Carbohydrate conjugated RNA agents and process for their preparation
This disclosure relates to an improved process for the preparation of carbohydrate conjugates. The disclosure also relates to carbohydrate conjugated iRNA agents comprising these carbohydrate conjugates, which have improved purity and are advantageous for the in vivo delivery of the iRNA agents.
1 . A compound of formula (VIII):
wherein A is a C 6 -C 14 alkylene linker; each R is, independently, an acid protecting group; and R x is an acid protecting group.
2 . The compound of claim 1 , wherein A is a C 8 -C 12 alkylene linker.
3 . The compound of claim 1 , wherein A is —(CH 2 ) 10 —.
4 . The compound of claim 1 , wherein each R is, independently, substituted or unsubstituted alkyl.
5 . The compound of claim 1 , wherein each R is t-butyl.
6 . The compound of claim 1 , wherein R x is substituted or unsubstituted alkyl.
7 . The compound of claim 1 , wherein R x is methyl.
8 . The compound of claim 1 , wherein R x is different from all the R groups.
9 . The compound of claim 1 that is:
10 . A compound of formula (II):
and a counterion, wherein Z is an acid protecting group; n is 0-20; and each occurrence of r and s is independently 1-7.
11 . The compound of claim 10 , wherein the counterion is CF 3 SO 3 −.
12 . The compound of claim 10 , wherein n is 0-15.
13 . The compound of claim 10 , wherein n is 4-15.
14 . The compound of claim 10 , wherein n is 7.
15 . The compound of claim 10 , wherein r is 1.
16 . The compound of claim 10 , wherein s is 1.
17 . The compound of claim 10 , wherein Z is alkyl, substituted alkyl, aryl, or substituted aryl.
18 . The compound of claim 11 , wherein Z is methyl, ethyl, sec-butyl, tert-butyl, chloromethyl, bromomethyl, 2-iodoethyl, 2-fluoropropyl, phenyl, 2-bromophenyl, 4-4 chlorophenyl, 4-methoxyphenyl, p-tolyl, o-tolyl, 4-benzyloxyphenyl, 3-carbamoylphenyl, 4-chloro-3-cyanophenyl, 4-methoxy-2-tolyl, 4- trifluoromethylphenyl, benzyl, 4-methoxybenzyl, 4-iodobenzyl, 3-methanesulfonamidobenzyl, 3-nitrobenzyl, 3-chloro-4-benzyloxybenzyl, 2-ethylbenzyl, phenoxymethyl, 4- bromophenoxymethyl, 2-methoxyphenoxymethyl, 4-tolyloxymethyl, 4-chlorophenoxymethyl, 4-carbamoylphenoxymethyl, or 3-chloro-4-ethoxyphenoxymethyl.
19 . The compound of claim 10 that is:
20 . A compound of the formula (XII):
wherein Z is an acid protecting group;
n is 0-20;
each occurrence of r and s is independently 1-7; and
P is an amino protecting group.
21 . The compound of claim 20 , wherein n is 0-15.
22 . The compound of claim 20 , wherein n is 4-15.
23 . The compound of claim 20 , wherein n is 7.
24 . The compound of claim 20 , wherein r is 1.
25 . The compound of claim 20 , wherein s is 1.
26 . The compound of claim 20 , wherein P is Boc.
27 . The compound of claim 20 , wherein Z is alkyl, substituted alkyl, aryl, or substituted aryl.
28 . The compound of claim 20 , wherein Z is methyl, ethyl, sec-butyl, tert-butyl, chloromethyl, bromomethyl, 2-iodoethyl, 2-fluoropropyl, phenyl, 2-bromophenyl, 4-chlorophenyl, 4-methoxyphenyl, p-tolyl, o-tolyl, 4-benzyloxyphenyl, 3-carbamoylphenyl, 4-chloro-3-cyanophenyl, 4-methoxy-2-tolyl, 4- trifluoromethylphenyl, benzyl, 4-methoxybenzyl, 4-iodobenzyl, 3-methanesulfonamidobenzyl, 3-nitrobenzyl, 3-chloro-4-benzyloxybenzyl, 2-ethylbenzyl, phenoxymethyl, 4- bromophenoxymethyl, 2-methoxyphenoxymethyl, 4-tolyloxymethyl, 4-chlorophenoxymethyl, 4-carbamoylphenoxymethyl, or 3-chloro-4-ethoxyphenoxymethyl.
29 . The compound of claim 20 that is
30 . A compound of formula (IV):
wherein Z is an acid protecting group;
n is 0-20;
q, r, and s are independently 1-7;
X is a hydroxy protecting group or hydrogen; and
Y is an amine protecting group.
31 . The compound of claim 30 , wherein all occurrences of X are the same, all occurrences of Y are the same, all occurrences of q are the same, all occurrences of r are the same, and all occurrences of s are the same.
32 . The compound of claim 30 , wherein X is benzyl (Bz) or acetyl (Ac).
33 . The compound of claim 30 , wherein Y is acetyl.
34 . The compound of claim 30 , wherein X is benzyl (Bz) or acetyl (Ac); and Y is acetyl.
35 . The compound of claim 30 , wherein n is 7, q is 1, r is 1, and s is 1.
36 . The compound of claim 30 , wherein n is 6, q is 1, r is 1, and s is 1.
37 . The compound of claim 30 , that is:
38 . A compound that is: