NARCISTATIN PRODRUGS

• US 20090082569A1
• Filed: 09/10/2008
• Published: 03/26/2009
• Est. Priority Date: 12/09/2002
• Status: Active Grant

• Current Assignee: Arizona Board of Regents (University of Arizona)
• Original Assignee: Arizona Board of Regents (University of Arizona)
• Inventors: Pettit, George R., Melody, Noeleen
• Granted Patent: US 7,994,320 B2
• Time in Patent Office: Days
• US Class Current: 546/23
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07F 9/65744 condensed with carbocyclic or heterocyclic rings or ring systems

Abstract

The present invention provides prodrugs derived from the sparingly soluble anticancer isocarbostyril narciclasine, a component of various Narcissus species, said prodrugs having potential for use against animal and human cancers. Also disclosed is an efficient procedure for the synthetic conversion of narciclasine to several more soluble cyclic phosphate compounds, including “narcistatin”.

Claims

1-4. -4. (canceled)

5. A method for synthesizing pyridinium narcistatin, comprising reacting:

narciclasine;

tetrabutylammonium dihydrogen phosphate;

dicyclohexylcarbodiimide; and

p-toluenesulfonic acid in pyridine,

to form a reaction mixture and forming pyridinium narcistatin.

6. The method of claim 5, further comprising heating the reaction mixture to cause precipitation of pyridinium narcistatin.

7. A method for synthesizing pyridinium narcistatin, comprising reacting

narciclasine;

tetrabutylammonium dihydrogen phosphate; and

dicyclohexylcarbodiimide in pyridine,

to form a reaction mixture and forming pyridinium narcistatin.

8. The method of claim 7, further comprising heating the reaction mixture to cause precipitation of pyridinium narcistatin.

9. A method for synthesizing a compound having the formula:

wherein Z is a H⁺ or a metal cation,

comprising reacting;

narciclasine;

tetrabutylammonium dihydrogen phosphate;

dicyclohexylcarbodiimide; and

p-toluenesulfonic acid in pyridine,

to form a reaction mixture and forming pyridinium narcistatin;

forming a solution of pyridinium narcistatin; and

passing the solution of pyridinium narcistatin through a cation exchange resin,

wherein the resin is a hydrogen form or bears a metal cation, to form the compound.

10. The method of claim 9, wherein Z is a metal cation selected from the group consisting of Li, Na, K or Cs.

11. The method of claim 10, wherein Z is Na.

12. A method for synthesizing a compound having the formula:

wherein Z is a metal cation,

comprising reacting;

narciclasine;

tetrabutylammonium dihydrogen phosphate;

dicyclohexylcarbodiimide; and

p-toluenesulfonic acid in pyridine,

to form a reaction mixture and forming pyridinium narcistatin;

suspending the pyridinium narcistatin in solvent; and

reacting with a metal acetate, to form the compound.

13. The method of claim 12, wherein the metal acetate is selected from the group consisting of acetates of Mg, Ca, Zn and Mn.

14. The method of claim 13, wherein the solvent in which the pyridinium narcistatin is suspended is comprised of methanol and water.

15. A method for synthesizing a compound having the formula:

wherein Z is an ammonium ion,

comprising reacting;

narciclasine;

tetrabutylammonium dihydrogen phosphate;

dicyclohexylcarbodiimide; and

p-toluenesulfonic acid in pyridine,

to form a reaction mixture and forming pyridinium narcistatin,

forming a solution of pyridinium narcistatin; and

reacting the pyridinium narcistatin with an amine, to form the compound.

16. The method of claim 15 wherein the amine reacted with the pyridinium narcistatin is selected from the group consisting of:

pyridine, quinidine, quinine, imidazole, morpholine and piperazine.