Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer

• US 10,471,160 B2
• Filed: 07/18/2018
• Issued: 11/12/2019
• Est. Priority Date: 10/18/2013
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Deutsches Krebsforschungszentrum
• Inventors: Eder, Matthias, Kopka, Klaus, Schafer, Martin, Bauder-Wust, Ulrike, Haberkorn, Uwe, Eisenhut, Michael, Mier, Walter, Benesova, Martina, Kliem, Hans-Christian, Kratochwil, Clemens
• Primary Examiner(s): Hartley, Michael G.
• Assistant Examiner(s): Samala, Jagadishwar R
• Application Number:
  US16/038,729
• Publication Number:
  US 20190008988A1
• Time in Patent Office: 482 Days
• CPC Class Codes: A61K 51/0402 carboxylic acid carriers, fatty acids amino acids A61K51/0406
• CPC Class Codes: A61K 51/0482 chelates from cyclic ligands, e.g. DOTA
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07B 59/002 Heterocyclic compounds
• CPC Class Codes: C07D 257/02 not condensed with other rings
• CPC Class Codes: C07D 295/145 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings

Abstract

The present invention generally relates to the field of radiopharmaceuticals and their use in nuclear medicine as tracers, imaging agents and for the treatment of various disease states of prostate cancer. Thus, the present invention concerns compounds that are represented by the general Formulae (Ia) or (Ib).

Claims

1. A compound of Formula (Ia) or (Ib):

2. The compound of claim 1, wherein Chelator is a radical of:

1,4,7,10-tetraazacyclododecane-N,N′

,N″

,N′

″

-tetraacetic acid (DOTA);

N,N″

-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N″

-diacetic acid (HBED-CC);

1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA);

2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA);

2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA);

1,4,7-triazacyclononane phosphinic acid (TRAP);

1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO);

3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA);

N′

-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO);

diethylenetriaminepentaacetic acid (DTPA);

trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA);

1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A);

p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA);

1-(p-isothiocyanatobenzyI)-3-methyl-DTPA (1B3M);

2-(p-isothiocyanatobenzyI)-4-methyl-DTPA (1M3B);

or

1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).

4. A radiolabeled compound of claim 1.

5. A radiolabeled compound of claim 2.

6. A metal complex comprising a radionuclide and a compound of claim 1.

7. The metal complex of claim 6, wherein the radionuclide is selected from ⁸⁹Zr, ⁴⁴Sc, ¹¹¹In, ⁹⁰Y, ⁶⁸Ga, ¹⁷⁷Lu, ^99mTc, ⁶⁴Cu, ⁶⁷Cu, ¹⁵³Gd, ¹⁵⁵Gd, ¹⁵⁷Gd, ²¹³Bi, or ²²⁵Ac.

8. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, or ester thereof, and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising the metal complex of claim 6, or a pharmaceutically acceptable salt, or ester thereof, and a pharmaceutically acceptable carrier.

10. A method of imaging a region in a patient comprising:

administering to the patient a diagnostically effective amount of the metal complex of claim 6,

exposing the region of the patient to a scanning device, and obtaining an image of the region in the patient.

11. A method of diagnosing prostate cancer and/or metastasis thereof comprising:

administering to the patient a diagnostically effective amount of the metal complex of claim 6,

exposing the region of the patient to a scanning device, and

obtaining an image of the region in the patient,

wherein the image of a PSMA-expressing tumor indicates a diagnosis of prostate cancer and/or metastasis thereof.

12. A method of treating prostate cancer and/or metastasis thereof comprising administering to a patient in need thereof a therapeutically effective amount of the metal complex of claim 6, or a pharmaceutically acceptable salt or solvate of the complex.

13. A method of treating prostate cancer and/or metastasis thereof comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 9.

14. The method of claim 10 wherein the region of the patient is a head, thorax, spleen, kidney, or PSMA-expressing tumor tissue.

15. The method of claim 11 wherein the region of the patient is a head, thorax, spleen, kidney, or PSMA-expressing tumor tissue.

16. The method of claim 12 wherein the metastasis is in lung, liver, kidney, bone, brain, spinal cord, or bladder.

17. A metal complex comprising a radionuclide and a compound of claim 1.

18. The metal complex of claim 17, wherein the radionuclide is selected from ⁸⁹Zr, ⁴⁴Sc, ¹¹¹In, ⁹⁰Y, ⁶⁸Ga, ¹⁷⁷Lu, ^99mTc, ⁶⁴Cu, ⁶⁷Cu, ¹⁵³Gd, ¹⁵⁵Gd, ¹⁵⁷Gd, ²¹³Bi, or ²²⁵Ac.

19. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, or ester thereof, and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising the metal complex of claim 17, or a pharmaceutically acceptable salt, or ester thereof, and a pharmaceutically acceptable carrier.

21. A method of imaging a region in a patient comprising:

administering to the patient a diagnostically effective amount of the metal complex of claim 17,

exposing the region of the patient to a scanning device, and obtaining an image of the region in the patient.

22. A method of diagnosing prostate cancer and/or metastasis thereof comprising:

administering to the patient a diagnostically effective amount of the metal complex of claim 17,

exposing the region of the patient to a scanning device, and

obtaining an image of the region in the patient,

wherein the image of a PSMA-expressing tumor indicates a diagnosis of prostate cancer and/or metastasis thereof.

23. A method of treating prostate cancer and/or metastasis thereof comprising administering to a patient in need thereof a therapeutically effective amount of the metal complex of claim 17, or a pharmaceutically acceptable salt or solvate of the complex.

24. A method of treating prostate cancer and/or metastasis thereof comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 20.

25. The method of claim 21, wherein the region of the patient is a head, thorax, spleen, kidney, or PSMA-expressing tumor tissue.

26. The method of claim 22, wherein the region of the patient is a head, thorax, spleen, kidney, or PSMA-expressing tumor tissue.

27. The method of claim 23, wherein the metastasis is in lung, liver, kidney, bone, brain, spinal cord, or bladder.

3. A compound selected from the following:

28. An R′

-LINKER-R compound with R″

=radical of DOTA and R=radical of Glu-Urea-Lys, and having a structure of;