HK1143164A - Derivatives of 1-oxo-1,2-dihydroisoquinoline-5-carboxamides and of 4-oxo-3,4-dihydroquinazoline-8-carboxamides, preparation thereof and application thereof in therapeutics - Google Patents

Description

Derivatives of 1-oxo-1, 2-dihydroisoquinoline-5-carboxamides and of 4-oxo-3, 4-dihydroquinazoline-8-carboxamides, preparation thereof and therapeutic use thereof

The present invention relates to derivatives of 1-oxo-1, 2-dihydroisoquinoline-5-carboxamides and 4-oxo-3, 4-dihydroquinazoline-8-carboxamide derivatives, to their preparation and to their therapeutic use.

The presence of multiple senile plaques (multiple plaques) in brain tissue is one of the major histopathological lesions observed in alzheimer's disease; these plaques are formed by the deposition of fibrillar aggregates (agregatsfibrillaires) of the 4kDa peptide (40-42 amino acids) called amyloid β (Α β). According to the amyloid cascade (hypoth ase d' unecascade)) The production and progressive accumulation of this peptide plays a decisive role in the initiation and progression of Alzheimer's disease (D.Se1ko et al Nature399A(1999) 23; roggo et al Top. Med. chem2(2002) 359; ghosh et al curr.med.chem.9(2002)1135)。

A β peptide derived from APP protein (amyloid precursor protein), which can be cleaved by at least three different proteolytic activities: 1) cleavage (cleavage) in the a β region by α -secretase activity (thus preventing the formation of a β); 2) cleavage at the N-terminus of a β by β -secretase activity; 3) cleavage at the C-terminus of a β by γ -secretase activity. The sequential cleavage of APP protein at the β and γ sites results in the formation of a β peptide (m.citron, nat. rev. neurosci).5(2004) 677-; beer et al Expert opin invest drugs14(2005)1385-1409)。

There is therefore a real interest in finding compounds that inhibit the production of a β peptide (t.b. durham et al curr. opin. drug disc. dev.9(2006)776-791)。

It has now been found that the compounds 1-oxo-1, 2-dihydroisoquinoline-5-carboxamide and 4-oxo-3, 4-dihydroquinazoline-8-carboxamide derivatives have strong inhibitory activity against β -secretase activity.

The object of the present invention is a compound corresponding to the general formula (I):

wherein:

r1 represents a hydrogen atom, or a hydrogen atom₁-C₁₀) Alkyl, (C)₃-C₇) Cycloalkyl group, (CH)₂)_n-(C₁-C₆) Alkenyl group, (CH)₂)_n-(C₁-C₆) Alkynyl, (C)₁-C₆) alkyl-Z- (C)₁-C₆) Alkyl, wherein Z represents a radical selected from O, N and S (O)_mOr R1 represents COOR, S (O)_mR, aryl or aralkyl; (C)₁-C₁₀) Alkyl, (C)₃-C₇) Cycloalkyl group, (CH)₂)_n-(C₁-C₆) Alkenyl group, (CH)₂)_n-(C₁-C₆) Alkynyl, (C)₁-C₆) alkyl-Z- (C)₁-C₆) Alkyl, wherein aryl or aralkyl is optionally substituted with one or more groups selected from: halogen atom, (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl, halo (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, halo (C)₁-C₆) Alkoxy, NR7R8, nitro, cyano, OR, COOR, CONR7R8, S (O)_mNR7R8 or aryl;

r2 represents one or more groups selected from: a hydrogen atom, a halogen atom, and (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₁-C₆) Alkenyl, (C)₁-C₆) Alkynyl, (C)₁-C₆) alkyl-Z- (C)₁-C₆) Alkyl, wherein Z represents a radical selected from O, N and S (O)_mOr R2 represents halo (C)₁-C₆) Alkyl, halo (C)₁-C₆) Alkoxy, hydroxy, (C)₁-C₆) Alkoxy, nitro, cyano, amino, NR7R8, COOR, CONR7R8, OCO (C)₁-C₆) Alkyl, S (O)_m-NR7R8, aryl, wherein aryl may be optionally substituted with one or more groups selected from: halogen atom, (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl, halo (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, halo (C)₁-C₆) Alkoxy, NR7R8, OR, nitro, cyano, COOR, CONR7R8, S (O)_mNR7R8；

R3 represents trifluoromethyl;

r4 and R5 represent a hydrogen atom, or R4 and R5 form, together with the carbon atoms that carry them, a saturated ring comprising from 3 to 6 carbon atoms and optionally from 0 to 1 heteroatom chosen from O, N or S;

r6 represents a group selected from: a hydrogen atom, a halogen atom, and (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₃-C₇) Cycloalkyl (C)₁-C₆) Alkyl, halo (C)₁-C₆) Alkyl, nitro, amino, NR7R8, COOR, NR7 (SO)₂) R8, c (o) NR7R8, aryl optionally substituted with one or more groups selected from: halogen atom, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy or cyano;

r, R7 and R8 represent, independently of one another, one or more groups selected from: hydrogen atom, (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₃-C₇) Cycloalkyl (C)₁-C₆) Alkyl, aryl (C)₁-C₆) Alkylene, or R7 and R8 may form, together with the atoms which carry them, a saturated, partially unsaturated or unsaturated ring containing from 5 to 7 carbon atoms and optionally additionally containing a substituent selected from O, N or S (O)_mA heteroatom of (a);

x represents a carbon atom or a nitrogen atom;

m represents an integer which may take a value of 0, 1 or 2, and n represents an integer which may take a value of 1, 2, 3, 4, 5 or 6;

the carbon bearing the benzyl group substituted with R2 is in the S absolute configuration;

the carbon bearing the hydroxyl group is in the absolute R configuration,

the compounds of formula (I) may contain one or more asymmetric carbon atoms. They may therefore exist as enantiomers or diastereomers. These enantiomers, diastereomers and mixtures thereof, including racemic mixtures, form part of the present invention.

The compounds of formula (I) may be present in the form of a base or an addition salt with an acid. Such addition salts form part of the present invention.

These salts may be prepared using pharmaceutically acceptable acids, but salts of other acids which may be used, for example, in the purification or isolation of the compounds of formula (I) also form part of the invention.

In the context of the present invention, the following are understood:

-C_t-C_z(wherein t and z may take values of 1-10) carbon chains or rings which may have t-z carbon atoms, e.g. C₁-C₃Carbon chains having 1-3 carbon atoms can be characterized;

-a halogen atom: fluorine, chlorine, bromine or iodine;

-an alkyl group: a straight or branched chain saturated aliphatic group. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and the like;

-a cycloalkyl group: a cyclic alkyl group. For example, there may be mentioned cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;

-alkylene groups: a linear or branched saturated divalent aliphatic group. E.g. C_1-3Alkylene represents a linear or branched divalent carbon chain having 1 to 3 carbon atoms, such as methylene (-CH)₂-) ethylene (-CH₂CH₂-, 1-methylethylidene (-CH (CH)₃)CH₂-) or propylene (-CH)₂CH₂CH₂-)；

-alkenyl: linear or branched mono-or polyunsaturated aliphatic groups, for example containing 1 or 2 ethylenic unsaturations;

-alkynyl: linear or branched mono-or polyunsaturated aliphatic groups, for example containing 1 or 2 acetylenic unsaturations;

-an alkoxy group: -O-alkyl, wherein alkyl is as previously defined;

-halo (C)₁-C₆) Alkyl groups: alkyl groups whose hydrogen atom or atoms have been substituted with halogen atoms. For example, CF may be mentioned₃、CH₂CF₃、CHF₂、CCl₃；

-halo (C)₁-C₆) Alkoxy groups: -O-alkyl, wherein alkyl is as defined above and which is substituted by one or more halogen atoms which may be the same or different. By way of example, OCF may be mentioned₃、OCHF₂、OCCl₃；

The sulphur and nitrogen atoms may be present in the oxidised state (N-oxide, sulphoxide, sulphone).

-aryl: cyclic aryl groups containing 6 to 14 carbon atoms. Aryl, for example, phenyl or naphthyl;

within the object of the present invention compounds of formula (I), a first group of compounds consists of the compounds for which:

x represents a carbon atom.

Among the compounds of formula (I) object of the present invention, the second group of compounds consists of the compounds for which:

x represents a nitrogen atom.

Among the compounds of formula (I) object of the present invention, the third group of compounds consists of the compounds for which:

r1 represents (C)₁-C₁₀) Alkyl, optionally with one or more (C)₁-C₆) Alkyl substitution;

r2, R4 and R5 represent a hydrogen atom; and

r6 represents a group selected from a hydrogen atom or a halogen atom.

Combinations of groups 1-3 as defined above also form part of the present invention.

Among the compounds of formula (I) object of the present invention, mention may be made in particular of the following compounds:

n- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) -1, 2-dihydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -6-chloro-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide and its hydrochloride (1: 1).

Another subject of the invention is also a process for the preparation of the compounds of formula (I).

In the following, a protecting group Pg is understood to mean, on the one hand, a protection of the reactive function, such as a hydroxyl group or an amine, during the synthesis and, on the other hand, a regeneration of the intact reactive function at the end of the synthesis. Such protecting Groups and methods of protection and deprotection are given in "Protective Groups in organic Synthesis", Green et al, 2 nd edition (John Wiley & Sons Inc., New York) 1991.

In the following, "leaving group" is understood to be a group which can be easily cleaved from a molecule by heterolytic bond cleavage and which carries away an electron pair. Such a group can thus be easily replaced with another group, for example during a substitution reaction. Such leaving groups are, for example, halogen or activated hydroxy groups, such as methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl, acetate and the like. Examples of leaving groups and references for their preparation are given in "Advances in Organic Chemistry", J.March, 3 rd edition, Wiley Interscience, 1985, p.310-316.

In the schemes that follow, the starting compounds and reactants, when their methods of preparation are not described, are commercially available or described in the literature, or can be prepared according to the methods described herein or known to those skilled in the art.

Abbreviations and symbols used to describe the synthetic methods and to describe the compounds are as follows:

BOC for tert-butoxyformates

-DCC for dicyclohexylcarbodiimide

DMF is used for dimethylformamide,

EDCI for (1-ethyl-3, 3-dimethylaminopropyl) carbodiimide,

NMP for N-methyl-2-pyrrolidone,

PyBOP for benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate

THF was used for tetrahydrofuran.

According to the present invention, the compound of the general formula (I) can be prepared according to the method illustrated by the following scheme 1.

Scheme 1

According to scheme 1, the compounds of general formula (I) are prepared from compounds of general formula (III), wherein R1 and R6 are as defined in general formula (I), by condensing the amine function of compounds of general formula (II), wherein R2, R3, R4 and R5 are as defined in general formula (I), on the compounds of general formula (III). The reaction is carried out in a solvent such as dichloromethane, THF, ether or chloroform at a temperature between 20 ℃ and the reflux temperature of the solvent in a preferably inert anhydrous medium such as nitrogen or argon by using conventional reagents for coupling acids with amines such as DCC, PyBOP or EDCl.

According to the process illustrated by scheme 2 below, the compounds of formula (II), in which R2, R3, R4 and R5 are as defined in formula (I), can be prepared from compounds of formula (IV), in which R2, R3, R4 and R5 are as defined in formula (I), by deprotecting the primary amine by the action of an acid (for example hydrochloric acid) dissolved in an ethereal (er) solvent (for example diethyl ether) and/or a chlorinated solvent (for example dichloromethane) or a mixture of solvents.

Compounds of formula (IV) wherein R2, R3, R4 and R5 are as defined in formula (I) can be prepared by reacting a benzylamine derivative of formula (VI) wherein R3, R4 and R5 are as defined in formula (I) with an oxirane of formula (V) wherein R2 is as defined in formula (I), in a preferably inert anhydrous medium, such as nitrogen or argon, in a chlorine-containing solvent, such as dichloromethane, and in the presence of a triflate anion, such as scandium triflate.

Scheme 2

Compounds of general formula (IIIa), wherein X represents a carbon atom and R1 is as described above, can be prepared according to the method described in scheme 3 below.

Scheme 3

The compounds of formula (IIIa) can be obtained by reacting a compound of formula (XXVI) with carbon monoxide in the presence of (potassium or sodium) acetate ions, alkali metal iodides (e.g. sodium iodide or potassium iodide), palladium-containing catalysts (e.g. palladium acetate), phosphines (e.g. triphenylphosphine) (dissolved in an organic solvent, e.g. dimethylformamide or dimethylsulfoxide) and in the presence of water. The reaction is carried out at a carbon monoxide pressure of 1 to 100 atmospheres and at a temperature of 20 ℃ to 120 ℃ in analogy to D.Milstein et al J.am.chem.Soc. (1989)8742 and T.W.Ku et al Tetrahedron Lett. (1997) 3131.

Compounds of formula (XXVI) may be prepared from 5-iodo-2H-isoquinolin-1-one as described in the literature below, (M.D.Threadgill et al, J.chem.Soc.Perkin Trans.1(2002)335), after alkylation with an alkylating agent of formula R1-Hal. The reaction is carried out as a solution in an organic solvent (e.g. toluene or dichloromethane), in the presence of a base (e.g. sodium hydroxide, potassium hydroxide or sodium hydride) and a tetraalkylammonium halide (e.g. tetrabutylammonium bromide) and at a temperature between 20 ℃ and the reflux temperature of the solvent.

Compounds of general formula (IIIb), wherein X represents a nitrogen atom, R6 represents a halogen atom, for example chlorine, R1 is as described above, can be prepared according to the method described in scheme 4 below.

Scheme 4

The compounds of the formula (IIIb) can be obtained from compounds of the formula (XXVIII) under the same conditions as for the preparation of compounds of the formula (IIIa).

The compound of formula (XXVIII) can be prepared by the action of an orthoformate (e.g., methyl orthoformate) on a compound of formula (XXIX) dissolved in an alcoholic solvent (e.g., methanol or ethanol) in the presence of a base (e.g., sodium methoxide or sodium ethoxide). The reaction is preferably carried out at a temperature between 0 ℃ and the reflux temperature of the solvent.

The compound of formula (XXIX) may be prepared by reaction of a compound of formula R1-NH in the presence of trimethylaluminium in an organic solvent, such as toluene, at a temperature of from 20 ℃ to the reflux temperature of the solvent₂The action of the amine on methyl 2-amino-5-chloro-3-iodobenzoate is prepared.

The compounds of formula (IIIa) and (IIIb) are useful as intermediates in the synthesis of compounds of formula (I).

If desired and if necessary, the product of formula (I) may be subjected to one or more of the following conversion reactions in any order to obtain a product of formula (I) or converted to other products of formula (I):

a) an esterification or amidation reaction of the acid function,

b) the hydrolysis of the ester function to the acid function,

c) the reaction of the hydroxyl function to the alkoxy function,

d) oxidation of the alcohol function to an aldehyde, ketone or acid function,

e) reduction of the acid, aldehyde or ketone function to the alcohol function,

f) reductive amination of the aldehyde or ketone function,

g) the oxidation of an alkylene to an aldehyde or ketone function,

h) the oxidation of a thioether to a sulfone or sulfoxide,

i) the alkylation reaction of the sulfamide is carried out,

j) the reaction of dehydration of a hydroxyalkyl group to an alkenyl group,

k) the reaction of dehydrohalogenation of halogenated derivatives,

l) reaction of complete or partial hydrogenation of alkenyl or alkynyl groups to alkenyl or alkyl groups,

m) catalytic coupling of halogenated derivatives and organometallic derivatives (such as tin or boron derivatives) to introduce alkyl, alkenyl, alkynyl or aryl substituents,

n) a protection reaction of the reactive function,

o) elimination of the protective group which is carried by the protected reactive function,

p) salt formation using inorganic or organic acids or using bases to obtain the corresponding salts,

q) resolution of the racemic form into enantiomers, the product of formula (I) thus obtained optionally being in all possible racemic, enantiomeric or diastereomeric isomeric forms,

r) reduction of nitro derivatives to nitroso or amino derivatives,

s) mono-or dialkylation of amine functions,

t) sulfonylation of primary or secondary amines,

u) acylation of amine functions.

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

In schemes 1-4, the starting compounds and reactants, when their manner of preparation is not described, are commercially available or described in the literature, or can be prepared according to the methods described herein or known to those skilled in the art.

The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and serve only to illustrate the invention. The numbering of the exemplified compounds refers to the numbering given in the table below, in which the chemical structures and physical properties of some compounds according to the invention are illustrated.

The nomenclature used for the Compounds illustrated belowVersion 10.0 software was created.

Proton nuclear magnetic resonance (¹H NMR) spectra were taken at 250MHz, 300MHz, 400MHz or 500MHz on a Bru ker instrument (chemical shifts (. delta., ppm) -in dimethylsulfoxide-d 6(DMSO-d6) solvent, reference 2.50ppm at 303K). Abbreviations used to characterize the signals are as follows: s is singlet, m is multiplet, d is doublet, t is triplet, q is quartet.

Example 1:

the preparation of 5-iodo-2H-isoquinolin-1-one is described in the literature: threadgill, m.d. et al, j.chem.soc., Perkin trans.1, 2002, 335.

1.1: base N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) -1, 2-dihydroisoquinoline-5-carboxamide

1.1.1: 5-iodo-2- (1-propylbutyl) isoquinolin-1 (2H) -one

Under an inert atmosphere, while refluxing the solvent, 0.2g of 5-iodo-2H-isoquinolin-1-one and 234mg of 4-bromoheptan-e are stirredAlkane, 62mg finely ground potassium hydroxide, 79mg tetrabutylammonium bromide and then 28cm³Toluene for 6 hours. The reaction mixture was filtered through sintered glass. The filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. 320mg of the brown oil obtained are purified by flash chromatography on silica (column: 35 g; particle size: 20-40 μm, spherical; eluent: 80% heptane/20% ethyl acetate). After concentrating the fractions under reduced pressure, 165mg of 5-iodo-2- (1-propylbutyl) isoquinolin-1 (2H) -one are obtained in the form of a yellow solid.

·¹H NMR (300MHz, DMSO-d6) d ppm 0.83(t, J ═ 7.1Hz, 6H)1.11(m, 4H)1.68(m, 4H)5.01 (width m, 1H)6.65(d, J ═ 7.8Hz, 1H)7.25(t, J ═ 7.8Hz, 1H)7.57(d, J ═ 7.8Hz, 1H)8.24(d, J ═ 7.8Hz, 1H)8.27(d, J ═ 7.8Hz, 1H)

·MS-EI：369⁽⁺⁾＝M⁽⁺⁾

1.1.2: 1-oxo-2- (1-propylbutyl) -1, 2-dihydroisoquinoline-5-carboxylic acid

210mg of 5-iodo-2- (1-propylbutyl) -2H-isoquinolin-1-one, 6cm in that order, are added at a temperature close to 20 deg.C³Dimethylformamide, 0.37cm³Water, 0.212g of potassium acetate, 94mg of potassium iodide, 25mg of palladium acetate and 60mg of triphenylphosphine were introduced into a stirred three-necked flask which was purged with carbon monoxide. The reaction mixture was subjected to carbon monoxide bubbling and then heated at 100 ℃ for 1 hour. The reaction mixture was cooled to 20 ℃ and stirred for 20 hours. The dimethylformamide was evaporated under reduced pressure (5kPa) using a rotary evaporator. The obtained residue was dissolved in 10cm³Water and 10cm³In ethyl acetate. pH 1cm³Is alkalinized with 5M sodium hydroxide. The water phase used was 10cm³And washing with ethyl acetate. Then using 1cm of the mixture while stirring³Acidified with 5M hydrochloric acid (pH 1) and then diluted with 10cm³Extraction was carried out with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). 0.149g of 1-oxo-2- (1-propylbutyl) -1, 2-dihydroisoquinoline-5-carboxylic acid is obtained in the form of a beige solid。

·LC-MS-DAD-ELSD：286(^-)＝(m-H)(^-)；288(⁺)＝(M+H)(⁺)

·¹H NMR (300MHz, DMSO-d6) d ppm 0.84(t, J ═ 7.3Hz, 6H)1.01-1.22(m, 4H)1.57-1.82(m, 4H)5.03 (width m, 1H)7.44-7.61(m, 3H)8.27(dd, J ═ 7.5, 1.5Hz, 1H)13.04 (width bulk peak m, 1H).

1.1.3: n- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) -1, 2-dihydroisoquinoline-5-carboxamide

Under an inert atmosphere at a temperature close to 20 deg.C, 77mg of 1-oxo-2- (1-propylbutyl) -1, 2-dihydroisoquinoline-5-carboxylic acid is dissolved in 4.5cm³In dichloromethane. 110mg of (2R, 3S) -3-amino-4-phenyl-1- { [3- (trifluoromethyl) benzyl]Amino } butane-2-ol hydrochloride (1: 1), 5mg hydroxybenzotriazole, 61mg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added to the solution. Is measured at a distance of 0.22cm³The N, N-diisopropylethylamine (II) is poured into the reaction medium. It was kept stirring at ambient temperature for 20 hours. Is divided into 10cm³Water is added to the reaction medium. 5cm for organic phase³The sodium chloride saturated aqueous solution was washed, dried over magnesium sulfate and concentrated under reduced pressure (5kPa) using a rotary evaporator. The crude product obtained is purified by flash chromatography on silica (column: 15 g; particle size: 20-40 μm, spherical; flow rate: 20 cm)³Min; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 84mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are obtained in the form of a white solid]Amino } propyl group]-1-oxo-2- (1-propylbutyl) -1, 2-dihydroisoquinoline-5-carboxamide.

·LC-MS-DAD-ELSD：606(^-)＝(M-H)(^-)；608(⁺)＝(M+H)(⁺)

·¹H NMR(400MHz，DMSO-d6)d ppm 0.82(t，J＝7.4Hz，3H)0.83(t，J＝7.4Hz，3H)097-1.16(m, 4H)1.53-1.78(m, 4H)2.56-2.77(m, 3H)3.16(dd, J-14.0, 3.7Hz, 1H)3.63(m, 1H)3.83(d, J-14.2 Hz, 1H)3.88(d, J-14.2 Hz, 1H)4.21(m, 1H)5.00 (width m, 1H)5.02(d, J-5.7, 1H)6.29(d, J-8.1 Hz, 1H)7.14-7.34(m, 7H)7.41(t, J-7.7 Hz, 1H)7.53(t, J-7.7, 1H)7.58 (d, J-7.58 (d, 7.65, J-7.7, 7H) 7.53 (d, 7, 7.7H) 7, 7.7H (d, 7H)7, 7.7H) 7, 7H) 7(d, 7, 7.7, 7, 7.7.7, 7H) 1H, 7.

1.2: the salt N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) -1, 2-dihydroisoquinoline-5-carboxamide hydrochloride (1: 1)

84mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are reacted at a temperature close to 20 deg.C]-amino } propyl group]-1-oxo-2- (1-propylbutyl) -1, 2-dihydroisoquinoline-5-carboxamide is dissolved in 4cm³In diethyl ether. While stirring and under argon, 0.2cm was added³4M hydrochloric acid solution in dioxane. The reaction mixture precipitated. The stirring was stopped. The supernatant was removed and 5cm were added³Diethyl ether. This operation was performed three times. The final suspension was concentrated under reduced pressure (5 kPa). 87mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are obtained in the form of a white solid]-amino } propyl group]-1-oxo-2- (1-propylbutyl) -1, 2-dihydroisoquinoline-5-carboxamide hydrochloride (1: 1).

·¹H NMR (400MHz, DMSO-d6) d ppm 0.83(t, J ═ 7.3Hz, 3H)0.84(t, J ═ 7.3Hz, 3H)0.98-1.19(m, 4H)1.68(m, 4H)2.68(dd, J ═ 14.1, 11.1Hz, 1H)2.96(m, 1H)3.12-3.26(m, 2H)3.91(m, 1H)4.23(m, 1H)4.35(m, 2H)5.01 (width m, 1H)5.96(d, J ═ 6.6Hz, 1H)6.23(d, J ═ 7.8Hz, 1H)7.15-7.33(m, 6H)7.41(d, J ═ 6.8 Hz, 1H)7.15-7.33(m, 6H)7.41 (J, J ═ 7.8, 7.8H) 7.8 (t, 7.8H) 7.8 (J ═ 7.8, 7.8H) 7.8 (d, 7.8H) 7.8 (H) 7.8, 7.8 (H) 7.8, 7.8H) 7.8 (J ═ 7.8, 7.8H) 7.8 (d, 7.8 (H) 7.8 (1, 7.8 (d, 7, 1H)9.32 (Wide integral peak m, 1H)

·LC-MS-DAD-ELSD：606(^-)＝(M-H)(^-)；608(⁺)＝(M+H)(⁺).

Example 2:

2.1: base N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -6-chloro-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide

2.1.1: 2-amino-5-chloro-3-iodo-N- (1-propylbutyl) benzamide

To 3g of methyl 2-amino-5-chloro-3-iodobenzoate at 100cm under an inert atmosphere and at a temperature close to 20 deg.C³2.2g of 4-aminoheptane followed by 12cm of solution in toluene were added³2M trimethylaluminum solution in toluene. The reaction mixture was heated at 100 ℃ for 16h while stirring, then it was cooled to 20 ℃ so as to then be poured into 250g of a water/ice mixture and 150cm³On ethyl acetate. The suspension obtained is filtered over a piece of celite 545 (culot de celite 545). Using 3 times 100cm³The aqueous phase was extracted with ethyl acetate. The combined organic phases were then incubated with 100cm³The sodium chloride was washed with a saturated aqueous solution, dried over magnesium sulfate and concentrated under reduced pressure (5kPa) using a rotary evaporator. 12g of the crude product obtained are purified by flash chromatography on silica (column: 200 g; particle size: 15-40 μm; eluent: 100% dichloromethane). After concentrating the fraction under reduced pressure, 3.21g of 2-amino-5-chloro-3-iodo-N- (1-propylbutyl) benzamide was obtained.

·LC-MS-DAD-ELSD：393(^-)＝(M-H)(^-)；395(⁺)＝(M+H)(⁺)

·¹H NMR (400MHz, DMSO-d6) d ppm 0.87(t, J ═ 7.3Hz, 6H)1.15-1.52(m, 8H)3.93(m, 1H)6.37 (width S, 2H 7.55(d, J ═ 2.4Hz, 1H)7.76(d, J ═ 2.4Hz, 1H)8.14(d, J ═ 9.0Hz, 1H).

2.1.2: 6-chloro-8-iodo-3- (1-propylbutyl) quinazolin-4 (3H) -one

To 4.43g of ethanolSodium is in 250cm³The solution in ethanol was poured into 3.21g of 2-amino-5-chloro-3-iodo-N- (1-propylbutyl) benzamide at 120cm³Solution in ethanol, then poured in 3.3cm³And (3) ethyl formate. The reaction mixture was heated at reflux under argon for 16 hours. It was then cooled to effect evaporation under reduced pressure (5kPa) using a rotary evaporator. While stirring, 200cm of the concentrated residue was added³Methylene chloride and 150cm³And (3) water. The aqueous phase used was 50cm³Extraction was carried out with dichloromethane. The combined organic phases were then incubated with 50cm³The sodium chloride was washed with a saturated aqueous solution, dried over sodium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The resulting tan product was purified by flash chromatography on silica (column: 200 g; particle size: 15-40 μm; eluent: 100% dichloromethane). After concentration of the fractions under reduced pressure, 2.09g of 6-chloro-8-iodo-3- (1-propylbutyl) quinazolin-4 (3H) -one are obtained.

·MS-EI：404(⁺)＝M(⁺)

·¹H NMR (300MHz, DMSO-d6) d ppm 0.85(t, J ═ 7.2Hz, 6H)1.03-1.29(m, 4H)1.62-1.97(m, 4H)4.73-4.82 (width m, 1H)8.12(d, J ═ 2.3Hz, 1H)8.42(d, J ═ 2.3Hz, 1H)8.57(s, 1H).

2.1.3: 6-chloro-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxylic acid

To a stirred three-necked flask purged with carbon monoxide, 2.05g of 6-chloro-8-iodo-3- (1-propylbutyl) quinazolin-4 (3H) -one, 60cm were introduced in sequence at a temperature close to 20 deg.C³Dimethylformamide, 3cm³Water, 1.89g potassium acetate, 168mg potassium iodide, 455mg palladium acetate and 1.063g triphenylphosphine. The reaction mixture was subjected to carbon monoxide bubbling and then heated at 100 ℃ for 6 hours 30 minutes. It is cooled to a temperature close to 20 ℃ in order to be filtered over a piece of Cellit 545 (culot Cellit 545), using 20cm³Dimethylformamide and 20cm³And washing with ethyl acetate. The filtrate was evaporated under reduced pressure (5kPa) using a rotary evaporator. Will obtainThe resulting orange solution was dissolved in 100g of ice/water mixture and 100cm³In ethyl acetate. The pH was raised to 10 with 5M sodium hydroxide. After decanting, the aqueous phase was used twice 40cm³And washing with ethyl acetate. While stirring, the aqueous phase was acidified with 5M hydrochloric acid solution (pH 1) and then 3 times 40cm³Extraction was carried out with ethyl acetate. The combined organic phases were then washed with 30cm³The sodium chloride was washed with a saturated aqueous solution, dried over magnesium sulfate and concentrated under reduced pressure (5kPa) using a rotary evaporator. The yellow/green oil obtained is purified by flash chromatography on silica (column: 90 g; particle size: 15-40 μm; eluent: gradient from 100% dichloromethane to 95% dichloromethane/5% methanol). After concentrating the fractions under reduced pressure, 0.28g of 6-chloro-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxylic acid was obtained.

·LC-MS-DAD-ELSD：321(^-35Cl)＝(M-H)(^-)；323⁽⁺⁾³⁵Cl＝(M+H)⁽⁺⁾

·¹H NMR (300MHz, DMSO-d6) d ppm 0.85(t, J ═ 7.3Hz, 6H)1.09-1.28(m, 4H)1.67-1.93(m, 4H)4.81 (width m, 1H)8.23(d, J ═ 2.5Hz, 1H)8.29(d, J ═ 2.5Hz, 1H)8.27(s, 1H)14.50 (width bulk peak m, 1H).

2.1.4: n- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -6-chloro-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide

To 270mg of 6-chloro-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxylic acid, 344mg of (2R, 3S) -3-amino-4-phenyl-1- { [3- (trifluoromethyl) benzyl ] acid at a temperature close to 20 deg.C]Amino } butane-2-ol hydrochloride (1: 1), 17mg of hydroxybenzotriazole and 200mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride at 27cm³The suspension in dichloromethane was poured in 0.573cm³N, N-diisopropylethylamine. The solution was kept stirring for 20 hours at 20 ℃. Mixing 15cm³Water is added to the reaction medium. The water phase used was 15cm³Extraction was carried out with dichloromethane. The organic phases were combined and used for 10cm³Saturated and water-soluble sodium chlorideThe solution was washed, dried over sodium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). 740mg of the product obtained are purified by flash chromatography on silica (column: 70 g; particle size: 15-40 μm; eluent: gradient from 100% dichloromethane to 95% dichloromethane/5% methanol). After concentrating the fractions under reduced pressure, 300mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are obtained]Amino } propyl group]-6-chloro-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide.

LC/MS ELSD Tr (min) ═ 4.07; MH + ═ 643 +; MH- ═ 641-; MH- + HCO₂H＝687-；

·¹H NMR (400MHz, DMSO-d6) d ppm 0.85(t, J ═ 7.5Hz, 3H)0.86(t, J ═ 7.5Hz, 3H)1.07-1.25(m, 4H)1.70-1.96(m, 4H)2.59-2.74(m, 2H)2.79(dd, J ═ 13.8, 9.6Hz, 1H)3.04(dd, J ═ 13.8, 3.9Hz, 1H)3.72(m, 1H)3.82(S, 2H)4.32(m, 1H)4.79 (width m, 1H)5.06 (width d, J ═ 5.1Hz, 1H)7.12(t, J ═ 7.5, 1H)7.19(t, J ═ 7.5, J ═ 7.19, J ═ 2.5, 7.8 (J ═ 7.8, 7.8H) 1H (1H), 7.8 (J ═ 7.8, 7H) 2H (1H), 7.8 (d, 7.8H) 2H) 4.9 Hz, 1H) 4.6 Hz, 1H, and 7H (d ═ 7.9H).

2.2: the salt N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -6-chloro-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide hydrochloride (1: 1)

100mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are reacted at a temperature close to 20 deg.C]-amino } propyl group]-6-chloro-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide in a solution of 1.2cm³In diethyl ether. While stirring and under argon, at a temperature of 5 ℃ 0.3cm was added³4M hydrochloric acid solution in dioxane. The reaction mixture precipitated and then the precipitate was dissolved. Adding 5cm³Diethyl ether. The solution was concentrated under reduced pressure (5 kPa). 95mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] m-colored amorphous solid form were obtained]Amino } propyl group]-6-chloro-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide hydrochloride (1: 1).

LC/MS ELSD Tr (min) ═ 4.04; MH + ═ 643 +; MH- ═ 641-; MH- + HCO₂H＝687

NMR: 0.87(t, J ═ 7.5Hz, 3H); 0.88(t, J ═ 7.5Hz, 3H); 1.12-1.25(m, 4H); 1.80(m, 2H); 1.89(m, 2H); 2.80(dd, J ═ 10.5 and 14.0Hz, 1H); 2.97(m, 1H); 3.17(dd, J ═ 3.0 and 14.0Hz, 1H); 3.22(m, 1H); 3.96(m, 1H); 4.17-4.31(m, 3H); 4.81 (width m, 1H); 5.89 (broad overall peak m, 1H); 7.15(t, J ═ 7.5Hz, 1H); 7.22(t, J ═ 7.5Hz, 2H); 7.32(d, J ═ 7.5Hz, 2H); 7.64(t, J ═ 7.5Hz, 1H); 7.73(d, J ═ 7.5Hz, 1H); 7.81(d, J ═ 7.5Hz, 1H); 7.92(s, 1H); 8.10(d, J ═ 2.5Hz, 1H); 8.24(d, J ═ 2.5Hz, 1H); 8.58(s, 1H); 9.10 (broad overall peak m, 2H); 10.0(d, J ═ 8.5Hz, 1H).

Example 3:

3.1: base N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide

195mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are stirred in an autoclave under 10 bar of hydrogen]-amino } propyl group]-6-chloro-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide, 5cm³Dioxane, 30mg of 10% palladium on charcoal (wet to 50% in water). Since no reaction was carried out, 30mg of dry 10% palladium on charcoal was added and the reaction mixture was stirred in an autoclave under 15 bar of hydrogen. The catalyst was filtered and the filtrate was concentrated under reduced pressure (5 kPa). 185mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are obtained]Amino } propyl group]-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide.

·LC-MS-DAD-ELSD：653⁽⁺⁾Not (M + formic acid-H)⁽⁺⁾；609⁽⁺⁾＝(M+H)⁽⁺⁾

·¹H NMR(400MHz，DMSO-d6)d ppm 0.87(t, J ═ 7.3Hz, 3H)0.88(t, J ═ 7.3Hz, 3H)1.11-1.30(m, 4H)1.72-2.01(m, 4H)2.81(dd, J ═ 14.1, 9.8Hz, 1H)2.98(d, J ═ 12.5, 9.8Hz, 1H)3.19(dd, J ═ 14.1, 4.2Hz, 1H)3.28 (partially masked m, 1H)3.99(m, 1H)4.17-4.32(m, 3H)4.86 (width m, 1H)5.93 (width s, 1H)7.14(t, J ═ 7.5Hz, 1H)7.21(t, J ═ 7.5, 7.5H) 7.21(t, J ═ 7.7.5, 7H) 7.7.8 (H), 7H) 7.7.7.7.7.8 (d, 7.8H) 2 (dd, 7.7.7.8H), 7.7.7.7.8H) 7.7.7.7.7.7.7.7.8 (dd, 7.8H) 1, 7.7.7.7.8H) H, 7.7.8 (d, 7.8H) 1.7.8H) 2, 7.7.7.7.7.7.7.7.8 (dd, 7.8H) 1.8 (d, 7.7.7.7.7.7.7.8H) H, 7.8H, 7., 1H)10.14(d, J ═ 8.3Hz, 1H).

3.2: the salt N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide hydrochloride (1: 1)

180mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] at a temperature close to 20 deg.C]-amino } propyl group]-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide in a solution of 2.5cm³In diethyl ether. While stirring and under argon, 0.53cm was added at a temperature of 5 deg.C³4M hydrochloric acid solution in dioxane. The reaction mixture precipitated. The suspension was stirred for 10 minutes and then the stirring was stopped to remove the supernatant. Then 5cm of³Diethyl ether. This operation was performed 3 times. The final suspension was concentrated under reduced pressure (5 kPa). 160mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are obtained in the form of a pale yellow solid]Amino } propyl group]-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide hydrochloride (1: 1).

NMR: 0.87(t, J ═ 7.5Hz, 3H); 0.88(t, J ═ 7.5Hz, 3H); 1.19(m, 4H); 1.80(m, 2H); 1.91(m, 2H); 2.81(dd, J ═ 10.5 and 14.0Hz, 1H); 3.01(m, 1H); 3.19(dd, J ═ 3.0 and 14.0Hz, 1H); 3.27(m, 1H); 3.99 (partially masked m, 1H); 4.21(m, 1H); 4.31(m, 2H); 4.84 (width m, 1H); 5.96(very broad overall peak m, 1H); 7.14(t, J ═ 7.5Hz, 1H); 7.22(t, J ═ 7.5Hz, 2H); 7.33(d, J ═ 7.5Hz, 2H); 7.61(t, J ═ 8.0Hz, 1H); 7.64(t, J ═ 7.5Hz, 1H); 7.75(d, J ═ 7.5Hz, 1H); 7.84(d, J ═ 7.5Hz, 1H); 7.95(s, 1H); 8.24(dd, J ═ 1.5 and 8.0Hz, 1H); 8.30(dd, J ═ 1.5 and 8.0Hz, 1H); 8.58(s, 1H); 9.04 (broad overall peak m, 1H); 9.22 (broad overall peak m, 1H); 10.15(d, J ═ 8.5Hz, 1H).

·LC-MS-DAD-ELSD：653^(-)Not (M + formic acid-H)^(-)；609⁽⁺⁾＝(M+H)⁽⁺⁾

Melting point: 152 deg.C

Table 1 below illustrates the chemical structures and physical properties of some examples of compounds according to the invention. In this table:

melting point (. degree.C.) represents the melting point of the compound (degree.C.);

in the column "salts", "represents the compound in free base form and" HCl "the compound in hydrochloride salt form, the ratio between brackets being (acid: base) ratio;

- "nd": indicates not measured;

-R3 represents trifluoromethyl.

The compounds described in the tables were prepared according to the methods described previously.

TABLE 1：

Compound (I)	R1	X	R2	R4，R5	R6	Salt (salt)	Melting Point (. degree.C.)
								1	(n-C3H7)2CH-	C	H	H-，H-	H-	HCl(1∶1)	nd(a)
2	(n-C3H7)2CH-	N	H-	H-，H-	6-Cl-	HCl(1∶1)	nd(b)
								3	(n-C3H7)2CH-	N	H-	H-，H-	H-	HCl(1∶1)	152

(a) By passing¹H NMR spectra and characterization by liquid chromatography in conjunction with a mass spectrometer

(b) By passing¹Characterization by H NMR Spectroscopy

The compounds according to the invention are intended as pharmacological test objects, which enable their inhibitory effect on the activity of beta-secretase to be determined.

The assay consists in measuring the in vitro inhibition of beta-secretase activity by the compounds of the invention by using the "BACE-1 f retassay Kit, Red" assay from PanVera-Invitrogen inc.

The measured β -secretase activity corresponds to the activity of a purified recombinant form of human BACE1 aspartyl-protease produced by expression in drosophila cells (the latter comprising a hexahistidine tag at the C-terminus). Purified enzyme contains NaCl (0.45M), MnCl₂(0.9mM)、CaCl₂(0.9mM), α -D-methyl mannoside and 10% glycerol in TRIS buffer pH7.5 (18mM) and stored at-80 ℃ until use.

BACE1 activity was measured according to the cleavage (based on the principle of energy transfer by Fluorescence Resonance (FRET) and conforming to the Rh-EVNLDAEFK-Quencher sequence) of a fluorogenic peptide substrate (PANVERA BACE1/β -secretase FRETplayassay kit, Red; reference number P2985) sold by INVITROGEN; cleavage of the peptide was measured according to the increase of the fluorescence signal emitted by the rhodamine derivative (Rh).

Assays were performed in 96-well black microplates to determine inhibition of enzyme activity by the products of the invention. The peptide substrate solution (Panvera, reference P2986) was sold at a concentration of 75. mu.M (in 50nM ammonium bicarbonate) and stored at-20 ℃ protected from light until use. Dilutions of the product to be tested were prepared in DMSO using 10mM stock solutions. The product of the invention, at a final concentration of 0.003-100. mu.M, is typically incubated for 60 minutes at ambient temperature with the peptide substrate (final concentration 0.25. mu.M) and the purified enzyme (final concentration 10nM) in sodium acetate buffer (50mM, pH4.5) (buffer of a commercial kit, reference P2988) in the dark. The final percentage of DMSO does not exceed 10%. When the incubation was complete, fluorescence was measured in a spectrofluorimeter at an excitation wavelength of about 543nm and an emission wavelength of about 585 nm. For each concentration of test product, the fluorescent signal was compared to the maximum signal obtained when the peptide substrate was incubated with the enzyme alone.

Nonlinear regression analysis (computer application software XIfit, IDBS) was then used by measuring CI50 (concentration of product giving 50% inhibition of enzyme activity)^TM) The products of the invention were evaluated for inhibitory activity.

CI₅₀Is 0.1-5. mu.M.

For example, compounds No.1 and 3 show CI of 2.6 and 0.83. mu.M, respectively₅₀。

It is therefore apparent that the compounds according to the invention have inhibitory activity on the activity of β -secretase.

The compounds according to the invention can therefore be used for the preparation of medicaments, in particular medicaments which inhibit the production of a β.

Thus, according to another aspect of the invention, the object is a medicament comprising a compound of formula (I) or an addition salt of the latter with a pharmaceutically acceptable acid.

These drugs can be used in therapeutics, in particular in the treatment and prevention of diseases associated with the production of A.beta.peptides, among which mention may be made of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeld-Jakob disease, Down's syndrome (syndrome de Down), dementia with Lewy bodiesSenile dementia, frontotemporal dementia, cerebral and systemic amyloidosis (c é blale et sys mique), mild cognitive impairment, cerebral amyloid angiopathy, primary and secondary memory disorders, amyotrophic lateral sclerosis, multiple sclerosis, peripheral neuropathy, diabetic neuropathy, migraine, affective disorders, depression, anxiety, vascular diseases, such as atherosclerosis, cerebral vascular ischemia, tumors and cell proliferation disorders.

These medicaments are particularly useful for the treatment and prevention of neurodegenerative diseases such as alzheimer's disease, parkinson's disease, down's syndrome, dementia with lewy bodies, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild cognitive impairment, cerebral amyloid angiopathy, primary and secondary memory disorders and cerebral vascular ischemia.

According to another aspect of the invention, it relates to a pharmaceutical composition comprising a compound according to the invention as active ingredient. These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable excipient.

The excipients are selected from the usual excipients known to those skilled in the art according to the pharmaceutical form and the desired method of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its optional salt, solvate or hydrate thereof, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the disorders or diseases mentioned above.

Suitable unit administration forms include oral route forms (e.g. tablets, soft or hard capsules, powders, granules and oral solutions or suspensions), sublingual, buccal, intratracheal, intraocular, intranasal administration forms, administration forms by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical administration, the compounds according to the invention may be used in creams, gels, salves or lotions.

For example, a unit administration form (in the form of a tablet) of a compound according to the invention may comprise the following components:

compound according to the invention 50.0mg

Mannitol 223.75mg

Croscarmellose sodium 6.0mg

Corn starch 15.0mg

Hydroxypropyl methylcellulose 2.25mg

Magnesium stearate 3.0mg

According to another aspect of the present invention, it also relates to a method of treating the pathologies indicated above, which comprises administering to the patient an effective dose of a compound according to the present invention or of one of its pharmaceutically acceptable salts or of its hydrates or of its solvates.

Claims (11)

1. A compound corresponding to the general formula (I):

wherein:

r1 represents a hydrogen atom, or a hydrogen atom₁-C₁₀) Alkyl, (C)₃-C₇) Cycloalkyl group, (CH)₂)_n-(C₁-C₆) Alkenyl group, (CH)₂)_n-(C₁-C₆) Alkynyl, (C)₁-C₆) alkyl-Z- (C)₁-C₆) Alkyl, wherein Z represents a heteroatom selected from O, N and S (O) m, or R1 represents COOR, S (O)_mR, aryl or aralkyl; (C)₁-C₁₀) Alkyl, (C)₃-C₇) Cycloalkyl group, (CH)₂)_n-(C₁-C₆) Alkenyl group, (CH)₂)_n-(C₁-C₆) Alkynyl, (C)₁-C₆) alkyl-Z- (C)₁-C₆) Alkyl, wherein aryl or aralkyl is optionally substituted with one or more groups selected from: halogen atom, (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl, halo (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, halo (C)₁-C₆) Alkoxy, NR7R8, nitro, cyano, OR, COOR, CONR7R8, S (O)_mNR7R8, aryl;

r2 represents one or more groups selected from: a hydrogen atom, a halogen atom, and (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₁-C₆) Alkenyl, (C)₁-C₆) Alkynyl, (C)₁-C₆) alkyl-Z- (C)₁-C₆) Alkyl, wherein Z represents a radical selected from O, N and S (O)_mOr R2 represents halo (C)₁-C₆) Alkyl, halo (C)₁-C₆) Alkoxy, hydroxy, (C)₁-C₆) Alkoxy, nitro, cyano, amino, NR7R8, COOR, CONR7R8, OCO (C)₁-C₆) Alkyl, S (O)_m-NR7R8, aryl, wherein the aryl group may be optionally substituted with one or more groups selected from: halogen atom, (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl, halo (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, halo (C)₁-C₆) Alkoxy, NR7R8, OR, nitro, cyano, COOR, CONR7R8, S (O)_mNR7R8；

R3 represents trifluoromethyl;

r4 and R5 represent a hydrogen atom, or R4 and R5 form, together with the carbon atoms that carry them, a saturated ring comprising from 3 to 6 carbon atoms and optionally from 0 to 1 heteroatom chosen from O, N or S;

r6 represents a group selected from: a hydrogen atom, a halogen atom, and (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₃-C₇) Cycloalkyl (C)₁-C₆) Alkyl, halo (C)₁-C₆) Alkyl, nitro, amino, NR7R8, COOR, NR7 (SO)₂) R8, c (o) NR7R8 or aryl, said groups being optionally substituted by one or more groups selected from: halogen atom, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy or cyano;

r, R7 and R8 represent, independently of one another, one or more groups selected from: hydrogen atom, (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₃-C₇) Cycloalkyl (C)₁-C₆) Alkyl, aryl (C)₁-C₆) Alkylene, or R7 and R8 may form, together with the atoms which carry them, a saturated, partially unsaturated or unsaturated ring containing from 5 to 7 carbon atoms and optionally additionally containing a substituent selected from O, N or S (O)_mA heteroatom of (a);

x represents a carbon atom or a nitrogen atom;

m represents an integer which may take a value of 0, 1 or 2, and n represents an integer which may take a value of 1, 2, 3, 4, 5 or 6;

the carbon bearing the benzyl group substituted with R2 is in the S absolute configuration;

the carbon bearing the hydroxyl group is in the absolute R configuration,

in the form of a base or of an addition salt with an acid.

2. A compound of formula (I) according to claim 1, characterized in that X represents a carbon atom, in the form of a base or of an addition salt with an acid.

3. A compound of formula (I) according to claim 1, characterized in that X represents a nitrogen atom, in the form of a base or of an addition salt with an acid.

4. A compound of formula (I) according to any one of claims 1 to 3, characterized in that R1 represents (C)₁-C₁₀) Alkyl, optionally with one or more (C)₁-C₆) The substitution of the alkyl group is carried out,

r2, R4 and R5 represent a hydrogen atom,

r6 represents a group selected from a hydrogen atom or a halogen atom, in the form of a base or of an addition salt with an acid.

5. The compound of formula (I) according to any one of claims 1 to 4, characterized in that it is selected from

N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) -1, 2-dihydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -6-chloro-4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -4-oxo-3- (1-propylbutyl) -3, 4-dihydroquinazoline-8-carboxamide and its hydrochloride (1: 1).

6. Pharmaceutical, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 5, or an addition salt of such a compound with a pharmaceutically acceptable acid.

7. Pharmaceutical composition, characterized in that it comprises a compound of formula (I), or a pharmaceutically acceptable salt, according to any one of claims 1 to 5, and at least one pharmaceutically acceptable excipient.

8. The use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the prevention and treatment of any disease in which β -secretase activity is involved.

9. The use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment and prevention of alzheimer's disease, parkinson's disease, huntington's disease, Creutzfeld-Jakob disease, down's syndrome, dementia with lewy bodies, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild cognitive impairment, cerebral amyloid angiopathy, primary and secondary memory disorders, amyotrophic lateral sclerosis, multiple sclerosis, peripheral neuropathy, diabetic neuropathy, migraine, affective disorders, depression, anxiety, vascular diseases such as atherosclerosis, cerebral vascular ischemia, tumors and cell proliferation disorders.

10. The use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment and prevention of alzheimer's disease, parkinson's disease, down syndrome, dementia with lewy bodies, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild cognitive impairment, cerebral amyloid angiopathy, primary and secondary memory disorders and cerebrovascular ischemia.

11. A compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment and prevention of alzheimer's disease, parkinson's disease, huntington's disease, Creutzfeld-Jakob disease, down syndrome, dementia with lewy bodies, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild cognitive impairment, cerebral amyloid angiopathy, primary and secondary memory disorders, amyotrophic lateral sclerosis, multiple sclerosis, peripheral neuropathy, diabetic neuropathy, migraine, affective disorders, depression, anxiety, vascular diseases such as atherosclerosis, cerebrovascular ischemia, tumors and cell proliferation disorders.