Backbone modified oligonucleotide analogs

• US 5,378,825 A
• Filed: 05/21/1991
• Issued: 01/03/1995
• Est. Priority Date: 07/27/1990
• Status: Expired due to Term

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Sanghvi, Yogesh S., Cook, Philip D.
• Primary Examiner(s): Rollins, John W.
• Assistant Examiner(s): Wilson, James O.
• Application Number:
  US07/703,619
• Time in Patent Office: 1,323 Days
• Field of Search: 536/23, 536/24, 536/26, 536/27, 536/28, 536/29, 536/23.1, 536/25.3, 536/25.34, 536/25.33, 536/25.6, 536/25.31
• US Class Current: 536/25.34
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07H 11/00 Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof halo-sugars C07H5/02; thio-, seleno-, or telluro-sugars C07H5/08
• 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 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

Therapeutic oligonucleotide analogs which have improved nuclease resistance and improved cellular uptake are provided. Replacement of the normal phosphorodiester inter-sugar linkages found in wild type oligomers with four atom linking groups forms unique di- and poly- nucleosides and nucleotides useful in regulating RNA expression and in therapeutics. Methods of synthesis and use are also disclosed.

Claims

1. A method for synthesizing a compound having the structure:

##STR9## wherein;

B_x is a nucleosidic base;

Q is O;

X is H, OH, F, or O-alkyl;

L₁ and L₄ are CH₂ ; and

L₂ and L₃ are, independently, P(O)R₄, O, or NR₃, provided that L₂ and L₃ are not both O;

or

L₁, L₂, L₃ and L₄, together, comprise a --CH═

N--NH--CH₂ -- or --CH₂ --O--N═

CH-- moiety;

R₃ is H or lower alkyl; and

R₄ is OH;

comprising the steps of;

providing a first moiety comprising the structure;

##STR10## and a second moiety comprising the structure;

##STR11## wherein E₁ and E₂ are the same or different and are halomethyl, trifluoromethyl sulfonylmethyl, p-methyl-benzene sulfonylmethyl, or formyl; and

coupling said first and second moleties with a linking group through said electrophilic reactive groups to form said compound.

2. The method of claim 1 wherein the electrophilic reactive group of the first moiety is C-formyl.

3. The method of claim 1 wherein the electrophilic reactive group of the second moiety is C-formyl.

4. The method of claim 1 wherein said linking group is hydrazine or hydroxylamine.

5. The method of claim 1 wherein L₁, L₂, L₃ and L₄, together, are --CH₂ --NR₃ --NR₃ --CH₂ --.

6. The method of claim 1 wherein L₁, L₂, L₃ and L₄, together, are --CH₂ --NR₃ --O--CH₂ --.

7. The method of claim 1 wherein L₁, L₂, L₃ and L₄, together, are --CH₂ --O--NR₃ --CH₂ --.

8. The method of claim 1 wherein L₁, L₂, L₃ and L₄, together, are --CH₂ O--P(O)R₄ --CH₂ --.

9. The method of claim 1 wherein L₁, L₂, L₃ and L₄, together, are --CH₂ --P(O)R₄ --O--CH₂ --.

10. The method of claim 1 wherein at least one of E₁ or E₂ is halomethyl.

11. The method of claim 1 wherein at least one of E₁ or E₂ is trifluoromethyl sulfonylmethyl.

12. The method of claim 1 wherein at least one of E₁ or E₂ is p-methyl-benzene sulfonylmethyl.

13. The method of claim 1 wherein an least one of E₁ or E₂ is formyl.