Claims for Patent: 6,222,025

Summary for Patent: 6,222,025

Title:	Process for the synthesis of 2′-O-substituted pyrimidines and oligomeric compounds therefrom
Abstract:	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. Improved processes for the synthesis of 2'-O-substituted pyrimidine nucleosides are also 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.
Inventor(s):	Phillip Dan Cook, Yogesh S. Sanghvi, Kelly G. Sprankle, Bruce S. Ross, Rich H. Griffey, Robert H. Springer
Assignee:	Ionis Pharmaceuticals Inc
Application Number:	US08/894,899
Patent Claims:	1. An oligomeric compound comprising at least one monomeric sub-unit of structure I: wherein: X is amino; R is halo or C1-C6 alkyl or substituted C1-C6 alkyl wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; L is oxygen or sulfur; Z is fluoro or O—R1X1, where R1 is C1-C6 alkyl, C6-C10 aryl, C7-C18 alkaryl and X1 is H, NH2 or imidazole; and one of Q1 and Q2 is attached via a phosphorus containing linking moiety to a nucleotide, or an oligonucleotide, and the other of said Q1 and Q2, is a hydroxyl, a protected hydroxyl, an activated solid support, a nucleotide, an oligo-nucleotide, an activated phosphate, a phosphate, an activated phosphite, or a phosphite. 2. The oligomeric compound of claim 1, wherein L is O. 3. The oligomeric compound of claim 1, wherein Z is F. 4. The oligomeric compound of claim 1, comprising from 5 to 200 sub-units. 5. The oligomeric compound of claim 1, comprising from 5 to 50 sub-units. 6. The oligomeric compound of claim 1, comprising from 10 to 20 sub-units. 7. The oligomeric compound of claim 1, wherein said linking moiety comprises a phosphodiester, phosphotriester, hydrogen phosphonate, alkylphosphonate, alkylphosphonothioate, arylphosphonothioate, phosphorothioate, phosphorodithioate, or phosphoramidate. 8. The oligomeric compound of claim 1 having a plurality of monomeric sub-units of structure I. 9. The oligomeric compound of claim 8 wherein said monomeric sub-units are located at preselected positions. 10. An oligomeric compound comprising at least one monomeric sub-unit of structure II: wherein: X is hydroxyl or amino; R is halo or C1-C6 alkyl or substituted C1-C6 alkyl wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; L is oxygen or sulfur; and one of Q1 and Q2 is attached via a phosphorus containing linking moiety to a nucleotide or an oligonucleotide, and the other of said Q1 and Q2, is a hydroxyl, a protected hydroxyl, an activated solid support, a nucleotide, an oligonucleotide, an activated phosphate, a phosphate, an activated phosphite, or a phosphite. 11. The oligomeric compound of claim 10, wherein L is O. 12. The oligomeric compound of claim 10, comprising from 5 to 50 sub-units. 13. The oligomeric compound of claim 10, comprising from 10 to 20 sub-units. 14. The oligomeric compound of claim 10, wherein said linking moiety comprises a phosphodiester, phosphotriester, hydrogen phosphonate, alkylphosphonate, alkylphosphonothioate, arylphosphonothioate, phosphorothioate, phosphorodithioate, or phosphoramidate. 15. The oligomeric compound of claim 10 having a plurality of monomeric sub-units of structure II. 16. The oligomeric compound of claim 15 wherein said monomeric sub-units are located at preselected positions. 17. An oligomeric compound comprising at least one monomeric sub-unit of structure III: wherein: X is hydroxyl; R is halo or C1-C6 alkyl or substituted C1-C6 alkyl wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; L is oxygen or sulfur; R1 is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, 2-methylpropyl, 2-methyl-4-ethylbutyl, 2,4-diethylpropyl, 3-propylbutyl, 2,8-dibutyldecyl, 6,6-dimethyloctyl, 6-propyl-6-butyloctyl, 2-methylbutyl, 2-methylpentyl, 3-methylpentyl, 2-ethylhexyl, vinyl, allyl, crotyl, or propargyl; X1 is H, NH2 or imidazole; and one of Q1 and Q2 is attached via a phosphorus containing linking moiety to a phosphorothioate oligonucleotide, and the other of said Q1 and Q2, is a hydroxyl, a protected hydroxyl, an activated solid support, a nucleotide, an oligonucleotide, an activated phosphate, a phosphate, an activated phosphite, or a phosphite. 18. The oligomeric compound of claim 17, wherein L is O. 19. The oligomeric compound of claim 17, comprising from 5 to 50 sub-units. 20. The oligomeric compound of claim 17, comprising from 5 to 50 sub-units. 21. The oligomeric compound of claim 17, wherein said linking moiety comprises a phosphodiester, phosphotriester, hydrogen phosphonate, alkylphosphonate, alkylphosphonothioate, arylphosphonothioate, phosphorothioate, phosphorodithioate, or phosphoramidate. 22. The oligomeric compound of claim 17 having a plurality of monomeric sub-units of structure I. 23. The oligomeric compound of claim 21 wherein said monomeric sub-units are located at preselected positions. 24. An oligomeric compound comprising at least one monomeric sub-unit of formula: wherein: A is hydroxyl or amino; R is halo or C1-C6 alkyl or substituted C1-C6 alkyl wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; L is oxygen or sulfur; Z′ is substituted C1-C30 alkyl, substituted or unsubstituted C1-C30 alkenyl, substituted or unsubstituted C1-C30 alkynyl, substituted C6-C14 aryl, or substituted C7-C30 aralkyl, wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; and one of Q1 and Q2 is attached via a phosphorus containing linking moiety to a nucleotide or oligonucleotide, and the other of said Q1 and Q2, is a hydroxyl, a protected hydroxyl, an activated solid support, a nucleotide, an oligonucleotide, an activated phosphate, a phosphate, an activated phosphite, or a phosphite. 25. The oligomeric compound of claim 24, wherein L is O. 26. The oligomeric compound of claim 24, wherein Z is —(CH2)n—O—(CH2)m—CH3. 27. The oligomeric compound of claim 24, wherein n is 2 and m is 0. 28. The oligomeric compound of claim 24, comprising from 5 to 200 sub-units. 29. The oligomeric compound of claim 24, comprising from 5 to 50 sub-units. 30. The oligomeric compound of claim 24, comprising from 10 to 20 sub-units. 31. The oligomeric compound of claim 24, wherein said linking moiety comprises a phosphodiester, phosphotriester, hydrogen phosphonate, alkylphosphonate, alkylphosphonothioate, arylphosphonothioate, phosphorothioate, phosphorodithioate, or phosphoramidate. 32. The oligomeric compound of claim 24 having a plurality of monomeric sub-units of said formula. 33. The oligomeric compound of claim 24 wherein said monomeric sub-units are located at preselected positions.