Pyrimidine nucleosides as therapeutic and diagnostic agents
First Claim
1. A compound selected from the group consisting of ##STR12## wherein:
- X is independently selected from the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl, alkoxy, --NR102, and --C(O)CH(R8)C(R8)2 NR1 R, and wherein at least one of X is --C(O)CH(R8)C(R8)2 NR1 R;
R1 and R2 are independently selected from the group consisting of H, C1 -C18 alkyl, alkenyl or alkynyl, phenyl, aralkyl, alkaryl, an ester or amide derivative of an alkanoic acid, a peptide fragment, an HIV aspartyl protease inhibitor, a group that is cleaved intracellularly, and a group that increases the hydrophilicity or hydrophobicity of the compound;
R3 is H;
R4 and R5 are independently selected from the group consisting of H, --OH, protected oxy-, NH2, F, N3, --CN, --NC, --OAC, --Sac, --OBz and --OSiR73, wherein R7 is C1 -C4 alkyl or phenyl;
R6 is selected from the group consisting of --OH, protected oxy-, phosphate, diphosphate, triphosphate, phosphate ester, phosphoramidite, phosphorothionate and phosphorodithionate;
R9 is independently selected from the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl, alkoxy and --C(O)--R9, where R9 is selected form the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl and alkoxy;
R10 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, alkaryl, and R9 C(O);
the protected oxy- groups R4 and R5 taken together represent an isopropylidene group of the formula --OC(CH3)2 O-- or an orthoformate group of the formula --OCH(OR7)O--; and
the protected oxy- groups of the R4 and R5 taken together can represent a 3'"'"'-5'"'"'-tetraalkyldisiloxane group of the formula --OS(alkyl)2 OSi(alkyl)2 O--;
wherein said compound is optionally modified with a label selected from the group consisting of radiolabels and fluorescent labels.
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Accused Products
Abstract
Modified nucleosides and methods of making and using the nucleosides are disclosed. The compounds can be prepared by reacting nucleoside starting materials that contain a suitable leaving group at one or more of the carbon atoms in the purine or pyrimidine ring, with a vinylstannane, carbon monoxide, and a palladium catalyst to provide 1-ene-3-one intermediates. These intermediates are then reacted with suitably functionalized primary or secondary amines via a Michael reaction. When the intermediate is a 5-position modified pyrimidine ring, and the amine contains a second hydrogen, it can do a second Michael reaction with the ene-one or the ene-imine in the pyrimidine ring. Appropriate modification of the amine reactant can yield products with various bioactivities. The nucleosides can be used therapeutically as anti-cancer, anti-bacterial or anti-viral drugs. The nucleosides can also be used for diagnostic applications, for example, by incorporating a radiolabel or fluorescent label into the molecule. The nucleosides can be used to prepare oligonucleotides for use in various applications, either alone or in combination with other modified nucleosides and/or naturally occurring nucleosides.
22 Citations
10 Claims
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1. A compound selected from the group consisting of ##STR12## wherein:
- X is independently selected from the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl, alkoxy, --NR102, and --C(O)CH(R8)C(R8)2 NR1 R, and wherein at least one of X is --C(O)CH(R8)C(R8)2 NR1 R;
R1 and R2 are independently selected from the group consisting of H, C1 -C18 alkyl, alkenyl or alkynyl, phenyl, aralkyl, alkaryl, an ester or amide derivative of an alkanoic acid, a peptide fragment, an HIV aspartyl protease inhibitor, a group that is cleaved intracellularly, and a group that increases the hydrophilicity or hydrophobicity of the compound; R3 is H; R4 and R5 are independently selected from the group consisting of H, --OH, protected oxy-, NH2, F, N3, --CN, --NC, --OAC, --Sac, --OBz and --OSiR73, wherein R7 is C1 -C4 alkyl or phenyl; R6 is selected from the group consisting of --OH, protected oxy-, phosphate, diphosphate, triphosphate, phosphate ester, phosphoramidite, phosphorothionate and phosphorodithionate; R9 is independently selected from the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl, alkoxy and --C(O)--R9, where R9 is selected form the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl and alkoxy; R10 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, alkaryl, and R9 C(O); the protected oxy- groups R4 and R5 taken together represent an isopropylidene group of the formula --OC(CH3)2 O-- or an orthoformate group of the formula --OCH(OR7)O--; and the protected oxy- groups of the R4 and R5 taken together can represent a 3'"'"'-5'"'"'-tetraalkyldisiloxane group of the formula --OS(alkyl)2 OSi(alkyl)2 O--; wherein said compound is optionally modified with a label selected from the group consisting of radiolabels and fluorescent labels. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10)
- X is independently selected from the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl, alkoxy, --NR102, and --C(O)CH(R8)C(R8)2 NR1 R, and wherein at least one of X is --C(O)CH(R8)C(R8)2 NR1 R;
Specification
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- Resources
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Current AssigneeGilead Sciences Inc.
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Original AssigneeNeXstar Pharmaceuticals, Inc. (Gilead Sciences Inc.)
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InventorsEaton, Bruce, Kirschenheuter, Gary P.
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Primary Examiner(s)Wilson, James O.
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Application NumberUS08/622,772Time in Patent Office1,280 DaysField of Search536/28.1, 536/28.2, 536/28.3, 536/28.4, 536/28.5, 536/28.51, 536/28.52, 536/28.53, 536/28.54, 536/26.26, 536/28.55, 536/26.6, 536/26.8, 536/25.3 4US Class Current536/26.26CPC Class CodesC07H 11/02 Nitrates; NitritesC07H 19/06 Pyrimidine radicalsC07H 19/16 Purine radicals
