[5-carboxamido or 5-fluoro]-[2',3'-unsaturated or 3'-modified]-pyrimidine nucleosides

• US 20040167140A1
• Filed: 01/16/2004
• Published: 08/26/2004
• Est. Priority Date: 01/27/1995
• Status: Active Grant

• Current Assignee: Emory University
• Original Assignee: Emory University
• Inventors: Liotts, Dennis C., Schinazi, Raymond F.
• Granted Patent: US 7,419,966 B2
• Time in Patent Office: Days
• US Class Current: 514/269
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07H 19/06 Pyrimidine radicals

Abstract

A method and composition for the treatment of HIV and HBV infections in humans and other host animals is disclosed that includes the administration of an effective amount of a [5-carboxamido or 5-fluoro]-2′,3′-dideoxy-2′,3′-didehydro-pyrimidine nucleoside or a [5-carboxamido or 5-fluoro]-3′-modified-pyrimidine nucleoside, or a mixture or a pharmaceutically acceptable derivative thereof, including a 5′ or N⁴ alkylated or acylated derivative, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

Claims

1. A compound of the structure:

2. The compound of claim 1, wherein Y is O or S;

Z is O;

R₁ is H;

R₂ is H; and

R₃ is H.

3. The compound of claim 1, wherein X is O or S;

Y is O;

Z is O;

R₁ is H;

R₂ is H;

R₃ is H, and R₄ is independently H or F1.

4. The compound of claim 1 in the form of a racemic mixture.

5. The compound of claim 1 in the form of a β

-D-enantiomer.

6. The compound of claim 1 in the form of a β

-L-enantiomer.

7. The compound of claim 1 in enantiomerically enriched form.

8. The compound of claim 1 selected from the group consisting of the racemic mixture, β

-D- or β

-L-enantiomer of 2-hydroxymethyl-5-(N-5′

-carboxamidouracil-4′

-yl)-1,3-oxathiolane;

2-hydroxymethyl-4-(N-5′

-carboxamidouracil-1′

-yl)-1,3-dioxolane;

2-hydroxymethyl-4-(N-5′

-fluorocytosin-1′

-yl)-1,3-dithiolane;

2-hydroxymethyl-4-(N-5′

-carboxamidouracil-1′

-yl)-1,3-dithiolane;

2-hydroxymethyl-4-(N-5′

-fluorocytosin-1′

-yl)-1,3-oxathiolane;

2-hydroxymethyl-4-(N-5′

-carboxamidouracil-1′

-yl)-1,3-oxathiolane;

2′

,3′

-dideoxy-2′

,3′

-didehydro-5-fluorocytidine;

2′

,3′

-dideoxy-2′

,3′

-didehydro-5-carboxamidocytidine;

2′

,3′

-dideoxy-5-fluorocytidine;

2′

,3′

-dideoxy-5-carboxamidocytidine;

2′

,3′

-dideoxy-2′

,3′

-didehydro-2′

,5-difluorocytidine;

2′

,3′

-dideoxy-2′

,3′

-didehydro-2′

-fluoro-5-carboxamidocytidine, 2′

,3′

-dideoxy-2′

,3′

-didehydro-3′

,5-difluorocytidine;

2′

,3′

-dideoxy-2′

,3′

-didehydro-3′

-fluoro-5-carboxamidocytidine;

2′

,3′

-dideoxy-2′

,3′

-didehydro-2′

,3′

,5-trifluorocytidine;

2′

,3′

-dideoxy-2′

,3′

-didehydro-2′

,3′

-difluoro-5-carboxamidocytidine;

2′

,3′

-dideoxy-2′

,3′

-didehydro-5-fluorocytidine;

2′

,3′

-dideoxy-2′

,3′

-didehydro-5-carboxamidocytidine;

2′

,3′

-dideoxy-5-fluorocytidine;

2′

,3′

-dideoxy-5-carboxamidocytidin;

2′

,3′

-dideoxy-2′

,3′

-didehydro-2′

,5-difluorocytidine;

2′

,3′

-dideoxy-2′

,3′

-didehydro-2′

-fluoro-5-carboxamidocytidine;

2′

,3′

-dideoxy-2′

,3′

-didehydro-3′

,5-difluorouridine;

2′

,3′

-dideoxy-2′

,3′

-didehydro-3′

-fluoro-5-carboxamidouridine;

2′

,3′

-dideoxy-2′

,3′

-didehydro-2′

,3′

,5-trifluorouridine; and

2′

,3′

-dideoxy-2′

,3′

-didehydro-2′

,3′

-difluoro-5-carboxamidouridine.

9. The compound of claim 1 selected from the group consisting of the racemic mixture, the β

-L-enantiomer and the β

-D-enantiomer of 5-carboxylic acid amide-2′

,3′

-dideoxy-3′

-thiacytidine.

10. A composition comprising an effective HIV or HBV treatment amount of a compound of claim 1 in combination with a compound selected from the group consisting of the (−

)-enantiomer of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC);

the (−

)-enantiomer of 2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC);

carbovir, acyclovir, interferon, AZT, DDI, DDC, L-(−

)-FMAU, and D4T.

11. A pharmaceutical composition comprising an effective amount to treat HIV or HBV infection in humans of a compound of claim 1 in the racemic or enantiomerically enriched form, or its physiologically acceptable salt, in a pharmaceutically acceptable carrier.

12. A method for treating HIV infection in humans comprising administering an effective amount of a compound of claim 1 or its physiologically acceptable derivative or physiologically acceptable salt, in a pharmaceutically acceptable carrier.

13. A method for treating HBV infection in humans comprising administering an effective amount of a compound of claim 1 or its physiologically acceptable derivative or physiologically acceptable salt, in a pharmaceutically acceptable carrier.