Pyrido[2,3-d]pyrimidine and pyrimido[4,5-d]pyrimidine nucleosides

• US 20030144502A1
• Filed: 12/31/2002
• Published: 07/31/2003
• Est. Priority Date: 07/06/2000
• Status: Active Grant

• Current Assignee: Mdrna Inc. (Adhera Therapeutics, Inc.)
• Original Assignee: Valeant Research & Development (Bausch Health Cos., Inc.)
• Inventors: Girardet, Jean-Luc, Hong, Zhi, Gunic, Esmir, Lau, Johnson, Pietrzkowski, Zbigniew, Wang, Guangyi
• Granted Patent: US 7,081,449 B2
• Time in Patent Office: Days
• US Class Current: 536/27.13
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Abstract

A purine nucleoside analog includes a pyrido[2,3-d]pyrimidine or a pyrimido[4,5-d]pyrimidine and further has a sugar moiety that is optionally modified at the C2′, C3′, C4′ and/or C5′ position. Particularly contemplated compounds also include prodrug forms of the purine nucleoside analogs, and both purine nucleoside analogs and the corresponding prodrugs are employed in the reduction of growth of neoplastic cells.

Claims

1. A nucleoside analog according to the formula (I)

2. The nucleoside analog of claim 1 wherein A is O, and B is a heterocyclic radical according to formula (II).

3. The nucleoside analog of claim 2 wherein X is NH₂, Z₁ is O, and Z₂ and Z₃ are CH.

4. The nucleoside analog of claim 3 wherein R₄ and R₅′

are hydrogen, and R₅ is OH.

5. The nucleoside analog of claim 1 having a structure according to formula (VI)

6. A prodrug comprising the nucleoside analog of claim 5.

7. The prodrug of claim 6 wherein the prodrug comprises a phosphate or phosphonate covalently coupled to the C₅ atom of the ribose.

8. The prodrug of claim 6 wherein the prodrug comprises a moiety that is covalently bound to at least one of the hydroxyl groups of the ribose, and that is cleaved from the at least one hydroxyl groups within a target cell.

9. The prodrug of claim 6 wherein the prodrug comprises a moiety that is covalently bound to the amino group of the base, and that is cleaved from the amino group within a target cell.

10. A method of inhibiting growth of a neoplastic cell comprising:

providing a compound according to claim 1;

and

presenting the compound to the cell in a dosage effective to inhibit the growth of a cell.

11. The method of claim 10 wherein A is O, and B is a heterocyclic radical according to formula (II).

12. The method of claim 11 wherein X is NH₂, Z₁ is O, and Z₂ and Z₃ are CH.

13. The method of claim 12 wherein R₄ and R₅′

are hydrogen, and R₅ is OH.

14. The method of claim 10 wherein the compound has a structure according to formula (VI)

15. The method of claim 14 wherein the compound comprises a phosphate or phosphonate covalently coupled to the C₅ atom of the ribose.

16. The method of claim 14 wherein the compound comprises a moiety that is covalently bound to at least one of the hydroxyl groups of the ribose, and that is cleaved from the at least one hydroxyl groups within a target cell.

17. The method of claim 14 wherein the compound comprises a moiety that is covalently bound to the amino group of the base, and that is cleaved from the amino group within a target cell.

18. The method of claim 14 wherein the neoplastic cell is a cell selected from the group consisting of a colon cancer cell, a breast cancer cell, a melanoma cell, a glioma cell, and a prostate cancer cell.

19. The method of claim 14 wherein the inhibition of the growth of the cell comprises apoptosis.

20. The method of claim 19 wherein the apoptosis is triggered at least in part by MEK-phosphorylation.

21. The method of claim 14 wherein the inhibition of the growth of the cell comprises inhibition of at least one of RNA polymerase I, RNA polymerase II, and RNA polymerase III.