FR2919289A1 - New tetrahydropyrrolo(1,2-a)(1,4)-diazepine-carboxamide compounds are beta secretase inhibitors useful to treat e.g. senile dementia, mild cognitive disorder, Huntington disease, Creutzfeldt-Jakob disease, migraine and anxiety - Google Patents

Abstract

Tetrahydropyrrolo[1,2-a][1,4]-diazepine-carboxamide compounds (I) and their base or acid addition salts, hydrates or solvates are new. Tetrahydropyrrolo[1,2-a][1,4]-diazepine-carboxamide compounds of formula (I) and their base or acid addition salts, hydrates or solvates are new. R 1>H, 1-10C alkyl, 3-7C cycloalkyl, (CH 2) n-(1-6C)alkenyl, (CH 2) n-(1-6C)alkynyl, 1-6C alkyl-Z-(1-6C alkyl), aryl or aralkyl (all optionally substituted by halo, 1-6C alkyl, 3-7C cycloalkyl, halo(1-6C)alkyl, 1-6C alkoxy, halo(1-6C)alkoxy, NR 7>R 8>, nitro, cyano, OR, COOR, CONR 7>R 8>or S(O) mNR 7>R 8>), COOR or S(O) mR; Z : Heteroatom comprising O, N or S(O) m; R 2>halo(1-6C)alkyl, halo(1-6C)alkoxy, OH, 1-6C alkoxy, NO 2, CN, NH 2, NR 7>R 8>, COOR, CONR 7>R 8>, OCO(1-6C)alkyl, S(O) mNR 7>R 8>or aryl (all optionally substituted by one or more halo, 1-6C alkyl, 3-7C cycloalkyl, halo(1-6C)alkyl, (1-6C)alkoxy, halo(1-6C)alkoxy, NR 7>R 8>, NO 2, CN, OR, COOR, CONR 7>R 8>or S(O) mNR 7>R 8>), H (preferred), halo, 1-6C alkyl, 3-7C cycloalkyl, (1-6C)alkenyl, (1-6C)alkynyl or 1-6C alkyl-Z-(1-6C alkyl); R 3>CF 3; either R 4>, R 5>H; or CR 4>R 5>ring containing 3-6 carbon atoms (optionally saturated and optionally containing 0 or 1 heteroatom comprising O, N or S); R 6>H (preferred), halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-6C alkyl, NO 2, NH 2, NR 7>R 8>, COOR, NR 7>(SO 2)R 8>, CONR 7>R 8>or aryl; either R 7>, R 8>, R : H, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-6C alkyl, aryl, aryl(1-6C)alkylene or COR; or R 7>R 8>ring containing 5-7 carbon atoms (optionally saturated and substituted by heteroatom of O, N or S(O) m); m : 0-2; and n : 1-6. Where the carbon carrying the benzyl substituted by R2 is absolute configuration S, and the carbon carrying the hydroxyl is absolute configuration R. An independent claim is included for a substituted tetrahydro-1H-pyrrolo[1,4]diazepine-carboxylic acid compound of formula (III). [Image] [Image] ACTIVITY : Neuroprotective; Nootropic; Antiparkinsonian; Cerebroprotective; Vasotropic; Cardiovascular-gen.; Anticonvulsant; Antimigraine; Antidepressant; Tranquilizer; Antiarteriosclerotic; Cytostatic. MECHANISM OF ACTION : Beta-secretase inhibitor. The ability of (I) to inhibit beta-secretase was tested using fluorescence resonance energy transfer assay. The result showed that N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl]-1-oxo-2-(1-propylbutyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-7-carboxamide exhibited an IC 5 0value of 1.40 mu M.

Description

2,3,4,5-TETRAHYDROPYRROLO [1,2-a] [1,4] -DIAZEPINE-7-CARBOXAMIDES DERIVATIVES,

  THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION

  The present invention relates to 2,3,4,5-tetrahydropyrrolo [1,2-a] [1,4] diazepine-7-carboxamide derivatives, their preparation and their therapeutic application. The presence of multiple senile plaques in brain tissue is one of the major histopathological alterations observed in Alzheimer's disease; these plaques are formed by deposition of fibrillar aggregates of a 4 kDa peptide (40-42 amino acids), called amyloid peptide [3 (A8). 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 (Selko 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 A8 peptide is derived from the APP protein (Amyloid Precursor Protein), which can be cleaved by at least three different proteolytic activities: 1) cleavage in the AR region by α-secretase activity (thus preventing the formation of A (3); 2) cleavage at the N-terminus of A8 by 8-secretase activity; 3) Cleavage at the C-terminus of A8 by γ-secretase activity. Subsequent cleavage of the APP protein at the 8 sites and leads to the formation of the Ali peptide (M. Citron Nat Rev. Neurosci, 5 (2004) 677-685, D. Beher et al., Expert Opin. Invest Drugs 14 (2005) 1385-1409).

  There is therefore a real interest in finding compounds that inhibit the production of the AR peptide (T. B. Durham et al, Curr Opin Drug Disc, Dev 9 (2006) 776-791). It has now been found that compounds derived from 2,3,4,5-tetrahydropyrrolo [1,2-a] [1,4] diazepine-7-carboxarides have a strong inhibitory activity against 8-secretase activity.

  The subject of the present invention is the compounds corresponding to formula (I) R 6 in which: R 1 represents a hydrogen atom, a (C 1 -C 10) alkyl or (C 3 -C 7) cycloalkyl group, (CH 2) n - ( C 1 -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) R1, or R1 is COOR, S (O) mR, aryl or aralkyl; (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl, (CH 2) n - (C 1 -C 6) alkenyl, (CH 2) n - (C 1 -C 6) alkynyl, (C 1 -C 6) ) alkyl-Z- (C 1 -C 6) alkyl, aryl or aralkyl being optionally substituted by one or more groups selected from a halogen atom, a (C 1 -C 6) alkyl, (C 3 -C 5) cycloalkyl group, halo (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo (C 1 -C 6) alkoxy, NR 7 R 8, nitro, cyano, OR, COOR, CONR 7 R 8, S (O) m NR 7 R 8, R 2 represents one or more groups chosen from a hydrogen atom, a halogen atom, a (C 1 -C 6) alkyl, (C 3 -C 5) cycloalkyl, (C 1 -C 6) alkenyl, (C 1 -C 6) alkynyl group, (C 1 -C 6) , -C6) alkyl-Z- (C 1 -C 6) alkyl, wherein Z represents a heteroatom selected from O, N and S (O) m, or R2 represents a halo (C 1 -C 6) alkyl, halo (C 1 -C 6) alkoxy, hydroxy, (C 1 -C 6) alkoxy, nitro, cyano, amino, NR 7 R 8, COOR, CONR 7 R 8, OCO (C 1 -C 6) alkyl, S (O) m NR 7 R 8, a group aryl, the aryl group being optionally substituted by one or more groups selected from a halogen atom, a group e (C 1 -C 6) alkyl, (C 3 -C 5) cycloalkyl, halo (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo (C 1 -C 6) alkoxy, NR 7 R 8, OR, nitro, cyano , COOR, CONR7R8, S (O) mNR7R8, R3 represents a trifluoromethyl group, R4 and R5 represent, independently of one another, a hydrogen atom, or R4 and R5 form with the carbon atom which carries a saturated ring containing from 3 to 6 carbon atoms and optionally containing from 0 to 1 heteroatom selected from O, N or S, R6 represents a group chosen from a hydrogen atom, a halogen atom, a group ( C, -C6) alkyl, (C3-C) cycloalkyl, (C3-C) cycloalkyl (C1-C6) alkyl, nitro, amino, NR7R8, COOR, aryl, NR7 (SO2 ) R8 or CONR7R8, R, R7 and R8 represent, independently of one another, one or more groups selected from a hydrogen atom, a (C 1 -C 6) alkyl, (C 3 -C 5) cycloalkyl group; (C3-C) cycloalkyl (C1-C6) alkyl, aryl, aryl (C1-C6) alkylene, or R7 and R8 may form with the atom which s carries a saturated, partially unsaturated or unsaturated ring containing from 5 to 7 carbon atoms and optionally additionally containing a heteroatom selected from O, N or S (O) m, m represents an integer capable of assuming the values 0, 1; or 2 and n represents an integer which 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 exist in the form of 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. These 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.

  The compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.

  In the context of the present invention, the following terms are understood: ## STR2 ## where t and z may take the values from 1 to 10, a carbon chain or ring which may have from t to z carbon atoms, for example C1..C3 can characterize a carbon chain having 1 to 3 carbon atoms; a halogen atom: a fluorine, a chlorine, a bromine or an iodine; an alkyl group: a saturated linear or branched aliphatic group. By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and the like; a cycloalkyl group: a cyclic alkyl group. By way of examples, mention may be made of cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, and the like; an alkylene group: a divalent saturated, linear or branched aliphatic group. By way of example, a C 1-3 alkylene group represents a linear or branched divalent carbon chain of 1 to 3 carbon atoms, 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 -); a haloalkyl group: an alkyl group in which one or more hydrogen atoms have been substituted by a halogen atom. By way of examples, mention may be made of the groups CF3, CH2CF3, CHF2, CCI3; a haloalkoxy group: an alkoxy group in which one or more hydrogen atoms have been substituted by a halogen atom. As examples, there may be mentioned groups OCF3, OCHF2, OCCI3; an alkenyl group: a linear or branched, mono- or poly-unsaturated aliphatic group, comprising, for example, one or two ethylenic unsaturations; an alkynyl group: a linear or branched mono- or poly-unsaturated aliphatic group comprising, for example, one or two acetylenic unsaturations; an alkoxy group: an -O-alkyl radical where the alkyl group is as previously defined; An aryl group: a cyclic aromatic group comprising between 6 and 14 carbon atoms. As an example of an aryl group, mention may be made of phenyl or naphthyl; the sulfur and nitrogen atoms may be present in the oxidized state (N-oxide, sulphoxide, sulphone).

  In the different groups as defined below, the groups R1 to R6, when not defined, have the same definitions as those mentioned above. Among the compounds of formula (I) that are subjects of the invention, a first group of compounds is constituted by the compounds for which: R 1 represents a (C 1 -C 0) alkyl group optionally substituted with one or more groups (C, C6) alkyl. Among the compounds of formula (I) which are subjects of the invention, a second group of compounds is constituted by the compounds for which: R 1 represents a (C 1 -C 3) alkyl group optionally substituted by one or more groups (C, -C6) alkyl, R2, R4, R5 and R6 represent a hydrogen atom.

  The combination of groups one and two as defined above is also part of the invention.

  Among the compounds of formula (I) which are subjects of the invention, mention may be made especially of the following compound: • N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) ) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-7- carboxamide and its hydrochloride (1: 1). In what follows, the term protecting group Pg is understood to mean a group which 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 a reactive function. intact at the end of synthesis. Examples of protecting groups as well as methods of protection and deprotection are given in Protective Groups in Organic Synthesis, Green et al., 2nd Edition (John Wiley & Sons, Inc., New York), 1991. by leaving group, in the following, 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 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, 3rd Edition, Wiley Interscience, 1985, 310-316.

  In the following diagrams, 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 abbreviations and symbols used for the description of the synthetic processes and for the description of the compounds are as follows: BOC for tert-butoxycarboxylate, DCC for dicyclohexylcarbodiimide, DMF for dimethylformamide, EDAC for (1-ethyl-3,3-dimethylaminopropyl) carbodiimide, NMP for N-methyl-2-pyrrolidone, PyBOP for benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, THF for tetrahydrofuran.

  According to the invention, 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) can be prepared by condensation of the amine function of the compound of general formula (II), wherein R2, R3, R4 and R5 are as defined in general formula (I), on the carboxylic acid function of the compound of general formula (III), wherein R1 and R6 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 agents for coupling an acid function with an amine function such as DCC, PyBOP, EDAC, in solvents. such as dichloromethane, THF, ether or chloroform at a temperature between 20 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. R2 R4 R5 Sc: (TfO) 2 Rz HCl / O R4 R5 CH2Cl2 CH2Cl2 + H2N boc. NH (V) Scheme 2 The compound of general formula (IV), wherein R2, R3, R4 and R5 are as previously described, may be prepared by reacting a benzylamine derivative of general formula (VI), in which R 3, R 4 and R 5 are as defined in the general formula (I) with an oxirane of the general formula (V), in which R 2 is as defined in the general formula (I) by operating in anhydrous medium, preferably inert (nitrogen or argon for example), in a chlorinated solvent (dichloromethane for example) and in the presence of a Lewis acid such as scandium triflate.

  The compounds of general formula (III), in which R 1 and R 6 are as previously described, can be obtained according to the method of Scheme 3 which follows. CO (1 atm) KOAc / KI 1-R1 NHz / KI NBS% ~ Pd (OAc) 2 MeCN RIu N / --- \ 1 CCI4 R, ùN I PPh3 RN ~ `N - ~ N Br \ N CO2H 2 The compounds of the general formula (III) can be prepared by reacting the compound of the general formula (VII) with carbon monoxide, with the addition of carbon monoxide. or without acetate ions (potassium or sodium), with or without alkaline iodide (sodium iodide or potassium iodide for example), in the presence of a palladium catalyst (palladium acetate for example), a phosphine ( triphenylphosphine for example) in solution in an organic solvent (dimethylformamide for example) and in the presence of water. The reaction takes place at a temperature between 20 C and that of the reflux of the solvent. The halogenated derivative of general formula (VII), in which R 1 and R 6 are such that Br 1 (CH 2) 3 1> L 1 R 6 NaOH / Bu 4 Br Br (Br 2) 3 Br previously described, can be prepared from the derivative of general formula (VIII), by reaction with a halogenating agent such as N-bromosuccinimide in a chlorinated solvent (carbon tetrachloride, for example). The bicyclic derivative of general formula (VIII) may be prepared by aminolysis of the compound of general formula of formula (IX) with an amine of general formula R1-NH2. This reaction is carried out in the presence or absence of iodide ions (potassium iodide or sodium iodide for example) and in solution in an organic solvent (acetonitrile, dimethylformamide, ethanol, NMP, ether, THF, dioxane, toluene for example), a temperature between 20 C and the reflux temperature of the solvent. The amine derivative obtained intermediately is then cyclized in the presence of a cyclization agent (trimethylaluminium for example) dissolved in an organic solvent (toluene, for example) at a temperature of between 20 ° C. and the reflux temperature of the solvent. The compound of general formula (IX) may be prepared from the pyrrole-2-carboxylic acid derivative of general formula (X), by a monoalkylation reaction, by the action of 1,3-dibromopropane. This alkylation is carried out with a base such as cesium carbonate, potassium carbonate, potassium phosphate, potassium t-butoxide, sodium hydroxide, sodium hydride and in solvents such as ethanol, DMF, NMP, ether, THF, dioxane, acetonitrile, toluene or by phase transfer in the presence of an agent such as tetrabutylammonium chloride in dichloromethane or dichloroethane in the presence of water, or in benzene.

  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 following transformations, in any order: an acid function esterification or amidification reaction, an acid functional ester function hydrolysis reaction, a hydroxyl functional conversion reaction to an alkoxy function, an oxidation reaction of alcohol function according to aldehyde, ketone or acid, an alcohol function reduction reaction, alcohol-based aldehyde or ketone, a reductive amination reaction of an aldehyde or ketone function, an aldehyde-based alkenyl group oxidation reaction or ketone, an oxidation reaction of a thioether to sulfone or sulfoxide, an alkylation reaction of a sulfonamide, a dehydration reaction of hydroxyalkyl group to alkenyl group , a dehydrohalogenation reaction of a halogenated derivative, a total or partial hydrogenation reaction of alkenyl or alkynyl group in the alkenyl or alkyl group, a) b) c) d) e) f) g) h) i) J) k) I) m) a catalytic coupling reaction of a halogenated derivative and an organometallic derivative such as stannic or boronic to introduce an alkyl, alkenyl, alkynyl or aryl substituent, n) a reactive function protection reaction, o ) an elimination reaction of the protective groups which can carry the protected reactive functions, p) a salification reaction with a mineral or organic acid or a base to obtain the corresponding salt, q) a resolution reaction of the racemic enantiomeric forms wherein said products of formula (I) thus obtained are optionally in any isomeric racemic, enantiomeric and diastereoisomeric forms, r) a derivative reduction reaction. nitro or nitroso derivatives or amino, s) a reaction of mono- or di-alkylation of an amine function, t) a sulfonylation reaction of a primary or secondary amine, u) an acylation reaction of a amine function.

  The invention, according to another of its aspects, also relates to the compounds of formula (III). These compounds are useful as synthesis intermediates for the compounds of formula (I).

  The compounds of formula (I) can be purified by methods known to those skilled in the art, for example by crystallization, chromatography or extraction.

  The following example describes the preparation of a compound according to the invention. This example is not limiting and only illustrates the present invention. The nomenclature of the following compounds exemplified was established using the software ACDLabs version 10.0.

  The proton nuclear magnetic resonance spectra (1 H NMR) were carried out at 250 MHz, 300 MHz, 400 MHz or 500 MHz on Brüker apparatus (chemical shifts (8 ppm)) in the solvent dimethyl sulfoxide (DMSO). d6) referenced at 2.50 ppm at the temperature of 303K). The abbreviations used to characterize the signals are as follows: s = singlet, m = multiplet, d = doublet, t = triplet, q = quadruplet. Example 1: 1.1: N - [(1S, 2R) -1-Benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1) base propylbutyl) -2,4,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-7-carboxamide 1.1.1: 1- (3-bromopropyl) -1H- pyrrole-2-carboxylate ethyl 5,15 g of ethyl pyrrole-2-carboxylate, 18 cm3 of 1,3-dibromopropane, 22 cm3 of concentrated sodium hydroxide and 11.93 g of tetrabutylammonium bromide are stirred under an inert atmosphere during 48 h at a temperature close to 20 C. 80 cm3 of dichloromethane and 80 cm3 of water are added to the reaction medium. The aqueous phase is extracted with 3 times 40 cm3 of dichloromethane. The organic phases are combined and then washed with 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated by rotary evaporation under reduced pressure (5 kPa). The 50 g of oil obtained are purified by flash chromatography on silica (column: 400 g, particle size: 15-40 μm, eluent: 100% dichloromethane). After concentration of the fractions under reduced pressure, 9.8 g of ethyl 1- (3-bromopropyl) -1H-pyrrole-2-carboxylate are obtained. * MS-E1: 259 (+) 79Br = M (

  1.1.2: Ethyl 1- {3 - [(1-propylbutyl) amino] propyl} -1H-pyrrole-2-carboxylate 7 g of 1- (3-bromopropyl) -1H-pyrrole-2-carboxylate ethyl, 9.3 g of 4-aminoheptane, 4.46 g of potassium iodide and 140 cm3 of acetonitrile are stirred under an inert atmosphere for 20 hours at 70 ° C. and then cooled to a temperature close to 20 ° C. The mixture The reaction mixture is concentrated in a rotary evaporator under reduced pressure (5 kPa). 100 cm3 of dichloromethane and 100 cm3 of water are then added to the concentration residue. The aqueous phase is extracted with 3 times 50 cm3 of dichloromethane. The organic phases are combined, washed with 40 cm 3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated by rotary evaporation under reduced pressure (5 kPa). The product obtained is purified by flash chromatography on silica (column: 400 g, particle size: 15-40 μm, eluent: heptane gradient 75% -ethyl acetate 25% to 100% ethyl acetate). After concentration of the fractions under reduced pressure, 5.87 g of ethyl 1- {3 - [(1-propylbutyl) amino] propyl} -1H-pyrrole-2-carboxylate are obtained. • MS-E1: 2940.) = M (; 251 (= M (- C3H7)

  1.1.3: 2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepin-1-one at a temperature close to 20 C, 85 g of ethyl 1- {3 - [(1-propylbutyl) amino] propyl} -1H-pyrrole-2-carboxylate are dissolved under an inert atmosphere in 150 cm3 of toluene. 29.8 cm3 of 2M toluene solution of trimethylaluminium are poured on the reaction mixture in 5 min. The reaction mixture is heated with stirring for 20 h at 100 ° C. and is then cooled to a temperature close to 20 ° C. It is then poured into 200 g of ice and 100 cm 3 of ethyl acetate. The suspension obtained is filtered on a Celite 545 pellet. The aqueous phase is extracted with 3 times 40 cm 3 of ethyl acetate. The organic phases are combined and then washed with 40 cm3 of water, 40 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in a rotary evaporator under reduced pressure (5 kPa). The 4.71 g of crude product obtained are purified by flash chromatography on silica (column: 200 g, particle size: 15-40 μm, eluent: 100% dichloromethane gradient to 80% dichloromethane-20% ethyl acetate). After concentrating the fractions under reduced pressure, 2.97 g of 2- (1-propyl-butyl) -2,3,4,5-tetrahydro-pyrrolo [1,2-a] [1,4] diazepine are obtained. 1-one. • MS-E1: 248 (+) = M (; 249 (+) - (M + H) (1.1.4: 7-Bromo-2- (1-propylbutyl) -2,3,4,5-tetrahydro- 1 H-pyrrolo [1,2-a] [1,4] diazepin-1-one At a temperature close to 20 ° C., 1.5 g of 2- (1-propylbutyl) -2,3,4,5- tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepin-1-one are dissolved in 120 cm3 of carbon tetrachloride, 1.075 g of N-bromosuccinimide is added to the solution. The reaction mixture is concentrated on a rotary evaporator under reduced pressure (5 kPa) The solid residue obtained is purified by flash chromatography on silica (column: 200 g, particle size: 15-40 μm, eluent: 90% dichloromethane). 10% ethyl acetate) After concentration of the fractions under reduced pressure, 1.92 g of 7-bromo-2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1] are obtained. , 2-a] [1,4] diazepin-1-one • MS-E1: 326+) 79Br = M (1.1.5: 1-Oxo-2- (1-propylbutyl) -2,3,4-acid) , 5-Tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-7-carboxylic acid in a stirred tricolor and purged with carbon monoxide, 1 g of 7-bromo-2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepin-1 25 cm3 of dimethylformamide, 2.5 cm3 of water, 1.14 g of potassium acetate, 102 mg of potassium iodide, 275 mg of palladium acetate and 640 mg of triphenylphosphine are introduced successively at a temperature of temperature close to 20 C. The reaction mixture is bubbled with carbon monoxide and then heated at 100 C for 7 h. It is cooled to 20 ° C to be filtered on a Celite 545 pellet. The filtrate is evaporated on a rotary evaporator under reduced pressure (5 kPa). The oily residue obtained is taken up in 40 g of ice and 40 cm 3 of ethyl acetate. The pH is brought to 10 with 5M sodium hydroxide. After decantation, the aqueous phase is washed with 3 times 40 cm 3 of ethyl acetate and then filtered on a Celite 545 pellet. The filtrate is acidified with stirring with a solution. 5M hydrochloric acid (pH = 1) and then extracted with 3 times 40 cm3 of ethyl acetate. The organic phases are combined and then washed with 30 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated by rotary evaporation under reduced pressure (5 kPa). The product obtained (1 g) is purified by flash chromatography on silica (column: 90 g, particle size: 15-40 μm, eluent: 95% dichloromethane - 5% methanol). After concentration of the fractions under reduced pressure, 0.74 g of 1-oxo-2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] is obtained. [1,4] diazepine-7-carboxylic acid. • MS-E1: 292 (= M (

1.1.6: N - [(1S, 2R) -1-Benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl) - 2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-7-carboxamide To a suspension of 200 mg of 1-oxo-2- (1-propylbutyl) ) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-7-carboxylic acid, 281 mg of (2R, 3S) -3 hydrochloride (1: 1) 4-amino-phenyl-1 - {[3- (trifluoromethyl) benzyl] amino] butan-2-ol, 14 mg of hydroxybenzotriazole, 164 mg of 1- (3-dimethylaminopropyl) hydrochloride. ethylcarbodiimide in 25 cm3 of dichloromethane is poured 0.468 cm3 of N, N-diisopropylethylamine at a temperature close to 20 C. The solution obtained is stirred for 3 h 30 to 20 C under an inert atmosphere. 25 cm3 of dichloromethane and 15 cm3 of water are added to the reaction medium. The organic phase is washed with 20 cm3 of saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated by rotary evaporation under reduced pressure (5 kPa). The product obtained is purified by flash chromatography on silica (column: 15 g, granulometry: 20-40 pm spherical, eluent: 95% dichloromethane gradient - 5% methanol to 90% dichloromethane - 10% methanol). After concentration of the fractions under reduced pressure, 206 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo were obtained. -2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-7-carboxamide. LC-MS-DAD-ELSD: 6110 = (M-H); 6570 = (M + Formal Ac-H); 613 (+) = (M + H) (1.2: N- [(1S, 2R) -1-Benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] hydrochloride salt (1: 1) amino} propyl] -1-oxo-2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-7-30 carboxamide A a temperature close to 20 C, 200 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-7-carboxannide are dissolved in 2.5 cm3 of ethyl ether. 6 cm3 of a solution of 4M hydrochloric acid in dioxane is added with stirring under argon at a temperature of 5 ° C. The reaction mixture is partially precipitated and the suspension is concentrated under reduced pressure (5 kPa). 3 cm3 of ethyl ether are added, the suspension is stirred for 15 min, then the stirring is stopped and the supernatant is removed, this operation is carried out twice, the last suspension is then concentrated under reduced pressure (5 kPa). gets 183 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1) hydrochloride (1: 1) 2-propylbutyl) -2,4,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepine-7-carboxamide as a white solid. • NMR: 0.86 (t, J = 7.5Hz, 3H), 0.88 (t, J = 7.5Hz, 3H); de1,15à1,30 (m, 4H); 1.44 (m, 4H); 1.88 (m, 2H); 2.77 (dd, J = 11.0 and 14.0 Hz, 1H); 2.87 (m, 1H); from 2.96 to 3.17 (m, 4H); 3.87 (m, 1H); 3.97 (m, 1H); 4.17 (m, 1H); 4.31 (m, 2H); from 4.41 to 4.53 (m, 2H); 5.92 (m spread, 1H); 6.44 (d, J = 4.0 Hz, 1H); 6.62 (d, J = 4.0 Hz, 1H); 7.14 (m, 1H); 7.24 (m, 4H); 7.65 (t, J = 7.5 Hz, 1H); 7.76 (d, J = 7.5 Hz, 1H); 7.86 (d, J = 7.5 Hz, 1H); 7.96 (s, 1H); 8.18 (d, J = 9.0 Hz, 1H); 8.97 (spread m, 1H) 9.32 (m spread, 1H). LC-MS-DAD-ELSD: 611 (-): (M-H) (-); 6570 (M + Formal Ac H) O; 613 (+) _ (M + H) (+) The compounds according to the invention were the subject of pharmacological tests to determine their inhibitory effect vis-à-vis the activity (3-secretase.

  Assays consisted in measuring the in vitro inhibition of the β-secretase activity by the compounds of the invention The measured R-secretase activity corresponds to that of a purified recombinant form of human BACE1 aspartyl protease (the latter having 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 BACE1 activity is measured by cleavage of a substrate Fluorogenic peptide, designated FS1, originally described by Ermolieff et al. (2000, Biochemistry, 39, 12450-12456), and based on the principle of resonance fluorescence energy transfer (FRET); peptide cleavage FS1 is measured according to the increase of the fluorescent signal emitted by the EDANS group (or 5 - [(2-aminoethyl) amino] -na phthalene-1-sulphonic acid) The assay is performed in a 96-well microplate to determine the inhibition of enzymatic activity by the products of the invention. The FS1 substrate is solubilized at a concentration 3C) of 1 mM in 100% dimethylsulfoxide (DMSO) and stored at -20 C until use. Dilutions of the test products are prepared in DMSO from 10 mM stock solution. The products of the invention, at final concentrations of 0.003 to 10 μM, are incubated at 37 ° C. with the substrate FS1 (final concentration of 5 μM) and the purified enzyme (final concentration of 10 μM), in acetate buffer. sodium (0.1 M) pH 4.5 containing 0.02% CHAPS 35 detergent and 200 mM NaCl for 45 minutes. The final percentage of DMSO does not exceed 7%. When the incubation is complete, the fluorescence is measured in a spectrofluorimeter at excitation wavelengths of 355 nM and emission of 509 nM. For each concentration of product tested, the fluorescent signal is compared to the maximum signal obtained when the substrate FS1 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, IDBSTM)

  IC50s are between 0.1 and 5 M.

  For example, compound no. 1 showed an IC 50 of 1.40 μM.

  It therefore appears that the compounds according to the invention have an inhibitory activity vis-à-vis the activity of β-secretase.

  The compounds according to the invention can therefore be used for the preparation of medicaments, in particular medicinal products which inhibit the production of A (3) .Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of formula (I).

  These drugs find their therapeutic use, particularly in the treatment and prevention of diseases associated with the production of peptide A (3, among which mention may be made of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, the disease Huntington's disease, Creutzfeld-Jacob disease, Down's syndrome, Lewy body dementia, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild cognitive impairment, amyloid cerebral angiopathy , primary and secondary memory disorders, 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 disorders.

  These drugs are particularly useful in the treatment and prevention of 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 impairment, amyloid cerebral angiopathy, primary and secondary memory disorders, cerebrovascular ischemia.

  According to another of its aspects, 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, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient. Said excipients are chosen according to the pharmaceutical form and the mode of administration desired, from the usual excipients which are known to those skilled in the art. In the pharmaceutical 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. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions. By way of example, 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 Mannitol 223.75 mg Croscarmellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg

  The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration, to a patient, 3: 5 of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt or hydrate or solvate thereof.

Claims (9)

  A compound of formula (I) wherein R 1 is hydrogen, (C 1 -C 6) alkyl, (C 3 -C 5) cycloalkyl, (CH 2) n - C 1 -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 R1 is COOR, S (O) mR, aryl or aralkyl; (C 1 -C 6) alkyl, (C 3 -C 5) cycloalkyl, (CH 2) n - (C 1 -C 6) alkenyl, (CH 2), - (C 1 -C 6) alkynyl, (C -C6) alkyl-Z- (C 1 -C 6) alkyl, aryl or aralkyl being optionally substituted with one or more groups selected from a halogen atom, a (C 1 -C 6) alkyl group, (C 3 -C 5) cycloalkyl, halo (C1-C6) alkyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy, NR7R8, nitro, cyano, OR, COOR, CONR7R8, S (O) mNR7R8, R2 represents one or more groups chosen from a hydrogen atom, a halogen atom, a (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl, (C 1 -C 6) alkenyl, (C 1 -C 6) alkynyl group ( CIC6) alkyl-Z- (C 1 -C 6) alkyl, wherein Z represents a heteroatom selected from O, N and S (O) m, or R2 represents a halo (C 1 -C 6) alkyl, halo (C) , -C 6) alkoxy, hydroxy, (C 1 -C 6) alkoxy, nitro, cyano, amino, NR 7 R 8, COOR, CONR 7 R 8, O-CO (C 1 -C 6) alkyl, S (O) m NR 7 R 8, a group aryl, the aryl group being optionally substituted by one or more groups selected from a halogen atom , (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl, halo (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo (C 1 -C 6) alkoxy, NR 7 R 8, OR, nitro , cyano, COOR, CONR7R8, S (O) mNR7R8, R3 represents a trifluoromethyl group, R4 and R5 represent, independently of one another, a hydrogen atom, or R4 and R5 form with the atom of carbon which carries them 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 chosen from a hydrogen atom, a halogen atom, (C 1 -C 6) alkyl, (C 3 -C 5) cycloalkyl, (C 3 -C 5) cycloalkyl (C 1 -C 6) alkyl, nitro, amino, NR 7 R 8, COOR, aryl, a group NR 7 (SO 2) R 8 or CONR 7 R 8, R, R 7 and R 8 represent, independently of one another, one or more groups selected from a hydrogen atom, a (C 1 -C 6) alkyl group, C 1) cycloalkyl, (C 3 -C 5) cycloalkyl (C 1 -C 6) alkyl, aryl, aryl (C 1 -C 6) alkylene, COR, or R 7 and R 8 p may form with the atom carrying them a saturated, partially unsaturated or unsaturated ring containing from 5 to 7 carbon atoms and optionally additionally containing a heteroatom selected from O, N or S (O) m, m represents a whole number which can take the values 0, 1 or 2 and n represents an integer which 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, in the form of a base or addition salt with an acicle, as well as in the hydrate or solvate state. 10   2. Compound of formula (I) according to claim 1, characterized in that RI represents a group (C, -C, O) alkyl, optionally substituted by one or more (C, -C6) alkyl groups, in the state base or salt of addition to an acid, and in the state of hydrate or solvate.   3. Compound of formula (I) according to one of claims 1 or 2, characterized in that R1 represents a group (C, -C, o) alkyl, optionally substituted by one or more groups (C, -C6) alkyl, R 2, R 4, R 5 and R 6 represent a hydrogen atom, in the form of a base or an addition salt with an acid, as well as in the hydrate or solvate state. 2C)   4. Compound of formula (III) COZH R6 (III) wherein R1 and R6 are as defined in general formula (I) according to claim 1.   5. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, or a salt of addition of this compound to a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of formula (I). 30   6. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, and at least a pharmaceutically acceptable excipient.   7. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament for the treatment and prevention of any disease in which the beta-secretase activity is involved.   8. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament for the treatment and prevention of Alzheimer's disease, Parkinson's disease, the disease Huntington's disease, Creutzfeld-Jacob disease, Down's syndrome, Lewy body dementia, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild cognitive impairment, 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 disorders.   9. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament for the treatment and prevention of Alzheimer's disease, Farkinson's disease, the syndrome Down syndrome, Lewy body dementia, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild 2C) cognitive impairment, amyloid cerebral angiopathy, primary and secondary memory disorders, l cerebrovascular ischemia.