Bifunctional do2pa derivatives, chelates with metallic cations and use thereof

Patent metadata

Field	Value
Publication number	US-11266754-B2
Application number	US-201916579133-A
Country	US
Kind code	B2
Filing date	Sep 23, 2019
Priority date	Dec 5, 2014
Publication date	Mar 8, 2022
Grant date	Mar 8, 2022

Abstract

Disclosed are chelates resulting from the complexation of bifunctional do2pa derivatives ligands of formula (I), wherein the substituents R1, R1′, R2, R2′, R3, R3′, L1, L1′, L2 and L2′ are defined as in the claims, with metallic cations, especially Pb(II) and Bi(III). Also disclosed are bifunctional do2pa derivatives ligands of formula (I), as well as the use of chelates in nuclear medicine and the use of ligands in cations detection or epuration of effluents.

First claim

The invention claimed is:

1. A ligand of formula (Ia):

or a basic salt thereof;
wherein
R 1 and R 1′ each independently represents:
a hydrogen atom;
a coupling function, wherein the coupling function is selected from the group consisting of amine; isothiocyanate; isocyanate; N-hydroxysuccinimide ester, N-hydroxyglutarimide ester, maleimide ester; carboxylic acid; anhydride, acid halide; alcohol; alkyne; halide; azide; siloxy; phosphonic acid; thiol; tetrazine; norbornen; oxoamine; aminooxy; thioether; chloroacetamide, bromoacetamide, iodoacetamide; glutamate; glutaric anhydride, succinic anhydride, maleic anhydride; aldehyde; ketone; hydrazide; chloroformate, and maleimide; or
a bioactive group, wherein the bioactive group is a peptide;

L 1 and L 1′ each independently represents:
a single bond; or
a linker selected from the group consisting of alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkenyl, and alkynyl; wherein alkyl moieties are optionally interrupted by one or more heteroatoms selected from the group consisting of O, N, and S; optionally additionally comprising a residue of a coupling function through which R 1 and R 1′ are bounded to L 1 and L 1′ respectively;

provided that at least one of -L 1 -R 1 and -L 1′ -R 1′ represents a linker with a coupling function or a linker with a bioactive group.

2. The ligand according to claim 1 , wherein at least one of -L 1 -R 1 and -L 1′ -R 1′ is selected from formulae (a) and (b):

wherein n and m represent each independently an integer ranging from 1 to 10.

3. The ligand according to claim 1 , wherein at least one of -L 1 -R 1 and -L 1′ -R 1′ is selected from formulae (a) and (b):

wherein n and m represent each independently 1, 2, 3, or 4.

4. The ligand according to claim 1 , selected from the group consisting of:
6,6′-((4-(4-isothiocyanatobenzyl)-10-methyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid;
6,6′-((4-(3-aminopropyl)-10-methyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid;
6,6′-((4-(4-(3-(4-(6-((aminooxy)carbonyl)-2-(16-((aminooxy)carbonyl)-1-(1H-imidazol-4-yl)-4,7,10,18-tetraoxo-3,8,11,17-tetraazanonadecan-19-yl)-21-(1H-imidazol-4-yl)-4,12,15,18-tetraoxo-2,5,11,14,19-pentaazahenicosyl)phenyl)thioureido)benzyl)-10-methyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinate; and
basic salts thereof.

5. A process for manufacturing a ligand of formula (Ia) according to claim 1 , comprising starting from cyclen glyoxal:

and performing the following steps:
(a1) reacting with a compound M 1 -L 1 -X 1 wherein
L 1 is as defined in formula (Ia);
X 1 represents a halogen atom; and
M 1 represents R 1 , wherein R 1 is as defined in formula (Ia);
or M 1 represents a precursor of a coupling function;

(a1′) reacting with a compound M 1′ -L 1′ -X 1′ wherein
L 1′ is as defined in formula (Ia);
X 1′ represents a halogen atom; and
M 1′ represents R 1′ , wherein R 1′ is as defined in formula (Ia);
or M 1′ represents a precursor of a coupling function;

(b1) reacting with a compound of formula (i-a)

wherein
X represents a halogen atom; and
M 3 represents a protecting group selected from alkyl groups;

(b1′) reacting with a compound of formula (i′-a)

wherein
X represents a halogen atom; and
M 3′ represents a protecting group selected from alkyl groups;

(c) performing glyoxal bridge deprotection;
said steps being performed in the following order: (a1), (a1′), (c), (b1) and (b1′);
or alternatively (b1), (b1′), (c), (a1) and (a1′);
to afford an intermediate compound (ii-a)

wherein L 1 and L 1′ are as defined in formula (Ia) and wherein M 1 , M 1′ , M 3 and M 3′ are as defined above;
and where needed, conducting on intermediate compound (ii-a) one or more subsequent step selected from:
in the case wherein M 1 or M 1′ represents a precursor of a coupling function, converting the precursor to a coupling function to afford a compound of formula (Ia) wherein R 1 or R 1′ respectively represents a coupling function;
in the case wherein M 1 or M 1′ represents a coupling function, introducing a bioactive group to afford a compound of formula (Ia) wherein R 1 or R 1′ respectively represents a bioactive group; and
deprotecting the acidic functions protected by M 3 and M 3′ , to afford a compound of formula (Ia);

to afford the ligand of formula (Ia).

6. The process according to claim 5 , wherein the alkyl group is selected from the group consisting of methyl, ethyl, and t-butyl.

7. The process according to claim 5 , wherein X 1 represents an halogen atom selected from the group consisting of Br and I; X 1′ represents an halogen atom selected from the group consisting of Br and I; and X represents Cl.

8. The ligand according to claim 1 , wherein the peptide is di-HSGL.

Assignees

• Centre Nat Rech Scient
• Univ Bretagne Occidentale

Inventors

• Oukhatar Fatima
• Beyler Maryline
• Tripier Raphaël

Classifications

• C07F9/94 Primary

  Bismuth compounds · CPC title

• A61K51/1093 Primary

  conjugates with carriers being antibodies · CPC title

• C07D257/02

  not condensed with other rings · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D213/79

  Acids; Esters · CPC title