Base modified bicyclic nucleosides and oligomeric compounds prepared therefrom

摘要

Provided herein are novel base modified bicyclic nucleosides, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, novel pyrimidine bicyclic nucleosides are provided wherein each pyrimidine base is substituted at the 5 position with an optionally substituted, aromatic or heteroaromatic ring system comprising from 5 to 7 ring atoms selected from C, N, O and S. In certain embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

主权项

1. A bicyclic nucleoside having Formula I:wherein:
one of T1 and T2 is H or a hydroxyl protecting group and the other of T1 and T2 is H, a hydroxyl protecting group or a reactive phosphorus group; q1 and q2 are each, independently, H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, C1-C6 alkoxyl, substituted C1-C6 alkoxyl, acyl, substituted acyl, C1-C6 aminoalkyl or substituted C1-C6 aminoalkyl; Z1 is NH2 or NHPg and Z2 together with Z3 comprise a bond wherein Pg is a protecting group; or Z1 and Z2 together are ═X2 and Z3 is H; Q is thiazolyl or substituted thiazolyl; G is a diradical moiety selected from one or more linked groups, wherein each group is independently selected from —C(R1R2)—, —C(R1)═C(R2)—, —C(R1)═N—, —C[═C(R1R2)]—, —C(═O)—, —N(R1)—, —N(R1)—C(═X3)—, —O—, —S—, —S(═O)— or —S(═O)2— and wherein G forms a 5 or 6 membered ring with the furanose ring of the nucleoside; X1, X2 and X3 are each, independently, O or S; R1 and R2 are each independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, C1-C6 alkoxyl, substituted C1-C6 alkoxyl, acyl, substituted acyl, C1-C6 aminoalkyl or substituted C1-C6 aminoalkyl; each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), ═NJ1, SJ1, N3, CN, OC(=L)J1, OC(=L)-N(J1)(J2) and C(=L)N(J1)(J2); L is O, S or NJ3; and each J1, J2 and J3 is, independently, H, C1-C6 alkyl.