Imaging and radiotherapeutics agents targeting fibroblast-activation protein-alpha (FAP-alpha)

Patent metadata

Field	Value
Publication number	US-11938201-B2
Application number	US-202318354282-A
Country	US
Kind code	B2
Filing date	Jul 18, 2023
Priority date	Oct 23, 2017
Publication date	Mar 26, 2024
Grant date	Mar 26, 2024

Abstract

Imaging and radiotherapeutics agents targeting fibroblast-activation protein-α (FAP-α) and their use in imaging and treating FAP-α related diseases and disorders are disclosed.

First claim

That which is claimed:

1. A low molecular weight compound of Formula (I):
B-L-A  (I)

wherein:
A is a targeting moiety for FAP-α, wherein A has the structure of:

wherein:
R 1x and R 2x are each independently selected from the group consisting of H, OH, halogen, C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
R 3x is selected from the group consisting of H, —CN, —B(OH) 2 , —C(O)alkyl, —C(O)aryl-, —C═C—C(O)aryl, —C═C—S(O) 2 aryl, —CO 2 H, —SO 3 H, —SO 2 NH 2 , —PO 3 H 2 , and 5-tetrazolyl;
R 4x is H;
R 5x , R 6x , and R 7x are each independently selected from the group consisting of H, —OH, oxo, halogen, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 8x R 9x , —OR 12x , —Het 2 and —Ar 2 each of C 1-6 alkyl being optionally substituted with from 1 to 3 substituents selected from —OH and halogen;
R 8x , R 9x , and R 12x are each independently selected from the group consisting of H, —OH, halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —Ar 3 ;
R 10x , R 11x , R 13x and R 14x are each independently selected from the group consisting of H, —OH, halogen, —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl; Ar 1 , Ar 2 and Ar 3 are each independently a 5- or 6-membered aromatic monocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of Ar 1 , Ar 2 and Ar 3 being optionally and independently substituted with from 1 to 3 substituents selected from —NR 10x R 11x , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
Het 2 is a 5- or 6-membered non-aromatic monocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; Het 2 being optionally substituted with from 1 to 3 substituents selected from —NR 13x R 14x , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
v is 0, 1, 2, or 3; and

represents a 5 to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, said heterocycle optionally further comprising 1, 2 or 3 heteroatoms selected from O, N and S;
B is any optical or radiolabeled functional group suitable for optical imaging, positron-emission tomography (PET) imaging, single-photon emission computed tomography (SPECT) imaging, or radiotherapy; and L is a linker having bi-functionalization adapted to form a chemical bond with B and A; or
a stereoisomer, tautomer, racemate, salt, hydrate, or solvate thereof.

2. The compound of claim 1 , wherein B is any radiolabeled functional group suitable for positron-emission tomography (PET) imaging, single-photon emission computed tomography (SPECT) imaging, or radiotherapy.

3. A low molecular weight compound consisting essentially of components B-L-A; wherein:
A is a targeting moiety for FAP-α, wherein A has the structure of:

wherein:
R 1x and R 2x are each independently selected from the group consisting of H, OH, halogen, C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
R 3x is selected from the group consisting of H, —CN, —B(OH) 2 , —C(O)alkyl, —C(O)aryl-, —C═C—C(O)aryl, —C═C—S(O) 2 aryl, —CO 2 H, —SO 3 H, —SO 2 NH 2 , —PO 3 H 2 , and 5-tetrazolyl;
R 4x is H;
R 5x , R 6x , and R 7x are each independently selected from the group consisting of H, —OH, oxo, halogen, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 8x R 9x , —OR 12x , —Het 2 and —Ar 2 each of C 1-6 alkyl being optionally substituted with from 1 to 3 substituents selected from —OH and halogen;
R 8x , R 9x , and R 12x are each independently selected from the group consisting of H, —OH, halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —Ar 3 ;
R 10x , R 11x , R 13x and R 14x are each independently selected from the group consisting of H, —OH, halogen, —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl; Ar 1 , Ar 2 and Ar 3 are each independently a 5- or 6-membered aromatic monocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of Ar 1 , Ar 2 and Ar 3 being optionally and independently substituted with from 1 to 3 substituents selected from —NR 10x R 11x , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
Het 2 is a 5- or 6-membered non-aromatic monocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; Het 2 being optionally substituted with from 1 to 3 substituents selected from —NR 13x R 14x , —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl;
v is 0, 1, 2, or 3; and

represents a 5 to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, said heterocycle optionally further comprising 1, 2 or 3 heteroatoms selected from O, N and S;
B is any optical or radiolabeled functional group suitable for optical imaging, positron-emission tomography (PET) imaging, single-photon emission computed tomography (SPECT) imaging, or radiotherapy; and L is a linker having bi-functionalization adapted to form a chemical bond with B and A; or
a stereoisomer, tautomer, racemate, salt, hydrate, or solvate thereof.

Assignees

• Univ Johns Hopkins

Inventors

• Yang Xing
• Nimmagadda Sridhar
• Rowe Steven
• Slania Stephanie
• Pomper Martin G

Classifications

• A61K51/0485 Primary

  Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• A61K51/0478

  complexes from non-cyclic ligands, e.g. EDTA, MAG3 · CPC title

• A61K51/0482

  chelates from cyclic ligands, e.g. DOTA · CPC title

• A61K51/0455 Primary

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title