Granted Patent B2

US 12,447,217 · App. 18/474,209 · Granted Oct 21, 2025

Inventors: Leila Jaafar-Thiel (Erlangen, DE); Melpomeni Fani (Basel, CH); Jacopo Millul (Basel, CH); Francesco De Rose (Munich, DE)

Assignees: Nuclidium AG; University of Basel

A61K51/0482C07F1/08A61K2121/00A61K2123/00

Abstract

Claims (76)

1. A compound, wherein the compound is of Formula I:

wherein:

R 1 is R a ;

R 2 and R 3 are each R a or together form a C 2-9 heterocycle with the nitrogen atoms to which they are attached;

R 4 is -L-T;

R a , independently for each occurrence, is selected from H, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 2-9 heterocyclyl, or C 5-9 heteroaryl, wherein each C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 2-9 heterocyclyl, or C 5-9 heteroaryl is optionally substituted by one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH 2 , —NHR′, —N(R′) 2, —NHCOR′, —NR′COR′, halogen, —CN, —CO 2 H, —CO 2 R′, —CHO, —COR′, —CONH 2 , —CONHR′, —CON(R′) 2 , —NO 2 , —OP(O) (OH) 2 , —SO 3 H, —SO 3 R′, —SOR′, and —SO 2 R′, wherein R′, independently for each occurrence, is C 1-10 alkyl or C 3-10 cycloalkyl;

L is a bond or a divalent linker,

T comprises (a) a chelating moiety suitable for chelating a radionuclide, (b) an imaging agent, or (c) a drug;

n is an integer from 1 to 20; and

m is an integer from 1 to 20;

or is a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 is methyl or H.

3. The compound of claim 1 , wherein R 2 is H and R 3 is H.

4. The compound of claim 1 , wherein R 2 and R 3 together form a C 2-9 heterocycle with the nitrogen atoms to which they are attached.

5. The compound of claim 4 , wherein the C 2-9 heterocycle is a 6-membered heterocycle selected from a piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane.

6. The compound of claim 1 , wherein L is a divalent linker selected from an acid-labile linker, a hydrolysis-labile linker, an enzymatically cleavable linker, a reduction labile linker, a self-immolative linker, and a non-cleavable linker.

7. The compound of claim 1 , wherein T comprises a chelating moiety suitable for chelating a radionuclide.

8. The compound of claim 7 , wherein the chelating moiety is chelated to a radionuclide, and the radionuclide is selected from alpha radiation emitting isotopes, beta radiation emitting isotopes, gamma radiation emitting isotopes, Auger electron emitting isotopes, X-ray emitting isotopes, and fluorescence emitting isotopes.

9. The compound of claim 7 , wherein the radionuclide is selected from 225 Ac, 51 Cr, 66 Ga, 67 Ga, 68 Ga, [ 18 F]AlF, 111 In, 113m In, 52m Min, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 179 Yb, 153 Sm, 177m Sn, 166 Ho, 86 Y, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 52 Fe, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 142 Pr, 157 Gd, 159 Gd, 212 Bi, 213 Bi, 72 As, 77 As, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 197 Hg, 151 Eu, 153 Eu, 169 Eu, 201 Tl, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 203 Pb, 212 Pb, 151 Pm, 153 Pm, 142 Pr, 143 Pr, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 62 Zn, 188 Re, 198 Au, 199 Au, 227 Th, 111 Ag, 199 Ag, 211 At, 223 Ra, 88 Zr, and 89 Zr.

10. The compound of claim 9 , wherein the radionuclide is selected from 61 Cu, 64 Cu, and 67 Cu.

11. The compound of claim 7 , wherein the chelating moiety is selected from DOTAGA (1,4,7,10-tetraazacyclododececane, 1-(glutaric acid)-4,7,10-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTASA (1,4,7,10-tetraazacyclododecane-1-(2-succinic acid)-4,7,10-triacetic acid), CB-DO2A (10-bis (carboxymethyl)-1,4,7, 10-tetraazabicyclo [5.5.2] tetradecane), DEPA (7-[2-(Bis-carboxymethylamino)-ethyl]-4,10-bis-carboxymethyl-1,4,7, 10-tetraaza-cyclododec-1-yl-acetic acid)), 3p-C-DEPA (2-[(carboxymethyl)] [5-(4-nitrophenyl-1-[4,7,10-tris (carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl] pentan-2-yl) amino] acetic acid)), TCMC (2-(4-isothiocyanotobenzyl)-1,4,7, 10-tetraaza-1,4,7,10-tetra-(2-carbamonyl methyl)-cyclododecane), oxo-DO3A (1-oxa-4,7,10-triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid), p-NH 2 -Bn-Oxo-DO3A (1-Oxa-4,7,10-tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid), TE2A ((1,8-N,N′-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane), MM-TE2A, DM-TE2A, CB-TE2A (4,11-bis (carboxymethyl)-1,4,8,11-tetraazabicyclo [6.6.2] hexadecane), CB-TE1A1P (4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid), CB-TE2P (1,4,8,11-tetraazacyclotetradecane-1,8-bis (methanephosphonic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8, 11-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N′,N″-triacetic acid), NODA (1,4,7-triazacyclononane-1,4-diacetate), NODAGA (1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid) (also known as NOTAGA), NODA Deferoxamine (1,4,7-triazacyclononane-1,4-diyl) diacetic acid DFO), NETA ([4˜ [2-(bis-carboxymethylamino)-ethyl]-7-carboxymethl-[1,4,7]triazonan-1-yl}-acetic acid), TACN-TM (N,N′,N″, tris (2-mercaptoethyl)-1,4,7-triazacyclononane), Diamsar (1,8-Diamino-3,6,10, 13,16, 19-hexaazabicyclo (6,6,6) eicosane, 3,6, 10, 13, 16, 19-Hexaazabicyclo[6.6.6] eicosane-1,8-diamine), Sarar (1-N-(4-aminobenzyl)-3, 6,10,13, 16, 19-hexaazabicyclo [6.6.6] eicosane-1,8-diamine), AmBaSar (4-((8-amino-3,6,10,13,16,19-hexaazabicyclo [6.6.6] icosane-1-ylamino) methyl) benzoic acid), and 4,4′-((3,6,10,13,16, 19-hexaazabicyclo [6.6.6] ico-sane-1,8-diylbis (aza-nediyl)) bis(methylene) dibenzoic acid (BaBaSar).

12. The compound of claim 1 , wherein T comprises an imaging agent, wherein the imaging agent comprises a radionuclide or a fluorescent dye.

13. The compound of claim 1 , wherein T comprises a drug, wherein the drug comprises a chelating moiety chelated to a radionuclide.

14. The compound of claim 1 , wherein the compound is of Formula Ia or Formula (Ib):

15. The compound of claim 14 , wherein R 1 is H or methyl.

16. The compound of claim 15 , wherein T comprises a chelating moiety chelated to a radionuclide, wherein

the chelating moiety is selected from DOTAGA, DOTA, NOTA, NODAGA, and NODA; and

the radionuclide is selected from 61 Cu, 64 Cu, and 67 Cu.

17. The compound of claim 1 , wherein the compound is selected from:

Compound

Structure

*Cu-NODAGA-1

*Cu-NODAGA-2

*Cu-NODAGA-3

and

*Cu-NODAGA-4

18. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

19. A method of generating one or more images of a subject comprising:

administering to a subject an effective amount of a compound of Formula Ia or Formula Ib:

wherein:

n is an integer from 1 to 20;

R 1 is H or C 1-10 alkyl; and

R 4 is-L-T, wherein L is a bond and T comprises a chelating moiety chelated to a radionuclide, wherein

the chelating moiety is selected from DOTAGA, DOTA, NOTA, NODAGA, and NODA, and the radionuclide is selected from 61 Cu and 64 Cu; and

generating one or more images of at least a part of the subject's body.

20. The method of claim 19 , wherein the image is generated using positron emission tomography (PET), PET-computer tomography (PET-CT), or single-photon emission computerized tomography (SPECT).

21. The method of claim 19 , wherein the method further comprises determining the presence or absence of a disease in a subject based on the presence or absence of localization of the radionuclide in the one or more images of the subject's body.

22. The method of claim 21 , wherein the disease is selected from a cancer, inflammatory disease, infectious diseases, and immune disease.

23. The method of claim 22 , wherein the disease is a cancer, and the cancer is selected from breast cancer, pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharynx cancer, nasopharynx cancer, larynx cancer, myeloma cells, bladder cancer, cholangiocellular carcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP, thymus carcinoma, desmoid tumors, glioma, astrocytoma, cervix carcinoma, and prostate cancer.

24. The method of claim 22 , wherein the disease is selected from cardiovascular diseases, liver fibrosis and cirrhosis, arthritic disorders, IgG4-related disease, pulmonary fibrosis and interstitial lung disease, Crohn's disease, tuberculosis, sarcoidosis, and periprosthetic joint infections.

25. The method of claim 19 , wherein the compound is selected from 61 [Cu] Cu-NODAGA-1, 61 [Cu] Cu-NODAGA-2, 61 [Cu] Cu-NODAGA-3, and 61 [Cu]Cu-NODAGA-4.

26. The compound of claim 1 , wherein the compound is

NODAGA-1

or is a pharmaceutically acceptable salt thereof.

27. The compound of claim 1 , wherein the compound is

NODAGA-2

or is a pharmaceutically acceptable salt thereof.

28. The compound of claim 1 , wherein the compound is

NODAGA-3

or is a pharmaceutically acceptable salt thereof.

29. The compound of claim 1 , wherein the compound is

NODAGA-4

or is a pharmaceutically acceptable salt thereof.

30. The compound of claim 1 , wherein the compound is

*Cu-NODAGA-1

or is a pharmaceutically acceptable salt thereof, wherein *Cu is 61 Cu.

31. The compound of claim 1 , wherein the compound is

*Cu-NODAGA-2

or is a pharmaceutically acceptable salt thereof, wherein *Cu is 61 Cu.

32. The compound of claim 1 , wherein the compound is

*Cu-NODAGA-3

and

or is a pharmaceutically acceptable salt thereof, wherein *Cu is 61 Cu.

33. The compound of claim 1 , wherein the compound is

*Cu-NODAGA-4

or is a pharmaceutically acceptable salt thereof, wherein *Cu is 61 Cu.

Assignments (2)

Continuity (5)

References Cited (268)