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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
  • C07D217/24—Oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
  • C07D239/88—Oxygen atoms

Definitions

• the present invention relates to 1-oxo-1,2-dihydroisoquinoline-5-carboxamide derivatives and 4-oxo-3,4-dihydroquinazoline-8-carboxamide derivatives, to their preparation and to their therapeutic application.
• a ⁇ peptide amyloid ⁇
• the production and progressive accumulation of this peptide could play a crucial role in the onset and progression of Alzheimer's pathology, based on the hypothesis of an amyloid cascade (D. Seiko et al., Nature 399A (1999) 23 Roggo et al., Top Med, Chem 2. (2002) 359, A. Ghosh et al, Curr Med, Chem 9 (2002) 1135).
• the A ⁇ peptide comes from the APP protein (Amyloid Precursor Protein), which can be cleaved by at least three different proteolytic activities: 1) cleavage in the A ⁇ region by an ⁇ -secretase activity (thus preventing the formation of A ⁇ ); 2) cleavage at the N-terminus of A ⁇ by ⁇ -secretase activity; 3) cleavage at the C-terminal end of A ⁇ by ⁇ -secretase activity.
• the consecutive cleavage of the APP protein at the ⁇ and ⁇ sites leads to the formation of the A ⁇ peptide (M. Citron Nat Rev. Neurosci, 5 (2004) 677-685, D. Beher et al., Expert Opin. Invest Drugs 14 (2005) 1385-1409).
• R6 in which: R1 represents a hydrogen atom, a (Ci-C 10) alkyl, (C 3 -C 7) cycloalkyl, (CH 2) n - (Ci-C 6) alkenyl, (CH 2) n - (C 1 -C 6 ) alkynyl, (C 1 -C 6) alkyl-Z- (C 1 -C 6) alkyl, wherein Z represents a heteroatom selected from O, N and S (O) m , or R 1 represents a group COOR, S (O) R 01, aryl or aralkyl; (C 1 -C 10 ) alkyl, (C 3 -C 7 ) cycloalkyl, (CH 2 ) n - (C 1 -C 6 ) alkyl, (CH 2 ) n - (C 1 -C 6 ) alkynyl, (C 1 -C 6 ) alkyl-Z- (C 1 -C
• R 2 is one or more groups selected from hydrogen, halogen, (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 1 -C 4 ) alkenyl, (C 1 -C 6 alkyl), (C) 1 -
• R3 represents a trifluoromethyl group
• R4 and R5 represent a hydrogen atom, or R4 and R5 together with the carbon atom carrying them form a saturated ring containing from 3 to 6 carbon atoms and optionally containing from 0 to 1 heteroatom chosen from O, N or S
• R6 represents a group selected from a hydrogen atom, a halogen atom, a (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) cycloalkyl (C 1 - C 6 ) alkyl, halofd-C6 alkyl, nitro, amino, NR7R8, COOR, NR7 (SO 2 ) R8, CONR7R8, aryl, said aryl group being optionally substituted with one or more groups selected from halogen atom, a (CrC 6) alkyl, (C 1 -C 6 JaIcOXy or cyano,
• R, R7 and R8 represent, independently of one another, one or more groups selected from a hydrogen atom, a (CrCeJalkyle, (C 3 -C 7) cycloalkyl, (C 3 - C ⁇ cycloalkyletCrCeJalkyle, an aryl, aryl (C 1 -C 6 ) alkylene group, or else R 7 and R 8 may form, with the atom bearing them, a saturated, partially unsaturated or unsaturated ring containing from 5 to 7 carbon atoms and possibly containing, in addition, a heteroatom selected from O, N or S (O) 01,
• X represents a carbon atom or a nitrogen atom
• m represents an integer that can take the values O
• 1 or 2 and n represents an integer that can take the values 1, 2, 3, 4, 5 or 6,
• the carbon bearing the benzyl group substituted by R2 is of absolute configuration S
• the carbon carrying the hydroxyl group is of absolute configuration R.
• the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.
• the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
• salts can be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
• t and z may take the values from 1 to 10, a chain or carbon ring possibly containing from t to z carbon atoms, for example C 1 -C 3 can characterize a carbon chain having 1 to 3 carbon atoms;
• halogen atom a fluorine, a chlorine, a bromine or an iodine
• alkyl group a saturated linear or branched aliphatic group.
• alkyl group a saturated linear or branched aliphatic group.
• a cycloalkyl group a cyclic alkyl group.
• cyclopropyl methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, and the like;
• an alkylene group a divalent saturated, linear or branched aliphatic group.
• a C 1-3 -alkylene group represents a divalent carbon chain of 1 to 3 carbon atoms, linear or branched, such as a methylenyl (-CH 2 -), an ethylenyl (-CH 2 CH 2 - ), a 1-methylethylenyl (-CH (CH 3 ) CH 2 -), a propylenyl (-CH 2 CH 2 CH 2 -);
• alkenyl group a linear or branched, mono- or poly-unsaturated aliphatic group, comprising, for example, one or two ethylenic unsaturations;
• alkynyl group a linear or branched, mono- or poly-unsaturated aliphatic group, comprising, for example, one or two acetylenic unsaturations;
• alkoxy group an -O-alkyl radical in which the alkyl group is as previously defined
• a halo (C 1 -C 6 ) alkyl group an alkyl group in which one or more hydrogen atoms have been substituted by a halogen atom.
• a halo (C 1 -C 6 ) alkyl group an alkyl group in which one or more hydrogen atoms have been substituted by a halogen atom.
• halo (C 1 -C 6 ) alkoxy group an -O-alkyl radical in which the alkyl group is as defined above and which is substituted with one or more identical halogen atoms or different.
• groups OCF 3 , OCHF 2 and OCCI 3 By way of examples, mention may be made of groups OCF 3 , OCHF 2 and OCCI 3 .
• the sulfur and nitrogen atoms may be present in the oxidized state (N-oxide, sulphoxide, sulphone, etc.);
• aryl group a cyclic aromatic group comprising between 6 and 14 carbon atoms.
• aryl group mention may be made of phenyl or naphthyl.
• a first group of compounds consists of the compounds for which:
• X represents a carbon atom.
• a second group of compounds consists of the compounds for which:
• X represents a nitrogen atom.
• a third group of compounds consists of the compounds for which:
• R1 represents a (C 1 -C 10 ) alkyl group, optionally substituted with one or more (C 1 -C 10 ) alkyl groups;
• R2, R4 and R5 represent a hydrogen atom
• R6 represents a group selected from a hydrogen atom or a halogen atom.
• a protective group Pg is understood to mean a group that makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the intact reactive function at the end of synthesis. Examples of protecting groups and methods of protection and deprotection are given in "Protective Groups in Organic Synthesis", Green et al., 2 ⁇ d Edition (John Wiley & Sons, Inc., New York), 1991.
• leaving group is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with departure from an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example.
• Such leaving groups are, for example, halogens or an activated hydroxy group such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups as well as references for their preparation are given in Advances in Organic Chemistry, J. March, 3 rd Edition, Wiley Interscience, 1985, p. 310-316.
• the starting compounds and the reagents when their method of preparation is not described, are commercially available or described in the literature, or they can be prepared according to the methods described therein or are known to those skilled in the art.
• the compounds of general formula (I) can be prepared according to the process illustrated by the following scheme 1.
• the compound of general formula (I) is prepared from a compound of general formula (III), in which R 1 and R 6 are as defined in general formula (I), on which the amine function of the compound of general formula (II), wherein
• R2, R3, R4 and R5 are as defined in general formula (I).
• This reaction is carried out in an anhydrous medium, preferably inert (nitrogen or argon for example) and using conventional amine-acid coupling agents such as DCC, PyBOP, EDCI, in solvents such as dichloromethane, THF, ether or chloroform at a temperature between 20 0 C and the reflux temperature of the solvent.
• anhydrous medium preferably inert (nitrogen or argon for example) and using conventional amine-acid coupling agents such as DCC, PyBOP, EDCI, in solvents such as dichloromethane, THF, ether or chloroform at a temperature between 20 0 C and the reflux temperature of the solvent.
• the compound of general formula (II), wherein R2, R3, R4 and R5 are as defined in general formula (I), may be prepared from the compound of general formula (IV), wherein R2, R3, R4 and R5 are as defined in the general formula (I), by deprotection of the primary amine by the action of an acid (hydrochloric acid for example) in solution in a solvent or a mixture of ethereal solvent (diethyl ether for example) and / or chlorinated (dichloromethane for example), according to the process illustrated in Scheme 2 which follows.
• the compound of general formula (IV), wherein R2, R3, R4 and R5 are as defined in general formula (I), may be prepared by reacting a benzylamine derivative of general formula (VI), for which R 3, R 4 and R 5 are as defined in the general formula (I) with an oxirane of general formula (V), for which R 2 is as defined in the general formula (I), operating in an anhydrous medium, preferably inert (nitrogen or argon for example), in a chlorinated solvent (dichloromethane for example) and presence of triflate anion (scandium triflate for example).
• the compounds of general formula (MIa) can be obtained from compounds of general formula (XXVI), reacted with carbon monoxide in the presence of acetate ions (potassium or sodium), alkaline iodide (iodide sodium or potassium for example) a palladium catalyst (palladium acetate for example), a phosphine (triphenylphosphine for example) in solution in an organic solvent (dimethylformamide or dimethylsulfoxide for example) and in the presence of water .
• the reaction takes place under a pressure of carbon monoxide pressure of 1 to 100 atmospheres and at a temperature between 20 0 C and 12O 0 C, by analogy with the work of D. Milstein et al. J. Am. Chem. Soc. (1989) 8742 and TW Ku et al. Tetrahedron Lett. (1997) 3131.
• the compounds of general formula (IMb) can be obtained from compounds of general formula (XXVIII) under the same conditions as those used for the preparation of compounds of general formula (IHa).
• the compounds of general formula (XXVIII) can be prepared by the action of an orthoformate (methyl orthoformate for example) in the presence of a base (methanolate or sodium ethanolate for example) on compounds of general formula (XXIX) in solution in an alcoholic solvent (methanol or ethanol for example). The reaction is preferably carried out at a temperature between 0 ° C. and the reflux temperature of the solvent.
• the compounds of general formula (XXIX) can be prepared by the action of an amine of general formula RI-NH 2 on methyl 2-amino-5-chloro-3-iodobenzoate in the presence of trimethylaluminium in an organic solvent (toluene by example) at a temperature between 20 0 C and the reflux temperature of the solvent.
• the compounds of formula (HIa) and (HIb) are useful as synthesis intermediates of the compounds of formula (I).
• the products of formula (I) may be subjected, if desired and if necessary, to obtaining products of formula (I) or to being converted into other products of formula (I), to one or more of the reactions of the following transformations, in any order: a) an esterification or amidation reaction of an acid function, b) an ester functional hydrolysis reaction in the acid function, c) a hydroxyl functional conversion reaction in an alkoxy function, d) an alcohol function oxidation reaction based on aldehyde, ketone or acid, e) an alcohol function reduction reaction, aldehyde or ketone alcohol function, f) a reductive amination reaction of an aldehyde or ketone function , g) an alkenyl group oxidation reaction according to aldehyde or ketone, h) an oxidation reaction of a thioether to sulfone or sulfoxide, i) an alkylation reaction of a sulfonamide, j)
• the compounds of formula (I) may be purified by methods known to those skilled in the art, for example by crystallization, chromatography or extraction.
• Example 1 The preparation of 5-iodo-2H-isoquinolin-1-one is described in the literature; Threadgill M.D. et al., J.Chem.So ⁇ , Perkin Trans 1 2002, 335.
• the 320 mg 0 of brown oil obtained are purified by flash chromatography on silica (column: 35 g, granulometry: 20-40 ⁇ m spherical, eluent: heptane 80% - ethyl acetate 20%). After concentrating the fractions under reduced pressure, 165 mg of 5-iodo-2- (1-propylbutyl) isoquinolin-1 (2H) -one are obtained in the form of a yellow solid.
• the 12 g of crude product obtained are purified by flash chromatography on silica (column: 200 g, particle size: 15-40 ⁇ m, eluent: 100% dichloromethane). After concentrating the fractions under reduced pressure, 3.21 g of 2-amino-5-chloro-3-iodo- ⁇ - (1-propylbutyl) benzamide are obtained.
• the aqueous phase is extracted with 50 cm 3 of dichloromethane.
• the organic phases are combined, washed with 50 cm 3 of saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated by rotary evaporation under reduced pressure (5 kPa).
• the ocher product obtained is purified by flash chromatography on silica (column: 200 g, particle size: 15-40 ⁇ m, eluent: 100% dichloromethane). After concentration of the fractions under reduced pressure, 2.09 g of 6-chloro-8-iodo-3- (1-propylbutyl) quinazolin-4 (3H) -one are obtained.
• the reaction mixture is bubbled with carbon monoxide and is then heated at 100 ° C. for 6 h 30 min. It is cooled to a temperature close to 20 0 C to be filtered on a pellet of Celite 545, rinsed with 20 cm 3 of dimethylformamide and 20 cm 3 of ethyl acetate. The filtrate is evaporated on a rotary evaporator under reduced pressure (5 kPa). The orange solution obtained is taken up in a mixture of 100 g of ice-water and 100 cm 3 of ethyl acetate. The pH is brought to 10 with 5M sodium hydroxide. After decantation, the aqueous phase is washed with twice 40 cm 3 of ethyl acetate.
• the organic phases are combined and then washed with 30 cm 3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in a rotary evaporator under reduced pressure (5 kPa).
• the yellow-green oil obtained is purified by flash chromatography on silica (column: 90 g, particle size: 15-40 ⁇ m, eluent: 100% dichloromethane gradient at 100.degree. 95% dichloromethane - 5% methanol). After concentration of the fractions under reduced pressure, 0.28 g of 6-chloro-4-oxo-3- (1-propylbutyl) -3,4-dihydroquinazoline-8-carboxylic acid is obtained.
• the solution is stirred for 20 h at 20 ° C. 15 cm 3 of water are added to the reaction medium.
• the aqueous phase is extracted with 15 cm 3 of dichloromethane.
• the organic phases are combined, washed with 10 cm 3 of saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated in a rotary evaporator under reduced pressure (5 kPa).
• the 740 mg of product obtained are purified by flash chromatography on silica (column: 70 g, particle size: 15-40 ⁇ m, eluent: gradient 100% 100% dichloromethane to 95% dichloromethane-5% methanol).
• Table 1 which follows illustrates the chemical structures and the physical properties of some examples of compounds according to the invention.
• - PF ( 0 C) represents the melting point of the compound in degrees Celsius;
• the compounds according to the invention were the subject of pharmacological tests to determine their inhibitory effect vis-à-vis the ⁇ -secretase activity.
• Tests consisted in measuring the in vitro inhibition of the ⁇ -secretase activity by the compounds of the invention, by the use of the "BACE-1 FRET Assay Kit, Red” test available from PanVera-Invitrogen Inc.
• the ⁇ -secretase activity measured corresponds to that of a purified recombinant form of the human BACE1 aspartyl protease (the latter comprising a C-terminal hexa-histidine tag) produced by expression in Drosophila cells.
• the purified enzyme is packaged in TRIS buffer (18 mM) at pH 7.5 containing NaCl (0.45 M), MnCl 2 (0.9 mM), CaCl 2 (0.9 mM), alpha D methylmannoside, 10% glycerol, and stored at -80 ° C. until use.
• the BACE1 activity is measured according to the cleavage of a fluorogenic peptide substrate marketed by INVITROGEN (PANVERA BACE1 / ⁇ -secretase FRET assay kit,
• Red reference P2985
• FRET resonance fluorescence energy transfer
• the test is carried out in a 96-well black microplate to determine the inhibition of the enzymatic activity by the products of the invention.
• the commercial solution of peptide substrate (Panvera, reference P2986) is at a concentration of 75 ⁇ M in ammonium bicarbonate at 50 mM, and stored at -20 ° C. in the dark from light until use. Dilutions of the test products are prepared in DMSO from 10 mM stock solution.
• the products of the invention are incubated at room temperature with the peptide substrate (final concentration of 0.25 ⁇ M) and the purified enzyme (final concentration of 10 nM), in buffer sodium acetate (50 mM, pH 4.5) (commercial kit buffer, P2988), usually for 60 minutes, protected from light.
• the final percentage of DMSO does not exceed 10%.
• the fluorescence is measured in a spectrofluorometer at excitation wavelengths around 543 nM and emission around 585 nM. For each concentration of product tested, the fluorescent signal is compared to the maximum signal obtained when the peptide substrate is only incubated with the enzyme.
• the inhibitory activity of the products of the invention is then evaluated by measuring IC50 (product concentration giving 50% inhibition of the enzymatic activity) by means of a non-linear regression analysis (computer application Xlfit, IDBS TM).
• Cl 50 are between 0.1 and 5 ⁇ M.
• the compounds according to the invention can therefore be used for the preparation of medicaments, in particular inhibitory drugs for the production of A ⁇ .
• the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid.
• neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Parkinson's disease, Huntington, Creutzfeld-Jacob disease, Down's syndrome, Lewy body dementia, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild cognitive disorders, amyloid cerebral angiopathy, primary and secondary disorders of memory, amyotrophic lateral sclerosis, multiple sclerosis, peripheral neuropathies, diabetic neuropathies, migraine, mood disorders, depression, anxiety, vascular disorders such as atherosclerosis, cerebrovascular ischemia, tumors and cell proliferation.
• neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Parkinson's disease, Huntington, Creutzfeld-Jacob disease, Down's syndrome, Lewy body dementia, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild cognitive disorders, amyloid cerebral angiopathy, primary and secondary disorders of memory, amyotrophic lateral sclerosis, multiple sclerosis, peripheral
• neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Down's syndrome, Lewy body dementia, senile dementia, fronto- temporal dementia , cerebral and systemic amyloidosis, mild cognitive disorders, amyloid cerebral angiopathy, primary and secondary memory disorders, cerebrovascular ischemia.
• neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Down's syndrome, Lewy body dementia, senile dementia, fronto- temporal dementia , cerebral and systemic amyloidosis, mild cognitive disorders, amyloid cerebral angiopathy, primary and secondary memory disorders, cerebrovascular ischemia.
• the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
• These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, as well as at least one pharmaceutically acceptable excipient.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) above, or its salt, solvate or hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• the compounds according to the invention can be used in creams, gels, ointments or lotions.
• a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg
• the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates.

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