Urea nucleosides as therapeutic and diagnostic agents
First Claim
1. A compound of the formula:
-
wherein;
X is independently selected from the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl, alkoxy, —
NR102, and —
C(O)C(R8)2CH(R8)NR1R2, and wherein at least one of X is —
C(O)C(R8)2CH(R8)NR1R2;
R1 and R2 are independently selected from the group consisting of H, C1-C18 alkyl, alkenyl or alkynyl, phenyl, aralkyl, alkaryl, an alkanoic acid, 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, hydrophobicity, or hydrogen bonding capacity of the compound;
R3, 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 esters, phosphoramidites, phosphorothionates, and phosphorodithionates;
R8 is independently selected from the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl, alkoxy, and —
C(O)—
R9, where R9 selected from the group consisting of H, alkyl, aryl, aralkyl, alkaryl and alkoxy;
R10 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, alkaryl and R9C(O);
the protected oxy-groups of R4 and R5 taken together can represent an isopropylidene group of the formula (—
OC(CH3)2O—
) or an orthoformate group of the formula (—
OCH(OR7)O—
); and
the protected oxy-groups of R5 and R6 taken together can represent a 3′
,-5′
-tetraalkyldisiloxane group (—
OSi(alkyl)2OSi(alkyl)2O—
).
1 Assignment
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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.
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Citations
10 Claims
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1. A compound of the formula:
-
wherein; X is independently selected from the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl, alkoxy, —
NR102, and —
C(O)C(R8)2CH(R8)NR1R2, and wherein at least one of X is —
C(O)C(R8)2CH(R8)NR1R2;
R1 and R2 are independently selected from the group consisting of H, C1-C18 alkyl, alkenyl or alkynyl, phenyl, aralkyl, alkaryl, an alkanoic acid, 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, hydrophobicity, or hydrogen bonding capacity of the compound;
R3, 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 esters, phosphoramidites, phosphorothionates, and phosphorodithionates;
R8 is independently selected from the group consisting of H, aryl, aralkyl, alkyl, alkaryl, alkenyl, alkynyl, alkoxy, and —
C(O)—
R9, where R9 selected from the group consisting of H, alkyl, aryl, aralkyl, alkaryl and alkoxy;
R10 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, alkaryl and R9C(O);
the protected oxy-groups of R4 and R5 taken together can represent an isopropylidene group of the formula (—
OC(CH3)2O—
) or an orthoformate group of the formula (—
OCH(OR7)O—
); and
the protected oxy-groups of R5 and R6 taken together can represent a 3′
,-5′
-tetraalkyldisiloxane group (—
OSi(alkyl)2OSi(alkyl)2O—
).- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10)
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Specification