N4-acylcytosine-1,3-dioxolane nucleosides for treatment of viral infections
First Claim
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1. A compound of the formula:
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or a pharmaceutically acceptable salt thereof, whereini) R1 is chosen from hydrogen and halogen;
ii) R2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C6H4R6 where R6 is chosen from halogen, CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;
iii) R3 is chosen from halogen, CN, CF3, N3, NO2, alkyl, alkenyl, and alkynyl;
iv) R3′
is chosen from H, halogen, methyl, or ethyl; and
v) R4 is chosen from H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol.
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Abstract
The present invention is directed to a compound, method and composition of treating or preventing viral infections, in particular, human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections, in human patients or other animal hosts, comprising the administration of N4-acylcytosine-1,3-dioxolane and pharmaceutically acceptable salts, prodrugs, and other derivatives thereof.
9 Citations
43 Claims
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1. A compound of the formula:
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or a pharmaceutically acceptable salt thereof, wherein i) R1 is chosen from hydrogen and halogen;
ii) R2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C6H4R6 where R6 is chosen from halogen, CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;
iii) R3 is chosen from halogen, CN, CF3, N3, NO2, alkyl, alkenyl, and alkynyl;
iv) R3′
is chosen from H, halogen, methyl, or ethyl; and
v) R4 is chosen from H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol. - View Dependent Claims (2, 3, 22)
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4. A compound selected from the group consisting of β
- -D-N4-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β
-D-N4-p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane, β
-D-N4-p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane, β
-D-N4-p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane, β
-D-N4-p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane, and β
-D-N4-p-t-butylbenzoyl-5-fluoro-cytidine-1,3-dioxolane.
- -D-N4-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β
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5. A compound selected from the following, or its pharmaceutically acceptable salt:
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β
-D-5-fluoro-N4-(4-iodobenzoyl)cytidine-1,3-dioxolane of the structure;
β
-D-5-fluoro-N4-(4-fluorobenzoyl)cytidine-1,3-dioxolane of the structure;
β
-D-N4-(4-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;
β
-D-N4-(4-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;
β
-D-5-fluoro-N4-(3-fluorobenzoyl)cytidine-1,3-dioxolane of the structure;
β
-D-N4-(3-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;
β
-D-N4-(3-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;
β
-D-5-fluoro-N4-(4-nitrobenzoyl)cytidine-1,3-dioxolane of the structure;
β
-D-5-fluoro-N4-p-toluoylcytidine-1,3-dioxolane of the structure;
β
-D-5-fluoro-N4-(m-toluoyl)cylidine-1,3-dioxolane of the structure;
β
-D-N4-(4-ethylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;
β
-D-5-fluoro-N4-(4-propylbenzoyl)cytidine-1,3-dioxolane of the structure;
β
-D-N4-(4-tert-butylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;
β
-D-5-fluoro-N4-(2-thiophenecarbonyl)cytidine-1,3-dioxolane of the structure;
β
-D-N4-(benzo-[b]-thiophene-2-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure;
and β
-D-N4-(cyclohexane-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure;
- View Dependent Claims (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 31, 32, 33, 34)
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23. A pharmaceutical composition that includes an effective HIV or HBV treatment amount of a compound selected from the group consisting of β
- -D-N4-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β
-D-N4-p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane, β
-D-N4-p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane, β
-D-N4-p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane, β
-D-N4-p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane, and β
-D-N4-p-t-butylbenzoyl-5-fluoro-cytidine-1,3-dioxolane.
- -D-N4-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β
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24. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of the formula:
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or a pharmaceutically acceptable salt thereof, wherein iv) R1 is chosen from hydrogen and halogen;
v) R2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C6H4R6 where R6 is chosen from halogen, CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;
vi) R3 is chosen from H, halogen, CN, CF3, N3, NO2, alkyl, alkenyl, and alkynyl;
vii) R3′
is chosen from H, halogen, methyl, or ethyl; and
viii) R4 is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol, in a pharmaceutically acceptable carrier. - View Dependent Claims (28, 29)
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25. A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of the formula:
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or a pharmaceutically acceptable salt thereof, wherein ix) R1 is chosen from hydrogen and halogen;
x) R2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C6H4R6 where R6 is chosen from halogen, CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;
xi) R3 is chosen from H, halogen, CN, CF3, N3, NO2, alkyl, alkenyl, and alkynyl;
xii) R3′
is chosen from H, halogen, methyl, or ethyl; and
xiii) R4 is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol, in a pharmaceutically acceptable carrier.
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26. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of the formula:
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or a pharmaceutically acceptable salt thereof, wherein xiv) R1 is chosen from hydrogen and halogen;
xv) R2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C6H4R6 where R6 is chosen from halogen, CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;
xvi) R3 is chosen from H, halogen, CN, CF3, N3, NO2, alkyl, alkenyl, and alkynyl;
xvii) R3′
is chosen from H, halogen, methyl, or ethyl; and
xviii) R4 is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol, in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.
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27. A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of the formula:
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or a pharmaceutically acceptable salt thereof, wherein xix) R1 is chosen from hydrogen and halogen;
xx) R2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C6H4R6 where R6 is chosen from halogen, CN, CF3, N3, NO2, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;
xxi) R3 is chosen from H, halogen, CN, CF3, N3, NO2, alkyl, alkenyl, and alkynyl;
xxii) R3′
is chosen from H, halogen, methyl, or ethyl; and
xxiii) R4 is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol, in a pharmaceutically acceptable carrier in combination with another anti-HIV anti-HBV agent.
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30. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound selected from the group consisting of β
- -D-N4-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β
-D-N4-p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane, β
-D-N4-p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane, β
-D-N4-p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane, β
-D-N4-p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane, and β
-D-N4-p-t-butylbenzoyl-5-fluoro-cytidine-1,3-dioxolane.
- -D-N4-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β
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35. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of the formula:
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36. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound in a pharmaceutically acceptable carrier in combination with another anti-HBV agent, wherein the compound has the formula:
- 37. A compound of the formula:
Specification