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Last Updated: March 28, 2024

Claims for Patent: 7,772,208


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Summary for Patent: 7,772,208
Title:2\',3\'-dideoxynucleoside analogues for the treatment or prevention of Flaviviridae infections
Abstract: A method for the treatment or prevention of Flaviviridae infections, in particular, hepatitis C virus infection, in a host, and in particular, a human, is provided that includes administering an effective amount of a .beta.-L- or .beta.-D-2\',3\'-dideoxynucleoside or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable diluent or excipient.
Inventor(s): Schinazi; Raymond (Atlanta, GA), Striker; Robert (Madison, WI), Shi; Junxing (Duluth, GA)
Assignee: Pharmasset, Inc. (Princeton, NJ) Leland Stanford Junior University (Palo Alto, CA) Emory University (Atlanta, GA)
Application Number:11/970,908
Patent Claims:1. A pharmaceutical composition for the treatment of an HCV infection in a host, comprising an effective treatment amount of a 2',3'-dideoxynucleoside of the formula: ##STR00009## or a pharmaceutically acceptable salt thereof, wherein (i) X is S.dbd.O, SO.sub.2, NR.sup.1, N.sup.+R.sup.1R.sup.2, CHF or CR.sup.3R.sup.4; R.sup.1 and R.sup.2 are independently C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or C.sub.3-8 cycloalkyl; R.sup.3 and R.sup.4 are independently hydrogen, halogen (F, Cl, Br, or I), OH or OR.sup.5, with the proviso that R.sup.3 and R.sup.4 are not both hydrogen; R.sup.5 is hydrogen, an alkyl, an acyl, or a silyl; (ii) Y is NH.sub.2, NHR.sup.6, NR.sup.6R.sup.7, OH or OR.sup.8 each R.sup.6, R.sup.7 and R.sup.7 is independently H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, cyclopropyl, or C.sub.2-6 acyl; (iii) Z is chosen from hydrogen, halogen (F, Cl, Br, or I), C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, CN, CF.sub.3, N.sub.3, NO.sub.2, aryl, heteroaryl and COR.sup.9; R.sup.9 is chosen from H, OH, SH, C.sub.1-6 alkyl, C.sub.1-6 aminoalkyl, C.sub.1-6 alkoxy and C.sub.1-6 thioalkyl; and (iv) R is phosphate; acyl; --C(O)R.sup.10, alkyl; sulfonate ester; sulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group; R.sup.10 is a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, monophosphate, diphosphate, triphosphate, or --P(O)(OR.sup.11).sub.2; each R.sup.11 is independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or a hydroxyl-protecting group; together with pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1, wherein Z is not hydrogen.

3. The pharmaceutical composition of claim 1, wherein Z is a halogen (F, Cl, Br, or I).

4. The pharmaceutical composition of claim 3, wherein Z is F.

5. The pharmaceutical composition of claim 1, wherein the 2',3'-dideoxynucleoside is in the .beta.-L-configuration.

6. The pharmaceutical composition of claim 5, wherein the .beta.-L-2',3'-dideoxynucleoside is enantiomerically enriched.

7. The pharmaceutical composition of claim 5, wherein the .beta.-L-2',3'-dideoxynucleoside is substantially free of the .beta.-D-2',3'-dideoxynucleoside.

8. The pharmaceutical composition of claim 5, wherein the .beta.-L-2',3'-dideoxynucleoside is in isolated form.

9. A pharmaceutical composition for the treatment of an HCV infection in a host, comprising an effective amount of a compound of the formula: ##STR00010## or a pharmaceutically acceptable salt, wherein Z' is CF.sub.3 or N.sub.3; together with a pharmaceutically acceptable carrier.

10. A pharmaceutical composition for the treatment of an HCV infection in a host, comprising an effective amount of a compound of the formula: ##STR00011## or a pharmaceutically acceptable salt thereof, wherein (i) R.sup.6 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, cyclopropyl, or C.sub.2-6 acyl; and (ii) R is hydrogen, phosphate, acyl, --C(O)R.sup.10, alkyl, sulfonate ester, sulfonyl, a lipid, an amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group; (iii) Z' is CF.sub.3 or N.sub.3; together with a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10, wherein the .beta.-L-2',3'-dideoxynucleoside is enantiomerically enriched.

12. The pharmaceutical composition of claim 10, wherein the .beta.-L-2',3'-dideoxynucleoside is substantially free of the .beta.-D-2',3'-dideoxynucleoside.

13. The pharmaceutical composition of claim 10, wherein the .beta.-L-2',3'-dideoxynucleoside is in an isolated form.

14. A pharmaceutical composition for reducing the biological activity of a Flaviviridae viral infection in a host comprising an effective amount of a 2',3'-dideoxynucleoside of the formula: ##STR00012## or a pharmaceutically acceptable salt thereof, wherein (i) X is S.dbd.O, SO.sub.2, NR.sup.1, N.sup.+R.sup.1R.sup.2, CHF or CR.sup.3R.sup.4; R.sup.1 and R.sup.2 are independently C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or C.sub.3-8 cycloalkyl; R.sup.3 and R.sup.4 are independently hydrogen, halogen (F, Cl, Br, or I), OH or OR.sup.5, with the proviso that R.sup.3 and R.sup.4 are not both hydrogen; R.sup.5 is hydrogen, an alkyl, an acyl, or a silyl; (ii) Y is NH.sub.2, NHR.sup.6, NR.sup.6R.sup.7, OH or OR.sup.8 each R.sup.6, R.sup.7 and R.sup.7 is independently H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, cyclopropyl, or C.sub.2-6 acyl; (iii) Z is chosen from hydrogen, halogen (F, Cl, Br, or I), C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, CN, CF.sub.3, N.sub.3, NO.sub.2, aryl, heteroaryl and COR.sup.9; R.sup.9 is chosen from H, OH, SH, C.sub.1-6 alkyl, C.sub.1-6 aminoalkyl, C.sub.1-6 alkoxy and C.sub.1-6 thioalkyl; and (iv) R is phosphate; acyl; --C(O)R.sup.10, alkyl; sulfonate ester; sulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group; R.sup.10 is a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, monophosphate, diphosphate, triphosphate, or --P(O)(OR.sup.11).sub.2; each R.sup.11 is independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or a hydroxyl-protecting group; together with a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14, wherein Z is not hydrogen.

16. The pharmaceutical composition of claim 14, wherein Z is a halogen (F, Cl, Br, or I).

17. The pharmaceutical composition of claim 16, wherein Z is F.

18. The pharmaceutical composition of claim 14, wherein the 2',3'-dideoxynucleoside is in the .beta.-L-configuration.

19. A pharmaceutical composition for reducing the biological activity of a Flaviviridae viral infection in a host comprising an effective amount of a compound of the formula: ##STR00013## or a pharmaceutically acceptable salt thereof, wherein Z' is CF.sub.3 or N.sub.3; together with a pharmaceutically acceptable carrier.

20. A pharmaceutical composition for reducing the biological activity of a Flaviviridae viral infection in a host comprising an effective amount of a compound of the formula: ##STR00014## or a pharmaceutically acceptable salt thereof, wherein (i) R.sup.6 is H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, cyclopropyl, or C.sub.2-6 acyl; and (ii) R is phosphate; acyl; --C(O)R.sup.10, alkyl; sulfonate ester; sulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group; (iii) Z' is CF.sub.3 or N.sub.3; together with a pharmaceutically acceptable carrier.

21. The pharmaceutical composition according to claim 14, wherein the Flaviviridae viral infection is an HCV infection.

22. The pharmaceutical composition according to claim 1, further comprising one or more other antiviral agent(s).

23. The pharmaceutical composition according to claim 22, wherein the antiviral agent is selected from the group consisting of ribavirin, interferon, PEGASYS (pegylated interferon alfa-2a), INFERGEN (interferon alfacon-1), OMNIFERON (natural interferon), ALBUFERON, REBIF (interferon beta-1a), Omega Interferon, Oral Interferon Alpha, Interferon gamma-1b, Interleukin-10, IP-501, Merimebodib VX-497, AMANTADINE (Symmetrel), HEPTAZYME, IDN-6556, XTL-002, HCV/MF59, CIVACIR, LEVOVIRIN, VIRAMIDINE, ZADAXIN (thymosin alfa-1), CEPLENE (histamine dihydrochloride), VX 950/LY 570310, ISIS 14803, IDN-6556 and JTK 003.

24. The pharmaceutical composition according to claim 1, wherein the host is a human.

25. The pharmaceutical composition according to claim 14, wherein the host is also infected with HIV and/or HBV.

26. The pharmaceutical composition according to claim 25, wherein the host is a human.

Details for Patent 7,772,208

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Biogen Inc. AVONEX interferon beta-1a For Injection 103628 05/17/1996 ⤷  Try a Trial 2022-08-01
Biogen Inc. AVONEX interferon beta-1a Injection 103628 05/28/2003 ⤷  Try a Trial 2022-08-01
Biogen Inc. AVONEX interferon beta-1a Injection 103628 02/27/2012 ⤷  Try a Trial 2022-08-01
Kadmon Pharmaceuticals Llc INFERGEN interferon alfacon-1 Injection 103663 10/06/1997 ⤷  Try a Trial 2022-08-01
Emd Serono, Inc. REBIF interferon beta-1a Injection 103780 03/07/2002 ⤷  Try a Trial 2022-08-01
Emd Serono, Inc. REBIF interferon beta-1a Injection 103780 12/17/2004 ⤷  Try a Trial 2022-08-01
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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