogen or a compound selected from the group consisting of mercaptomethyl (S-methyl), methoxy (O-methyl), or carboxymethyl, and their use as inhibitors of serine proteases, and the low molecular weight molecular probes to detect the catalytically active forms of the enzymes.
A process for preparing 1-aminoalkylphosphonate diaryl esters of formula I, in which Bt represents biotin, W is a hydrocarbon linker chain of 5 to 10 carbon atoms, Y is the amino acid residues in an amount of 0 to 4, R is a substituent corresponding to the side chain of valine, alanine, leucine, phenylalanine, 4-guanidinephenylglycine, or 2-aminobutyric acid (Abu), X is the hydrogen or a compound selected from the group consisting of mercaptomethyl (S-methyl), methoxy (O-methyl), or carboxymethyl relies on application of triaryl phosphite, obtained from the phenol substituted at para position phosphorus (III) chloride in refluxing acetonitrile and is subjected to amidoalkylation reaction with benzyl carbamate and an aldehyde such as acetaldehyde, propionic aldehyde, iso -butyric aldehyde, phenylacetic aldehyde, p-nitrobenzoic aldehyde and isovaleric aldehyde, followed by the synthesis of hydrobromide salts of 1-aminoalkylphosphonate diaryl esters, in which the benzyloxycarbonyl (Cbz) protective group is removed, and in the next step is reacted with an amino acid containing protected α-amino group in the presence of a coupling reagent. The resulting phosphonic dipeptide containing tert-butoxycarbonyl (t-Boc) protective group is subjected to deprotection of α-amino group and obtained dipeptidyl 1-aminoalkylphosphonate diaryl ester is coupled with another amino acid with protected α-amino group, biotin or a derivative thereof in a manner analogous to that described above.

摘要翻译： 本发明的主题涉及式I的1-氨基烷基膦酸二芳基酯，其中Bt表示生物素，W是5至10个碳原子的烃连接体，Y是0-4的氨基酸残基，R 是对应于缬氨酸，丙氨酸，亮氨酸，苯丙氨酸，4-胍基苯基甘氨酸或2-氨基丁酸（Abu）的侧链的取代基，X是氢或选自巯基甲基（S-甲基）， 甲氧基（O-甲基）或羧甲基，以及它们作为丝氨酸蛋白酶抑制剂的用途，以及用于检测酶的催化活性形式的低分子量分子探针。 制备式I的1-氨基烷基膦酸二芳基酯的方法，其中Bt表示生物素，W是5至10个碳原子的烃连接体，Y是0-4的氨基酸残基，R是取代基 对应于缬氨酸，丙氨酸，亮氨酸，苯丙氨酸，4-胍基苯基甘氨酸或2-氨基丁酸（Abu）的侧链，X是氢或选自巯基甲基（S-甲基），甲氧基（O - 甲基）或羧甲基取代于亚磷​​酸三芳基酯，由在对位位置上的氯取代的苯酚在回流的乙腈中得到，并与氨基甲酸苄酯和醛如乙醛，丙醛，异 - 丁醛，苯乙醛，对硝基苯甲醛和异戊醛，然后合成1-氨基烷基膦酸二芳基酯的氢溴酸盐，其中苄氧羰基（Cbz）p 除去脱水基团，并在下一步骤中与偶联剂存在下与含有保护的±氨基的氨基酸反应。 将所得到的含有叔丁氧基羰基（t-Boc）保护基的膦酸二肽进行± - 氨基脱保护，得到了具有保护的± - 氨基，生物素或其衍生物的另一个氨基酸的二氨基苯基-1-氨基烷基膦酸二芳基酯 以类似于上述方式。