5' AND 2' BIS-SUBSTITUTED NUCLEOSIDES AND OLIGOMERIC COMPOUNDS PREPARED THEREFROM

• US 20110269821A1
• Filed: 10/23/2009
• Published: 11/03/2011
• Est. Priority Date: 10/24/2008
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Swayze, Eric E., Prakash, Thazha P.
• Granted Patent: US 8,883,752 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

The present invention provides modified nucleosides and oligomeric compounds prepared therefrom. More particularyl, the present invention provides modified nucleosides having at least one 5′-substituent and a 2′-O-substituent, oligomeric compounds comprising at least one of these modified nucleosides and methods of using the oligomeric compounds. In some embodiments, the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

Claims

1-205. -205. (canceled)

206. An oligomeric compound comprising one monomer of Formula N:

207. The oligomeric compound of claim 206 wherein Bx is uracil, thymine, cytosine, 5-methyl cytosine, adenine or guanine.

208. The oligomeric compound of claim 206 wherein G₁ is OCH₃, OCH₂F, OCHF₂, OCF₃, OCH₂CH₃, O(CH₂)₂F, OCH₂CHF₂, OCH₂CF₃, OCH₂—

CH═

CH₂, O(CH₂)₂—

OCH₃, O(CH₂)₂—

SCH₃, O(CH₂)₂—

OCF₃, O(CH₂)₃—

N(R₄)(R₅), O(CH₂)₂—

ON(R₄)(R₅), O(CH₂)₂—

O(CH₂)₂—

N(R₄)(R₅), OCH₂C(═

O)—

N(R₄)(R₅), OCH₂C(═

O)—

N(R₆)—

(CH₂)₂—

N(R₄)(R₅) or O(CH₂)₂—

N(R₆)—

C(═

NR₇)[N(R₄)(R₅)] wherein R₄, R₅, R₆ and R₇ are each, independently, H or C₁-C₆ alkyl.

209. The oligomeric compound of claim 206 wherein G₁ is F, OCH₃, O(CH₂)₂—

OCH₃, OCH₂C(═

O)—

N(H)CH₃ or OCH₂C(═

O)—

N(H)—

(CH₂)₂—

N(CH₃)₂.

210. The oligomeric compound of claim 206 wherein said phosphorus moiety has the formula:

211. The oligomeric compound of claim 206 wherein Q₁, Q₂, Q₃ and Q₄ are each H.

212. The oligomeric compound of claim 206 wherein one of Q₁, Q₂, Q₃ and Q₄ is F or C₁-C₆ alkyl and the other three of Q₁, Q₂, Q₃ and Q₄ are each H.

213. The oligomeric compound of claim 206 wherein two of Q₁, Q₂, Q₃ and Q₄ are F.

214. The oligomeric compound of claim 213 wherein Q₃ and Q₄ are each F and Q₁ and Q₂ are each H.

215. The oligomeric compound of claim 206 wherein Q₁ is CH₃ and Q₂, Q₃ and Q₄ are each H or Q₂ is CH₃ and Q₁, Q₃ and Q₄ are each H.

216. The oligomeric compound of claim 206 wherein each monomer of Formula IV has the configuration:

217. The oligomeric compound of claim 206 wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.

218. The oligomeric compound of claim 206 wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group.

219. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with an oligomeric compound of claim 206 wherein said oligomeric compound is complementary to a target RNA.

220. The method of claim 219 wherein said cells are in a human.

221. The method of claim 219 wherein said target RNA is selected from mRNA, pre-mRNA and micro RNA.

222. The method of claim 221 wherein said target RNA is human mRNA.

223. The method of claim 219 wherein said target RNA is cleaved thereby inhibiting its function.

224. The method of claim 219 further comprising detecting the levels of target RNA.

225. The method of claim 219, wherein said oligomeric compound activates, alone or in combination with a complementary strand, an endogenous ribonuclease.

226. The method of claim 225, wherein said endogenous ribonuclease is RNase H or a double-strand ribonuclease.

227. The method of claim 226, wherein the double-strand ribonuclease is an argonaute protein.

228. A double stranded composition comprising:

a first oligomeric compound and a second oligomeric compound wherein the first oligomeric compound is complementary to the second oligomeric compound and the second oligomeric compound is complementary to a nucleic acid target;

at least one of the first and second oligomeric compounds is an oligomeric compound according to claim 206; and

wherein said composition optionally comprises one or more 5′

or 3′

terminal groups.

229. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with a double stranded composition of claim 228 wherein said oligomeric compound is complementary to a target RNA.