Conformationally constrained L-nucleosides

• US 6,525,191 B1
• Filed: 05/11/2000
• Issued: 02/25/2003
• Est. Priority Date: 05/11/1999
• Status: Expired due to Term

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Kanda S. Ramasamy
• Inventors: Ramasamy, Kanda S.
• Primary Examiner(s): Fredman, Jeffrey
• Assistant Examiner(s): MAUPIN, CHRISTINE L
• Application Number:
  US09/569,183
• Time in Patent Office: 1,020 Days
• Field of Search: 514/45, 514/50, 514/49, 514/43, 435/6, 435/91.1, 336/26, 336/24, 536/28.7
• US Class Current: 536/28.7
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/056 Triazole or tetrazole radicals

Abstract

L-nucleosides are conformationally constrained by at least one additional ring formed by a bridge connecting at least two atoms within a sugar moiety of the nucleoside. While a single additional ring is formed by bridging C₁-C₄ atoms, two additional rings are formed by bridging both C₁-C₂, and C₃-C₄ atoms, or C₁-C₃ and C₂-C₄ atoms by bridges having the general structure A—B—Z. The conformationally constrained nucleosides may be incorporated into oligonucleotides and dinucleotides, and it is contemplated that compositions including the conformationally constrained nucleosides may have superior viral inhibitory or antineoplastic properties.

Claims

1. A nucleoside having a nucleobase glycosidically bound to a sugar moiety wherein the sugar. moiety has an L-configuration and has at least one additional ring that is formed via a bridge connecting a first and a second atom in the sugar moiety, wherein the first and the second atom are separated by at least a third atom in the sugar moiety.

2. The nucleoside of claim 1 having the structure:

wherein Base is a nucleobase covalently bound to the C₁-atom via a nitrogen- or carbon atom in the nucleobase;

X is O, S, CHOH, CH₂ or N—

COCH₃;

A is O, S, (CH₂)_n, N—

R, or nothing, and when both B and Z are independently O, S or N—

R then A is (CH₂)_n, wherein R is H, OH, CO—

, OPO₃²⁻

, lower alkyl or COCH₃, and n is 1-5;

B and Z are independently O, S, (CH₂)_n, or N—

R, and when both A and B are independently O, S or N—

R then Z is (CH₂)_n, wherein R is H, OH, CO—

, OPO₃²⁻

, lower alkyl or COCH₃, and n is 1-5;

wherein no more than two of A, B, and Z are an atom other than a carbon atom; and

R₂ and R₃ are independently H, OH, OPO₃²⁻

, CN, halogen, N₃, CH₂OH, methylidene, lower alkyl or lower alkyl amine, and R₄ is H, OH, OPO₃²⁻

.

3. The nucleoside of claim 2 wherein the nucleoside is covalently coupled to at least one nucleotide, and wherein the covalent coupling involves at least one of R₂, R₃, R₄, and B.

4. The nucleoside of claim 3 wherein the nucleoside is covalently coupled to an oligonucleotide to form a modified oligonucleotide.

5. The nucleoside of claim 4 wherein the coupling to the oligonucleotide is on at least one of a 5′

-end and a 3′

-end of the oligonucleotide.

6. The nucleoside of claim 3 wherein the nucleoside is covalently coupled to a mononucleotide to form a modified dinucleotide.