Polymeric nucleoside prodrugs

• US 20040132684A1
• Filed: 12/17/2003
• Published: 07/08/2004
• Est. Priority Date: 05/09/2000
• Status: Abandoned Application

• Current Assignee: Joseph A. Toce, Sourena Nadji, Umashanker Sampath
• Original Assignee: Joseph A. Toce, Sourena Nadji, Umashanker Sampath
• Inventors: Sampath, Umashanker, Nadji, Sourena, Toce, Joseph A.
• Application Number:
  US10/739,965
• Publication Number:
  US 20040132684A1
• Time in Patent Office: Days
• US Class Current: 514/44
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07F 9/65515 the oxygen atom being part of a five-membered ring
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical

Abstract

Disclosed are polymeric compounds which are useful as prodrugs, comprising a chain of monomeric nucleosides, nucleoside analogs or abasic nucleosides, wherein at least one of the nucleosides or nucleoside analogs or a heterocyclic derivative thereof is pharmaceutically active and the nucleosides, nucleoside analogs or abasic nucleosides are linked by a phosphodiester group, a phosphorothioate group or an H—, alkyl or alkenyl phosphonate group.

Claims

1. A heteropolymeric compound comprising a chain of monomeric nucleosides, nucleoside analogs, abasic nucleosides, or heterocyclic derivatives thereof, wherein each of said nucleosides, nucleoside analogs, abasic nucleosides, or heterocyclic derivatives thereof is pharmaceutically active and said nucleosides, nucleoside analogs, abasic nucleosides or heterocyclic derivatives thereof are linked by a phosphodiester group comprising a 3′

or 5′

terminal moiety, phosphorothioate group, or H—

, alkyl or alkenyl phosphonate group.

2. The compound of claim 1, wherein said nucleosides are selected from the group consisting of adenosine, 5-azacytidine, cladribine, cytarabine, doxifluridine, enocitabine, floxuridine, fludarabine, gemcitabine, pentostatin, brivudine, edoxudine, fiacitabine, fialuridine, ibacitabine, idoxuridine, ribavirin, trifluridine and vidarabine.

3. The compound of claim 1, wherein said nucleoside analogs are carbacylic analogs or L-nucleosides.

4. The compound of claim 1, wherein said nucleoside analogs are selected from the group consisting of acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, cidofovir, adefovir, lobucavir and ribavirin.

5. The compound of claim 1, wherein said nucleobases are selected from the group consisting of mercaptopurine, thioguanine and azathioprine.

6. The compound of claim 1, wherein said chain comprises from 2 to 100 monomeric nucleoside, nucleoside analogs, abasic nucleosides or heterocyclic derivatives thereof.

7. The compound of claim 1, wherein at least one of said nucleosides, nucleoside analogs, abasic nucleosides or heterocyclic derivatives thereof are antiviral.

8. The compound of claim 1, wherein at least one of said nucleosides, nucleoside analogs, abasic nucleosides or heterocyclic derivatives thereof is pharmaceutically active against cancer.

9. The compound of claim 1, wherein at least one of said nucleosides, nucleoside analogs, abasic nucleosides or heterocyclic derivatives thereof are antimicrobial.

10. A method of treating a viral infection in a patient in need thereof, said method comprising administering an effective amount of a compound of claim 7.

11. A method of treating cancer in a patient in need thereof, said method comprising administering an effective amount of a compound of claim 8.

12. A method of treating a microbial infection in a patient in need thereof, said method comprising administering an effective amount of a compound of claim 9.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

14. A heteropolymeric compound of general formula (I)

15. The compound of claim 14, wherein R¹ is selected from the group consisting of

16. The compound of claim 14, wherein each R¹ is selected from the group consisting of nucleoside analogs.

17. The compound of claim 14, wherein said nucleoside analog is an acyclic, monocyclic or polycyclic moiety.

18. The compound of claim 14 wherein each R⁴ is O—

.

19. The compound of claim 14, wherein R¹ is independently selected from the group consisting of optionally substituted adenine, guanine, cytosine, uracil and thymine or a heterocyclic base derivative thereof.

20. The compound of claim 14, wherein each R¹ is independently selected from the group consisting of adenine, cytosine, 2,6-diaminopurine, 2-chloroadenine, 6-mercaptopurine, thioguanine, 5-Fluorouracil and 2-Fluoroadenine.

21. A compound of general formula II

22. The compound of claim 21, wherein R is —

OCH₂CH₂OCH₃.

26. The compound of claim 21, appended singly or as multimers or as groups of multimers to an oligonucleotide or analog at the 3′

-, 5′

- or at both termini.

23. A compound of general formula III

24. The compound of claim 23, wherein R is alkoxy.

25. The compound of claim 23, wherein R is —

OCH₂CH₂OCH₃.

27. The compound of claim 23, appended singly or as multimers or as groups of multimers to an oligonucleotide or analog at the 3′

-, 5′

- or at both termini

28. A compound of general formula (IV)

29. The compound of claim 28, wherein R is methyl or ethyl.

30. The compound of claim 29, wherein R is methyl.

31. The compounds of claim 28 wherein R is OCH₂CH₂OCH₃.