Sugar modified nucleosides and oligonucleotides

• US 5,681,940 A
• Filed: 11/02/1994
• Issued: 10/28/1997
• Est. Priority Date: 11/02/1994
• Status: Expired due to Term

• Current Assignee: Mdrna Inc. (Adhera Therapeutics, Inc.)
• Original Assignee: ICN Pharmaceuticals, Inc (Bausch Health Cos., Inc.)
• Inventors: Wang, Guangyi, Ramasamy, Kandasamy, Seifert, Wilfried E.
• Primary Examiner(s): Marschel, Ardin H.
• Assistant Examiner(s): Riley, Jezia
• Application Number:
  US08/333,545
• Time in Patent Office: 1,091 Days
• Field of Search: 514/44, 536/22.1, 536/23.1, 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 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:

##STR6## 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 bearing a blocking group;

X is selected from the group consisting of S and NH;

B is a modified or unmodified nucleoside base selected from the group consisting of Adenine, Guanine, Cytosine, Uracil and Thymine;

R₁ '"'"', R₃ '"'"', R₄ '"'"' and R₅ '"'"' are independently selected from the group consisting of H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, provided that R₁ '"'"', R₃ '"'"', R₄ '"'"' and R₅ '"'"' cannot all be H at the same time;

wherein;

any alkyl portion of R₁ '"'"', R₃ '"'"', R₄ '"'"' and R₅ '"'"' is C₁ to C₁₀ linear or branched, saturated or unsaturated;

the substituted portion of at least one of the substituted alkyl, substituted aralkyl and substituted aryl is selected from the group consisting of CN, NO₂, N₃, CF₃, NH₂, NR₂, OH, OR, SH, COOH, COOR, SO₃ R, F, Cl, Br, and I, where R is selected from the group consisting of H, alkyl, aralkyl, aryl, Ac, CF₃ CO, Ts; and

any aryl portion of R₁ '"'"', R₃ '"'"', R₄ '"'"' and R₅ '"'"' is a phenyl, polycyclic ring or heterocycle.

2. The nucleoside of claim 1 wherein R₁ '"'"' is selected from the group consisting of alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, and R₃ '"'"', R₄ '"'"' and R₅ '"'"' are all H.

3. The nucleoside of claim 1 wherein R₃ '"'"' is selected from the group consisting of alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, and R₁ '"'"', R₄ '"'"' and R₅ '"'"' are all H.

4. The nucleoside of claim 1 wherein R₄ '"'"' is selected from the group consisting of alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, and R₁ '"'"', R₃ '"'"' and R₅ '"'"' are all H.

5. The nucleoside of claim 1 wherein R₅ '"'"' is selected from the group consisting of alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, and R₁ '"'"', R₃ '"'"' and R₄ '"'"' are all H.

6. An oligonucleotide containing the nucleoside of claim 1 wherein R₁ '"'"' is selected from the group consisting of alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, and R₃ '"'"', R₄ '"'"' and R₅ '"'"' are all H.

7. An oligonucleotide containing the nucleoside of claim 1 wherein R₃ '"'"' is selected from the group consisting of alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, and R₁ '"'"', R₄ '"'"' and R₅ '"'"' are all H.

8. An oligonucleotide containing the nucleoside of claim 1 wherein R₄ '"'"' is selected from the group consisting of alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, and R₁ '"'"', R₃ '"'"' and R ₅ '"'"' are all H.

9. An oligonucleotide containing the nucleoside of claim 1 wherein R₅ '"'"' is selected from the group consisting of alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, and R₁ '"'"', R₃ '"'"' and R₄ '"'"' are all H.