PROCESS FOR PRODUCTION OF HETERODIMERS OF GLUTAMIC ACID

• US 20110008253A1
• Filed: 06/15/2010
• Published: 01/13/2011
• Est. Priority Date: 06/15/2009
• Status: Active Grant

• Current Assignee: Molecular Insight Pharmaceuticals Incorporated (Lantheus Holdings, Inc.)
• Original Assignee: Molecular Insight Pharmaceuticals Incorporated (Lantheus Holdings, Inc.)
• Inventors: Maresca, Kevin P., Babich, John W., Zimmerman, Craig
• Granted Patent: US 8,465,725 B2
• Time in Patent Office: Days
• US Class Current: 424/1.85
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 59/001 Acyclic or carbocyclic compounds
• CPC Class Codes: C07C 273/1854 by reactions not involving the formation of the N-C(O)-N- moiety
• CPC Class Codes: C07C 275/16 being further substituted by carboxyl groups
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 275/30 being further substituted by halogen atoms, or by nitro or nitroso groups
• CPC Class Codes: C07C 303/40 by reactions not involving the formation of sulfonamide groups
• CPC Class Codes: C07C 311/19 to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07F 7/2208 Compounds having tin linked only to carbon, hydrogen and/or halogen

Abstract

A manufacturing process for the preparation of radiolabeled compounds of formula (I)

includes reacting compounds of formula (II) with a source of readionuclide of a halogen in the presence of an oxidant under acidic condition,

• • wherein:
    • *I is ¹²³I, ¹²⁴I, ¹²⁵I or ¹³¹I;
    • R is lower alkyl, optionally substituted with one or more fluorine atoms;
    • Q is C(O), O, NR′, S, S(O)₂, C(O)₂, (CH₂)_p;
    • Y is C(O), O, NR′, S, S(O)₂, C(O)₂, (CH₂)_p;
    • R′ is H, C(O), S(O)₂, C(O)₂;
    • Z is H, C₁-C₄ alkyl, benzyl, substituted benzyl or trialkylsilyl;
    • m is 0, 1, 2, 3, 4 or 5;
    • n is 0, 1, 2, 3, 4, 5 or 6; and
    • p is 0, 1, 2, 3, 4, 5 or 6.

Claims

1. A process for the preparation of a radiolabeled compound of formula (I)

2. The process of claim 1, wherein the acidic conditions comprise a pH of less than about 3.

3. The process of claim 1, wherein R is methyl.

4. The process of claim 1, wherein the metal salt of *I is a Group IA metal salt of *I wherein *I is ¹²³I, ¹²⁴I, ¹²⁵I or ¹³¹I.

5. The process of claim 4, wherein the metal salt is a sodium salt.

6. The process of claim 1, wherein the oxidant comprises a peracid.

7. The process of claim 1, wherein the reacting comprises adding an acid to the compound of formula (II) and metal salt of *I, prior to adding the oxidant.

8. The process of claim 7, wherein the acid comprises a mineral acid or an organic acid.

9. The process of claim 8, wherein the mineral acid is a non-halogen bearing or releasing acid.

10. The process of claim 8, wherein the acid comprises phosphoric acid, sulfuric acid or acetic acid.

11. The process of claim 8, wherein an amount of the acid is sufficient to maintain a pH of from 1 to 3.

12. The process of claim 1 further comprising reacting a low concentration of a cold metal iodide with the compound of formula (II), the metal salt of *I, and the oxidant.

13. The process of claim 12, wherein the low concentration is from 0.1 to 10 μ

g of cold metal iodide per 50 mCi of the metal salt of *I.

14. The process of claim 13, wherein the cold metal iodide is Na¹²⁷I.

15. The process of claim 1, wherein the compound of formula (I) is:

16. The process of claim 15, wherein Z is tert-butyl.

17. The process of claim 1, wherein the compound of formula (I) is

24. The process of claim 1 further comprising chromatographically purifying the radiolabeled compound of the formula (I).

25. The process of claim 24 further comprising adding 2-3% sodium gentisate and 5-6% ascorbate/asorbic acid at a pH of from 4.5 to 5.5 to stabilize the radiolabeled compound represented by formula (I).

18. A compound of formula (II),

19. The compound of claim 18, wherein the compound of formula (II) is

20. The compound of claim 18, wherein the compound of formula (II) is

21. The compound of claim 18, wherein the compound of formula (II) is

22. The compound of claim 18, wherein the compound of formula (II) is

23. The compound of claim 18, wherein the compound of formula (II) is

26. A stable composition comprising a radiolabeled compound of the formula (I)

27. The stable composition of claim 26, wherein the pharmaceutically acceptable excipients comprise an ascorbate/asorbic acid and a stabilizing amount of a gentisate stabilizer selected from gentisic acid and soluble, pharmaceutically acceptable salts thereof.