Amine-derivatized nucleosides and oligonucleosides

• US 6,783,931 B1
• Filed: 09/03/1993
• Issued: 08/31/2004
• Est. Priority Date: 01/11/1990
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Cook, Phillip Dan, Guinosso, Charles J., Manoharan, Muthiah
• Primary Examiner(s): Siew, Jeffrey
• Application Number:
  US08/117,363
• Time in Patent Office: 4,015 Days
• Field of Search: 536/24.5, 536/25.32, 435/6
• US Class Current: 435/6.12
• 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 47/51 the non-active ingredient being a modifying agent
• 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: C07J 51/00 Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
• 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 15/1131 against viruses
• CPC Class Codes: C12N 15/1132 against retroviridae, e.g. HIV
• CPC Class Codes: C12N 15/1133 against herpetoviridae, e.g. HSV
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/3125 Methylphosphonates
• CPC Class Codes: C12N 2310/315 : Phosphorothioates
• CPC Class Codes: C12N 2310/318 : where the PO2 is completely replaced, e.g. MMI or formacetal
• 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

Nucleosides and oligonucleosides functionalized to include alkylamino functionality, and derivatives thereof. In certain embodiments, the compounds of the invention further include steriods, reporter molecules, reporter enzymes, lipophilic molecules, peptides or proteins attached to the nucleosided through the alkylamino group.

Claims

1. A compound comprising a plurality of linked nucleosides, wherein:

each nucleoside includes a pentofuranosyl sugar portion and a base portion; and

at least one of said nucleosides bears at a 2′

-O-position, a 3′

-O-position, or a 5′

-O-position of said pentofuranosyl sugar a terminal substituent having formula;

2. The compound of claim 1 wherein more than one of said nucleosides bear said substituent at a 2′

-O-position, a 3′

-O-position, or a 5′

-O-position.

3. The compound of claim 1 wherein R_A is (CH₂)_n where n is an integer from 1 to about 10.

4. The compound of claim 3 wherein n is 6.

5. The compound of claim 1 wherein said R_1a is H and R_1b, together, are phthalimido.

6. The compound of claim 1 wherein R_1a is H and R_1b is C(O)—

(CH₂)_n—

R₂ where n is an integer from 1 to about 10.

7. The compound of claim 1 wherein R_1a is H and R_1b is R₂.

8. The compound of claim 1 wherein R_1a is H and R_1b is C(O)—

O—

R₂.

9. The compound of claim 1 wherein R_1a and R_1b both are alkyl.

10. The compound of claim 1 wherein R_1a is H and R_1b is C(O)—

(CH₂)_n—

R₂ where n is an integer from 1 to about 10.

11. The compound of claim 10 wherein R₂ has formula —

(CH₂)₅—

NH—

.

12. The compound of claim 1 wherein R_1a is H and R_1b is C(S)—

NH—

R₂.

13. The compound of claim 1 wherein R₂ includes pyrene, fluorescein, dinitrophenyl, cholesterol, acridine.

14. The compound of claim 1 wherein R_1a is H and R_1b is C(O)—

R₂.

15. The compound of claim 14 wherein R₂ has formula —

O—

(CH₂CH₂—

O—

)_x—

R₃.

16. A nucleoside comprising a pentofuranosyl sugar portion and a base portion, wherein said nucleoside bears at a 2′

-O-position of said pentofuranosyl sugar, a 3′

-O-position, or a 5′

-O-position a substituent having the formula;

17. The nucleoside of claim 16 wherein R_A is (CH₂)_n where n is an integer from 1 to about 10.

18. The nucleoside of claim 16 wherein n is 6.

19. The nucleoside of claim 16 wherein said R_1a is H and R_1b, together are phthalamido.

20. The nucleoside of claim 16 wherein R_1a is H and R_1b is C(O)—

(CH₂)_n—

R₂ where n is an integer from 1 to about 10.

21. The nucleoside of claim 16 wherein R_1a is H and R_1b is R₂.

22. The nucleoside of claim 16 wherein R_1a is H and R_1b is C(O)—

O—

R₂.

23. The nucleoside of claim 16 wherein R_1a and R_1b both are alkyl.

24. The nucleoside of claim 16 wherein R_1a is H and R_1b is C(O)—

(CH₂)_n—

R₂ where n is an integer from 1 to about 10.

25. The nucleoside of claim 24 wherein R₂ has formula —

(CH₂)₅—

NH—

.

26. The nucleoside of claim 16 wherein R_1a is H and R_1b is C(S)—

NH—

R₂.

27. The nucleoside of claim 16 wherein R₂ includes pyrene, fluorescein, dinitrophenyl, cholesterol, acridine.

28. The nucleoside of claim 16 wherein R_1a is H and R_1b is C(O)—

R₂.

29. The nucleoside of claim 28 wherein R₂ has formula —

O—

(CH₂CH₂—

O—

)_x—

R₃.