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Last Updated: December 24, 2024

Claims for Patent: 6,222,025


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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): 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)
Application Number:08/894,899
Patent 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.

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