Isis Pharmaceuticals, Inc.

Other

Isis Pharmacueticals, Inc.

Yogesh S Sanghvi

Phillip Dan Cook

Kelly G Sprankle

Bruce S Ross

Rich H Griffey

Susan M Freier

David J Ecker

Zhiqiang Guo

Philip D Cook

Jean Jacques Vasseur

Francoise Debart

Muthiah Manoharan

Brett P Monia

Robert H Springer

Kelly Teng

Jacqueline R Wyatt

Thomas W Bruice

Timothy A Vickers

Kevin P Anderson

Emmanuel A Theodorakis

Ronnie C Hanecak

Quanlai Song

Peter W Davis

Vickie L Brown-Driver

Pei Pei Kung

Ke Wen

Vicente Gotor

Susana Fernandez

Javier Garcia

Miguel Ferrero

Snehlata Tripathi

Krishna Misra

Francois Morvan

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.

Backbone modified oligonucleotide analogues

Novel chiral compounds that mimic and/or modulate the activity of wild-type nucleic acids are disclosed. In general, the compounds are phosphorothioate oligonucleotides wherein the 5', and the 3&#x2032;-terminal internucleoside linkages are chirally Sp and internal internucleoside linkages are chirally Rp.

Gapped oligomers having site specific chiral phosphorothioate internucleoside linkages

Methods for preparing deoxynucleosides from their corresponding ribonucleosides by forming 3-tert-butylphenoxythiocarbonylderivatives of the ribonucleosides and subsequently effecting radical deoxygenation reactions at the carbon atoms to be deoxygenated.

Preparation of deoxynucleosides

The present invention discloses methods for synthesizing oligomeric compounds. The methods include a modified phosphoramidite protocol wherein the oxidation and capping steps are combined into a single step. The methods result in increased efficiency and are especially amenable to the large scale synthesis of oligomeric compounds.

Process for the preparation of oligonucleotides

Silylating reagents having a group other than a divalent oxygen separating two silyl groups provide regioselective protection of reactive groups under robust conditions, such as basic conditions used in alkylation, acylation and deoxygenation. In particular, silylating reagents having a group other than oxygen separating two silyl groups are useful for protecting two hydroxy groups of a ribonucleic or deoxyribonucleic acid. Alkylation of a 2&prime;-hydroxy group of a ribonucleoside protected with the inventive silylating agents in the presence of an excess of a mild hindered base such as sodium HMDS may be carried out without protecting the exocyclic amine and oxo functionalities of nucleobases.

Reagent and process for protecting nucleoside hydroxyl groups

The present invention is directed to methods for the preparation of 3&prime;-O and 5&prime;-O-levulinyl nucleosides from common precursors using an enzymatic approach.

Building blocks for the solution phase synthesis of oligonucleotides

Oligonucleotide analogs are disclosed having pyrimidine monomeric sub-units therein that are modified at the 2&prime; and 5&prime; positions. Monomeric sub-units having these modifications may be further modified at the 2&prime; position. Improved processes for the synthesis of 2&prime;-O-substituted pyrimidine nucleosides are also provided. The processes feature alkylation of a 2,2&prime;-anhydropyrimidine nucleoside or a 2S,2&prime;-anhydropyrimidine nucleoside with a weak nucleophile in the presence of a Lewis acid.

Process for the synthesis of 2&prime;-O-substituted pyrimidines and oligomeric compounds therefrom

Methods for selectively protecting the exocyclic amino function of a purine nucleoside are provided using activating agents to effect acylation at the exocyclic amino site. Methods are also provided for recycling polymer bound coupling supports from the reaction mixtures produced upon N-acylation.

Process for selective N-acylation of purine nucleosides

Compositions and methods are provided for the modulation of expression of the human ras gene in both the normal and activated forms. Oligonucleotides are provided that have methylene(methylimino) linkages alternating with phosphorothioate or phosphodiester linkages. Further oligonucleotides are provide that have a first region having a methylene(methylimino) linkage alternating with a phosphorothioate or phosphodiester linkage and a second region having phosphorothioate linkages. Such oligonucleotides can be used for diagnostics as well as for research purposes including methods for diagnosis, detection and treatment of conditions arising from the activation of the H-ras gene.

Antisense inhibition of ras gene with chimeric and alternating oligonucleotides

The present invention relates to improved methods for the preparation of nucleoside phosphoramidites and oligonucleotides. In one aspect, the methods of the invention are used to prepare phosphitylating reagents using pyridinium salts as activators. In a further aspect, the methods of the invention are used to prepare internucleoside linkages using activators which include at least one pyridinium salt and at least one substituted imidazole. In a further aspect, methods are provided preparation of internucleoside linkages between nucleosides having 2&prime;-substituents using imidazolium or benzimidazolium salts as an activator. In a further aspect, methods are provided preparation of internucleoside linkages between nucleosides having bioreversible protecting group that confers enhanced chemical and biophysical properties, without exocyclic amine protection, using imidazolium or benzimidazolium salts as an activator.

Activators for oligonucleotide synthesis

Novel compounds that mimic and/or modulate the activity of wild-type nucleic acids. In general, the compounds contain a selected sequence of nucleosidic bases or other reactive groups that are covalently bound through nitrogen-containing linear, hairpin, dumbbell, and circular shaped tethers.

Oligonucleotide mimics having nitrogen-containing linkages

The present invent n provides a method for the preparation of triarylmethyl protecting group reagents. The reagents are prepared from reaction effluent from the cleavage step of oligonucleotide synthetic regimes.

Recovery of triarylmethyl halide protecting groups cleaved during oligonucleotide synthesis

Oligonucleotide analogs are disclosed having pyrimidine monomeric sub-units therein that are modified at the 2&prime; and 5 positions. Monomeric sub-units having these modifications may be further modified at the 2 position. Improved processes for the synthesis of 2&prime;-O-substituted pyrimidine nucleosides are also provided. The processes feature alkylation of a 2,2&prime;-anhydropyrimidine nucleoside or a 2S,2&prime;-anhydropyrimidine nucleoside with a weak nucleophile in the presence of a Lewis acid.

Novel compounds that mimic and/or modulate the activity of wild-type nucleic acids. In general, the compounds contain a selected nucleoside sequence wherein the nucleosides are covalently bound through linking groups that contain adjacent nitrogen atoms.

Oligonucleoside linkages containing adjacent nitrogen atoms

Oligonucleotide analogs are disclosed having pyrimidine monomeric sub-units therein that are modified at the 2' and 5 positions. Monomeric sub-units having these modifications may be further modified at the 2 position.

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Encinitas, CA, United States of America

Yogesh S Sanghvi