Azobenzene derivatives, process for their preparation and their use for therapeutic treatment associated with ionizing radiations

Patent metadata

Field	Value
Publication number	US-12414991-B2
Application number	US-202017428406-A
Country	US
Kind code	B2
Filing date	Feb 7, 2020
Priority date	Feb 8, 2019
Publication date	Sep 16, 2025
Grant date	Sep 16, 2025

Abstract

The present invention relates to new ionizing radiation-activatable derivatives, their preparation process and their therapeutic uses.

First claim

The invention claimed is:

1. A compound having the formula (IA):

in which:
M represents a metal atom selected from Ce(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), Mg(II), Ca(II), Mn(II), Fe(II), Fe(III), Cu(II), Zn(II), Ga(III), Y(III), Zr(III), Tc(IV), Tc(VI), Tc(VII), Ru(II), Ru(III), Ru(IV), Pd(II), Ag(I), In(III), Hf(IV), Re(VI), W(II), W(III), W(IV), W(V), W(VI), Os(III), Os(IV), Ir(III), Ir(IV), Pt(II), Au(I), Au(III), Tl(III), Zr(IV), Nb(III), Bi(III);
n is 1, 2, 3, 4, 5, 6, or 7;
V and V′, which may be identical or different, are hydrogen atoms or linear or branched C1-C10 alkyl or alkoxy chains, or C1-C10 alkyl chains linked together and comprising one or more heteroatoms selected from N, O, or S, optionally substituted with one or more substituents independently selected from halogen atoms, and nitrile, nitro, thio, amino, amido, aryl, heteroaryl, hydroxyl, carboxylic acid or carboxylate groups, to form a ring;
R1, R1′, R2, R2′, which may be identical or different, are hydrogen atoms, or linear or branched C1-C10 alkyl or alkoxy chains optionally substituted with one or more substituents independently selected from halogen atoms, and nitrile, nitro, thio, amino, amido, aryl, heteroaryl, hydroxyl, carboxylic acid or carboxylate groups;
R3 and R3′, which may be identical or different, are hydrogen atoms or linear or branched C1-C10 alkyl or alkoxy chains optionally substituted with one or more substituents independently selected from halogen atoms, and nitrile, nitro, thio, amino, amido, aryl, heteroaryl, hydroxyl, carboxylic acid or carboxylate groups, or R3 and R3′ are linked together to form a 5- to 14-membered heterocycle or heteroaryl;
m and m′, which may be identical or different, are equal to 1 or 2;
p is an integer between 0 and 6;
X is selected from hydrogen and halogen atoms;
R is a linear or branched C1-C12 alkyl group;
the N═N double bond is in cis or trans form;
wherein the n cationic charges of M are optionally neutralized by 0 to n carboxylate groups (—COOH) substituted on R1, R1′, R2, R2′, R3, R3′, V, V′, and/or by 0 to n of the counterions present in solution, and cis and/or trans isomers and mixtures thereof.

2. A compound having the general formula (IB):

in which
M represents a metal atom selected from Ce(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), Mg(II), Ca(II), Mn(II), Fe(II), Fe(III), Cu(II), Zn(II), Ga(III), Y(III), Zr(III), Tc(IV), Tc(VI), Tc(VII), Ru(II), Ru(III), Ru(IV), Pd(II), Ag(I), In(III), Hf(IV), Re(VI), W(II), W(III), W(IV), W(V), W(VI), Os(III), Os(IV), Ir(III), Ir(IV), Pt(II), Au(I), Au(III), Tl(III), Zr(IV), Nb(III), Bi(II);
n is 1, 2, 3, 4, 5, 6, or 7;
p is an integer between 0 and 6;
X is selected from H; halogen atoms; alkoxy, alkyl or cycloalkyl groups optionally interrupted or substituted with one or more heteroatom(s) or group(s) COOH, CONH 2 , COSH, OH, NH 2 , SH; 5- to 12-membered aryl or heteroaryl groups optionally substituted with one or more COOH, CONH 2 , COSH groups; COOH or NH 2 groups; and
R represents H, or linear or branched C1-C18 alkyl or alkoxy chain, optionally substituted with one or more substituents independently selected from halogen atoms, and nitrile, nitro, thio, amino, amido, aryl, heteroaryl, hydroxyl, carboxylic acid or carboxylate groups.

3. A compound having the general formula (IC):

in which
M represents a metal atom selected from Ce(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), Mg(II), Ca(II), Mn(II), Fe(II), Fe(III), Cu(II), Zn(II), Ga(III), Y(III), Zr(III), Tc(IV), Tc(VI), Tc(VII), Ru(II), Ru(III), Ru(IV), Pd(II), Ag(I), In(III), Hf(IV), Re(VI), W(II), W(III), W(IV), W(V), W(VI), Os(III), Os(IV), Ir(III), Ir(IV), Pt(II), Au(I), Au(III), Tl(III), Zr(IV), Nb(III), Bi(III);
n is 1, 2, 3, 4, 5, 6, or 7;
X may be selected from H; halogen atoms; alkoxy, alkyl or cycloalkyl groups optionally interrupted or substituted with one or more heteroatom(s) or group(s) COOH, CONH 2 , COSH, OH, NH 2 , SH; 5- to 12-membered aryl or heteroaryl groups optionally substituted with one or more COOH, CONH 2 , COSH groups; COOH or NH 2 groups;
and cis and/or trans isomers and mixtures thereof.

4. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

in which:
M represents a metal atom selected from Ce(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), MO(II, Ca(II), Mn(II), Fe(II), Fe(III), Cu(II), Zn(II), Ga(III), Y(III), Zr(III), Tc(IV), Tc(VI), Tc(VII), Ru(II), Ru(III), Ru(IV), Pd(II), Ag(I), In(III), Hf(IV), Re(VI), W(II), W(III), W(IV), W(V), W(VI), Os(III), Os(IV), Ir(III), Ir(IV), Pt(II), Au(I), Au(III), Tl(III), Zr(IV), Nb(III), Bi(III);
n is 1,2,3,4,5,6, or 7;
V and V′, which may be identical or different, are hydrogen atoms or linear or branched C1-C10 alkyl or alkoxy chains, or C1-C10 alkyl chains linked together and comprising one or more heteroatoms selected from N, O, or S, optionally substituted with one or more substituents independently selected from halogen atoms, and nitrile, nitro, thio, amino, amido, aryl, heteroaryl, hydroxyl, carboxylic acid or carboxylate groups, to form a ring;
R1, R1′, R2, R2′, which may be identical or different, are hydrogen atoms, or linear or branched C1-C10 alkyl or alkoxy chains optionally substituted with one or more substituents independently selected from halogen atoms, and nitrile, nitro, thio, amino, amido, aryl, heteroaryl, hydroxyl, carboxylic acid or carboxylate groups;
R3 and R3′, which may be identical or different, are hydrogen atoms or linear or branched C1-C10 alkyl or alkoxy chains optionally substituted with one or more substituents independently selected from halogen atoms, and nitrile, nitro, thio, amino, amido, aryl, heteroaryl, hydroxyl, carboxylic acid or carboxylate groups, or R3 and R3′ are linked together to form a 5- to 14-membered heterocycle or heteroaryl;
m and m′, which may be identical or different, are equal to 1 or 2;
X, X′, X″, X″′, Y, Y′, Y″, Y″′, which may be identical or different, are independently selected from H; halogen atoms; alkoxy, alkyl or cycloalkyl groups optionally interrupted or substituted with one or more heteroatom(s) or group(s) COOH, CONH 2 , COSH, OH, NH 2 , SH: 5- to 12-membered aryl or heteroaryl groups optionally substituted with one or more COOH, CONH 2 , COSH groups; COOH or NH 2 groups;
Z represents an alkyl group optionally interrupted or substituted with one or more heteroatom(s) or a COOH, CONH 2 , COSH, OH, NH 2 , SH group; a 5- to 12-membered aryl or heteroaryl group optionally substituted with one or more COOH, CONH 2 , COSH groups; or a COOH or NH 2 group;
W and W′, which may be the same or different, independently represent a CH 2 group; or an aryl or cycloalkyl group; an oxygen or nitrogen atom (secondary or ternary); an amide linkage; an ester linkage; a thioether linkage;
U and U′, which may be the same or different, represent

Assignees

• Centre Nat Rech Scient
• Univ Paris Saclay
• Inst Curie
• Univ Paris Saclay—Raison Sociale Obsolete

Inventors

• Bort Guillaume
• Couvreur Patrick
• Mura Simona
• Pouzoulet Frédéric

Classifications

• C07D257/02

  not condensed with other rings · CPC title

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• A61K31/555

  containing heavy metals, e.g. hemin, hematin, melarsoprol · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title