Chemgenes Corporation

Oligos Etc. Inc.

Syed K Raza

Suresh C Srivastava

Amy Arrow

Roderic M Dale

Saresh C Srivastava

This invention relates to synthetic oligonucleotides that are useful for antisense based therapeutic applications. The synthetic oligonucleotides of this invention have modifications in the sugar phosphate backbone for improved antisense properties.

Oligonucleotide phosphate esters

The present invention describes a novel 2'-O-alkylation reaction to produce a novel series of nucleosides carrying the 2'-O-propargyl group, using propargyl bromide, dibutyl tin oxide and tetrabutyl ammonium bromide. The procedure involves novel techniques for regioselective introduction of 2'-/3'-O-propargyl group directly on the 5'-DMT-N-protected- nucleosides using dibutyl tin oxide as a mild base in conjunction with a phase transfer catalyst, tetrabutyl ammonium bromide. The reaction process has many significant features and leads to isomeric ratios in favor of the 2'-regio isomer. This allows the synthesis of the corresponding phosphoramidites of high purity.

Propargyl modified nucleosides and nucleotides

This invention is directed to processes for producing high purity N-protected-2'-O-methyl-5'-dimethoxytrityl-3' ribonucleoside methoxy, N,N-diisopropyl phosphoramidites (group 1), and N-protected-2'-O-methyl-5'-dimethoxytrityl-3'-ribonucleoside ethoxy, N,N-diisopropyl phosphoramidites (group 2). This invention is further directed to the process for producing high purity 2'-O-methyl-5'-dimethoxytrityl-inosine (structure IX; group 3), and 2'-O-methyl-5'-dimethoxytrityl-inosine-3'-cyanoethyl, N,N-diisopropyl phosphoramidite (structure Xa; group 3). This invention is also directed to the process for producing high purity N-protected-3'-O-methyl-5'-dimethoxytrityl ribonucleosides (group 6), and N-protected-3'-O-methyl-5'-dimethoxytrityl-2'-ribonucleoside cyanoethyl, N,N-diisopropyl phosporamidites (group 7).

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Waltham, MA, United States of America

Syed K Raza