Use of FGF inhibiting substituted 1,2,3 indolizine derivatives in the preparation of medicaments which can be used to treat diseases linked to pathological choroidal angiogenesis

1. A method for the treatment of a disease related to pathological choroidal angiogenesis, the method comprising administering to a patient in need thereof a pharmaceutically effective dose of a 1,2,3-substituted indolizine derivative compound of the following general formula (I):

in which:

R 1 represents a hydroxyl radical, a linear or branched alkoxy radical of 1 to 5 carbon atoms, a carboxyl radical, an alkoxycarbonyl radical of 2 to 6 carbon atoms or a radical of formula:

—NR 5 R 6

—NH—SO 2 -Alk

—NH—SO 2 -Ph

—NH—CO-Ph

—N(Alk)-CO-Ph

—NH—CO—NH-Ph

—NH—CO-Alk

—NH—CO 2 -Alk

—O—(CH 2 ) n - c Alk

—O-Alk-COOR 7

—O-Alk-O—R 8

—O-Alk-OH

—O-Alk-C(NH 2 ):NOH

—O-Alk-NR 5 R 6

—O-Alk-CN

—O—(CH 2 ) n -Ph

—O-Alk-CO—NR 5 R 6

—CO—NH—(CH 2 ) m —COOR 7

—CO—NH-Alk

in which

Alk represents an alkyl radical or an alkylene radical which is linear or branched and which has from 1 to 5 carbon atoms,

cAlk represents a cycloalkyl radical of 3 to 6 carbon atoms,

n represents an integer from 0 to 5,

m represents an integer from 1 to 5,

R 5 and R 6 , which are identical or different, each represent a hydrogen atom, a linear or branched alkyl radical of 1 to 5 carbon atoms or a benzyl radical,

R 7 represents a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms,

R 8 represents an alkyl radical of 1 to 5 carbon atoms or a —CO-Alk radical,

Ph represents a phenyl radical optionally substituted by one or more halogen atoms, by one or more alkoxy radicals of 1 to 5 carbon atoms, by one or more carboxyl radicals or by one or more alkoxycarbonyl radicals of 2 to 6 carbon atoms,

R 2 represents a hydrogen atom, an alkyl radical of 1 to 5 carbon atoms, an alkyl halide radical of 1 to 5 carbon atoms comprising 3 to 5 halogen atoms, a cycloalkyl radical of 3 to 6 carbon atoms or a phenyl radical optionally substituted by one or more halogen atoms, by one or more alkoxy radicals of 1 to 5 carbon atoms, by one or more carboxyl radicals or by one or more alkoxycarbonyl radicals of 2 to 6 carbon atoms,

A represents a —CO—, —SO— or —SO 2 — radical,

R 3 and R 4 , which are identical or different, each represent a hydrogen atom, an alkoxy radical of 1 to 5 carbon atoms, an amino radical, a carboxyl radical, an alkoxycarbonyl radical of 2 to 6 carbon atoms, a hydroxyl radical, a nitro radical, a hydroxyamino radical, a radical of formula

-Alk-COOR 7

—NR 5 R 6

—NH-Alk-COOR 7

—NH—COO-Alk

—N(R 11 )—SO 2 -Alk-NR 9 R 10

—N(R 11 )—SO 2 -Alk

—N(R 11 )-Alk-NR 5 R 6

—N(R 11 )—CO-Alk-NR 9 R 10

—N(R 11 )—CO-Alk

—N(R 11 )—CO—CF 3

—NH-Alk-HetN

—O-Alk-NR 9 R 10

—O-Alk-CO—NR 5 R 6

—O-Alk-HetN

in which n, m, Alk, R 5 , R 6 and R 7 have the meaning given above for R 1 ; and

R 9 and R 10 , which are identical or different, each represent a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms,

R 11 represents a hydrogen atom or an -Alk-COOR 12 radical where R 12 represents a hydrogen atom, an alkyl radical of 1 to 5 carbon atoms or a benzyl radical,

HetN represents a 5- or 6-membered heterocycle comprising at least one nitrogen atom and optionally one other heteroatom chosen from nitrogen and oxygen;

or else R 3 and R 4 together form an unsaturated 5- to 6-membered heterocycle, provided, however, that, when R 3 represents an alkoxy radical and R 4 represents an —O-Alk-NR 9 R 10 radical or a hydroxyl radical, R 1 does not represent an alkoxy radical,

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein in the compound of general formula (I):

R 1 represents a hydroxyl radical, a linear or branched alkoxy radical of 1 to 5 carbon atoms, a carboxyl radical, an alkoxycarbonyl radical of 2 to 6 carbon atoms or a radical of formula:

—NR 5 R 6

—NH—SO 2 -Alk

—NH—SO 2 -Ph

—NH—CO-Ph

—N(Alk)-CO-Ph

—NH—CO—NH-Ph

—NH—CO-Alk

—NH—CO 2 -Alk

—O—(CH 2 ) n - c Alk

—O-Alk-COOR 7

—O-Alk-O—R 8

—O-Alk-OH

—O-Alk-NR 5 R 6

—O-Alk-CN

—O—(CH 2 ) n -Ph

—O-Alk-CO—NR 5 R 6

—CO—NH—(CH 2 ) m —COOR 7

—CO—NH-Alk

in which

Alk represents an alkyl radical or an alkylene radical which is linear or branched and which has from 1 to 5 carbon atoms,

cAlk represents a cycloalkyl radical of 3 to 6 carbon atoms,

n represents an integer from 0 to 5,

m represents an integer from 1 to 5,

R 5 and R 6 , which are identical or different, each represent a hydrogen atom, a linear or branched alkyl radical of 1 to 5 carbon atoms or a benzyl radical,

R 7 represents a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms,

R 8 represents an alkyl radical of 1 to 5 carbon atoms or a —CO-Alk radical,

Ph represents a phenyl radical optionally substituted by one or more halogen atoms, by one or more alkoxy radicals of 1 to 5 carbon atoms, by one or more carboxyl radicals or by one or more alkoxycarbonyl radicals of 2 to 6 carbon atoms,

R 2 represents an alkyl radical of 1 to 5 carbon atoms, a trifluoromethyl radical, a cycloalkyl radical of 3 to 6 carbon atoms or a phenyl radical optionally substituted by one or more halogen atoms, by one or more alkoxy radicals of 1 to 5 carbon atoms, by one or more carboxyl radicals or by one or more alkoxycarbonyl radicals of 2 to 6 carbon atoms,

A represents a —CO— or —SO 2 — radical,

R 3 and R 4 , which are identical or different, each represent a hydrogen atom, an alkoxy radical of 1 to 5 carbon atoms, an amino radical, a carboxyl radical, an alkoxycarbonyl radical of 2 to 6 carbon atoms, a nitro radical, a hydroxyamino radical, a radical of formula

-Alk-COOR 7

—NR 5 R 6

—NH-Alk-COOR 7

—NH—COO-Alk

—N(R 11 )—SO 2 -Alk-NR 9 R 10

—N(R 11 )—SO 2 -Alk

—N(R 11 )-Alk-NR 5 R 6

—N(R 11 )—CO-Alk-NR 9 R 10

—N(R 11 )—CO-Alk

—N(R 11 )—CO—CF 3

—NH-Alk-HetN

in which n, m, Alk, R 5 , R 6 and R 7 have the meaning given above for R 1 ; and R 9 and R 10 , which are identical or different, each represent a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms,

R 11 represents a hydrogen atom or an -Alk-COOR 12 radical where R 12 represents a hydrogen atom, an alkyl radical of 1 to 5 carbon atoms or a benzyl radical,

HetN represents a 5- or 6-membered heterocycle comprising at least one nitrogen atom and optionally one other heteroatom chosen from nitrogen and oxygen,

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein in the compound of general formula (I):

R 1 represents an alkoxy radical of 1 to 5 carbon atoms, a carboxyl radical, an —O-Alk-COOH radical in which Alk represents a linear or branched alkylene radical of 1 to 5 carbon atoms, a radical of formula —O-Alk-Ph in which Alk represents an alkylene radical of 1 to 5 carbon atoms and Ph represents a phenyl radical optionally substituted by one or more halogen atoms or by one or more alkoxy radicals of 1 to 5 carbon atoms or by one or more carboxyl radicals, a radical of formula —NH—CO-Ph, a radical of formula —NH—SO 2 -Ph or a radical of formula —NH—CO—NH-Ph,

R 2 represents an alkyl radical of 1 to 5 carbon atoms,

A represents a —CO— radical,

R 3 and R 4 , which are different, each represent a hydrogen atom, an alkoxy radical of 1 to 5 carbon atoms, an amino radical, a carboxyl radical or an alkoxycarbonyl radical of 2 to 6 carbon atoms,

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein the compound of general formula (I) is chosen from:

(4-amino-3-methoxyphenyl)(1-methoxy-2-methylindolizin-3-yl)methanone,

3-(4-amino-3-methoxybenzoyl)-2-methylindolizin-1-ylcarboxylic acid,

2-{[3-(4-amino-3-methoxybenzoyl)-2-methylindolizin-1-yl]oxy}acetic acid,

(4-amino-3-methoxyphenyl){1-[(4-chlorobenzyl)oxy]-2-methylindolizin-3-yl}-methanone,

(4-amino-3-methoxyphenyl){1-[(3-methoxybenzyl)oxy]-2-methylindolizin-3-yl}-methanone,

4-({[3-(4-amino-3-methoxybenzoyl)-2-methylindolizin-1-yl]oxy}methyl)benzoic acid,

3-(4-carboxybenzoyl)-2-methylindolizin-1-ylcarboxylic acid,

methyl 3-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]benzoate,

4-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]benzoic acid,

2-amino-5-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]benzoic acid,

2-amino-5-({1-[(3-methoxybenzoyl)amino]-2-methylindolizin-3-yl}carbonyl)benzoic acid,

2-amino-5-({2-methyl-1-[(3,4,5-trimethoxybenzoyl)amino]indolizin-3-yl}carbonyl)benzoic acid,

2-amino-5-({1-{[(3-methoxyphenyl)sulfonyl]amino}-2-methylindolizin-3-yl}-carbonyl)benzoic acid,

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein the disease related to pathological choroidal angiogenesis is chosen from age-related macular degeneration (AMD), severe myopia, pseudoxanthoma, presumed histoplasmosis syndrome, toxoplasmosis, sarcoidosis or Behcet's disease.

6. The method of claim 1 , wherein the compound is administered orally, intraocularly or locally.

7. The method of claim 6 wherein the compound is administered orally and the dose is between 1 and 900 mg/kg/day.

8. The method of claim 7 , wherein the dose is between 3 and 300 mg/kg/day.

9. The method of claim 7 , wherein the dose is between 1 and 100 mg/kg/day.

10. The method of claim 7 , wherein the compound is in the form of a pharmaceutically active salt.