Sodium channel blockers

• US 8,350,076 B2
• Filed: 09/11/2008
• Issued: 01/08/2013
• Est. Priority Date: 04/18/2002
• Status: Active Grant

• Current Assignee: University of Virginia Patent Foundation (University of Virginia)
• Original Assignee: University of Virginia Patent Foundation (University of Virginia)
• Inventors: Brown, Milton L.
• Primary Examiner(s): OH, TAYLOR V
• Application Number:
  US12/209,065
• Publication Number:
  US 20090030056A1
• Time in Patent Office: 1,580 Days
• Field of Search: 560/39, 560/41, 562/405, 562/433, 562/489, 564/123
• US Class Current: 560/39
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/421 1,3-Oxazoles, e.g. pemoline, trimethadione
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 235/34 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 237/04 the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07D 233/74 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
• CPC Class Codes: C07D 233/76 with substituted hydrocarbon radicals attached to the third ring carbon atom
• CPC Class Codes: C07D 233/78 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 235/02 condensed with carbocyclic rings or ring systems

Abstract

The present invention is directed to novel phenyloin derivative compounds and the use of such compounds as sodium channel blockers. Such compositions have utility as anti-cancer agents and can be used to limit or prevent PCa growth and/or metastasis.

Claims

1. A sodium channel blocker represented by the structure:

2. The sodium channel blocker of claim 1, wherein R₂ is —

(CH₂)_nCONH₂ and R₃ is C₁-C₄ alkoxy;

R₂ is —

(CH₂)_nCONH—

C₁-C₄ alkyl and R₃ is hydroxyl;

or R₂ is —

(CH₂)_nCONH—

C₁-C₄ alkyl and R₃ is C₁-C₄ alkoxy.

3. The sodium channel blocker of claim 2, wherein R is selected from the group consisting of C₅-C₁₂ alkyl, C₂-C₈ alkenyl, and C₆-C₉ alkynyl.

4. The sodium channel blocker of claim 2, wherein R₄ and R₅ are independently selected from the group consisting of H, halo and C₁-C₄ alkyl;

and

R₆ is selected from the group consisting of H,

5. The sodium channel blocker of claim 4, wherein R₄ and R₆ are both H, and R₅ is Cl or F.

18. The sodium channel blocker of claim 1, wherein R is —

(CH₂)_nC₃-C₆ cycloalkyl.

6. A pharmaceutical composition comprising a compound represented by the formula:

9. The composition of claim 6, wherein R is selected from the group consisting of C₁-C₁₂ alkyl;

R₄ and R₅ are independently selected from the group consisting of H, halo and C₁-C₄ alkyl; and

R₆ is selected from the group consisting of H,

7. A pharmaceutical composition comprising a compound represented by the formula:

8. The composition of claim 7, wherein the anti-tumor agent is a chemotherapeutic.

10. A method of specifically inhibiting voltage-gated sodium channels, said method comprising the step of contacting said sodium channel with a compound represented by the structure:

11. The method of claim 10, wherein R is selected from the group consisting of C₁-C₁₂ alkyl;

R₄ and R₅ are independently selected from the group consisting of H, halo and C₁-C₄ alkyl; and

R₆ is selected from the group consisting of H,

12. A sodium channel blocker represented by the structure

13. The compound of claim 12, wherein R₄, R₅ and R₆ are independently H or halo.

14. A sodium channel blocker represented by the structure:

15. The sodium channel blocker of claim 14, wherein R is selected from the group consisting of C₅-C₆ alkyl and C₉-C₁₂ alkyl.

16. The sodium channel blocker of claim 14, wherein R is —

(CH₂)_nC₃-C₆ cycloalkyl.

17. The sodium channel blocker of claim 14, wherein R is selected from the group consisting of C₂-C₉ alkenyl, C_6-9 alkynyl, —

(CH₂)_mCOOH, —

(CH₂)_mNH₂, —

(CH₂)_mCONH₂, —

(CH₂)_nC₃-C₆ cycloalkyl, —

(CH₂)_naryl, and —

(CH₂)_pNCH₃(CH₂)_p, wherein m is an integer ranging from 3-8, each n is individually an integer ranging from 0-4 and p is an integer ranging from 1-4.