Compositions for inhibiting RNA activity

• US 5,514,786 A
• Filed: 09/10/1992
• Issued: 05/07/1996
• Est. Priority Date: 01/11/1990
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Guinosso, Charles J., Kawasaki, Andrew M., Cook, Phillip D., Bruice, Thomas
• Primary Examiner(s): Jones, W. Gary
• Assistant Examiner(s): Schreiber, David
• Application Number:
  US07/942,961
• Time in Patent Office: 1,335 Days
• Field of Search: 536/23.1, 514/44, 435/6
• US Class Current: 536/23.1
• 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: A61P 31/12 Antivirals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C07K 14/005 from viruses
• 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 2310/3511 : intercalating or cleaving agent
• 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 2740/16322 : New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• 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: C12Q 1/6813 : Hybridisation assays
• CPC Class Codes: C12Y 113/11012 : Linoleate 13S-lipoxygenase (1.13.11.12)

Abstract

Compositions and methods for modulating the activity of RNA are disclosed. In accordance with preferred embodiments, antisense compositions are prepared comprising targeting and reactive portions. The reactive portions preferably comprise one or two imidazole functionalities conjugated to the targeting oligonucleotide via linkers with or without intervening intercalating moieties. Therapeutics, diagnostics and research methods also are disclosed, as are synthetic nucleosides and nucleoside fragments that can be elaborated into oligonucleotides.

Claims

1. A compound of the structure:

space="preserve" listing-type="equation">G.sub.0 --G.sub.1 --G.sub.2 --G.sub.3

wherein;

G₀ is a nucleoside, a nucleotide or an oligonucleotide;

G₁ is O--alkyl, O--alkenyl, or O--alkynyl;

G₂ is an aryl moiety; and

G₃ includes at least one imidazole moiety.

2. The compound of claim 1 wherein G₂ is a polycyclic moiety having from two to six rings, at least two of said rings being joined to form a conjugated ring system.

3. The compound of claim 2 wherein G₂ is an intercalator.

4. The compound of claim 1 wherein G₂ is naphthalene, anthracene, phenanthrene, benzonaphthalene, fluorene, or pyrene.

5. The compound of claim 1 wherein G₃ is an imidazole;

a C2-substituted imidazole;

an imidazole substituted at a C4 or C5 position with an electrophilic catalyst;

a bis-imidazole;

a C2-substituted bis-imidazole;

a bis-imidazole wherein at least one C4 or C5 position is substituted with an electrophilic catalyst;

a bis-imidazole wherein both C4 positions or both C5 positions are substituted with electrophilic catalyst;

or a bis-imidazole wherein the linkage between the imidazole rings is substituted with an electrophilic catalyst.

6. The compound of claim 5 wherein said electrophilic catalyst comprises a nitrogen functionality that can be protonated.

7. The compound of claim 6 wherein said nitrogen functionality is an amine, a nitrogen heterocycle, guanidine or amidine.

8. The compound of claim 1 wherein G₂ and G₃ are connected through a single covalent bond.

9. The compound of claim 8 wherein G₃ includes at least one imidazole moiety covalently bound through a C4 or C5 position.

10. The compound of claim 1 wherein G₁ connects to G₀ at a 2'"'"' sugar position of said G₀.

11. A compound of the structure:

##STR10## T₅ is H, a hydroxyl protecting group, a phosphate group, a nucleotide or an oligonucleotide;

T₃ is H, a hydroxyl protecting group, a nucleotide, an oligonucleotide, a phosphate group, an activated phosphate group or solid phase support;

G_1'"'"' is O;

G_1" is alkyl, alkenyl, or alkynyl;

G₂ is an aryl moiety;

G₃ includes at least one imidazole moiety; and

Bx is a heterocyclic base moiety.

12. The compound of claim 11 wherein G₂ is an intercalator.

13. The compound of claim 11 wherein G_1" is alkynyl.

14. The compound of claim 11 wherein G₂ includes a polycyclic system.

15. The compound of claim 14 wherein said polycyclic system has two to six rings and at least two of said rings are conjugated.

16. The compound of claim 11 wherein G₂ is naphthalene, anthracene, phenanthrene, benzonaphthalene, fluorene, or pyrene.

17. The compound of claim 11 wherein G₃ is an imidazole moiety.

18. The compound of claim 11 wherein G₃ is a bis-imidazole moiety.

19. The compound of claim 11 wherein Bx is a purine heterocyclic base.

20. A compound of the structure:

##STR11## T₅ is H, a hydroxyl protecting group, a phosphate group, a nucleotide or an oligonucleotide;

T₃ is H, a hydroxyl protecting group, a nucleotide, an oligonucleotide, a phosphate group, an activated phosphate group or a solid phase support;

G_1'"'"' is O;

G_1" is alkynyl; and

Bx is a heterocyclic base moiety, provided that when Bx is uracil then T₃ and T₅ are not H or acetyl.

21. The compound of claim 20 wherein G_1" is propargyl.