发明名称 Diether based biodegradable cationic lipids for siRNA delivery
摘要 Disclosed herein are novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides. The cationic lipids can demonstrate enhanced efficacy along with lower liver toxicity as a result of lower lipid levels in the liver. The present invention employs low molecular weight cationic lipids with one short lipid chain coupled with inclusion of hydrolysable functionality in the lipid chains to enhance the efficiency and tolerability of in vivo delivery of siRNA.
申请公布号 US9604908(B2) 申请公布日期 2017.03.28
申请号 US201615269197 申请日期 2016.09.19
申请人 Sima Therapeutics, Inc. 发明人 Stanton Matthew G.;Budzik Brian W.;Colletti Steven L.
分类号 C07C217/28;C07C217/40;A61K9/14;A61K31/713 主分类号 C07C217/28
代理机构 Nixon Peabody LLP 代理人 Nixon Peabody LLP
主权项 1. A cationic lipid of Formula A: wherein: R1 and R2 are independently selected from H, (C1-C6)alkyl, heterocyclyl, and polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one to three substituents selected from R1; or R1 and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one to three substituents selected from R′; R5 is independently selected from (C4-C8)alkylene or (C4-C8)alkenylene, said alkylene or alkenylene optionally substituted with one to three substituents selected from R′; R6 is (C1-C2)alkyl, said alkyl optionally substituted with one to three substituents selected from R′; Q2 is a bond, —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —OC(S)—, —S—S, —C(R″)═N—, —N═C(R″)—, —C(R″)═N—O—, —O—N═C(R″)—, —C(O)(NR″)—, —N(R″)C(O)—, —C(S)(R″)—, —(R″)C(O)—, —N(R″)C(O)N(R″)—, —OC(O)O—, OSi(R″)2O—, —C(O)(CR″2)C(O)O—, or —OC(O)(CR″2)C(O)—, with the proviso that when either Q1 or Q2 is a bond then the other is not a bond; each occurrence of R′ is independently selected from halogen, R″, OR″, SR″, CN, CO2R″ or CON(R″)2; R″ is independently selected from H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with halogen and OH; n is 0, 1, 2, 3, 4 or 5; and -R3-Q1-R4 is selected from the group consisting of or a pharmaceutically acceptable salt or stereoisomer thereof.
地址 Cambridge MA US