Process for the synthesis of 2′-O-substituted pyrimidines and oligomeric compounds therefrom
First Claim
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1. An oligomeric compound comprising at least one monomeric sub-unit of structure I:
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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.
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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.
117 Citations
33 Claims
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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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
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10. An oligomeric compound comprising at least one monomeric sub-unit of structure II:
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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. - View Dependent Claims (11, 12, 13, 14, 15, 16)
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17. An oligomeric compound comprising at least one monomeric sub-unit of structure III:
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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. - View Dependent Claims (18, 19, 20, 21, 22, 23)
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24. An oligomeric compound comprising at least one monomeric sub-unit of formula:
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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. - View Dependent Claims (25, 26, 27, 28, 29, 30, 31, 32, 33)
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Specification
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Current AssigneeISIS Pharmaceuticals Incorporated
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Original AssigneeISIS Pharmaceuticals Incorporated
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InventorsCook, Phillip Dan, Ross, Bruce S., Sprankle, Kelly G., Sanghvi, Yogesh S., Griffey, Rich H., Springer, Robert H.
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Primary Examiner(s)Riley, Jezia
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Application NumberUS08/894,899Time in Patent Office1,203 DaysField of Search435/6, 536/22.1, 536/23.1, 536/24.3, 536/25.3, 536/25.31, 536/25.32, 536/25.33, 536/26.1, 536/26.12, 536/26.22US Class Current536/23.1CPC Class CodesA61P 31/12 AntiviralsA61P 31/18 for HIVA61P 35/00 Antineoplastic agentsA61P 37/04 ImmunostimulantsC07H 19/06 Pyrimidine radicalsC07H 21/00 Compounds containing two or...Y02P 20/55 Design of synthesis routes,...Y02P 20/582 Recycling of unreacted star...
