Folate conjugates
    8.
    发明授权
    Folate conjugates 有权
    叶酸共轭物

    公开(公告)号:US08507455B2

    公开(公告)日:2013-08-13

    申请号:US12328537

    申请日:2008-12-04

    CPC分类号: C12N15/113 A61K47/55

    摘要: The present invention provides iRNA agent including at least one monomer having the structure shown in formula (I′) wherein: A and B are each independently for each occurrence O, N(RN) or S; X is H, a protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z′)(Z″)O-nucleoside, —P(Z′)(Z″)O-oligonucleotide, a lipid, a PEG, a steroid, a polymer, —P(Z′)(Z″)O-L6-Q′-L7-OP(Z′″)(Z′″″)O-oligonucleotide, a nucleotide, or an oligonucleotide; Y is H, a protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z′)(Z″)O-nucleoside, —P(Z′)(Z″)O-oligonucleotide, a lipid, a PEG, a steroid, a lipophile, a polymer, —P(Z′)(Z″)O-L6-Q′-L7-OP(Z′″)(Z′″″)O-oligonucleotide, a nucleotide, or an oligonucleotide; R is folate, a folate analog a folate mimic or a folate receptor binding ligand; L6 and L7 are each independently for each occurrence —(CH2)n—, —C(R′)(R″)(CH2)n—, —(CH2)nC(R′)(R″)—, —(CH2CH2O)mCH2CH2—, or —(CH2CH2O)mCH2CH2NH—; Q′ is NH, O, S, CH2, C(O)O, C(O)NH, —NH—CH(Ra)—C(O)—, —C(O)—CH(Ra)—NH—, CO, where Ra is H or amino acid side chain; R′ and R″ are each independently H, CH3, OH, SH, NH2, NH(Alkyl=Me, Et, Pr, isoPr, Bu, Bn) or N(diAlkyl=Me2, Et2, Bn2); Z′, Z″, Z′″ and Z″″ are independently O or S; n represent independently for each occurrence 1-20; and m represent independently for each occurrence 0-50.

    摘要翻译: 本发明提供包含至少一种具有式(I')所示结构的单体的iRNA试剂,其中:A和B各自独立地为O,N(RN)或S; X是H,保护基,磷酸基,磷酸二酯基,活化磷酸酯基,活化亚磷酸酯基,亚磷酰胺,固体载体,-P(Z')(Z“)O-核苷,-P (Z')(Z“)O-寡核苷酸,脂质,PEG,类固醇,聚合物,-P(Z')(Z”)O-L6-Q'-L7-OP(Z“ ')(Z“”)O-寡核苷酸,核苷酸或寡核苷酸; Y是H,保护基,磷酸基,磷酸二酯基,活化磷酸酯基,活化亚磷酸酯基,亚磷酰胺,固体载体,-P(Z')(Z“)O-核苷,-P (Z')(Z“)(Z”)O-寡核苷酸,脂质,PEG,类固醇,亲脂性,聚合物,-P(Z')(Z“)O-L6-Q'-L7-OP Z“')(Z”“)O-寡核苷酸,核苷酸或寡核苷酸; R是叶酸,叶酸类似物叶酸类似物或叶酸受体结合配体; L 6和L 7各自独立地为 - (CH 2)n - , - C(R')(R“)(CH 2)n - , - (CH 2)n C(R')(R” (CH 2 CH 2 O)mCH 2 CH 2 - 或 - (CH 2 CH 2 O)m CH 2 CH 2 NH-; Q'是NH,O,S,CH2,C(O)O,C(O)NH,-NH-CH(Ra)-C(O) - , - (O)-CH(Ra) ,CO,其中Ra为H或氨基酸侧链; R'和R“各自独立地为H,CH 3,OH,SH,NH 2,NH(烷基= Me,Et,Pr,isoPr,Bu,Bn)或N(二烷基= Me 2,Et 2,Bn 2); Z',Z“,Z”“和”Z“独立地为O或S; n每次出现1-20,独立地表示1-20; 而m代表每次出现的0-50。