Backbone modified oligonucleotide analogues

• US 5,965,721 A
• Filed: 12/11/1996
• Issued: 10/12/1999
• Est. Priority Date: 07/27/1990
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Debart, Francoise, Sanghvi, Yogesh Shantilal, Vasseur, Jean Jacques, Cook, Phillip Dan
• Primary Examiner(s): Marschel, Ardin H.
• Application Number:
  US08/763,354
• Time in Patent Office: 1,035 Days
• Field of Search: 435/6, 435/810, 436/501, 530/300, 530/350, 536/22.1, 536/25.3, 536/23.1, 536/24.5, 536/25.6, 536/26.1, 935/77, 935/78, 514/44
• US Class Current: 536/23.1
• 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: A61K 49/0006 Skin tests, e.g. intradermal testing, test strips, delayed hypersensitivity
• 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 19/073 with 2-deoxyribosyl as the saccharide radical
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical

Abstract

Therapeutic oligonucleotide analogues which have improved nuclease resistance and improved cellular uptake are provided. Replacement of the normal phosphorodiester inter-sugar linkages found in natural 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. An oligonucleotide analogue in which at least one of the subunits of the analogue have the structure:

##STR9## wherein B_x is a variable base;

Q is O;

X is C₁ to C₁₀ lower alkyl, substituted lower alkyl, alkaryl or aralkyl;

F;

Cl;

Br;

CN;

CF₃ ;

OCF₃ ;

OCN;

O--, S--, or N-alkyl;

O--, S--, or N-alkenyl;

SOCH₃ ;

SO₂ CH₃ ;

ONO₂ ;

NO₂ ;

N₃ ;

NH₂ ;

heterocycloalkyl;

heterocycloalkaryl;

aminoalkylamino;

polyalkylamino;

or substituted silyl;

L₁ is CH₂ ;

L₂ is P(O)R₄ ;

L₃ is O;

L₄ is CH₂ ;

R₄ is OH, SH, NH₂, O-alkyl, S-alkyl, NH-alkyl, O-alkylheterocyclo, S-alkylheterocyclo, N-alkylheterocyclo or a nitrogen-containing heterocycle.

2. The oligonucleotide analogue of claim 1 wherein X is O-alkyl.

3. The oligonucleotide analogue of claim 1 wherein X is F.

4. The oligonucleotide analogue of claim 1 wherein X is O-alkenyl.

5. The oligonucleotide analogue of claim 1 wherein B_x is adenine, guanine, uracil, thymine, cytosine, 2-aminoadenosine or 5-methylcytosine.

6. The oligonucleotide analogue of claim 1 wherein R₄ is OH.

7. The oligonucleotide analogue of claim 1 comprising from 5 to 50 subunits having said structure.

8. The oligonucleotide analogue of claim 1 wherein all of the subunits have said structure.

9. The oligonucleotide analogue of claim 1 wherein alternating subunits have said structure.

10. The oligonucleotide analogue of claim 1 in a pharmaceutically acceptable carrier.

11. The oligonucleotide analogue of claim 1 which exhibits improved nuclease resistance as compared to corresponding natural oligonucleotides.