MXPA06008864A - Use of substituted 1,2,3 indolizine derivatives for treating diseases associated with a pathological choroidal angiogenesis - Google Patents

Abstract

The invention relates to the use of substituted 1,2,3 indolizine derivatives for the preparation of medicaments that are useful in treating diseases associated with a pathological choroidal angiogenesis. The derivatives correspond to general formula (I).

Description

USE OF INDOLYZINE DERIVATIVES 1, 2.3 REPLACED FOR THE TREATMENT OF DISEASES ASSOCIATED WITH A PATHOLOGICAL ANGIOGENESIS COROIDEA It has been shown in vitro and in vivo that several growth factors participate in the creation of a "proangiogen" imbalance, which leads to the uncontrolled proliferation of endothelial cells, observed in neovascularization phenomena. The FGF2 or bFGF (Fibroblast Growth Factor 2 or b) is the first and best characterized. FGF2 is an 18,000D protein that induces proliferation, migration and production of proteases by endothelial cells in culture and neovascularization in vivo. FGF2 interacts with endothelial cells by means of two classes of receptors, the high affinity receptor tyrosine kinase activity (FGFR) and the low affinity receptors of the heparan sulfate proteoglycan (HSPG) type located on the surface of cells and in the extracellular matrices. While the paracrine role of FGF2 on endothelial cells has been widely described, FGF2 could also intervene on these cells through an autocrine process. Thus, FGF2 and its receptors represent very relevant targets for therapies aimed at inhibiting angiogenesis processes (Keshet E, Ben-Sasson SA, J. Clin. Invest, (1999), vol 501, pp104-1497; Presta M , Rusnati M, Dell'Era P, Tanghetti E, Urbinati C, Giuliani R et al, New York: Plenum Publishers, (2000), pp7-34, Billottet C, Janji B, Thiery JP, Jouanneau J, Oncogene, (2002) ) vol 21. pp8128-8139).

A recent study has shown, through a model of experimental study performed on a mouse eye, the involvement of FGF on neovascularization (Rousseau et al., "Involvement of Fibroblasts Growth Factors in choro? Dal angiogenesis and retinal vascularization", Experimental Eye Research, Laboratoire des Mécanismes Moleculaires de l'angiogenése, INSERM EML01 -13, University of Bordeaux, France, May 13, 2003, p.147-156). The precise role of FGF and its receptors in the processes of pathological angiogenesis of the eye, in particular of the choroid, is however unknown and opens a path to sometimes divergent hypotheses (Tobe et al., "Targeted disruption of the FGF2 gene does not prevent choro? dal neovascularization in a murine model, "Am. J. Pathol., 153, 1641-1646, 1998 / Yamada et al.," Cell injury unmasks a latent proangiogenic phenotype in mice with increased expression of FGF2 in the Retina, J. Cell Physiol 185, 135-142, 2000) International patent application WO 03/084956 discloses derivatives, inhibitors of FGF, useful among others, in the treatment of pathologies in which angiogenesis seems to influence important form in progression, such as, for example, chronic inflammatory diseases such as rheumatoid arthritis or IBD (Intestinal Inflammatory Diseases). International patent application WO 03/084956 also discloses that such compounds They are useful for the treatment of diseases resulting from vascular complications of diabetes, such as diabetic retinopathy in which the blood vessels of the retina can crack or become clogged. It has now been found that certain substituted 1, 2, 3 indolizine derivatives, which are antagonists of the FGF receptors, called FGFR, are useful for the treatment of diseases associated with choroidal pathological angiogenesis. Surprisingly, these compounds are also active when administered orally or locally, especially intraocularly. The present invention thus relates to the use of substituted indolizine derivatives 1, 2, 3 for the preparation of medicaments useful for the treatment of diseases associated with a choroidal pathological angiogenesis, derivatives corresponding to the following general formula I: wherein: Ri represents a hydroxy radical, a linear or branched alkoxy radical of 1 to 5 carbon atoms, a carboxy radical, an alkoxycarbonyl radical of 2 to 6 carbon atoms or a radical of the formula: -NR5R6 -NH-SO2-Alk -NH-SO2-Ph-NH-CO-Ph-N (Alk) -CO-Ph -NH-CO-NH-Ph -NH-CO-Alk -NH-CO2-Alk -O- (CH2) n-cAlk -O-Alk-COOR7 -O-Alk-OH -O-Alk-C (NH2) : NOH -O-Alk-NR5R6 10 -O-Alk-CN -O- (CH2) n-Ph -O-Alk-CO-NR5R6 -CO-NH- (CH2) m-COOR7 -CO-NH-Alk 15 wherein Alk represents an alkyl radical or a linear or branched alkylene radical of 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, Re and Re equal or different each represent a hydrogen atom, a linear alkyl radical or branched from 1 to 5 carbon atoms or a benzyl radical, • R represents a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, • R8 represents an alkyl radical of 1 to 5 carbon atoms or a radical- CO-Alk, • Ph represents a phenyl radical optionally substituted with one or more halogen atoms, with one or more alkoxy radicals of 1 to 5 carbon atoms, with one or more carboxy radicals or with one or more 2-alkoxycarbonyl radicals 6 carbon atoms, R2 represents a hydrogen atom, an alkyl radical of 1 to 5 carbon atoms, an alkyl halide radical of 1 to 5 carbon atoms comprising from 3 to 5 halogen atoms, a cycloalkyl radical of 3 to 6 carbon atoms or a phenyl radical optionally substituted with one or more halogen atoms, with one or more alkoxy radicals of 1 to 5 carbon atoms, one or more carboxy radicals or with one or more alkoxycarbonyl radicals of 2 to 6 carbon atoms, A represents an identical or different radical-CO -, - SO- or -SO2-, R3 and R each represents a hydrogen atom, an alkoxy radical of 1 to 5 carbon atoms, a radical amino, a carboxy radical, an alkoxycarbonyl radical of 2 to 6 carbon atoms, a hydroxy radical, a nitro radical, a hydroxyamino radical, a radical of the formula • -Alk-COOR7 -NR5R6 -NH-Alk-COOR7 -NH-COO -Alk -NÍRnj-SO? -Alk-NRgRio -N (Rn) -SO2-Alk -N (Rn) -Alk-NR5R6 -N (Rn) -CO-Alk-NR9R? Or -N (Rn) -CO- Alk -N (R11) -CO-CF3 • -NH-Alk-HetN -O-Alk-NR9R10 -O-Alk-CO-NR5R6 -O-Alk-HetN in which n, m, Alk, R5, R6) and R, have the meaning given above for R1; and R9 and R10 which are different or different each represent a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, Rn represents a hydrogen atom or a radical-Alk-COOR12 where R12 represents a hydrogen atom, a radical alkyl 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 another heteroatom selected from nitrogen and oxygen; or R3 and R together form a 5 to 6 membered unsaturated heterocycle, provided, however, that when R3 represents an alkoxy radical and R represents a radical-O-Alk-NR9R10 or a hydroxy radical, RT does not represent a radical alkoxy, optionally in the form of one of its pharmaceutically acceptable salts. It is preferred to use the compounds of general formula I in which: RI represents a hydroxy radical, a linear or branched alkoxy radical of 1 to 5 carbon atoms, a carboxy radical, an alkoxycarbonyl radical of 2 to 6 carbon atoms or a radical of formula: • -NR5R6 -NH-SO2-Alk -NH-SO2-Ph -NH-CO-Ph -N (Alk) -CO-Ph • -NH-CO-N H-Ph -NH-CO-Alk- NH-CO2-Alk -O- (CH2) n-cAlk -O-Alk-COOR7 -O-Alk-OH -O-Alk-NR5R6 -O-Alk-CN -O- (CH2) n-Ph. -O-Alk-CO-NR5R6 -CO-NH- (CH2) m-COOR7 -CO-NH-Alk in which • Alk represents an alkyl radical or a linear or branched alkylene radical of 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, • R5 and R6 equal or different represent each a hydrogen atom , a linear or branched alkyl radical of 1 to 5 carbon atoms or a benzyl radical, • R7 represents a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, • R8 represents an alkyl radical of 1 to 5 carbon atoms; carbon or a radical-CO-Alk • Ph represents a phenyl radical optionally substituted with one or more halogen atoms, with one or more alkoxy radicals of 1 to 5 carbon atoms, one or more carboxy radicals or with one or more alkoxycarbonyl radicals of 2 to 6 carbon atoms, R2 represents an alkyl radical of 1 to 5 át carbon atoms, a trifluoromethyl radical, a cycloalkyl radical of 3 to 6 carbon atoms or a phenyl radical optionally substituted with one or more • halogen atoms, with one or more alkoxy radicals of 1 to 5 carbon atoms, with one or more carboxy radicals or with one or more alkoxycarbonyl radicals of 2 to 6 carbon atoms, A represents a radical -CO-, - SO2 -, R3 and R equal or different each represent a hydrogen atom, an alkoxy radical of 1 to 5 carbon atoms, an amino radical, a carboxy radical, an alkoxycarbonyl radical of 2 to 6 carbon atoms, a nitro radical, a hydroxyamino radical, a radical of the formula -Alk-COOR7 -NR5R6 -NH-Alk-COOR7 -NH-COO-Alk • -N (Rn) -S? 2-Alk-NR? R? or -N (Rn) -SO2- Alk -N (Rn) -CO-Alk • -N (Rn) -CO-CF3 -NH-Alk-HetN in which n, m, Alk, R5, Re, and 7, have the meaning given above for Ri, and 9 and R10 equal or different each represent a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, R ?? represents a hydrogen atom or a radical-Alk-COOR12 where R12 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 atom of nitrogen and optionally another heteroatom chosen from nitrogen and oxygen, optionally in the form of one of its pharmaceutically acceptable salts. The use of the compounds of general formula I in which Ri represents an alkoxy radical of 1 to 5 carbon atoms, a carboxy radical, a radical-O-Alk-COOH in which Alk represents a linear or branched alkylene radical of 1 to 5 carbon atoms, a radical of formula-O -AIk-Ph in which Alk represents an alkylene radical of 1 to 5 carbon atoms and Ph represents a phenyl radical optionally substituted with one or more halogen atoms or with one or more alkoxy radicals of 1 to 5 carbon atoms or with one or several carboxy radicals, a radical of formula-NH-CO-Ph, a radical of formula -NH-SO2-Ph or a radical of formula -NH-CO-NH-Ph, R2 represents an alkyl radical of 1 to 5 atoms of carbon, A represents a radical -CO-, R3 and R4 each represent each a hydrogen atom, an alkoxy radical of 1 to 5 carbon atoms, an amino radical, a carboxy radical, an alkoxycarbonyl radical of 2 to 6 atoms carbon, optionally in the form of one of its pharmaceutically acceptable salts, is particularly p referred.

It is preferred to use more particularly the compounds of formula I chosen from: - (4-amino-3-methoxyphenyl) (1-methoxy-2-methylindolizin-3-yl) methanone - 3- (4-amino-3-methoxybenzoyl) 2-methylindolizin-1-carboxylic acid 2-. { [3- (4-amino-3-methoxybenzoyl) 2-methylindolizin-1-yl] oxy} acetic - (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-methyIindolizin-1-yl] oxy} methyl) benzoic acid 3- (4-carboxybenzoyl) 2-methylindolizin-1 acid -carboxylic acid - methyl 3 - [(1-methoxy-2-methylindolizin-3-yl carbonyljbenzoate - 4 - [(1-methoxy-2-methylindolizin-3-yl) carbonyl] benzoic acid - 2-amino-5- acid [(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 optionally in the form of one of its pharmaceutically acceptable salts.Chinoidal pathological angiogenesis It is a process of generation of new capillary vessels of the choroid.The choroid is a very vascularized eye membrane: a network of fine capillaries ensures the nutrition of the iris and the retina in the periphery where she is. The choroidal pathological angiogenesis is mainly due to the creation of a "pro angiogenic" imbalance, but also to alterations of the Bruch membrane, located below the retina. Thus, choroidal capillaries proliferate uncontrollably and, through a defect in Bruch's membrane, invade the sub-retinal space (Lafaut et al., Br. J. Ophtalmol 84, 239-243). Among the diseases associated with a choroidal pathological angiogenesis and especially as a consequence of a Bruch membrane abnormality, we can mention macular degeneration due to age (DMLA), strong myopia (Quaranta et al., Graefe's Arch. Clin. Exp. Ophtalmol., 238, 101-103), pseudo xanthoma, presumed histoplasmosis syndrome, toxoplasmosis, sarcoidosis and Behcet's disease. Thus, according to one of its aspects, the present invention relates to the use of 1, 2,3-substituted indolizine derivatives of general formula I, for the preparation of medicaments useful for the treatment of diseases associated with choroidal pathological angiogenesis, such such as age-related macular degeneration (AMD), strong myopia, pseudo xanthoma, presumed histoplasmosis syndrome, toxoplasmosis, sarcoidosis, Behcet's disease. According to another of its aspects, the present invention has for its object a pharmaceutical composition containing at least one active principle corresponding to a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in association with one or more suitable and inert excipients, useful for the treatment of diseases associated with choroidal pathological angiogenesis. The subject of the present invention is in particular a pharmaceutical composition containing at least one active ingredient corresponding to a compound of formula I chosen from: - (4-amino-3-methoxyphenyl) (1-methoxy-2-methylindolizin-3-) il) methanone - 3- (4-amino-3-methoxy-benzoyl) -2-methyllindolizin-1-ylcarboxylic acid 2- acid. { [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-methoxy-benzoyl) -2-methylindolizin-1-yl] oxy} .methyl) benzoic acid 3- (4-carboxybenzoyl) -2-methylindolizin 1-methylcarboxyl-3 - [(1-methoxy-2-methyl-indolizin-3-yl carbonyl-benzoate-4 - [(1-methoxy-2-methyl-indolizin-3-yl) carbonyl-benzoic acid-2-amino-5- acid [(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-tr'methoxybenzoyl) amino] indolizin-3-yl} carbonyl) benzoic acid 2-amino-5- ( { 1 - { [(3-methoxyphenyl) sulfonyl] amino} -2-methylindolizin-3-yl.} Carbonyl) benzoic optionally in association with one or more inert excipients and appropriate Such excipients are chosen according to the pharmaceutical form and the desired mode of administration: oral, intraocular or local The pharmaceutical compositions according to the present invention are preferably administered e orally or intraocularly. The pharmaceutical compositions according to the present invention are particularly preferably administered orally. In the pharmaceutical compositions of the present invention for oral administration, the active ingredients can be administered in unit dosage form, in admixture with conventional pharmaceutical carriers. Suitable unit administration forms comprise, for example, optionally divisible tablets, capsules, powders, granules and oral solutions or suspensions. When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets of sucrose or other suitable materials can be coated or they can even be treated so that they have a prolonged or delayed activity and continuously release a predetermined amount of active principle. A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the obtained mixture into the soft or hard capsules.

A preparation in the form of syrup or elixir may contain the active ingredient together with a sweetener, preferably caloric, methylparaben and propylparaben as antiseptics, as well as a taste donor and an appropriate colorant. Powders or granules dispersible in water may contain the active ingredient mixed with dispersing agents or wetting agents or suspending agents, such as polyvinylpyrrolidone, also with sweeteners or taste correctors. The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives. In the pharmaceutical compositions according to the present invention, the active principle may also be in the form. of inclusion complex in cyclodextrins, their ethers or their esters. The pharmaceutical compositions for local administration may be in the form of different ophthalmic formulations. They may contain, together with the active ingredient, ophthalmologically acceptable preservatives, surfactants, viscosity agents, agents that promote the penetration of the active principle, buffers, sodium chloride, as well as water to obtain sterile solutions or suspensions for ophthalmological use. Ophthalmic solutions can be prepared by dissolving the active ingredients in isotonic buffer solutions. These solutions may contain surfactants to facilitate the dissolution of the active principle. To allow a better application, the ophthalmic solutions may also contain a thickening agent such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose or polyvinyl pyrrolidone. To prepare sterile ophthalmic ointments, the active ingredient is combined with a preservative in an appropriate vehicle, for example liquid lanolin. Sterile gels can be prepared by suspending the active ingredient in a hydrophilic base containing carbopol-940 or other analogous compounds. For a local application, the pharmaceutical compositions according to the invention are preferably in the form of solutions or suspensions having a pH of 4 to 8. The concentration of the active principle should be from 0.0001% to 5% w / w, preferably 0 , 0001 to 1%. It can be administered according to the medical prescription of one to two drops of these compositions 1 to 4 times per day. The amount of active principle to be administered depends, as always, on the degree of progression of the disease as well as on the age and weight of the patient. In particular, the orally administrable pharmaceutical compositions according to the invention contain recommendable doses of active principle comprised between 1 and 900 mg / kg / day. Preferably, the orally administrable pharmaceutical compositions according to the invention contain recommendable doses of active principle comprised between 3 and 300 mg / kg / day. The orally administrable pharmaceutical compositions according to the invention particularly preferably contain recommended doses of active principle comprised between 1 and 100 mg / kg / day.

The following example, given by way of non-limiting, illustrates the present invention. Example: Laser induction of choroidal neovascularization. 1 . Material and method C57BI6 mice were used in these experiments. A model of laser-induced choroidal neovascularization (4 hits per eye around the papilla) has been applied to the animals as described in Tobe et al. J. Pathol, 1998). On day 14 after the induction and after an angiographic control that allows to estimate the percentage of lesions that develop a neovascularization, the animals are sacrificed and the balloons are removed for histological analysis. The mice are treated with one of the compounds of formula I during the last 7 days orally. The dose chosen for the sodium salt monohydrate of 2-amino-5 - [(1-methoxy-2-methylindolizin-3-yl) carbonyl] benzoic acid is 30 mg / kg / day. The vehicle used is a solution of methylcellulose in water at 0, 6%. Four mice are used for the control lot and six for the treated lot. The size of the neovascular reaction is estimated by morphometric evaluation of the thickness with the help of a computerized system of image analysis from frozen sections. The latter are either simply colored with hematoxillin, well examined with immunofluorescence using an antibody that allows localization of the vascular structures (anti-CD31). The estimation is made by measuring the B / C ratio between, on the one hand, the EPR and the peak of the neovascular reaction ("B") and, on the other hand, the thickness of the adjacent intact choroidal layer ("C"). ). This quantification system has been preferred to a lesion surface measurement, because it is independent of the orientation of the histological sections. 2.Results: The angiographies performed on day 14 showed the induction of neovessels in 72% of the lesions created with laser in the control mouse. Histological analysis and immunohistochemistry carried out with the help of anti-CD31 antibody confirmed the presence of neoformed capillaries at the level of areas that show a significant diffusion of fluorescein in the angiography in the control group. On the other hand, the animals treated with the compound did not present more than a moderate thickening of the choriocapillaris at the level of the impacts, without evident sign of neovascularization. The quantification of the laser-induced reaction effected by the measurement of the B / C ratio, has shown a significant reduction in the order of 50% of the reaction (p <; 0.001) in the mice treated with the compound comparatively with the control mice. These results confirm the great interest of the use of compounds of formula I for the preparation of medicaments useful for the treatment of diseases associated with a pathological angiogenesis - - choroidal

Claims (10)

CLAIMS 1. Use of 1, 2,3-substituted indolizine derivatives of the following general formula I: (I) wherein: Ri represents a hydroxy radical, a linear or branched alkoxy radical of 1 to 5 carbon atoms, a carboxy radical, an alkoxycarbonyl radical of 2 to 6 carbon atoms or a radical of the formula: • -NR5R6 -NH-SO2-Alk -NH-SO2-Ph -NH-CO-Ph -N (Alk) -CO-Ph • -NH-CO-NH-Ph -NH-CO-Alk -NH-CO2-Alk -O - (CH2) n-cAlk -O-Alk-COOR7 • -O-Alk-O-R8 • -O-Alk-OH • -O-Alk-C (NH2): NOH • -O-Alk-NR5R6 • - O-Alk-CN • -O- (CH2) n-Ph • -O-Alk-CO-NR5R6 • -CO-NH- (CH2) m-COOR7 • -CO-NH-Alk in which • Alk represents a alkyl radical or a linear or branched alkylene radical of 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 of 1 to 5, • R 5 and R 6 equal 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 a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, • R8 represents an alkyl radical of 1 to 5 carbon atoms or a radical -CO-AIk, • Ph represents a phenyl radical optionally substituted with one or more atoms of halogen, with one or more alkoxy radicals of 1 to 5 carbon atoms, with one or more carboxy radicals or with one or more alkoxycarbonyl radicals of 2 to 6 carbon atoms, R2 represents a hydrogen atom, an alkyl radical of 1 at 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 with one or more atoms of halogen, with one or more alkoxy radicals of 1 to 5 carbon atoms, one or more carboxy radicals or with one or more alkoxycarbonyl radicals of 2 to 6 carbon atoms, A represents a radical -CO -.- SO- or- SO2-, R3 and R4 equal or different Each represents each a hydrogen atom, an alkoxy radical of 1 to 5 carbon atoms, an amino radical, a carboxy radical, an alkoxycarbonyl radical of 2 to 6 carbon atoms, a hydroxy radical, a nitro radical, a hydroxyamino radical , a radical of the formula • -Alk-COOR7 -NR5R6 -NH-Alk-COOR7 -NH-COO-Alk -N (R1 1) -SO2-Alk-NR9R10 • -N (R1 1) -SO2-Alk -N ( R1 1) -Alk-NR5R6 -N (R1 1) -CO-Alk-NR9R10 -N (R1 1) -CO-Alk -N (R1 1) -CO-CF3 • -NH-Alk-HetN • -O- Alk-NR9R10 • -O-Alk-CO-NR5R6 • -O-Alk-HetN wherein n, m, Alk, R5, R6, and R, have the meaning given above for R1; and R9 and R10 equal or different each represent a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, Rn represents a hydrogen atom or a radical-Alk-COOR12 where R12 represents a hydrogen atom, an alkyl radical from 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 another heteroatom selected from nitrogen and oxygen; or R3 and R4 together form an unsaturated heterocycle of 5 to 6 members, with the proviso, however, that when R3 represents an alkoxy radical and R represents a radical-O-Alk-NR9R 0 or a hydroxy radical, Ri does not represent an alkoxy radical, optionally in the form of one of its pharmaceutically acceptable salts. for the preparation of medicines useful for the treatment of diseases associated with choroidal pathological angiogenesis. 2. Use according to claim 1 of compounds of general formula I in which: Ri represents a hydroxy radical, a linear or branched alkoxy radical of 1 to 5 carbon atoms, a carboxy radical, an alkoxycarbonyl radical of 2 to 6 carbon atoms carbon or a radical of the formula: • -NR5R8 • -NH-SO2-Alk • -NH-SO2-Ph • -NH-CO-Ph • -N (Alk) -CO-Ph • -NH-CO-NH-Ph • -NH-CO-Alk • -NH-CO2-Alk • -O- (CH2) n-cAlk • -O-Alk-COOR7 • -O-Alk-O-R8 • -O-Alk-OH • -O -Alk-NR5R6 • -O-Alk-CN • -O- (CH2) n-Ph • -O-Alk-CO-NR5R6 • -CO-NH- (CH2) m-COOR7 • -CO-NH-Alk in those which • Alk represents an alkyl radical or a linear or branched alkylene radical of 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, • R5 and d equal or different each represents a hydrogen atom , a linear or branched alkyl radical of 1 to 5 carbon atoms or a benzyl radical, • R7 represents a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, • R8 represents an alkyl radical of 1 to 5 carbon atoms; carbon or a radical-CO-Alk • Ph represents a phenyl radical optionally substituted with one or several halogen atoms, with one or more alkoxy radicals of

1 to 5 carbon atoms, one or more carboxy radicals or with 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 with one or more halogen atoms, with one or more alkoxy radicals of 1 to 5 carbon atoms, with one or more carboxy radicals or with one or more alkoxycarbonyl radicals of 2 to 6 atoms of carbon, A represents a radical - CO -, - SO2 -, R3 and R4 equal or different each represents a hydrogen atom, an alkoxy radical of 1 to 5 carbon atoms, an amino radical, a carboxy radical, a radical alkoxycarbonyl of 2 to 6 carbon atoms, a nitro radical, a hydroxyamino radical, a radical of the formula • -Alk-COOR7 • -NR5R6 -NH-Alk-COOR7 -NH-COO-Alk -NYRn J-SOz-Alk-NRgRm -N (Rn) -SO2-Alk -N (Rn) -Alk-NR5R6 -N (Rn) -CO-Alk-NR9R? Or -N (Rn) -CO-Al k -N (Rn) -CO-CF 3 -NH-Alk-HetN wherein n, m, Alk, R 5, R 6, and R 7 have the meaning given above for R 1; and 9 and R 10 equal or different each represent a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, R n represents a hydrogen atom or a radical-Alk-COOR 12 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 another heteroatom chosen from nitrogen and oxygen, optionally in the form of one of its pharmaceutically acceptable salts. 3. Use according to any one of claims 1 to 2, of compounds of general formula I, in which: RI represents an alkoxy radical of 1 to 5 carbon atoms, a carboxy radical, a radical-O-Alk-COOH 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 with one or more halogen atoms or with one or more alkoxy radicals of 1 to 5 carbon atoms or with one or more carboxy radicals, a radical of formula -NH-CO-Ph, a radical of formula -NH-SO2- 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 radical-CO-, R 3 and R each represent each a hydrogen atom, a radical alkoxy of 1 to 5 carbon atoms, an amino radical, a carboxy radical, an alkoxycarbonyl radical of 2 to 6 carbon atoms, optionally in the form of one of its pharmaceutically acceptable salts. 4. Use according to any one of claims 1 to 3, of compounds of general formula I selected from among (4-amino-3-methoxyphenyl) (1-methoxy-2-methylindolizin-3-yl) methanone 3- (4-amino) -3-methoxy benzoyl) 2-methylindolizin-1-ylcarboxylic acid 2-. { [3- (4-amino-3-methoxybenzoyl) 2-methylindolizin-1-yl] oxy} acetic acid (4-amino-3-methoxyphenol). { 1 - [(4-Chlorobenzyl) oxy] 2-methylindolizin-3-ylmetanone (4-amino-3-methoxyphenyl). { 1 - [(3-methoxybenzyl) oxy] 2-methylindolizin-3-yl} methanone 4- ( { [3- (4-amino-3-methoxy benzoyl) 2-methylindolizin-1-yl] oxy} methyl) benzoic acid 3- (4-carboxybenzoyl) 2-methylindolizin 1-methylcarboxylic acid 3 - [(1-methoxy-2-methylindolizin-3-ylcarbonylbenzoate 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-tri-methoxy-benzoyl) -amino] -dolizin-

3-yl} -carbonyl) benzoic acid 2-amino-5-acid - ( { 1 - { [(3-methoxyphenyl) sulfonyl] amino.} -2-methylindolizin-3-yl.} Carbonyl) benzoic optionally in the form of one of its pharmaceutically acceptable salts. 5. Use according to any one of claims 1 to 4 of compounds of general formula I, for the preparation of medicines useful for the treatment of diseases associated with choroidal pathological angiogenesis, such as age-related macular degeneration (AMD), strong myopia, pseudo xanthoma, presumed histsmosis syndrome, toxsmosis, sarcoidosis, Behcet's disease. 6. Pharmaceutical composition containing at least one active ingredient corresponding to a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in association with one or more inert excipients, for the manufacture of a medicament for the treatment of diseases associated with a choroidal pathological angiogenesis. 7. Pharmaceutical composition according to claim 6, characterized in that it contains at least one active principle corresponding to a compound of formula I chosen from (

4-amino-3-methoxyphenyl) (1-methoxy-2-methylindolizin-3-yl) methanone. 3- (4-amino-3-methoxy-benzoyl) -2-methylindolizin-1-i-carboxylic acid 2- acid. { [3- (4-amino-3-methoxybenzoyl) 2-methylindolizin-1-yl] oxy} acetic (4-amino-3-methoxyphenyl). { 1 - [(4-Chlorobenzyl) oxy] 2-methylindolizin-3-yl} methanone (4-amino-3-methoxypheni) 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 methyl 3 - [(1-methoxy-2-methylindolizin-3-yl) carbonyl-benzoate 4 - [(1-methoxy-2-methylindolizin-3-yl) carbonyl-benzoic acid 2-amino-

5 - [(1-methylcarbonyl)] -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 optionally in association with one or more suitable and inert excipients. 8. Pharmaceutical composition according to any one of claims 6 to 7, characterized in that it is administrable orally, infraocularly or locally. 9. An orally administrable pharmaceutical composition according to claim 8, characterized in that it contains recommended doses of active principle, optionally in the form of one of its pharmaceutically active salts, comprised between 1 to 900 mg / kg / day, preferably comprised between 3 and 300 mg / kg / day, preferably between 1 to 100 mg / kg / day. 10. Pharmaceutical composition according to claim 8, provided for a local administration, in the form of solution or suspension, characterized in that it has a concentration of active principle of 0.0001% to 1%.