3-deazapurines

• US 5,457,191 A
• Filed: 03/05/1993
• Issued: 10/10/1995
• Est. Priority Date: 01/11/1990
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Andrews, Robert S., Cook, P. Dan, Acevedo, Oscar L.
• Primary Examiner(s): Robinson, Douglas W.
• Assistant Examiner(s): WILSON, JAMES O
• Application Number:
  US08/027,011
• Time in Patent Office: 949 Days
• Field of Search: 536/26.7, 536/27.13, 536/27.6, 536/27.7, 536/27.81, 536/27.3, 544/264, 546/118
• US Class Current: 536/27.13
• 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: 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

This invention relates to compounds based on the 3-deazapurines ring system and to methods for making such compounds. The invention also generally relates to the field of "antisense" agents, agents that are capable of specific hybridization with a nucleotide sequence of an RNA. The 3-deazapurine-containing compounds of this invention can be useful for modulating the activity of RNA when incorporated into oligonucleotides. Oligonucleotides and their analogs are used for a variety of therapeutic and diagnostic purposes, such as treating diseases, regulating gene expression in experimental systems, assaying for RNA and for RNA products through the employment of antisense interactions with such RNA, diagnosing diseases, modulating the production of proteins and cleaving RNA in site specific fashions.

Claims

1. A compound having the formula:

##STR7## wherein G is C or N;

R₁ is NH₂, alkyl having from one to about 12 carbons, substituted alkyl having from one to about 12 carbons, alkenyl having from one to about 12 carbons, substituted alkenyl having from one to about 12 carbons, aralkyl having from about 6 to about 30 carbons, amino, R₂ is amino, alkyl having from one to about 12 carbons, substituted alkyl having from one to about 12 carbons, alkenyl having from one to about 12 carbons, substituted alkenyl having from one to about 12 carbons, aralkyl having from about 6 to about 30 carbons; and

Y is H, a nitrogen protecting group, ribose or deoxyribose.

2. The compound of claim 1 wherein Y is ribose or deoxyribose.

3. The compound of claim 1 wherein R₂ is amino.

4. The compound of claim 1 wherein R₁ is alkyl having from one to about 12 carbon atoms.

5. The compound of claim 1 wherein R₁ is alkenyl having from two to about 12 carbon atoms.

6. The compound of claim 1 wherein R₁ is aralkyl having from about 6 to about 30 carbon atoms.

7. The compound of claim 2 wherein R₁ is alkyl having from one to about 12 carbon atoms.

8. The compound of claim 2 wherein R₁ is alkenyl having from two to about 12 carbon atoms.

9. The compound of claim 2 wherein R₁ is aralkyl having from about 6 to about 30 carbon atoms.

10. The compound of claim 1 wherein G is N;

R₁ is alkyl having from one to about 12 Garbon atoms;

R₂ is amino; and

Y is ribose or deoxyribose.

11. The compound of claim 1 wherein G ie N;

R₁ is alkenyl having from two to about 12 carbon atoms;

R₂ is amino; and

Y is ribose or deoxyribose.

12. The compound of claim 1 wherein G is N;

R₁ is aralkyl having from about 6 to about 30 Garbon atoms;

R₂ is amino; and

Y is ribose or deoxyribose.

13. The compound of claim 1 wherein G is N;

R₁ is 1-methyl octane, 1-propene, phenyl methyl, or napthylethyl;

R₂ is amino; and

Y is ribose or deoxyribose.

14. The compound of claim 1 wherein Y is ribose or deoxyribose, said ribose or deoxyribose having an activated phosphate group at the 3'"'"' position.

26. The compound of claim 1 wherein G is N;

R₃ is 1-methyl octane, 1-propene, phenyl methyl, or napthylethyl;

R₄ is NH₂ ; and

Y is ribose or deoxyribose.

15. A compound having the formula:

##STR8## wherein G is C or N;

R_B is H, NH₂, alkyl having from one to about 12 carbons, substituted alkyl having from one to about 12 carbons, alkenyl having from one to about 12 carbons, substituted alkenyl having from one to about 12 carbons, aralkyl having from about 6 to about 30 carbons, amino;

R₄ is NH₂, alkyl having from one to about 12 carbons, substituted alkyl having from one to about 12 carbons, alkenyl having from one to about 12 carbons, substituted alkenyl having from one to about 12 carbons, aralkyl having from about 6 to about 30 carbons, amino; and

Y is H, a nitrogen protecting group, ribose or deoxyribose;

provided that when R₃ is H, R₄ is not NH₂.

16. The compound of claim 15 wherein Y is ribose or deoxyribose.

17. The compound of claim 15 wherein R₃ is alkyl having from one to about 12 carbon atoms.

18. The compound of claim 15 wherein R₃ is alkenyl having from two to about 12 carbon atoms.

19. The compound of claim 15 wherein R₃ is aralkyl having from about 6 to about 30 carbon atoms.

20. The compound of claim 16 wherein R₃ is alkyl having from one to about 12 carbon atoms.

21. The compound of claim 16 wherein R₃ is alkenyl having from two to about 12 carbon atoms.

22. The compound of claim 16 wherein R₃ is aralkyl having up to about 6 to 30 carbon atoms.

23. The compound of claim 15 wherein G is N;

R₃ is alkyl having from one to about 12 carbon atoms;

R₄ is NH₂ ; and

Y is ribose or deoxyribose.

24. The compound of claim 15 wherein G is N;

R₃ is alkenyl having from two to about 12 carbon atoms;

R₄ is NH₂ ; and

Y is ribose or deoxyribose.

25. The compound of claim 15 wherein G is N;

R₃ is aralkyl having from about 6 to about 30 carbon atoms;

R₄ is NH_2;

and Y is ribose or deoxyribose.

27. The compound of claim 15 wherein Y is ribose or deoxyribose, said ribose or deoxyribose having an activated phosphate group at the 3'"'"' position.