Oligonucleotides containing 2′-O-modified purines

• US 7,101,993 B1
• Filed: 10/27/1992
• Issued: 09/05/2006
• Est. Priority Date: 01/11/1990
• Status: Expired due to Term

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Cook, Phillip Dan, McGee, Daniel Peter Claude, Guinosso, Charles John
• Primary Examiner(s): Jiang, Shaojia A.
• Assistant Examiner(s): Krishnan, Ganapathy
• Application Number:
  US07/967,267
• Time in Patent Office: 5,061 Days
• Field of Search: 536/24.5, 536/27.61, 536/27.81, 536/25.6, 536/26.1, 536/22.1
• US Class Current: 536/25.6
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• 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 19/20 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
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds
• CPC Class Codes: C07J 43/003 not condensed
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/3125 Methylphosphonates
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/32 of the sugar
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/33 of the base
• CPC Class Codes: C12N 2310/333 Modified A
• CPC Class Codes: C12N 2310/336 Modified G
• CPC Class Codes: C12N 2310/3521 : Methyl
• CPC Class Codes: C12N 2310/3523 : Allyl
• CPC Class Codes: C12N 2310/3527 : Other alkyl chain
• CPC Class Codes: C12N 2310/3531 : Hydrogen
• CPC Class Codes: C12N 2310/3533 : Halogen
• CPC Class Codes: C12N 9/0069 : acting on single donors with incorporation of molecular oxygen, i.e. oxygenases (1.13)
• CPC Class Codes: C12Q 1/68 : involving nucleic acids
• CPC Class Codes: C12Y 113/11012 : Linoleate 13S-lipoxygenase (1.13.11.12)

Abstract

Compounds are provided containing purine nucleotides that bear moieties X at the 2′ position thereof wherein X is R₁—(R₂)_n; R₁ is C₃-C₂₀ alkyl, C₄-C₂₀ alkenyl or C₂-C₂₀ alkynyl; R₂ is halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, or a group that enhances the pharmacokinetic properties of oligonucleotides; and n is an integer from 0 to about 6. Such compounds are useful for modulating the synthesis of proteins.

Claims

1. A compound having the structure:

wherein

X is R₁—

(R₂)_n;

R₁ is C₂-C₂₀ alkyl, C₂-C₂₀ alkenyl, or C₂-C₂₀ alkynyl and n is 1 to 6;

R₂ is halogen, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, imidazole, N-phthalimido, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether; and

either one of T₃ and T₅ is OH, a hydroxyl blocking group, phosphate or an activated phosphate group and the other of T₃ and T₅ is a nucleotide or both T₃ and T₅ are nucleotides.

3. The compound of claim 1 wherein R₁ is C₄-C₂₀ alkyl.

4. The compound of claim 1 wherein R₁ is C₅-C₂₀ alkyl.

5. The compound of claim 1 wherein R₁ is C₃-C₂₀ alkyl and n is 1.

6. The compound of claim 1 wherein R₁ is C₄-C₂₀ alkenyl and n is 1.

7. The compound of claim 1 wherein R₁ is C₂-C₂₀ alkynyl and n is 1.

8. The compound of claim 1 wherein R₁ is C₂-C₂₀ alkyl and n is 1 to 6.

9. The compound of claim 1 wherein R₁ is C₂-C₂₀ alkenyl and n is 1 to 6.

2. A compound having the structure:

wherein

X is R₁—

(R₂)_n;

R₁ is C₁-C₂₀ alkyl, C₄-C₂₀ alkenyl, or C₂-C₂₀ alkynyl;

R₂ is halogen, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, imidazole, N-phthalimido, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, or polyether;

either one of T₃ and T₅ is OH, a hydroxyl blocking group, phosphate or an activated phosphate group and the other of T₃ and T₅ is a nucleotide, or both T₃ and T₅ are nucleotides; and

n is an integer from 1 to 6.

11. The compound of claim 2 wherein R₁ is C₁-C₂₀ alkyl.

12. The compound of claim 2 wherein R₁ is C₄-C₂₀ alkenyl.

13. The compound of claim 2 wherein R₁ is C₂-C₂₀ alkynyl.

10. The compound of claim wherein R₁ is C₂-C₂₀ alkynyl and n is 1 to 6.

14. A compound having the structure:

wherein

X is R₁—

(R₂)_n;

R₁ is C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, or C₂-C₂₀ alkynyl and n is 0;

or R₁ is C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, or C₂-C₂₀ alkynyl and n is 1 to 6;

R₂ is hydroxyl, thiol, keto, carboxyl, or amino; and

either one of T₃ and T₅ is OH, a hydroxyl blocking group, phosphate or an activated phosphate group and the other of T₃ and T₅ is a nucleotide or both T₃ and T₅ are nucleotides.

15. A compound having the structure:

wherein

X is R₁—

(R₂)_n;

R₁ is C₁-C₂₀ alkyl, C₄-C₂₀ alkenyl, or C₂-C₂₀ alkynyl;

R₂ is hydroxyl, thiol, keto, carboxyl, or amino;

either one of T₃ and T₅ is OH, a hydroxyl blocking group, phosphate or an activated phosphate group and the other of T₃ and T₅ is a nucleotide, or both T₃ and T₅ are nucleotides; and

n is an integer from 0 to 6.