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

• US 20150126725A1
• Filed: 10/03/2014
• Published: 05/07/2015
• Est. Priority Date: 10/24/2008
• Status: Abandoned Application

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Swayze, Eric E., Prakash, Thazha P.
• Application Number:
  US14/506,392
• Publication Number:
  US 20150126725A1
• Time in Patent Office: Days
• US Class Current: 536/26.8
• 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 particularly, 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. A compound having Formula III:

207. The compound of claim 206 wherein Bx is an optionally protected uracilyl, thyminyl, cytosinyl, 5-methylcytosinyl, adeninyl or guaninyl.

208. The 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 compound of claim 206 wherein G₁ is OCH₃, OCF₃, OCH₂CH₃, OCH₂CF₃, OCH₂—

CH—

CH₂, O(CH₂)₂—

OCH₃, O(CH₂)₂—

O(CH₂)₂—

N(CH₃)₂, OCH₂C(═

O)—

N(H)CH₃, OCH₂C(═

O)—

N(H)—

(CH₂)₂—

N(CH₃)₂ or OCH₂—

N(H)—

C(═

NH)NH₂.

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

OCH₃, OCH₂C(═

O)—

N(H)CH₃ or OCH₂C(═

O)—

N(H)—

(CH₂)₂—

N(CH₃)₂.

211. The compound of claim 206 wherein G₁ is F.

212. The compound of claim 206 wherein R_a and R_c are each OCH₃ and R_b is O.

213. The compound of claim 206 wherein R_a and R_c are each OCH₂CH₃ and R_b is O.

214. The compound of claim 206 wherein R_b is O.

215. The compound of claim 206 wherein R_b is S.

216. The compound of claim 206 wherein T₆ is diisopropylcyanoethoxy phosphoramidite.

217. The compound of claim 206 wherein T₆ is H-phosphonate.

218. The compound of claim 206 wherein one of Q₁, Q₂, Q₃ and Q₄ is substituted C₁-C₆ alkyl.

219. The compound of claim 206 wherein one of Q₁, Q₂, Q₃ and Q₄ is C₁-C₆ alkyl.

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

221. The compound of claim 220 wherein said C₁-C₆ alkyl is methyl.

222. The compound of claim 206 wherein at least one of Q₁, Q₂, Q₃ and Q₄ is F.

223. The compound of claim 222 wherein one of Q₃ and Q₄ is F.

224. The compound of claim 222 wherein Q₃ and Q₄ are each F.

225. The compound of claim 224 wherein Q₁ and Q₂ are each H.

226. The compound of claim 206 having the configuration: