Granted Patent B2

US 10,471,160 · App. 16/038,729 · Granted Nov 12, 2019

Inventors: Matthias Eder (Mannheim, DE); Klaus Kopka (Dossenheim, DE); Martin Schäfer (Neckarsteinach, DE); Ulrike Bauder-Wüst (Schriesheim, DE); Uwe Haberkorn (Schwetzingen, DE); Michael Eisenhut (Heidelberg, DE); Walter Mier (Bensheim, DE); Martina Benesova (Heidelberg, DE); Hans-Christian Kliem (Heppenheim, DE); Clemens Kratochwil (Hirschberg a.d.B, DE)

Assignees: DEUTSCHES KREBSFORSCHUNGSZENTRUM; RUPRECHT-KARLS-UNIVERSITÄT HEIDELBERG

A61K51/0482C07B59/002C07D257/02C07D295/145

Abstract

Claims (63)

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

wherein:

n is chosen from 0 or 1;

m is chosen from 1, 2, 3, or 4;

X is chosen from Naphthyl, Phenyl, Biphenyl, Indolyl (=2,3-benzopyrrolyl), or Benzothiazolyl;

Y is chosen from Aryl, Alkylaryl, Cyclopentyl, Cyclohexyl, or Cycloheptyl; and

Z is independently chosen from —CO 2 H, —SO 2 H, —SO 3 H, —SO 4 H, —PO 2 H, —PO 3 H, or —PO 4 H 2 , with the proviso that the compound is not

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).

3. A compound selected from the following:

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 89 Zr, 44 Sc, 111 In, 90 Y, 68 Ga, 177 Lu, 99m Tc, 64 Cu, 67 Cu, 153 Gd, 155 Gd, 157 Gd, 213 Bi, or 225 Ac.

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 89 Zr, 44 Sc, 111 In, 90 Y, 68 Ga, 177 Lu, 99m Tc, 64 Cu, 67 Cu, 153 Gd, 155 Gd, 157 Gd, 213 Bi, or 225 Ac.

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.

28. An R′-LINKER-R compound with R″=radical of DOTA and R=radical of Glu-Urea-Lys, and having a structure of:

wherein the R′-LINKER-R compound is selected from:

Assignments (11)

Priority Claims (2)

Continuity (3)

Cited By (6)

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