Sugar modified nucleosides

• US 6,191,266 B1
• Filed: 12/16/1996
• Issued: 02/20/2001
• Est. Priority Date: 11/02/1994
• Status: Expired due to Fees

• Current Assignee: Valeant Pharmaceuticals North America LLC (Bausch Health Cos., Inc.)
• Original Assignee: ICN Pharmaceuticals, Inc (Bausch Health Cos., Inc.)
• Inventors: Wang, Guangyi
• Primary Examiner(s): Riley, Jezia
• Application Number:
  US08/766,991
• Time in Patent Office: 1,527 Days
• Field of Search: 536/22.1, 536/23.1, 536/24.3, 536/24.33, 536/25.3
• US Class Current: 536/22.1
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 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

A number of modified nucleosides are disclosed composed of modified sugar moieties which contain substituents at C1 and C4 positions, or branched substituents at C3 and C5 positions of deoxyribose or ribose. Each nucleoside is converted to or properly protected and then converted to the corresponding phosphoramidites. These phosphoramidites are used to assemble oligonucleotides in which there is at least one of the forenoted nucleosides. These sugar modified oligonucleotides have the potential to be used as antisense therapies since they are expected to enhance nuclease resistance and cellular uptake while they maintain sequence-specificity and affinity to nucleic acid targets in vitro or in vivo.

Claims

1. A nucleoside having the structure:

wherein;

R₂ is selected from the group consisting of H, OH, alkoxy, aralkoxy and aryloxy;

R₃ and R₅ are independently selected from the group consisting of OH, OCEPA and a hydroxyl blocking group;

X is selected from the group consisting of O and CH₂;

B is a nucleoside base;

when X is CH₂,

R₁′

, R₃′

, R₄′ and

R₅′

are independently selected from the group consisting of H, CN,

N₃, NO₂, CF₃, alky, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, provided that R₁′

, R₃′

, R₄′ and

R₅′

cannot all be H at the same time and R₄′

is not a label;

when X is O,

R₄′ and

R₅′

are H, and

R₁′

is selected from the group consisting of N₃, NO₂, CF₃, alky, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, where the substituted portion of at least one of the substituted alkyl substituted aralkyl and substituted aryl is selected from the group consisting of NO₂, N₃, CF₃, SH, SR, COOH, COOR, SO₃H SO₃R, F, Cl, Br, I, Ts, Ac, CF₃CO, acyl, where R is selected from lower alkyl aralkyl and aryl; and

R₃′

is selected from the group consisting of CN, N₃, NO₂, CF₃, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, where the substituted portion of at least one of the substituted akl, substituted aralkyl and substituted aryl is selected from the group consisting of CN, NO₂, N₃, CF₃, NH₂, NR₂, OR, SH, SR, COOH, COOR, SO₃R, F, Cl, Br, I Ts, Ac, CF₃CO, acyl, where R is selected from lower alkyl, aralkyl and aryl; and

wherein

any alkyl portion of R₁′

, R₃′

, R₄′ and

R₅′

is C1 to C10, linear, branched, saturated or unsaturated.

2. The nucleoside of claim 1 wherein X is CH₂.

3. The nucleoside of claim 1 wherein X is O.