Nucleosides for imaging and treatment applications

• US 6,682,715 B2
• Filed: 08/30/2001
• Issued: 01/27/2004
• Est. Priority Date: 10/30/1997
• Status: Expired due to Fees

• Current Assignee: The United States of America As Represented By The Secretary of Agriculture
• Original Assignee: The United States of America As Represented By The Secretary of Agriculture
• Inventors: Anderson, Lawrence, Collins, Jerry M., Klecker, Raymond W., Katki, Aspandiar G.
• Primary Examiner(s): Riley, Jezia
• Application Number:
  US09/941,721
• Publication Number:
  US 20030049201A1
• Time in Patent Office: 880 Days
• Field of Search: 514/1, 514/44, 536/25.3, 424/1.11
• US Class Current: 424/1.11
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• 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

Abstract

Methods of diagnosing and/or of treating tumors by administering a nucleoside analog which is activated by thymidylate synthase and/or thymidine kinase enzyme into a diagnostic or toxic metabolite, and uridine analog compounds, and compositions of same having a pharmaceutically acceptable carrier. For diagnostic applications, compounds containing a label and methods of use of such compounds are described.

Claims

1. A method of treating tumors or cancer, comprising:

administering a uridine analogue selected by a method comprising the steps of;

providing a uridine analogue unsubstituted in the 5-position;

testing said uridine analog for activation by thymidylate synthase; and

selecting said uridine analog when found to be activated by thymidylate synthase;

in an effective amount to reduce or inhibit replication or spread of tumor or cancer cells.

6. The method of claim 1, wherein the uridine analogue is selected form the group consisting of FAU, d-Urd and ara-U.

7. The method of claim 1, wherein the uridine analogue is administered to a human or animal in a tumor-inhibiting amount.

8. The method of claim 1, wherein said uridine analogue is administered in combination with other pharmaceutical agents and/or other drugs used to inhibit tumor growth.

9. The method of claim 1, wherein the uridine analogue is of the following general formula:

wherein;

A=N, C;

B=H, hydroxy, halogen, acyl (C₁-C₆), alkyl, C₁-C₆),alkoxy (C₁-C₆)

D=O, S, NH₂; and

G=substituted or unsubstituted cyclic sugar, substituted or unsubstituted acyclic sugar, substituted or unsubstituted mono, di, or tri-phospho-cyclic-sugar phosphate;

substituted or unsubstituted mono, di, or tri-phospho-acyclic-sugar phosphate;

substituted or unsubstituted mono, di, or tri-phospho-cyclic sugar analogues, substituted or unsubstituted mono, di, or tri-phospho-acyclic sugar analogues wherein the substituents are alkyl (C₁-C₆) alkoxy (C₁ to C₆), halogen.

2. A method of alleviating cytopathic effects associated with tumors, comprising administering to an afflicted patient an effective amount of a uridine analogue selected by a method comprising the steps of:

providing a uridine analogue unsubstituted in the 5-position;

testing said uridine analog for activation by thymidylate synthase; and

selecting said uridine analog when found to be activated by thymidylate synthase;

such that said cytopathic effects are alleviated.

10. The method of claim 2, wherein the uridine analogue is of the following general formula:

wherein;

A=N, C;

B=H, hydroxy, halogen, acyl (C₁-C₆), alkyl, C₁-C₆),alkoxy (C₁-C₆)

D=O, S, NH₂; and

G=substituted or unsubstituted cyclic sugar, substituted or unsubstituted acyclic sugar, substituted or unsubstituted mono, di, or tri-phospho-cyclic-sugar phosphate;

substituted or unsubstituted mono, di, or tri-phospho-acyclic-sugar phosphate;

substituted or unsubstituted mono, di, or tri-phospho-cyclic sugar analogues, substituted or unsubstituted mono, di, or tri-phospho-acyclic sugar analogues wherein the substituents are alkyl (C₁-C₆) alkoxy (C₁ to C₆), halogen.

11. The method of claim 2, wherein the uridine analogue is selected form the group FAU, d-Urd and ara-U.

3. A composition for reducing or inhibiting the replication or spread of tumor cells, comprising:

a uridine analogue selected by a method comprising the steps of;

providing a uridine analogue unsubstituted in the 5-position;

testing said uridine analog for activation by thymidylate synthase; and

selecting said uridine analog when found to be activated by thymidylate synthase;

and a pharmaceutically acceptable carrier.

4. A method of treating cancer comprising:

administering to a cancer patient a therapeutically effective amount of a composition according to claim 3.

5. The composition of claim 3, wherein the uridine analogue is of the following general formula:

wherein;

A=N, C;

B=H, hydroxy, halogen, acyl (C₁-C₆), alkyl, C₁-C₆), alkoxy (C₁-C₆)

D=O, S, NH₂; and

G=substituted or unsubstituted cyclic sugar, substituted or unsubstituted acyclic sugar, substituted or unsubstituted mono, di, or tri-phospho-cyclic-sugar phosphate;

substituted or unsubstituted mono, di, or tri-phospho-acyclic-sugar phosphate;

substituted or unsubstituted mono, di, or tri-phospho-cyclic sugar analogues, substituted or unsubstituted mono, di, or tri-phospho-acyclic sugar analogues wherein the substituents are alkyl (C₁-C₆) alkoxy (C₁ to C₆), halogen.

12. A method of treating cancer, comprising:

administering a uridine analog in an amount effective to inhibit the replication or spread of cancer cells, said uridine analog selected by a method comprising the steps of;

providing a uridine analogue unsubstituted in the 5-position;

testing said uridine analog for activation by thymidylate synthase; and

selecting said uridine analog when found to be activated by thymidylate synthase.