Isis Pharmaceuticals, Inc.

Gilead Sciences, Inc.

Gilead Pharmasset LLC

Bruce S Ross

Phillip Dan Cook

Michael Joseph Sofia

Kelly G Sprankle

Suguna Rachakonda

Byoung-Kwon Chun

Ganapati Reddy Pamulapati

Quanlai Song

Robert H Springer

Yogesh S Sanghvi

Rich H Griffey

Peiyuan Wang

Hai-Ren Zhang

Eric E Swayze

Punit P Seth

Michael T Migawa

Mingming Han

Muthiah Manoharan

Dhanapalan Nagarathnam

Jinfa Du

Oscar L Acevedo

Robert S Andrews

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.

Bicyclic cyclohexose nucleic acid analogs

The present disclosure provides bicyclic cyclohexitol nucleoside analogs of formula I and oligomeric compounds comprising these nucleoside analogs. These bicyclic nucleoside analogs are expected to be useful for enhancing properties of oligomeric compounds including for example nuclease resistance. 

Bicyclic cyclohexitol nucleic acid analogs

A scalable process for purification of phosphorodiamidite includes steps of solubilizing a crude phosphorodiamidite in an apolar organic solvent, contacting the non-polar organic solvent with a polar phase comprising a polar organic solvent to remove impurities from the solubilized phosphorodiamidite, and removing the non-polar organic solvent from the phosphorodiamidite.

Process for manufacturing purified phosphorodiamidite

A process of purifying phosphoramidite precursors useful in inter alia synthesis of oligonucleotides comprises dissolving a crude phosphoramidite in a polar phase, adding a basic compound to the polar phase, adding a portion of water to the polar phase, contacting the polar phase with a first apolar phase to extract impurity into the apolar phase, separating the first apolar phase from the polar phase, adding a second aliquot of water to the polar phase, and contacting the polar phase with a second apolar phase, whereby the phosphoramidite partitions into the second apolar phase.

Process of purifying phosphoramidites

A process of manufacturing protected nucleosides comprises reacting a nucleoside with a protecting reagent in the presence of a regioselective activator to produce a regioselectively protected nucleoside. In some embodiments of the inventive method, an optionally substituted trityl or optionally substituted pixyl group is selectively added to the 5'-O-position of a nucleoside in the presence of lutidine as activator or activator/solvent. The inventive method results in improved selectivity of the 5&#x2032;-O-position over the 3&#x2032;-O-position, thereby improving overall product yield and purity, and permitting simplified purification protocols, in some cases obviating the need for chromatography to produce a purified protected nucleoside suitable for automated synthesis of oligonucleotides, such as primers, probes and antisense molecules.

Protection of nucleosides

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

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.

This invention presents novel processes for incorporating 2-aminoadenosine and 2-aminoadenosine analogs into oligonucleotides. A halogenated adeninosine is incorporated into an oligonucleotide using standard synthesis methods, such as phosphoramidited protocols. Subsequent reaction with an amine results in the desired product. The oligonucleotides produced provide stronger hybridization to their target sequences. These oligonucleotides can be useful compounds, inter alia for diagnostic and therapeutic applications.

Process for the synthesis of oligonucleotides incorporating 2-aminoadenosine

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.

Oligomeric compounds having pyrimidine nucleotide (S) with 2'and 5

Improved processes for the synthesis of 2'-O-substituted pyrimidine nucleosides are provided. The processes feature alkylation of a 2,2'-anhydropyrimidine nucleoside or a 2S,2'-anhydropyrimidine nucleoside with a weak nucleophile in the presence of a Lewis acid.

Process for the synthesis of 2'-O-substituted pyrimidines

For large scale preparation of pyrimidine ribonucleosides, the intermediate 2-O-methyl-(or ethyl)-1,3,5-tri-O-benzoyl-.alpha.-D-ribose can be prepared using a diazomethane (or diazoethane) reaction that is controlled via an inert solvent transferring system. This transfer system allows for large scale preparations of the pyrimidine ribonucleosides.

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Princeton, NJ, United States of America

Bruce S Ross