Back to results
US 11,633,482 B2Granted
Conjugates and preparation and use thereof
AssigneeSuzhou Ribo Life Science Co., Ltd.
InventorsHongyan Zhang, Zhiwei Yang, Liqiang Cao, Liangyi Wan
Life of this patent
Estimating the term…
Abstract
A compound for forming a conjugate with an active agent such as an oligonucleotide having a structure represented by Formula (321). The present disclosure also provides a corresponding conjugate. The conjugate of the present disclosure can specifically target hepatocytes, thereby effectively solve the problems associated with delivery of oligonucleotide drugs in vivo, and have low toxicity and excellent delivery efficiency while maintaining high stability for the delivered oligonucleotide.
Claims42
A compound having a structure represented by Formula (321):
- wherein,
- n1 is an integer of 1-2, n3 is an integer of 0-1, and n1+n3=2-3;
- each of m1, m2, and m3 is independently an integer of 2-10;
- each of R10, R11, R12, R13, R14 and R15 is independently selected from H, C1-C10 alkyl, C1-C10 haloalkyl, and C1-C10 alkoxy;
- R4 is a moiety capable of binding to an active drug or active agentvia a covalent bond;
- each L1 is a linear alkylene of 1 to 70 carbon atoms in length, wherein one or more carbon atoms are optionally replaced with any one or more of the group consisting of:
- C(O), NH, O, S, CH═N, S(O)2, C2-C10 alkenylene, C2-C10 alkynylene, C6-C10 arylene, C3-C18 heterocyclylene, and C5-C10 heteroarylene, and wherein L1 is optionally substituted by any one or more of the group consisting of:
- C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl, C1-C10 haloalkyl, —OC1-C10 alkyl, —OC1-C10 alkylphenyl, —C1-C10 alkyl-OH, —OC1-C10 haloalkyl, —SC1-C10 alkyl, —SC1-C10 alkylphenyl, —C1-C10 alkyl-SH, —SC1-C10 haloalkyl, halo, —OH, —SH, —NH2, —C1-C10 alkyl-NH2, —N(C1-C10 alkyl)(C1-C10 alkyl), —NH(C1-C10 alkyl), —N(C1-C10 alkyl)(C1-C10 alkylphenyl), —NH(C1-C10 alkylphenyl), cyano, nitro, —CO2H, —C(O)OC1-C10 alkyl, —CON(C1-C10 alkyl)(C1-C10 alkyl), —CONH(C1-C10 alkyl), —CONH2, —NHC(O)(C1-C10 alkyl), —NHC(O)(phenyl), —N(C1-C10 alkyl)C(O)(C1-C10 alkyl), —N(C1-C10 alkyl)C(O)(phenyl), —C(O)C1-C10 alkyl, —C(O)C1-C10 alkylphenyl, —C(O)C1-C10 haloalkyl, —OC(O)C1-C10 alkyl, —SO2(C1-C10 alkyl), —SO2(phenyl), —SO2(C1-C10 haloalkyl), —SO2NH2, —SO2NH(C1-C10 alkyl), —SO2NH(phenyl), —NHSO2(C1-C10 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C10 haloalkyl);
- each S1 is independently an M1, wherein any active hydroxyl, if any, is protected with a hydroxyl protecting group;
- each M1 is independently selected from a ligand capable of binding to a cell surface receptor;
- and
- wherein the receptor is an asialoglycoprotein receptor on human hepatocytes.
9 more elements
A conjugate having a structure represented by Formula (1):
- wherein,
- n1 is an integer of 1-2, n3 is an integer of 0-1, and n1+n3=2-3;
- each of m1, m2, and m3 is independently an integer of 2-10;
- each of R10, R11, R12, R13, R14 and R15 is independently selected from H, C1-C10 alkyl, C1-C10 haloalkyl, and C1-C10 alkoxy;
- R3 is an active drug;
- R2 is a linear alkylene of 1 to 20 carbon atoms in length, wherein one or more carbon atoms are optionally replaced with any one or more of the group consisting of:
- C(O), NH, O, S, CH═N, S(O)2, C2-C10 alkeylene, C2-C10 alkynylene, C6-C10 arylene, C3-C18 heterocyclylene, and C5-C10 heteroarylene, and wherein R2 is optionally substituted by any one or more of the group consisting of:
- C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl, C1-C10 haloalkyl, —OC1-C10 alkyl, —OC1-C10 alkylphenyl, —C1-C10 alkyl-OH, —OC1-C10 haloalkyl, —SC1-C10 alkyl, —SC1-C10 alkylphenyl, —C1-C10 alkyl-SH, haloalkyl, halo, —OH, —SH, —NH2, —C1-C10 alkyl-NH2, —N(C1-C10 alkyl)(C1-C10 alkyl), —NH(C1-C10 alkyl), —N(C1-C10 alkyl)(C1-C10 alkylphenyl), —NH(C1-C10 alkylphenyl), cyano, nitro, —CO2H, —C(O)OC1-C10 alkyl, —CON(C1-C10 alkyl)(C1-C10 alkyl), —CONH(C1-C10 alkyl), —CONH2, —NHC(O)(C1-C10 alkyl), —NHC(O)(phenyl), —N(C1-C10 alkyl)C(O)(C1-C10 alkyl), —N(C1-C10 alkyl)C(O)(phenyl), —C(O)C1-C10 alkyl, —C(O)C1-C10 alkylphenyl, —C(O)C1-C10 haloalkyl, —OC(O)C1-C10 alkyl, —SO2(C1-C10 alkyl), —SO2(phenyl), —SO2(C1-C10 haloalkyl), —SO2NH2, —SO2NH(C1-C10 alkyl), —SO2NH(phenyl), —NHSO2(C1-C10 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C10 haloalkyl);
- each L1 is independently a linear alkylene of 1 to 70 carbon atoms in length, wherein one or more carbon atoms are optionally replaced with any one or more of the group consisting of:
- C(O), NH, O, S, CH═N, S(O)2, C2-C10 alkeylene, C2-C10 alkynylene, C6-C10 arylene, C3-C18 heterocyclylene, and C5-C10 heteroarylene, and wherein L1 is optionally substituted by any one or more of the group consisting of:
- C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl, C1-C10 haloalkyl, —OC1-C10 alkyl, —OC1-C10 alkylphenyl, —C1-C10 alkyl-OH, —OC1-C10 haloalkyl, —SC1-C10 alkyl, —SC1-C10 alkylphenyl, —C1-C10 alkyl-SH, —SC1-C10 haloalkyl, halo, —OH, —SH, —NH2, —C1-C10 alkyl-NH2, —N(C1-C10 alkyl)(C1-C10 alkyl), —NH(C1-C10 alkyl), alkyl)(C1-C10 alkylphenyl), —NH(C1-C10 alkylphenyl), cyano, nitro, —CO2H, —C(O)OC1-C10 alkyl, —CON(C1-C10 alkyl)(C1-C10 alkyl), —CONH(C1-C10 alkyl), —CONH2, —NHC(O)(C1-C10 alkyl), —NHC(O)(phenyl), —N(C1-C10 alkyl)C(O)(C1-C10 alkyl), —N(C1-C10 alkyl)C(O)(phenyl), —C(O)C1-C10 alkyl, —C(O)C1-C10 alkylphenyl, —C(O)C1-C10 haloalkyl, —OC(O)C1-C10 alkyl, —SO2(C1-C10 alkyl), —SO2(phenyl), —SO2(C1-C10 haloalkyl), —SO2NH2, —SO2NH(C1-C10 alkyl), —SO2NH(phenyl), —NHSO2(C1-C10 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C10 haloalkyl);
- each M1 is selected from one of ligands capable of binding to a cell surface receptor;
- and
- wherein the receptor is an asialoglycoprotein receptor on human hepatocytes.
11 more elements
Dependencies are inferred from the claim text.