Details for Patent: 6,222,025
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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): | Cook; Phillip Dan (Escondido, CA), Sanghvi; Yogesh S. (Encinitas, CA), Sprankle; Kelly G. (Vista, CA), Ross; Bruce S. (Carlsbad, CA), Griffey; Rich H. (Vista, CA), Springer; Robert H. (Carlsbad, CA) |
Assignee: | Isis Pharmaceuticals, Inc. (Carlsbad, CA) |
Filing Date: | Jan 07, 1998 |
Application Number: | 08/894,899 |
Claims: | 1. An oligomeric compound comprising at least one monomeric sub-unit of structure I: ##STR10## wherein: X is amino; R is halo or C.sub.1 -C.sub.6 alkyl or substituted C.sub.1 -C.sub.6 alkyl wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; L is oxygen or sulfur; Z is fluoro or O--R.sub.1 X.sub.1, where R.sub.1 is C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.18 alkaryl and X.sub.1 is H, NH.sub.2 or imidazole; and one of Q.sub.1 and Q.sub.2 is attached via a phosphorus containing linking moiety to a nucleotide, or an oligonucleotide, and the other of said Q.sub.1 and Q.sub.2, 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: ##STR11## wherein: X is hydroxyl or amino; R is halo or C.sub.1 -C.sub.6 alkyl or substituted C.sub.1 -C.sub.6 alkyl wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; L is oxygen or sulfur; and one of Q.sub.1 and Q.sub.2 is attached via a phosphorus containing linking moiety to a nucleotide or an oligonucleotide, and the other of said Q.sub.1 and Q.sub.2, 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: ##STR12## wherein: X is hydroxyl; R is halo or C.sub.1 -C.sub.6 alkyl or substituted C.sub.1 -C.sub.6 alkyl wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; L is oxygen or sulfur; R.sub.1 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; X.sub.1 is H, NH.sub.2 or imidazole; and one of Q.sub.1 and Q.sub.2 is attached via a phosphorus containing linking moiety to a phosphorothioate oligonucleotide, and the other of said Q.sub.1 and Q.sub.2, 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: ##STR13## wherein: A is hydroxyl or amino; R is halo or C.sub.1 -C.sub.6 alkyl or substituted C.sub.1 -C.sub.6 alkyl wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; L is oxygen or sulfur; Z' is substituted C.sub.1 -C.sub.30 alkyl, substituted or unsubstituted C.sub.1 -C.sub.30 alkenyl, substituted or unsubstituted C.sub.1 -C.sub.30 alkynyl, substituted C.sub.6 -C.sub.14 aryl, or substituted C.sub.7 -C.sub.30 aralkyl, wherein said substitution is halo, amino, hydroxyl, thiol, ether or thioether; and one of Q.sub.1 and Q.sub.2 is attached via a phosphorus containing linking moiety to a nucleotide or oligonucleotide, and the other of said Q.sub.1 and Q.sub.2, 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 --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --CH.sub.3. 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. |