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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
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  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• New substituted indolizine derivatives 1,2,3,6,7,8, inhibitors of FGFs process for their preparation and pharmaceutical compositions containing them.
• the present invention relates to new substituted indolizine derivatives 1,2,3,6,7,8 which are inhibitors of FGFs (Fibroblast Growth Factor), their process of preparation and the pharmaceutical compositions containing them.
• FGFs are a family of polypeptides synthesized by a large number of cells during embryonic development and by cells of adult tissues under various pathological conditions.
• EP 302,792, EP 0 382,628, and EP 0 235,111 are useful in the treatment of angina pectoris and arrhythmia. Inhibitory properties of calcium translocation are described for some of these compounds.
• Patent application EP 0 022 762 also describes certain indolizine derivatives which have an inhibiting activity of xanthine oxidase and adenosine deaminase as well as a uricosuric activity. These compounds can be used in the treatment of physiological disorders resulting from an excess of uric acid, disturbances of the immune system and parasitic agents.
• R at positions 6, 7 or 8 of indolizine represents a hydrogen atom, a halogen atom, a methyl radical, 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: -NR 5 R 6 -NH-SO 2 -Alk -NH-CO-Alk -NH-CO 2 -Alk • -O- Alk-COOR 7 -O-Alk-NR 5 R 6 -O- (CH 2 ) n -Ph -CO-NR 5 R 6 where • Alk represents an alkyl radical or a linear or branched alkylene radical of 1 to 5 atoms carbon, • n represents an integer from 0 to 5, • R 5 and R 6 identical or different each represent a hydrogen atom, a linear or branched alkyl radical of 1 to 5 carbon atoms or
• R 2 represents an alkyl radical of 1 to 5 carbon 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 from 1 to 5 carbon atoms,
• a compound of formula I is preferred in which:
• R in positions 6, 7 or 8 of indolizine represents a hydrogen atom, a halogen atom, a hydroxy radical, a linear or branched alkoxy radical of 1 to 5 carbon atoms, a carboxy radical, a alkoxycarbonyl radical of 2 to 6 carbon atoms or a radical of formula: -NR 5 R 6 -NH-SO 2 -Alk -NH-CO-Alk -NH-CO 2 -Alk -O-Alk-COOR 7 -O-Alk-NR 5 R 6 -CO-NR 5 R 6 where • Alk represents an alkyl radical or a linear or branched alkylene radical of 1 to 5 carbon atoms, • R 5 and R ⁇ 3 identical or different each represent a hydrogen atom, a linear or branched alkyl radical of 1 to 5 carbon atoms carbon or a benzyl radical, • R represents a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms,
• R 3 and R 4 which are identical or different, each represent a hydroxy radical, 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 radical of formula • -NR 5 R 6 • -NH-CO-Alk • -CO- NRsR ⁇ • -CO- NHOH where • Alk, R 5 and R ⁇ 5 have the meaning given above for R, provided however that when R represents a hydrogen atom, Ri does not represent a linear or branched alkoxy radical of 1 to 5 carbon atoms, a carboxy radical, or an alkoxycarbonyl radical of 2 to 6 carbon atoms, except in the case where R or R 4 represents a radical -CO-NR 5 R 6 or a radical -CO-NHOH, optionally in the form of one of their pharmaceutically acceptable salts.
• a compound of formula I is particularly preferred in which:
• R in positions 6, 7 or 8 of indolizine represents a hydrogen atom, a linear or branched alkoxy radical of 1 to 5 carbon atoms, an alkoxycarbonyl radical of 2 to 6 carbon atoms or a radical of formula : • -NR 5 R 6 • -CO-NR 5 R 6 where • R 5 and R 6 identical or different each represent a hydrogen atom, a linear or branched alkyl radical of 1 to 5 carbon atoms or a benzyl radical ,
• Ri represents • a linear alkoxy radical branched from 1 to 5 carbon atoms, • a carboxy radical, • a phenyl radical optionally substituted by one or more halogen atoms, by one or more alkoxy radicals from 1 to 5 carbon atoms, by one or more carboxy radicals or by one or more alkoxycarbonyl radicals of 2 to 6 carbon atoms, • a 5-membered heteroaryl radical comprising a heteroatom chosen from a sulfur atom, or an oxygen atom, or a nitrogen atom, optionally substituted by one or more halogen atoms, by one or more alkoxy radicals of 1 with 5 carbon atoms, with one or more carboxy radicals or with one or more alkoxycarbonyl radicals with 2 to 6 carbon atoms, • or a 6-membered heteroaryl radical containing 1 or 2 nitrogen atoms and which may be optionally substituted by a or more halogen atoms, by one or more alkoxy radicals of 1 to
• R 2 represents an alkyl radical of 1 to 5 carbon atoms
• R 3 and R 4 which are identical or different, each represent an alkoxy radical of 1 to 5 carbon atoms, an amino radical, a carboxy radical, a hydroxy radical, or a radical of formula CO-NR 5 R 6 where R 5 and R ⁇ have the meaning given above for R provided, however, that when R represents a hydrogen atom, Ri does not represent a linear or branched alkoxy radical of 1 to 5 carbon atoms, or a carboxy radical, except in the case where R 3 or 4 represents a radical -CO-NR 5 R 6> optionally in the form of one of their pharmaceutically acceptable salts.
• particularly preferred compounds are: • - [3- (4-amino-3-methoxybenzoyl) -6-methoxy-2-methylindolizin-l-yl] carboxylic acid (4-amino-3 -methoxyphenyl) [1- (4-methoxyphenyl) -2-methylindolizin-3-yl] methanone 3- (4-amino-3-methoxybenzoyl) - (l-methoxy-N, 2-dimethylindolizin-6-yl) carboxamide acid [3- (4-amino-3-methoxybenzoyl) -2-methyl-7- (methylamino) indolizin-1 - yl] carboxylic acid [3- (4-amino-3-methoxybenzoyl) -7- (dimethylamino) -2 -methylindolizin-1 - yl] carboxylic acid 2-amino-5 - ( ⁇ l-methoxy-2-methyl-6
• the present invention also relates to a process for the preparation of the compounds of formula I characterized in that A) condensing an indolizine derivative of formula II,
• R, Ri and R 2 have the meaning given for formula I but when Ri represents an alkoxycarbonyl radical, R does not represent in position 7 a radical -NR 5 R ⁇ 6 , a radical -NH-CO-Alk, a radical -NH-CO 2 -Alk or a radical -NH-SO 2 -Alk, with a derivative of formula III:
• X represents a halogen atom and R 3 or i either represent an alkoxy radical of 1 to 5 carbon atoms, a nitro radical, or an alkoxycarbonyl radical of 2 to 6 carbon atoms, or a trifluoroacetamido radical to obtain the compounds of formula la, Ib or le:
• R or R 4 represent an amino radical
• R t or R 3 represent a radical -NR 5 R ⁇ (in which R represents a hydrogen atom and R 6 represents an alkyl radical of 1 to 5 carbon atoms) or are subjected when R does not represent a hydroxy radical with an acylation to obtain the compounds of formula
• R4 or R represent a radical -NH-CO-Alk
• R and / or R 3 and / or Ri represent an alkoxycarbonyl radical saponification in order to obtain the compounds of formula le in which R and / or R 3 and / or t represents a carboxy radical
• R represents an alkoxy radical or a radical of formula -O-Alk-COOR 7 which can be optionally saponified to obtain a radical of formula -O-Alk-COOH. or d) when the compounds of formula la are subjected to O-alkylation when R represents a hydroxy radical, in order to obtain the compounds of formula Ii:
• R 3 or i have the meanings given for la and R represents an alkoxy radical, a radical of formula -0-Alk-NR 5 R 6 , or a radical of formula - O-Alk-COOR 7 , which subsequently may optionally be saponified to obtain a radical of formula -O-Alk-COOH, or e) when R 1 represents an alkoxycarbonyl radical, the compounds of formula I are subjected to a saponification to obtain the compounds of formula Ij:
• R does not represent a halogen atom such as bromine or iodine and R 2 and R 3 or Ri have the meanings given above and Ri represents a substituted phenyl radical or an optionally substituted 5 or 6-membered heteroaryl, or g) submitting when R does not represent a hydroxy or amino or carboxy radical and R 3 or 4 .
• R 3 or - 4 represents a radical -CO-NRsR ⁇ or -CO-NHOH
• FIGURE 1 GENERAL SUMMARY DIAGRAM
• the compounds of formula Id or Ig are obtained in which R or R represents an amino radical.
• R or R represents an amino radical.
• the compounds of formula If are obtained for which R 3 or R 4 represents a radical - NR 5 R 6 (in which R 5 represents a d atom 'hydrogen and R 6 has the meanings given above).
• R 3 or R 4 represents a radical -NH-CO-Alk.
• the compounds of formula Ih are obtained in which R represents a linear alkoxy radical of 1 to 5 carbon atoms, or a radical -O-Alk-C00R 7 .
• the latter radical can subsequently be optionally saponified in order to obtain a radical of formula -O-Alk-COOH.
• the compounds of formula Ii are obtained by subjecting these compounds to O-alkylation, or R represents an alkoxy radical of 1 to 5 carbon atoms, a radical of formula - O-Alk-COOR (which can then be optionally saponified to obtain a radical of formula -O-Alk-COOH), or a radical of formula -O-Alk-NR 5 R 6 and R 3 or R 5 represents a nitro radical.
• the compounds of formula Ij in which Ri is a carboxy radical are subjected to saponification.
• the compounds of formula Ik are obtained by bromination, or Ri represents a brorne atom and R, R 3 or R have the meanings given5 in the general formula.
• R 2 represents a methyl radical and R represents either a -CONHCH 3 radical in position 6 or a -NHCOOtBu radical in position 6 are prepared according to the following synthetic scheme in using the Tschitschibabin reaction (Synthesis, (1975), p209) as before.
• the compounds of formula I are potent antagonists of FGF-1 and 2
• Their ability to inhibit both the formation of new vessels from differentiated endothelial cells and to block the differentiation of adult human bone marrow cells CD34 + CD133 + in endothelial cells has been demonstrated in vitro.
• their ability to inhibit pathological angiogenesis has been demonstrated in vivo.
• the compounds of formula I have been shown to be potent antagonists of the FGF-1 receptor.
• FGFs are significantly involved via autocrine, paracrine or juxtacrine secretions in the phenomena of deregulation of the stimulation of cancer cell growth.
• FGFs affect tumor angiogenesis which plays a major role both in the growth of the tumor but also in the phenomena of metastasization.
• Angiogenesis is a process of generation of new capillary vessels from preexisting vessels or by mobilization and differentiation of bone marrow cells.
• endothelial cells an uncontrolled proliferation of endothelial cells and a mobilization of angioblasts from the bone marrow are observed in the neovascularization processes of tumors.
• growth factors have been shown in vitro and in vivo to stimulate endothelial proliferation, including FGF-1 or a-FGF and FGF-2 or b-FGF. These two factors induce the proliferation, migration and production of proteases by endothelial cells in culture and neovascularization in vivo.
• a-FGF and b-FGF receptors interact with endothelial cells via two classes of receptors, high affinity tyrosine kinase receptors (FGFs) and low affinity heparan sulfate proteoglycan receptors (HSPGs). located on the surface of cells and in extracellular matrices. While the paracrine role of these two factors on endothelial cells is widely described, a-FGF and b-
• a-FGF and b-FGF and their receptors represent very relevant targets for therapies aimed at inhibiting angiogenesis processes (Keshet E, Ben-Sasson SA.,. J. Clin. Invest, (1999), vol 501, ppl04-1497; Presta M, Rusnati M, Dell'Era P, Tanghetti E, Urbinati C, Giuliani R et al, New York: Plénum Publishers, (2000), pp7- 34, Billottet C, Janji B, Thiery JP, Jouanneau J, Oncogene, (2002) vol 21, pp8128- 8139).
• A-FGF and b-FGF play an important role in the growth and maintenance of prostate cells. It has been shown in both animal and human models that an alteration of the cellular response to these factors plays a key role in the progression of prostate cancer. Indeed, in these pathologies, there is both an increase in the production of a-FGF and b-FGF by fibroblasts and endothelial cells present at the level of the tumor and an increase in the expression of FGF receptors on tumor cells. . Thus paracrine stimulation of prostate cancer cells takes place, and this process would be a major component of this pathology.
• a compound having an FGF receptor antagonist activity such as the compounds of the present invention may represent a therapy of choice in these pathologies (Giri D, Ropiquet F., Clin.
• FGFRs both in human breast tumor lines (notably MCF7) and in tumor biopsies. These factors are responsible in this pathology for the appearance of a very aggressive phenotype and inducing strong metastasization.
• a compound possessing an antagonist activity of FGFRs receptors like the compounds of formula I, can represent a therapy of choice in these pathologies
• Cancerous melanomas are tumors which induce metastases with a high frequency and which are very resistant to various chemotherapy treatments.
• the angiogenesis process plays a major role in the progression of a cancerous melanoma.
• the probability of metastasis appears very strongly with increasing vascularization of the primary tumor.
• Melanoma cells produce and secrete different angiogenic factors including a-FGF and b-FGF.
• a compound having an antagonistic activity of FGF receptors such as the compounds of the present invention may represent a therapy of choice in these pathologies (Rofstad EK, Halsor EF., Cancer Res., 2000); Yayon A, Ma YS, Saffron M, Klagsbrun M, Halaban R., Oncogene, (1997), vol 14, pp 2999-3009).
• Glioma cells produce in vitro and in vivo a-FGF and b-FGF and have different FGF receptors on their surface. This therefore suggests that these two factors, through an autocrine and paracrine effect, play a pivotal role in the progression of this type of tumor. In addition, like most solid tumors, the progression of gliomas and their ability to induce metastases is very dependent on the angiogenic processes in the primary tumor. FGF-1 receptor antisense has also been shown to block the proliferation of human astrocytomas. In addition, naphthalenesulfonate derivatives are described to inhibit the cellular effects of a-FGF and b-FGF in vitro and the angiogenesis induced by these growth factors in vivo.
• a compound possessing an antagonist activity of a-FGF and / or b-FGF and / or FGF receptors can represent a therapy of choice in these pathologies (Yamada SM, Yamaguchi F, Brown R , Berger MS, Morrison RS, Glia, (1999), vol 76, pp28-66; Auguste P, Gt ⁇ rsel DB, Lemière S, Reimers D, Cuevas P, Carceller F et al., Cancer Res., (2001), vol 26, pp 61-1717).
• b-FGF has been detected in many lymphoblastic and hematopoietic tumor cell lines. FGF receptors are also present on the majority of these lines, suggesting a possible autocrine cellular effect of a-FGF and b-FGF inducing the proliferation of these cells. Furthermore, it has been reported that angiogenesis of the bone marrow by paracrine effects was correlated with the progression of some of these pathologies. More specifically, it has been shown in CLL (chronic lymphocytic leukemia) cells that b-FGF induces an increase in the expression of anti apoptotic protein (Bcl2) leading to an increase in the survival of these cells and therefore participates in important way to their cancerization.
• CLL chronic lymphocytic leukemia
• a compound possessing an antagonist activity of FGF receptors can represent a therapy of choice either alone or in combination with fludarabine or other products active in this pathology (Thomas DA, Giles FJ, Cortes J, Albitar M, Kantarjian HM., Acta Haematol, (2001), vol 207, ppl06-190; Gabrilove JL, Oncologist, (2001), vol 6, pp4-7).
• Thomas DA Giles FJ, Cortes J, Albitar M, Kantarjian HM.
• vascular smooth muscle cells contributes to intimal hypertrophy of the arteries and thus plays a predominant role in atherosclerosis and in restenosis after angioplasty and endoarterectomy.
• in vivo studies show, after carotid lesion by "balloon injury", local production of a-FGF and b-FGF.
• a neutralizing anti-FGF2 antibody inhibits the proliferation of vascular smooth muscle cells and thus reduces intimal hypertrophy.
• a chimeric protein FGF2 linked to a molecule such as saporin inhibits the proliferation of vascular smooth muscle cells in vitro and intimal hypertrophy in vivo (Epstein CE, Siegall CB, Biro S, Fu YM, FitzGerald D., Circulation, (1991 ), vol 87, pp84-778; Waltenberger J., Circulation, (1997), pp96-4083).
• the FGF receptor antagonists such as the compounds of the present invention represent a therapy of choice, either alone or in combination with antagonist compounds of other growth factors involved in these pathologies such as PDGF, in the treatment of pathologies linked to the proliferation of vascular smooth muscle cells such as atherosclerosis, post-angioplasty restenosis or following the placement of endovascular prostheses (stents) or during aortocoronary bypass surgery.
• vascular smooth muscle cells such as atherosclerosis, post-angioplasty restenosis or following the placement of endovascular prostheses (stents) or during aortocoronary bypass surgery.
• Cardiac hypertrophy occurs in response to stress in the ventricular wall induced by an overload in terms of pressure or volume. This overload can be the consequence of many physiological pathological conditions such as hypertension, AC
• vascular coarctation myocardial infarction
• various vascular disorders morphological, molecular and functional changes such as hypertrophy of cardiac myocytes, accumulation of matrix proteins and re-expression of fetal genes.
• B-FGF is involved in this pathology. Indeed, the addition of b-FGF to cultures of cardiomyocytes of newborn rats modifies the profile of the genes corresponding to the contractile proteins leading to a profile of fetal type genes. In addition, adult rat myocytes show a hypertrophic response under the effect of b-FGF, this response being blocked by neutralizing anti-b-FGF antibodies.
• vascular disorders due to diabetes are characterized by impaired vascular reactivity and blood flow, hyperpermeability, response proliferative exacerbated and increased deposition of matrix proteins. More specifically, a-FGF and b-FGF are present in the pre-retinal membranes of patients with diabetic retinopathies, in the membranes of the underlying capillaries and in the vitreous humor of patients suffering from proliferative retinopathies.
• a soluble FGF receptor capable of binding both a-FGF and b-FGF is developed in vascular disorders linked to diabetes (Tilton RG, Dixon RAF, Brock TA., Exp. Opin. Invest. Drugs, (1997 ), vol 84, pp6-1671).
• a compound such as the compounds of formula I possessing an antagonist activity of the FGFs receptors represents a therapy of choice either alone or in combination with antagonist compounds of other growth factors implicated in these pathologies such as VEGF.
• RA Rheumatoid arthritis
• Angiogenesis seems to significantly affect the progression of this pathology.
• a-FGF and b-FGF have been detected in the synovial tissue and in the joint fluid of patients with RA, indicating that this growth factor is involved in the initiation and / or progression of this pathology.
• AI A adjuvant-induced model of artliritis
• overexpression of b-FGF has been shown to increase the severity of the disease, while a neutralizing anti-b-FGF antibody blocks the progression of RA (Yamashita A, Yonemitsu Y, Okano S, Nakagawa K, Nakashima Y, Irisa T et al., J.
• IBD inflammatory bowel disease
• UC ulcerative colitis
• CD Crohn's disease
• IBDs are characterized by immune dysfunction resulting in the inappropriate production of inflammatory cytokines inducing the establishment of a local microvascular system. This angiogenesis of inflammatory origin results in intestinal ischemia induced by vasoconstriction. Significant circulating and local levels of b-FGF have been measured in patients with these pathologies (Kanazawa S, Tsunoda T, Onuma E,
• the compounds of the invention exhibiting significant anti-angiogenic activity in a model of inflammatory angiogenesis represent a therapy of choice in these pathologies.
• the FGF-1 receptors 2 and 3 are involved in the processes of chronogenesis and osteogenesis.
• ACH hypochondroplasia
• TD Teratophoric dysplasia
• ACH being the most common form of dwarfism. From a biochemical point of view, the sustained activation of these receptors is effected by dimerization of the receptor in the absence of ligand (Chen L., Adar R., Yang X. Monsonego EO, LI C, Hauschka PN, Yagon A. and Deng CX, (1999), The Journ. Of Clin. Invest., vol 104 n ° 11, pp 1517-1525).
• the compounds of the invention exhibiting an antagonistic activity of the binding of b-FGF to the FGF receptor and thus inhibiting the dimerization of the receptor represent a therapy of choice in these pathologies.
• adipose tissue is one of the rare tissues which in adults can develop or regress. This tissue is very vascular and a very dense network of micro vessels surrounds each adipocyte.
• an FGF receptor antagonist compound having a potent anti-angiogenic activity may represent a therapy of choice in pathologies linked to obesity.
• the compounds of the present invention find their application in the treatment of any carcinoma having a significant degree of vascularization (lung, breast, prostate, esophagus) or inducing metastases (colon, stomach , melanoma) or being sensitive to a-FGF or b-FGF in an autocrine manner or finally in pathologies such as lymphomas and leukemias.
• carcinoma having a significant degree of vascularization lung, breast, prostate, esophagus
• metastases colon, stomach , melanoma
• pathologies such as lymphomas and leukemias.
• the compounds according to the invention also find their application in the treatment of cardiovascular diseases such as atherosclerosis, post-angioplasty restenosis in the treatment of diseases related to complications arising from the insertion of endovascular prostheses and / or bypass surgery and other vascular grafts and cardiac hypertrophy or vascular complications of diabetes like diabetic retinopathies.
• cardiovascular diseases such as atherosclerosis, post-angioplasty restenosis
• the compounds according to the invention also find their application in the treatment of chronic inflammatory diseases such as rheumatoid arthritis or IBD.
• the compounds according to the invention can be used in the treatment of achondroplasia (ACH), hypochondroplasia (HCH) and TD (Thanatophoric dysplasia), as also in the treatment of obesity.
• ACH a
• the products according to the invention also find their application in the treatment of macular degeneration.
• a major feature of loss of vision in adults is neovascularization and subsequent hemorrhages which cause major functional disorders in the eye and which result in early blindness.
• Recently, the study of the mechanisms involved in the phenomena of ocular neovascularization has made it possible to highlight the implication of pro-angiogenic factors in these pathologies.
• By implementing a model of laser-induced choroidal neoangiogenesis it was possible to confirm that the products according to the invention also make it possible to modulate the neovascularization of the choroid.
• the products of the invention can be used in the treatment or prevention of tl thrombocytopenia due in particular to anti-cancer chemotherapy. It has indeed been demonstrated that the products of the invention can improve the levels of circulating platelets during chemotherapy.
• the subject of the present invention is a pharmaceutical composition containing, as active principle, a compound of formula I according to the invention or one of its pharmaceutically acceptable salts, optionally in combination with one or more inert excipients and appropriate.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration: oral, sublingual, subcutaneous, intramuscular, intravenous, transdemic, transmucosal, local or rectal.
• compositions according to the present invention are preferably administered orally.
• the active ingredients can be administered in unit administration form, in admixture with conventional pharmaceutical carriers.
• Suitable unit dosage forms include, for example, possibly scored tablets, capsules, powders, granules and oral solutions or suspensions.
• the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• the tablets can be coated with sucrose or other suitable materials or they can be treated in such a way that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
• a preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
• a preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.
• the water-dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or taste.
• the active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
• the active principle can also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.
• the amount of active ingredient to be administered depends, as always, on the degree of progression of the disease and on the age and weight of the patient.
• compositions according to the invention for oral administration, therefore contain recommended doses of 0.01 to 700 mg.
• the mixture When the introduction is complete, the mixture is allowed to return to ambient temperature and stirred for 2 hours.
• the reaction medium is poured onto water and ethyl acetate.
• the organic phase is decanted, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure.
• a mixture containing the two desired products is collected, which is separated by chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95-5 then 9-1). The two collected fractions are then evaporated.
• reaction medium is evaporated to dryness.
• a mixture of two products is collected which is separated by chromatography on silica gel, eluting with a mixture of toluene-ethyl acetate (9-1). This separation is followed by thin layer chromatography (TLC) using a mixture of dichloromethane and methanol (9-1) as eluent.
• TLC thin layer chromatography
• Step A [1-methoxy-3- (3-methoxy-4-nitrobenzoyI) -2-methylindolizin-6-yl] carboxylic acid
• the reaction medium is concentrated in vacuo and the residue is taken up with water and ethyl acetate.
• the aqueous phase is decanted and then acidified with 1.21ml IN hydrochloric acid.
• the precipitate formed is filtered, washed with water and dried. 280 mg of an orange solid are obtained.
• Stage BA 260mg (0.66 m.mole) of [l-methoxy-3- (3-methoxy-4-nitrobenzoyl) -2- methylindolizin-6-yl] carboxylic acid in 5 ml of iV, N-dimethylformamide or added 0.4 ⁇ l (0.74 m.mole) of triethylamine then 330 mg (0.74 m.mole) of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium liexafluorophosphate (BOP) and stirred for one hour at room temperature.
• BOP benzotriazol-1-yloxy-tris (dimethylamino) phosphonium liexafluorophosphate
• Example 22 (3-methoxy-4-nitrophenyI) [1- (4-methoxyphenyI) -2-methylindolizin-3-yl] methanone
• STEP A (3-methoxy-4-nitrophenyl) (2-methylindolizin-3-yI) methanone
• This compound is obtained by proceeding according to the preparation described in Example 1, by benzoylation of 2-methylindolizine, described in Pharmazie; (1980), vol 35 (4), pp 203-204, with 3-methoxy-4-nitrobenzoyl chloride. 6.52 g of an orange solid are obtained. Yield: 92% Melting point: 161 ° C
• the organic phase is decanted, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in dichloromethane and the product is purified by filtration on a bed of silica gel. After evaporation, 6.75 g of a yellow solid are collected.
• the reaction medium is poured onto water and extracted with ethyl acetate.
• the organic phase is decanted, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure.
• the product is purified by chromatography on silica gel, eluting with a mixture of toluene and ethyl acetate (92-8). After evaporation, 500 mg of an orange solid is collected. Yield: 93.5% Melting point: 169 ° C
• STEP BA a solution of 5.0 g (10.67 m.moles) of 4- [N- (tert-butoxycarbonyl) amino] -l- [2- (3-methoxy-4-nitrophenyl) -2-oxoethyl bromide ] pyridinium in 40 ml of dimethylformamide, 9.4 g (53.38 m.moles) of benzyl crotonate are successively added,
• the reaction mixture is then heated at 90 ° C for 4 hours then filtered through a silica bed, eluting with ethyl acetate.
• the filtrate is poured onto water and extracted with ethyl acetate. After decantation, the organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure.
• the product is purified by chromatography on silica gel, eluting with a toluene / ethyl acetate mixture (95/5 to 70/30). 2.6g of an orange powder are obtained.
• Step B from 1.8 g (4.1 m.moles) of 4- [N- (ethoxycarbonyl) amino] -l- bromide
• Example 56 (4-amino-3-methoxyphenyl) [1- (4-methoxyphenyl) -2-methylindolizin-3-yl] methanone
• the filtrate is concentrated under reduced pressure.
• the product is purified by chromatography on silica gel, eluting with a mixture of toluene and ethyl acetate (9-1 then 8-2). 400 mg of a yellow powder are obtained.
• the product is salified by dissolving the powder previously obtained in dioxane and then adding 1.18 ml (1.2 equivalent) of IN hydrochloric acid in ethyl ether. After addition of ethyl ether, the precipitate obtained is filtered, washed with ethyl ether and then dried. 400 mg of a yellow powder are collected in the form of the hydrochloride. Efficiency: 94%
• Example 67 [3- (4-amino-3-methoxybenzoyl) -6- (benzyloxy) -2-meth r lindolizin-l-yl] methyl carboxylate
• the mixture is heated to 70 ° C. for 3 hours then allowed to return to ambient temperature before pouring the reaction medium onto water and extracting with dichloromethane.
• Example 70 [3- (4-amino-3-methoxybenzoyl) -1- (4-methoxyphenyl) -2-methylindolizin-6-yl] carboxamide
• the reaction medium is filtered through talc and the catalyst is washed with methanol.
• the filtrate is concentrated under reduced pressure.
• the residue is purified by flash chromatography on a silica column, eluting with a dichloromethane-methanol mixture (98-2) then (95-5).
• the pure fractions are concentrated under reduced pressure and 610 mg of a yellow powder are collected.
• the product is salified by adding IN hydrochloric acid in ethyl ether. After addition of ethyl ether, the precipitate obtained is filtered, washed with ethyl ether and then dried. A yellow solid is collected in the form of hydrated hydrochloride (1.35 H 2 O).
• Example 71 to 77 Proceeding according to the preparation described in Example 70, the compounds described in Table VII below are synthesized, by reduction of the nitro function of the compounds of formula la with hydrazine hydrate in the presence of Pd / C at 10%> as catalyst.
• Example 78 [3- (4-amino-3-methoxybenzoyl) -6-hydroxy-2-methylindolizin-1-yI] methyl carboxylate
• the reaction mixture is stirred under 10 bar of hydrogen for 48 hours.
• An ultrafiltration is carried out (Millipore TM filter 5 ⁇ M) and the catalyst is washed with dimethylformamide.
• the filtrate is concentrated under reduced pressure to obtain 780ng of a yellow solid. Yield: 91% Melting point: 184 ° C
• Example 79 [3- (4-amino-3-methoxybenzoyl) -6-hydroxy-2-methylimdolizin-1-yl] carboxylic acid This compound is obtained according to the same process as the compound of Example 78 above by debenzylation of the hydroxy function and reduction of the nitro function, by catalytic hydrogenation under pressure of the compound of Example 97. A yellow solid is obtained which salified in the form of sodium salt. A yellow solid is obtained (Na salt, 1.5H 2 O) Yield: 70% Melting point: 214 ° C
• Example 83 [7- (acetylamino) -3- (4-amino-3-methoxybenzoyl) -2-methylindolizin-1-yl] carboxylic acid A 855 mg (1.76 m.mole) of [7- (acetylamino) -3 - (3-methoxy-4-nitrobenzoyl) -2-methylindolizin-1-yl] benzyl carboxylate suspended in 9 ml of dimethylformamide, 450 mg of Pd / C (10%) are added. The reaction mixture is stirred under 10 bar of hydrogen for 5 hours.
• Example 84 to 88 Proceeding according to the procedure described above, the compounds described in Table VIII below are synthesized by hydrogenation under pressure of the benzyl ester of Rj and reduction of the nitro of R 3 or Ri TABLE VIII
• the residue is taken up in water and the solution obtained is acidified to pH 3-4 with a 10% aqueous solution> of potassium hydrogen sulphate and then extracted with ethyl acetate.
• the organic phase is decanted, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure.
• the 398 mg of yellow solid obtained is then salified, in the form of sodium salt.
• Example 90 [3- (4-amino-3-methoxybenzoyl) -1-methoxy-2-methylindolizin-6-yl] carboxylic acid
• the aqueous phase is decanted, washed with ethyl acetate and then acidified with 2 ml of IN hydrochloric acid.
• the precipitate formed is filtered, washed with water and then dried.
• the 189 mg of orange solid obtained are then salified, in the form of sodium salt.
• Example 91 [3- (4-amino-3-methoxybenzoyl) -6- (benzyloxy) -2-methylindolizin-1-yl] carboxylic acid 800mg (1.79 m.mole) of [3- (4-amino- 3-methoxybenzoyl) -6- (benzyloxy) -2- methylindolizin-1-yl] methyl carboxylate dissolved in 30 ml of dioxane and 10 ml of methanol 358 mg (8.95 m.moles) of sodium hydroxide are added to the pellets and the mixture is heated at reflux for 16 hours. The reaction medium is concentrated under reduced pressure.
• the residue is taken up in water and the solution obtained is acidified to pH 5 with a 10% aqueous solution of potassium hydrogen sulphate.
• the precipitate formed is filtered, washed with water and then dried.
• the 760 mg of yellow solid obtained is then salified, in the form of sodium salt.
• Example 94 [3- (4-amino-3-methoxybenzoyl) -6- (carbomethoxy) -2-methylindolizin-1-yl] carboxylic acid 800mg (1.81 m.mole) of [3- (4-amino- 3-methoxybenzoyl) -6- (2-ethoxy-2-oxoethoxy) -2-methylindolizin-1-yl] methyl carboxylate in solution in 40 ml of dioxane and 20 ml of methanol is added 1.81 g (45.40 m.moles ) of sodium hydroxide pellets and heated to reflux for 72 hours.
• Example 95 [3- (4-Amino-3-methoxybenzoyl) -8- (carbomethoxy) -2-methylindolizin-1-yl] carboxylic acid
• This compound is obtained by proceeding according to the preparation described in Example 94 above, by saponification of the 2 ester functions of the compound [3- (4-amino-3-methoxybenzoyl) -8- (2-ethoxy-2-oxoethoxy) -2-methylindolizin-1 -yl] carb methyl oxylate with sodium hydroxide. After salification, a yellow powder is obtained (Na disel, 3H 2 O) Yield: 45% Melting point: 268 ° C
• Example 96 [3- (4-amino-3-methoxybenzoyI) -6- (methoxy) -2-methylindolizin-1-yl] carboxylic acid
• a 420mg (1.14 m.mole) of [3- (4-amino-3- methoxybenzoyl) -6- (methoxy) -2-methylindolizin-1-yl] methyl carboxylate dissolved in 12 ml of dioxane 48 mg (11.4 m.moles) of lithium hydroxide are added.
• the reaction mixture is heated at 70 ° C for 13 hours then cooled to room temperature, poured into water and extracted with ethyl acetate.
• the aqueous solution is acidified to pH 5 by adding an aqueous solution of sodium hydrogen sulfate at 10%>. Extraction is carried out with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. The 232 mg of yellow solid are then salified in the form of sodium salt, 1.5 H 2 O Yield: 80% Melting point: 242 ° C.
• Example 99 2-amino-5 - ( ⁇ 1-methoxy-2-methyl-6 - [(methylarnino) carbonyl] indolizin-3-yl ⁇ carbonyl) benzoic acid
• the reaction medium is heated at 60 ° C for 16 hours, then allowed to return to room temperature and concentrated under reduced pressure.
• Example 102 2-amino-5 - ⁇ [2-methyl-1- (2-thienyl) indolizin-3-yl] carbonyl ⁇ benzoic acid
• the reaction medium is evaporated to dryness.
• the residue is taken up in IN hydrochloric acid and extracted with ethyl acetate.
• Example 110 2-amino-5 - [(l-methoxy-2-methyIindolizin-3-yI) carbonyl] benzamide
• a 500mg (14.4 m.moles) 2-amino-5 - [(l-methoxy-2-methylindolizin -3- yl) sodium carbonyl] benzoate in 8 ml of dimethylformamide, 702.4 mg (15.9 m.moles) of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) are added and the mixture is stirred for one hour at temperature ambient then a stream of ammonia is bubbled through the reaction medium for 5 minutes and the mixture is left to stir at ambient temperature overnight.
• NBS plates (NBS plate 96 well solid white CORNING 3600) are coated with 100 ⁇ l of 0.1% gelatin per well, 2 hours at 37 ° C. At the end of the incubation, the coating is eliminated, the plates are rinsed and dried well. 100 ⁇ l of binding buffer are distributed (40 mM Bis Tris buffer, pH 7.0) in the plates. The dilutions of the compounds of the invention are distributed in the wells at a rate of 10 ⁇ l / well.
• the plate is read in a MIBROBETA TRILUX radioactivity counter (: WALLAC - PERKINELMER)
• the compounds of the invention have demonstrated a specific activity between
• FCS negative control 0% FCS positive control
• the cells are rinsed with 1 ml of PBS and 200 ⁇ l of trypsin, then they are recovered in the isoton. We proceed to the counting (n> 9 ⁇ m)
• the compounds of the invention demonstrated a specific activity of between 10 ⁇ 5 M and 10 ⁇ 9 M
• Non-Essential Amines 1% for PAECs. Stimulate with b-FGF (TEBU / Peprotech) 10 ng / ml or a-FGF (TEBU / Peprotech) 10 ng / ml in the presence or not of the intention products for 24 hours at 37 ° C in the presence of 5% CO 2 . After 24 hours, fix the cells and stain the slide with Masson trichrome before observation under the X4 objective microscope and image analysis (BIOCOM- Visiolab 2000 software).
• b-FGF TEBU / Peprotech
• a-FGF TEBU / Peprotech
• the compounds 7 1 1 of the invention demonstrated a specific activity of between 10 " M and 10 " M.
• Example 115 Model of inflammatory angiogenesis in mice Angiogenesis is required for the development of chronic inflammatory diseases such as rheumatoid arthritis, IBD, but also for the development of solid tumors.
• the formation of new vessels not only allows the perfusion of pathological tissues but also the transport of cytokines responsible for establishing the chronicity of the disease.
• the model described by Colville-Nash P et al (D. JPET., 1995, vol 274 n ° 3, ppl463-1472) makes it possible to study pharmacological agents capable of modulating the appearance of angiogenesis.
• mice non-consanguineous white mice weighing approximately 25 g, are anesthetized with sodium pentobarbital (60 mg / kg; Sanofi Nutrition Animal Health) intraperitoneally.
• An air pocket is created on the back of the mouse by injecting 3 ml of air subcutaneously.
• the animals receive a treatment in general by gavage and receive an injection of 0.5 ml of Freund's adjuvant (Sigma) with 0.1% croton oil (Sigma) in the pocket.
• the mice are again anesthetized and placed on a hot plate at 40 ° C.
• One ml of carmine red (5% in 10% gelatin - Aldrich Chemicals) is injected into the tail vein.
• the animals are then placed at 4 ° C for 2-3 hours.
• the skins are then removed and put to dry for 48 hours in an oven at 56 ° C.
• the dry tissues are weighed and put in 1.8 ml of digestive buffer (2 mM dithiothreitol, 20 mM Na 2 HPO 4 , 1 mM EDTA, 12U papain / ml) for 24 hours.
• the dye is then dissolved in 0.2 ml of 5M NaOH.
• the skins are centrifuged at 2000 g for 10 min.
• the supernatants are filtered through 0.2 ⁇ m cellulose acetate membranes.
• the filtrates are read in a spectrophotometer at 492 nm. against a standard range of carmine red.
• the results are expressed in mean values ( ⁇ wk). The differences between the groups are tested with an ANOVA followed by a Dunnet test, the reference group of which is the "solvent control" group.
• the compounds of the invention are active orally at doses of 0.1 to 100 mg / kg.
• Example 116 Model of MATRIGEL angiogenesis in mice
• the model described by Passaniti and al. (Laboratory Investigation (1992) 67 (4) pp519-524) makes it possible to study pharmacological agents capable of modulating the appearance of angiogenesis specifically induced by bFGF.
• FGF2 Pieristecch
• To Matrigel (Beckton Dickinson) maintained in liquid form at 4 ° C is added FGF2 (Peprotecch) at a rate of 300 ng / ml. After homogenization, the mixture (0.5ml) is injected subcutaneously into the lower back of female black mice (C57 / B16) weighing approximately 20g previously anesthetized with sodium pentobarbital (60 mg / kg; Sanofi Nutrition Animal Health) intraperitoneally.
• the animals are treated by force-feeding. After 5 days the mice are again anesthetized and the skin of the lower back is removed, at this stage, the qualitative differences in vascularization of the granuloma are evaluated (scored) and the granulomas are photographed. A DNA assay in the granulomas is then carried out to quantify the cellularity thereof. For this, the isolated granulomas are digested with collagenase (3 mg / ml) overnight at 37 ° C. After centrifugation at 850 g for 10 min, the supernatant is discarded and the pellet is redissolved in 1.2 ml of PBS buffer containing 1 mM CaCl 2 , 1 mM
• the granulomas are removed with the muscle and the skin, fixed overnight in a 10% formaldehyde solution and included in paraffin (Embedder Leica®). The granulomas are then cut using a microtome (Leica) and stained with Mason's Trichrome dye. The neovascularization of the granulomas is then evaluated. The levels of vascularization are between a value 0 and 5.
• the compounds of the invention are active orally at doses of 0.1 to 100 mg / kg
• Example 117 Model of tumor angiogenesis in mice This model makes it possible to study pharmacological agents capable of modulating the appearance of angiogenesis specifically induced by tumor development.
• mice weighing approximately 20 g are anesthetized with sodium pentobarbital (60 mg / kg; Sanofi Nutrition Animal Health) intraperitoneally.
• the tumors are established by subcutaneous injection on the back of mouse Lewis Lung cells at the rate of 2 10 5 cells / mouse. After 5 days, the mice are treated daily by gavage.
• the size of the tumors is measured twice a week for 21 days and the tumor volume is calculated using the formula: [ ⁇ / 6 ( ⁇ > ⁇ x ⁇ 2 x ⁇ 2 )], where ⁇ > ⁇ represents the largest diameter and ⁇ 2 represents the smallest diameter.
• thrombocytopenia is anti-cancer chemotherapy.
• One of the chemotherapy agents carboplatin.
• Has been widely used to induce thrombocytopenia in mice and thus be able to characterize the effect of compounds capable of improving the level of platelets such as, for example, thrombopoietin (Hokom MM et al, Blood (1995), 86, ⁇ p4486-4492).
• the compounds according to the invention or their solvent are administered orally for 5 days, starting treatment 7 days before the administration of carboplatin.
• the experiments are carried out on batches comprising 10-12 mice and the results are expressed as an average ⁇ standard error. Under these conditions, the compounds of the invention increase the level of circulating platelets at doses of 0.1 to 100 mg / kg.
• EXAMPLE 119 Argon Laser Induced CNV (Choroidal Neo-Vascularization) Model in Mice: A major characteristic of the loss of ocular transparency is neo-vascularization and the subsequent hemorrhages which cause major functional disorders in the eye and which result in early blindness. Recently, the study of the mechanisms involved in the phenomena of ocular neovascularization has made it possible to highlight the involvement of pro-angiogenic factors in these pathologies. The model of laser-induced choroidal neo-angiogenesis described by Rakic JM et al, in Invest Ophthalmol Vis Sci.
• mice are anesthetized by intraperitoneal injection of Avertin TM.
• the two pupils are dilated with a 1% solution> of tropicamide in topical application, and three lesions are produced around the optical disc using an argon laser (532 nm; spot size diameter 50 ⁇ m; duration 0.05 dry; 400 mW).
• the optical disc is then covered with a lens.
• mice 14 days later, the mice are sacrificed and the eyes enucleated and fixed in a buffer containing 3.5% of Formalin TM, coated in Tissue TeK TM (Miles Laboratories, Naperville, Illinois) and freeze in liquid nitrogen so as to be able to carry out sections using a cryostat.
• Formalin TM coated in Tissue TeK TM (Miles Laboratories, Naperville, Illinois) and freeze in liquid nitrogen so as to be able to carry out sections using a cryostat.
• the quantification of the choroidal neovascularization was carried out by a quantitative morphometric study making it possible to assess the thickness of the network of neovessels present at the level of the choroid, using an image analysis system assisted by a computer (Olympus Micro Image version 3.0 for Windows 95 / NT, Olympus Optical CO. Europe GmBH).
• the neovascularization is estimated by the ratio (B / C) of the thickness of the pigmented layer of the choroid at the level of the lesion (B) to the thickness of this same pigmented layer in a region adjacent to the lesion ( VS).
• the results are expressed in mean values ( ⁇ wk).
• the differences between the treated groups and the control groups are tested with an ANOVA followed by a Dunnet test, the reference group of which is the "solvent control" group.
• the compounds of the invention are active orally at doses of 0.1 to 100 mg / kg.

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