Galnac monomer comprising ribose ring or derivative structure thereof and use thereof in liver-targeted delivery of small nucleic acid drugs
AssigneeBeijing Youcare Kechuang Pharmaceutical Technology Co., Ltd.
InventorsZeao Huang, Gengshen Song, Zhikang Tian, Shuo Yang, Yucheng Wu, Rui Fu
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Abstract
The present disclosure provides a GalNAc monomer comprising a ribose ring or a derivative structure thereof and a use thereof in liver-targeted delivery of small nucleic acid drugs. Specifically provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof. The GalNAc-conjugated oligonucleotide prepared from the GalNAc compound provided by the present disclosure can achieve efficient liver-targeted delivery and enhance drug efficacy.
Claims20
A compound of formula (I) or a pharmaceutically acceptable salt thereof:
- R1 is O or S;
- R2 is H, C1-6 alkyl, C1-6 alkoxy, or halogen;
- R3 is H, a hydroxyl protecting group, a phosphorus-containing reactive group, —CO(CH2)xCONH-◯, or —CO(CH2)xCOOH, wherein x is an integer from 1 to 10, ◯ is controlled pore glass or polystyrene;
- R4 is H or a hydroxyl protecting group;
- A is —(CH2)a—, —(CH2CH2OCH2CH2)b—, or —(CH2OCH2)c—, wherein a is an integer from 1 to 10;
- b is an integer from 1 to 5;
- c is an integer from 1 to 7;
- L is —CONH— or —NHCO—;
- G is
- wherein
- T is the following group in which all hydroxyl groups are protected with acyl groups:
- N-acetyl-galactosamine, galactose, galactosamine, N-formal-galactosamine, N-propionyl-galactosamine, or N-butyryl-galactosamine;
- X1 is —(CH2)f— or —(CH2CH2O)fCH2—, wherein f is an integer from 1 to 5;
- X2 is —(CH2)g—, wherein g is an integer from 1 to 6;
- Y1 is 0 or 1;
- Y2 is 0, 1, or 2;
- Y3 is 1, 2, or 3;
- m is an integer from 0 to 4;
- n is an integer from 0 to 4.
A conjugate comprising an oligonucleotide and a GalNAc moiety, wherein the oligonucleotide and GalNAc are linked via a phosphoester group or a phosphorothioate group;
- the GalNAc moiety is formed by one or more GalNAc molecules linked via a phosphoester group or a phosphorothioate group;
- wherein the GalNAc molecule is a compound of formula I-2 or a pharmaceutically acceptable salt thereof,
- wherein R3-1 is a linking bond, and R4 is H;
- alternatively, R4-1 is a linking bond, and R3-1 is H;
- G is
- T1 is N-acetyl-galactosamine, galactose, galactosamine, N-formal-galactosamine, N-propionyl-galactosamine, or N-butyryl-galactosamine;
- Y3 is 1, 2, or 3;
- Y2 is 0, 1, or 2;
- X2 is —(CH2)g—, wherein g is an integer from 1 to 6;
- Y1 is 0 or 1;
- X1 is —(CH2)f— or —(CH2CH2O)fCH2—, wherein f is an integer from 1 to 5;
- m is an integer from 0 to 4;
- n is an integer from 0 to 4;
- R2 is H, C1-6 alkyl, C1-6 alkoxy, or halogen;
- R1 is O or S;
- A is —(CH2)a—, —(CH2CH2OCH2CH2)b—, or —(CH2OCH2)c—, wherein a is an integer from 1 to 10;
- b is an integer from 1 to 5;
- c is an integer from 1 to 7;
- L is —CONH— or —NHCO—.
Dependencies are inferred from the claim text.