Oligonucleotide-ligand conjugates and process for their preparation

1. A conjugate of the formula:

wherein

R A is a single stranded or double stranded oligonucleotide having (i) a 3′ end attached to the oxygen atom shown and (ii) a length ranging from 6 to about 30; and

R 3 is selected from the following wherein the arrow → or squiggle indicates the site of conjugation:

2. The conjugate of claim 1 , wherein n is 1-4.

3. The conjugate of claim 1 , wherein the conjugate has the formula:

4. The conjugate of claim 1 , wherein the oligonucleotide moiety in R A is double stranded and has a length ranging from 15 to about 30 nucleotide units.

5. The conjugate of claim 4 , wherein the oligonucleotide moiety has a length ranging from 18 to about 23 nucleotide units.

6. A conjugate of the formula:

wherein

R A is a single stranded or double stranded oligonucleotide having (i) a 3′ end attached to the oxygen atom shown and (ii) a length ranging from 6 to about 30 nucleotide units;

R B is selected from Table 2 or Table 2A

TABLE 2

wherein in Table 2,

each occurrence of Q is independently O, S, or CH 2 ;

each occurrence of Z is independently —CONH—, —NHCO—, —OC(O)NH—, or —NHC(O)O—;

each of R, X and represents the point of attachment to the rest of the conjugate;

each occurrence of R′ is independently Ac, COCF 3 or any amine protecting group compatible with oligonucleotide (RNA/DNA) synthesis and deprotection conditions;

each of the variables l, m, n, p, q, and r independently ranges from about 0 to about 10; and

TABLE 2A

wherein in Table 2A,

each occurrence of Q is independently O, S, or CH 2 ;

each occurrence of Z is independently —CONH—, —NHCO—, —OC(O)NH—, or —NHC(O)O—;

represents the point of attachment to the rest of the conjugate;

each occurrence of R is independently OH or NHAc; and

each of the variables l, m, n, p, q, and r independently ranges from about 0 to about 10.

7. The conjugate of claim 6 , wherein the oligonucleotide moiety in R A is double stranded and has a length ranging from 15 to about 30 nucleotide units.

8. The conjugate of claim 7 , wherein the oligonucleotide moiety has a length ranging from 18 to about 23 nucleotide units.

9. The conjugate of claim 6 , wherein the conjugate has the formula