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Bicyclic cyclohexose nucleic acid analogs

a technology of cyclohexose and bicyclic nucleic acids, applied in the field of new products, can solve problems such as loss of the normal function of the target rna

Inactive Publication Date: 2015-07-09
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The new bicyclic nucleoside analogs enhance nuclease resistance and specificity, allowing for effective hybridization with target RNA, reducing toxicity concerns and expanding their utility in therapeutic and diagnostic applications.

Problems solved by technology

In certain embodiments, the oligomeric compounds are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

Method used

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  • Bicyclic cyclohexose nucleic acid analogs
  • Bicyclic cyclohexose nucleic acid analogs
  • Bicyclic cyclohexose nucleic acid analogs

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of (1R,3R,4R,7S)-7-(2-cyanoethoxy(diisopropylamino)phosphin oxy)-1-(4,4′-dimethoxytrityloxymethyl)-3-(N-Bz-(Cytidin-1-yl)-2,5-dioxa-bicyclo[2.2.2]octane (14 U, 16 C)

[0268]

[0269]Note: Compound 4 was prepared from compound 1 by a slightly modified version of the procedures found in Tetrahedron Lett., 1993, 1653 and Tetrahedron, 2004, 6813.

Compound 1

[0270]The starting material, Compound 1, is prepared according to the procedure of Moffatt et al, J. Org. Chem., 1979, 44, 1301. Compound 1 is also commercially available from a number of vendors.

Compound 2

Alkylation of Diacetone Glucose

[0271]NaH (60% in Mineral oil, 49.2 g, 1.6 equivalents) was added to a 2 L round bottom flask flushed with nitrogen, and the NaH was washed with hexanes (2×1.0 L) to remove the mineral oil. After decanting the hexanes, DMF (700 mL) was added and the mixture was cooled in an ice bath. Diacetone glucose (1, 200 g, 0.77 moles) was then added over a period of 30 minutes. The ice-bath was removed and ...

example 2

Preparation of (1S,3R,4S,7R)-7-(2-cyanoethoxy(diisopropylamino)phosphin oxy)-1-(4,4′-dimethoxytrityloxymethyl)-3-(heterocyclic base radical)-2,5-dioxa-bicyclo[2.2.2]octane (27)

Route 1:

[0288]

Route 2: Alternative Procedures to Prepare Compound 20

[0289]

[0290]Compound 6 is prepared as per the procedures illustrated in Example 1.

example 3

Preparation of (1R,3R,4R,8R)-8-(2-cyanoethoxy(diisopropylamino)phosphin oxy)-1-(4,4′-dimethoxytrityloxymethyl)-3-(heterocyclic base radical)-2,5-dioxa-bicyclo[2.2.2]octane (39)

[0291]

[0292]Compound 6 is prepared as per the procedures illustrated in Example 1.

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PUM

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Abstract

The present invention provides bicyclic cyclohexose nucleoside analogs and oligomeric compounds comprising these nucleoside analogs. These bicyclic nucleoside analogs are useful for enhancing properties of oligomeric compounds including nuclease resistance.

Description

FIELD OF THE INVENTION[0001]Provided herein are novel bicyclic nucleoside analogs and oligomeric compounds and compositions prepared therefrom. More particularly, bicyclic nucleoside analogs are provided wherein the naturally occurring pentofuranose ring is replaced with a cyclohexyl ring that comprises one ring heteroatom and a bridge making the ring system bicyclic. In certain embodiments, the oligomeric compounds and compositions of the present invention are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA. The oligomeric compounds provided herein are also expected to be useful as primers and probes in diagnostic applications.SEQUENCE LISTING[0002]The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled CHEM0030USC1SEQ_ST25.txt, created on Mar. 18, 2015 which is 8 Kb in size. The information in the electronic format of the sequence listing...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N15/113C07H19/06
CPCC07H19/06C12N15/113C07H19/16C07H21/00
Inventor MIGAWA, MICHAEL T.SETH, PUNIT P.SWAYZE, ERIC E.ROSS, BRUCE S.SONG, QUANLAIHAN, MINGMING
Owner IONIS PHARMA INC