Isis Pharmaceuticals, Inc.

P Dan Cook

Muthiah Manoharan

Oscar L Acevedo

Robert S Andrews

Thazha P Prakash

Andrew Mamoru Kawasaki

Haoyun An

Allister S Fraser

Kanda S Ramasamy

Novel amine compounds are provided by the present invention. Methods of preparing and using said novel amine compounds are also provided.

Oligonucleotide and nucleotide amine analogs, methods of synthesis and use

Methods for the regioselective alkylation at the 2&prime;-hydroxy position over the 3&prime;-hydroxy position of nucleosides and nucleoside analogs, forming 2&prime;-O-ester modified compounds, are disclosed. Reduction and derivatization of the 2&prime;-O-ester provides 2&prime;-O-modified nucleosides and nucleoside analogs useful for the synthesis of oligomeric compounds having improved hybridization affinity and nuclease resistance.

Regioselective synthesis of 2&prime;-O-modified nucleosides

Oligonucleotide and nucleotide amine analogs and methods of preparing and using these compounds are provided by the present invention.

Methods of synthesis and use

Novel compounds are constructed to include a central aromatic, aliphatic, or heterocyclic ring system. Attached to the central ring system are two linear groups having nitrogenous moieties that are derivatized with chemical functional groups. The ring system can include further nitrogenous moieties, either as ring atoms or on pendant groups attached to the ring, that may also be derivatized with chemical functional groups. The totality of the chemical functional groups imparts certain conformational and other properties to the these compounds. In accordance with certain embodiments of the invention, libraries of such compounds are prepared utilizing permutations and combinations of the chemical functional groups and the nitrogenous moieties to build complexity into the libraries.

Compounds having a plurality of nitrogenous substituents

Novel compounds having the formula: ##STR1## wherein the constituent variables are defined herein. The compounds are constructed to include a central aromatic, aliphatic, or heterocyclic ring system. Attached to the central ring system are two linear groups having nitrogenous moieties that are derivatized with chemical functional groups. The ring system can include further nitrogenous moieties, either as ring atoms or on pendant groups attached to the ring, that may also be derivatized with chemical functional groups. The totality of the chemical functional groups imparts certain conformational and other properties to the these compounds. In accordance with certain embodiments of the invention, libraries of such compounds are prepared utilizing permutations and combinations of the chemical functional groups and the nitrogenous moieties to build complexity into the libraries.

Substituted heterocyclic compounds

This invention relates to compounds based on the 3-deazapurines ring system and to methods for making such compounds. The invention also generally relates to the field of 'antisense' agents, agents that are capable of specific hybridization with a nucleotide sequence of an RNA. The 3-deazapurine-containing compounds of this invention can be useful for modulating the activity of RNA when incorporated into oligonucleotides. Oligonucleotides and their analogs are used for a variety of therapeutic and diagnostic purposes, such as treating diseases, regulating gene expression in experimental systems, assaying for RNA and for RNA products through the employment of antisense interactions with such RNA, diagnosing diseases, modulating the production of proteins and cleaving RNA in site specific fashions.

Synthesis of 3-deazapurines

Amines and methods of making and using the same

This invention relates to compounds based on the 3-deazapurines ring system and to methods for making such compounds. The invention also generally relates to the field of 'antisense' agents, agents that are capable of specific hybridization with a nucleotide sequence of an RNA. The 3- deazapurine-containing compounds of this invention can be useful for modulating the activity of RNA when incorporated into oligonucleotides. Oligonucleotides and their analogs are used for a variety of therapeutic and diagnostic purposes, such as treating diseases, regulating gene expression in experimental systems, assaying for RNA and for RNA products through the employment of antisense interactions with such RNA, diagnosing diseases, modulating the production of proteins and cleaving RNA in site specific fashions.

3-deazapurines

This invention presents novel purine-based compounds for inclusion into oligonucleotides. The compounds of the invention, when incorporated into oligonucleotides are especially useful as agents that are capable of specific hybridization with a nucleotide sequence of an RNA. Oligonucleotides are used for a variety of purposes, such as regulating gene expression in experimental systems, assaying for RNA and for RNA products through the employment of interactions with such RNA, diagnosing diseases, modulating the production of proteins, and cleaving RNA in site specific fashions. The compounds of the invention include novel heterocyclic bases, nucleosides, and nucleotides. When incorporated into oligonucleotides, the compounds of the invention can be useful for modulating the activity of RNA.

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San Marcos, CA, United States of America

P Dan Cook