AU2024204379B2 — Carbohydrate conjugates as delivery agents for oligonucleotides

USPTO Abstract

#$%^&*AU2024204379B220250925.pdf##### 18749519_1 (GHMatters) P84321.AU.5 25/05/22 Abstract 5 The present invention provides iRNA agents comprising at least one subunit of the formula (I): wherein: A and B are each independently for each occurrence O, N(RN) or S; X and Y are each independently for each occurrence H, OH, a hydroxyl 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, -10 P(Z' )(Z")O-oligonucleotide, a lipid, a PEG, a steroid, a lipophile, a polymer, - P(Z')(Z")O-Linker-OP(Z"')(Z"")O-oligonucleotide, a nucleotide, an oligonucleotide, - P(Z’)(Z")-formula(I), -P(Z')(Z")- or -Linker-R; R is LG, -Linker-LG, or has the structure shown below: LG is independently for each occurrence a carbohydrate, e.g., monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, 15 polysaccharide; RN is independently for each occurrence H, methyl, ethyl, propyl, isopropyl, butyl, or benzyl; and Z', Z", Z"' and Z"" are each independently for each occurrence O or S. 20 Abstract X-A B N YI Linker R Formula (I) Linker-L Linker-LG Linker-L'G Linker-L Linker-LG is N Linker-L G , Linker-L° G , Linker-L°, or Linker-LG 5 The present invention provides iRNA agents comprising at least one subunit of the formula (I): wherein: A and B are each independently for each occurrence O, N(RN) or S; X and Y are each independently for each occurrence H, OH, a hydroxyl protecting group, a phosphate group, a phosphodiester group, an activated phosphate group, an 10 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-Linker-OP(Z")(Z"")O-oligonucleotide, a nucleotide, an oligonucleotide, - P(Z')(ZZ)'--formula(I) -P(Z')(Z")- or -Linker-R; R is LG, , -Linker-L G, or has the structure shown below: LG is independently for each occurrence a carbohydrate, e.g., 15 monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, polysaccharide; RN is independently for each occurrence H, methyl, ethyl, propyl, isopropyl, butyl, or benzyl; and Z', Z", Z" and Z"" are each independently for each occurrence O or S. 20 18749519_1 (GHMatters) P84321.AU.5 25/05/22 20 24 20 43 79 26 J un 2 02 4 2 6 J u n 2 0 2 4 A b s t r a c t X - A B N Y L i n k e r R 2 0 2 4 2 0 4 3 7 9 F o r m u l a ( I ) L i n k e r - L G L i n k e r - L G L i n k e r - L G L i n k e r - L G L i n k e r - L G N L i n k e r - L G , L i n k e r - L G , L i n k e r - L G , o r L i n k e r - L G ; 5 T h e p r e s e n t i n v e n t i o n p r o v i d e s i R N A a g e n t s c o m p r i s i n g a t l e a s t o n e s u b u n i t o f t h e f o r m u l a ( I ) : w h e r e i n : A a n d B a r e e a c h i n d e p e n d e n t l y f o r e a c h o c c u r r e n c e O , N ( R N ) o r S ; X a n d Y a r e e a c h i n d e p e n d e n t l y f o r e a c h o c c u r r e n c e H , O H , a h y d r o x y l p r o t e c t i n g g r o u p , a p h o s p h a t e g r o u p , a p h o s p h o d i e s t e r g r o u p , a n a c t i v a t e d p h o s p h a t e g r o u p , a n 1 0 a c t i v a t e d p h o s p h i t e g r o u p , a p h o s p h o r a m i d i t e , a s o l i d s u p p o r t , - P ( Z ' ) ( Z " ) O n u c l e o s i d e , - ) ( Z " ) O - o l i g o n u c l e o t i d e , a l i p i d , a P E G , a s t e r o i d , a l i p o p h i l e , a p o l y m e r , - P ( Z ) ( Z " ) O - L i n k e r - O P ( Z " ) ( Z " " ) O - o l i g o n u c l e o t i d e , a n u c l e o t i d e , a n o l i g o n u c l e o t i d e , - P ( Z ' ) ( Z ' ' ) - f o r m u l a ( I ) , - P ( Z ' ) ( Z " ) - o r - L i n k e r - R ; R i s L G , - L i n k e r - L G , o r h a s t h e s t r u c t u r e s h o w n b e l o w : L G i s i n d e p e n d e n t l y f o r e a c h o c c u r r e n c e a c a r b o h y d r a t e , e . g . , 1 5 m o n o s a c c h a r i d e , d i s a c c h a r i d e , t r i s a c c h a r i d e , t e t r a s a c c h a r i d e , o l i g o s a c c h a r i d e , p o l y s a c c h a r i d e ; R N i s i n d e p e n d e n t l y f o r e a c h o c c u r r e n c e H , m e t h y l , e t h y l , p r o p y l , i s o p r o p y l , b u t y l , o r b e n z y l ; a n d Z ' , Z " , Z " a n d Z " " a r e e a c h i n d e p e n d e n t l y f o r e a c h o c c u r r e n c e O o r S . 2 0 1 8 7 4 9 5 1 9 _ 1 ( G H M a t t e r s ) P 8 4 3 2 1 . A U . 5 2 5 / 0 5 / 2 2