4'-desmethyl nucleoside analog compounds

• US 5,223,618 A
• Filed: 08/13/1990
• Issued: 06/29/1993
• Est. Priority Date: 08/13/1990
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Sanghvi, Yogesh S., Cook, Philip D.
• Primary Examiner(s): Brown, Johnnie R.
• Assistant Examiner(s): WILSON, JAMES O
• Application Number:
  US07/566,836
• Time in Patent Office: 1,051 Days
• Field of Search: 536/27, 536/28, 536/29, 544/276, 544/277, 514/47, 514/48, 514/50, 514/51, 514/244, 514/243
• US Class Current: 544/276
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• 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

Novel oligonucleotide analogs are provided having improved cellular uptake, improved resistance to nucleases, and good hybridization to target RNA. Such analogs are provided having substantially non-chiral, non-ionic linking functionalities between the sugars and sugar analogs thereof. In accordance with preferred embodiments, the 4'"'"' position of a sugar or sugar analog at one nucleoside is linked to the 3'"'"' position of a second sugar or sugar analog of a second nucleoside by a linking function that comprises a two- or three- carbon backbone chain. In accordance with preferred embodiments, the linking functions comprise the formula)--R₁ --O where R₁ comprises a two or three carbon backbone. Such linking functions also, preferably comprise ether functionalities to effect such linkage. Processes for the automated synthesis of oligonucleotide analogs are also provided.

Claims

1. A composition of matter having the structure ##STR6## where:

R₁ is selected from the group consisting of ethyl, ethylene, acetylene, cyclopropyl, cyclobutyl, ethyleneoxy, ethyl aziridine, and ethyl aziridine substituted with amino, hydroxyl or carboxylic acid groups,

T is selected from the group consisting of tetrahydropyranyl, tert-butyl and bis-(p-methoxyphenyl)phenylemthyl,

R₂ is selected from the group consisting of trifluoromethylsulfonyl, methylsulfonyl, halogen, o-trichloroacetimidates, acyloxy, and 2,4,6-trichlorophenyl, B_x is a nucleosidic base, and

R₃ is OH, halogen, or H.

2. The composition of claim 1 wherein R₁ is ethyleneoxy.

3. The composition of claim 1 wherein T is tert-butyl.

4. The composition of claim 1 wherein R₂ is trifluoromethylsulfonyl or methylsulfonyl.

5. The composition of claim 1 wherein R₃ is hydroxyl.

6. The composition of claim 1 wherein R₁ is ethyleneoxy, T is tert-butyl, R₂ is trifluoromethylsulfonyl or methylsulfonyl, and R₃ is hydroxyl.