FGF-receptor agonist dimeric compounds

1. An FGF receptor agonist compound corresponding to the formula:

M 1 -L-M 2

in which M 1 and M 2 , which may be identical or different, are each, independently of one another, a monomer unit

corresponding to the following formula M:

wherein L is a linker group that links M 1 and M 2 covalently, and L is selected from a linear or branched alkylene radical containing from 2 to 25 carbon atoms, or L is selected from any of the following linker structures:

wherein:

x is an integer from 2 to 4;

n is an integer from 1 to 7;

p is an integer from 0 to 11;

r is an integer from 1 to 11;

m and m′ are identical or different and are an integer from 0 to 8;

R 1 ′ and R 1 ″, which may be identical or different, are selected from hydrogen atom and linear or branched alkyl radical containing from 1 to 5 carbon atoms;

R 2 ′ and R 2 ″, which may be identical or different, are selected from hydrogen atom, linear or branched alkyl radical containing from 1 to 5 carbon atoms, benzyl radical, and sulfate group, and

Z is a linear alkylene radical containing from 1 to 6 carbon atoms;

X is N or C—R 2 *, A is a —CO— radical,

* indicates the linkage site of L with, firstly, the monomer unit M 1 and, secondly, with the monomer unit M 2 ; said linkage site of each monomer unit M 1 or M 2 being located on one of the substituents R, R 1 or R 2 ;

R is a hydrogen atom, or a radical of formula:

—CO 2 R 5

—CO—NR 6 R 7

—CO—NR 6−

—O-Alk

—O-Alk-CO—NR 6 R 7

—O-Alk-CO—NR 6 —

—O-Alk-NR 6 R 7

—O-Alk-NR 6 —

8-O* or

6-O*,

in which:

R 5 is a hydrogen atom, a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a benzyl radical;

R 6 and R 7 , which may be identical or different, are each a hydrogen atom, a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a benzyl radical;

Alk is a linear or branched alkyl radical having from 1 to 5 carbon atoms or a linear or branched alkylene radical having from 1 to 5 carbon atoms;

Ph is a phenyl radical;

R 1 is a hydrogen atom or a radical of formula:

—O-Alk

—Ph-3-CO 2 H

4-pyridine

O*

NH*

—OCH 2 Ph-3-O*

—OCH 2 Ph-4-O*

—NHCOPh-3-O*

—NHCOPh-4-O*

—Ph-3-CONH*

NHCO*

—Ph-4-O*or

—Ph-3-O*;

R 2 is a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a phenyl radical of the formula CPh-4-O*and CPh-3-O*;

R 3 and R 4 are, independently of one another, a hydrogen atom, or a radical of formula:

—O-Alk

CO 2 H or

NH 2,

in which Alk, R 5 , R 6 and R 7 are as defined with respect to the group R;

in the form of a base or an addition salt with an acid or with a base, and/or in the form of a hydrate or a solvate.

2. The compound according to claim 1 , comprising the monomer unit of formula M in which:

X═C-R 2 ;

R on the 6-, 7- o r 8-position of the indolizine is a hydrogen atom, or a radical of formula:

—CO 2 R 5

—CO—NR 6 R 7

—CO—NR 6 —

—O-Alk

—O-Alk-NR 6 R 7

—O-Alk-CO-NR 6 —

—O-Alk-CO-NR 6 R 7

—O-Alk-NR 6 —

8-O*or

6-O*,

in which:

R 5 is a hydrogen atom, a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a benzyl radical;

R 6 and R 7 , which may be identical or different, are each a hydrogen atom, a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a benzyl radical;

Alk is a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a linear or branched alkylene radical containing from 1 to 5 carbon atoms;

Ph is a phenyl radical;

R 1 is a hydrogen atom or a radical of formula:

—O-Alk

—Ph-3-CO 2 H

4-pyridine

O*

NH*

—OCH 2 Ph-3-O*

—OCH 2 Ph-4-O*

—NHCOPh-3-O*

—NHCOPh-4-O*

—Ph-3-CONH*

NHCO*

—Ph-4-O*or

—Ph-3-O*

R 2 is a linear or branched alkyl radical containing from 1 to 5 carbon atoms, or a phenyl radical of the formula CPh-4-O*and CPh-3-O*

R 3 and R 4 , which may be identical or different, are each a hydrogen atom, or a radical of formula:

—O-Alk

—CO 2 H or

NH 2 ,

in which Alk is as defined with respect to the group R;

in the form of a base or of an addition salt with an acid or with a base, and also in the form of a hydrate or a solvate.

3. The compound according to claim 1 , comprising the monomer unit of formula M in which:

X ═C-R 2 ;

R on the 6-, 7- or 8-position of the indolizine is a hydrogen atom, or a radical of formula:

—CO 2 R 5

—O-Alk

—O-Alk-CO-NR 6 R 7 or

—O-Alk-NR 6 R 7 ,

in which:

R 5 is a hydrogen atom, a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a benzyl radical;

R 6 and R 7 , which may be identical or different, are each a hydrogen atom, a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a benzyl radical;

Alk is a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a linear or branched alkylene radical containing from 1 to 5 carbon atoms;

Ph is a phenyl radical;

R 1 is a halogen atom, or a radical of formula:

—O-Alk

—Ph-3-CO 2 H

4-pyridine

O*

NH*

—OCH 2 Ph-3-O*

—OCH 2 Ph-4-O*

—NHCOPh-3-O*

—NHCOPh-4-O*

—Ph-3-CONH*

NHCO*

—Ph-4-O*or

—Ph-3-O*;

R 2 is a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a phenyl radical of the formula CPh-4-O*and CPh-3-O*;

R 3 and R 4 , which may be identical or different, are each selected from —O-Alk, —CO 2 H, and NH 2 ,

in which Alk is as defined with respect to the group R;

in the form of a base or of an addition salt with an acid or with a base, and also in the form of a hydrate or a solvate.

4. The compound according to claim 3 , characterized in that R on the 6- or 8-position of the indolizine is a hydrogen atom;

R 1 is a radical of formula:

—O-Alk

—Ph-3-CO 2 H

4-pyridine

O*

NH*

—OCH 2 Ph-3-O*

—OCH 2 Ph-4-O*

—NHCOPh-3-O*

—NHCOPh-4-O*

—Ph-3-CONH*

NHCO*

—Ph-4-O*or

—Ph-3-O*,

in which Alk and Ph, are as defined in claim 3 ;

R 2 is linear or branched alkyl radical containing from 1 to 5 carbon atoms;

R 3 is selected from —O-Alk and —CO 2 H;

R 4 is NH 2 ;

in the form of a base or of an addition salt with an acid or with a base, and also in the form of a hydrate or a solvate.

5. The compound according to claim 1 , comprising the monomer unit of formula M in which:

X ═N;

R on the 5-, 6-, 7- or 8-position of the imidazo[1,5-α]pyridine is a hydrogen atom, or a radical of formula:

—CO 2 R 5

—CO—NR 6 R 7

—CO—NR 6 —

—O-Alk

—O-Alk-CO—NR 6 R 7

—O-Alk-CO—NR 6 —

—O-Alk-NR 6 R 7

—O-Alk-NR 6 —

8-O* or

6-O*,

in which:

R 5 is a hydrogen atom, a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a benzyl radical;

R 6 and R 7 , which may be identical or different, are each a hydrogen atom, a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a benzyl radical;

Alk is a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a linear or branched alkylene radical containing from 1 to 5 carbon atoms;

Ph is a phenyl radical;

R 1 is a hydrogen atom, or a radical of formula:

—Ph-3-CO 2 H

4-pyridine

O*

NH*

—OCH 2 Ph-3-O*

—OCH 2 Ph-4-O*

—NHCOPh-3-O*

—NHCOPh-4-O*

—Ph-3-CONH*

NHCO*

—Ph-4-O*or

—Ph-3-O*;

R 3 and R 4 , which may be identical or different, are each a hydrogen atom, or a radical of formula:

—O-Alk

CO 2 H or

NH 2 ;

in the form of a base or of an addition salt with an acid or with a base, and also in the form of a hydrate or a solvate.

6. The compound according to claim 5 , comprising the monomer unit of formula M in which:

X ═N;

R on the 6-, 7- or 8-position of the imidazo[1 ,5-α]pyridine is a hydrogen atom, or a radical of formula:

—CO 2 R 5

—CO—NR 6 R 7

—CO—NR 6 —

—O-Alk

8-O*or

6-O*,

in which:

R 5 is a hydrogen atom, a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a benzyl radical;

R 6 and R 7 , which may be identical or different, are each a hydrogen atom, a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a benzyl radical;

Alk is a linear or branched alkyl radical containing from 1 to 5 carbon atoms or a linear or branched alkylene radical containing from 1 to 5 carbon atoms;

Ph is a phenyl radical;

R 1 is a hydrogen atom, or a radical of formula:

—Ph-3-CO 2 H

4-pyridine

O*

NH*

—OCH 2 Ph-3-O*

—OCH 2 Ph-4-O*

—NHCOPh-3-O*

—NHCOPh-4-O*

—Ph-3-CONH*

NHCO*

—Ph-4-O*or

—Ph-3-O*,

R 3 and R 4 , which may be identical or different, are each a radical of the formula:

—O-Alk

CO 2 H, or

NH 2 ;

in the form of a base or of an addition salt with an acid or with a base, and also in the form of a hydrate or a solvate.

7. The compound according to claim 6 , characterized in that

R on the 8-position of the imidazo[1,5-α]pyridine is a hydrogen atom, or a carboxyl radical of formula —CO 2 R 5 , R 1 is a hydrogen atom, or a radical of formula:

—Ph-3-CO 2 H

4-pyridine

O*

NH*

—OCH 2 Ph-3-O*

—OCH 2 Ph-4-O*

—NHCOPh-3-O*

—NHCOPh-4-O*

—Ph-3-CONH*

NHCO*

—Ph-4-O*or

—Ph-3-O*;

R 3 is a radical of formula —O-Alk;

R 4 is a radical of formula NH 2 ;

in the form of a base or of an addition salt with an acid or with a base, and also in the form of a hydrate or a solvate.

8. The FGF receptor agonist compound according to claim 1 , characterized in that M 1 is a monomer unit of formula M as defined in claim 1 , and M 2 is a monomer unit of formula M as defined in claim 5 ;

in the form of a base or of an addition salt with an acid or with a base, and also in the form of a hydrate or a solvate.

9. The compound according to claim 1 , wherein:

L connects the 2 monomer units M 1 and M 2 by the radical R 1 or;

L connects the 2 monomer units M 1 and M 2 by the radical R 2 or;

L connects the 2 monomer units M 1 and M 2 by the radical R in its 8-position or;

L connects the 2 monomer units M 1 and M 2 by the radical R in its 7-position or;

L connects the 2 monomer units M 1 and M 2 by the radical R in its 6-position or;

L connects the 2 monomer units M 1 and M 2 , firstly, by the radical R in its 8-position and, secondly, by the radical R in its 7- or 6-position, or;

L connects the 2 monomer units M 1 and M 2 , firstly, by the radical R in its 7-position and, secondly, by the radical R in its 6-position or;

L connects the 2 monomer units M 1 and M 2 , firstly, by the radical R 2 and, secondly, by the radical R 1 or;

L connects the 2 monomer units M 1 and M 2 , firstly, by the radical R 1 and, secondly, by the radical R in its 8-position;

in the form of a base or of an addition salt with an acid or with a base, and also in the form of a hydrate or a solvate.

10. A pharmaceutical composition containing, as active ingredient, a compound corresponding to the formula M 1 L-M 2 according to claim 1 , optionally in combination with one or more inert and suitable excipients.

11. A method for preparing a compound of formula M 1 -L-M 2 according to claim 1 , comprising the reaction of at least one monomer unit of formula M-W with a reactant of formula U-L-U′, with

M and L being as defined in claim 1 ,

U and U′ being identical or different,

W and U and also W and U′ each being a functional group capable of reacting with one another so as to form a covalent bond of C—C, C—O C—N, C—C or C—S type, and

W being located on one of the substituents R, R 1 or R 2 as defined in claim 1 .

12. The method according to claim 11 , characterized in that W and U and also W and U′ are an amino, hydroxyl, carboxyl, amido, carbamate, halogen, sulphonyl chloride, acid chloride or acid fluoride group, a boronic ester or a boronic acid.

13. The method according to claim 12 , comprising the reaction of said monomer units of formula M-W, with R, R 1 , R 2 , R 3 or R 4 being or having a carboxylic acid, and R or R 1 being or having an amino group, with a silylation agent and a weak base, followed by an acylation reaction using a diacylating agent and a weak base, and then hydrolysis in an acidic medium.

14. A compound of formula M 1 -L-M 2 as defined in claim 1 , selected from:

- disodium salt of 3,3′-{3,6,9,12,15-pentaoxaheptadecane-1,17-diylbis[oxy(l-methoxy-2-methylindolizine -8,3-diyl)carbonyl] }bis(6-aminobenzoic acid);

- disodium salt of 3,3′-(3,6,9,12,15-pentaoxaheptadecane-1,17-diylbis{oxy[3-(4-amino-3-methoxybenzoyl) imidazo[1,5-α]pyridine-8, 1-diyl]})dibenzoic acid;

- disodium salt of 3,3′-{3,6,9,12,15,1 8-hexaoxaicosane- 1,20-diylbis[oxy(l-methoxy-2-methylindolizine -6,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{3,6,9,12,15-pentaoxaheptadecane-1,17-diylbis[oxy(l-methoxy-2-methylindolizine -6,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{3,6,9,12,15,1 8-hexaoxaicosane- 1,20-diylbis[oxy(2-methylindolizine -1 ,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{ ethane- 1,2-diylbis[oxyethane-2, l-diyloxy-3, 1-phenylenemethyleneoxy (2-methylindolizine-1,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{octane-1,8-diylbis[oxy-3,1-phenylenecarbonylimino(2-methylindolizine -1 ,3-diyl)carbonyl] 0 }bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{ethane-1,2-diylbis[oxyethane-2,1-diyloxy-3,1- phenylenecarbonylimino (2-methylindolizine-1,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{ (1,4-dioxobutane-1,4-diyl)bis[iminoethane-2, 1-diyloxy-3,1-phenylenecarbonylimino (2-methylindolizine-1,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{ carbonyl bis[iminoethane-2,1-diyloxy-3,1-phenylenecarbonylimino (2-methylindolizine-1,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{ ethane-1,2-diylbis[imino(2-oxoethane-2, l-diyl)oxy-3, 1-phenylenecarbonylimino (2-methylindolizine-1,3-diyl)carbonyl] }bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{propane-1,3-diylbis[imino(2-oxoethane-2,1-diyl)oxy-3,1-phenylenecarbonylimino (2-methylindolizine-1,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{ butane-1 ,4-diylbis[imino(2-oxoethane-2,1-diyl)oxy-3,1-phenylenecarbonylimino (2-methylindolizine-1,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{ ethane-1,2-diylbis[imino(2-oxoethane-2,1-diyl)oxy-4,1-phenylenecarbonylimino (2-methylindolizine-1,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{ ethane-1,2-diylbis[oxyethane-2,1-diyloxy-4,1-phenylenecarbonylimino (2-methylindolizine-1,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{ oxybis[ethane-2,1-diyloxyethane-2,1-diyloxy-4,1 -phenylene(2-methylindol izine-1,3-diyl)carbonyl]}bis(6-amino benzoic acid);

- disodium salt of 3,3′-{ ethane-1,2-diylbis[oxyethane-2, 1-diyloxy-3,1-phenylene(2-methylindolizine -1,3-diyl)carbonyl]bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{ oxybis[ethane-2,1 -diyloxyethane-2,1-diyloxy-3,1-phenylene(2-methylindolizine -1,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{hexane-1,6-diylbis[imino(2-oxoethane-2,1-diyl)oxy-3,1-phenylene(2-methylindolizine -1,3-diyl)carbonyl]}bis(6-aminobenzoic acid);

- disodium salt of 3,3′-{hexane-1,6-diylbis[imino(2-oxoethane-2,1-diyl)oxy-4,1-phenylene(2-methylindolizine -1,3-diyl)carbonyl]}bis(6-aminobenzoic acid); and

- disodium salt of 2-amino-5-[(1- {[3-(2- {[2-( }[3-({[3 -(4-amino-3-carboxybenzoyl) imidazo[1,5-α]pyridin- 1-yl]amino}carbonyl)phenoxy]acetyl} amino)ethyl]amino} -2-oxoethoxy) benzoyl]amino }-2-methylindolizin-3-yl)carbonyl]dibenzoic acid.

15. The compound according to claim 1 , wherein:

X is selected from CCH 3 , N, CPh-4-O*, and CPh-3-O*;

R is selected from 8-O*, 6-O*, H, 7-CONH*, 7—CO 2 H, and 6-OCH 2 CH 2 NH*;

R 1 is selected from OCH 3 , -Ph-3-CO 2 H, 4-pyridine, H, O*, —NH*, —OCH 2 Ph-3-O*, —OCH 2 Ph-4-O*,-NHCOPh-3-O*, -NHCOPh-4-O*,-Ph-3-CONH*, —NHCO*, -Ph-4-O* and-Ph-3-O*;

R 3 is selected from CO 2 H and OCH 3 ; and

R 4 is selected from NH 2 or H.