ZA200605824B

ZA200605824B - Acylaminothiazole derivates, preparation method thereof and use of same in therapeutics

Info

Publication number: ZA200605824B
Application number: ZA200605824A
Authority: ZA
Inventors: Baltzer Sylvie; Van Dorsselaer Viviane
Original assignee: Sanofi Anentis
Priority date: 2004-01-16
Filing date: 2005-01-07
Publication date: 2008-05-28
Also published as: FR2865206B1; CN1930155A; CN1930155B; FR2865206A1

Description

Acylaminothiazole derivatives, preparation method thereof and use of same in therapeutics

The present invention relates to acylaminothiazole derivatives and to their preparation and their therapeutic use.

Compounds derived from acylaminothiazole, described in documents WO 03/014095 A, WO 2004/009565 A and WO 2004/033439 A, which are inhibitors of formation of the P-amyloid (B-A4) peptide, are already known.

There is still a need to find and develop products that are inhibitors of the formation of the

B-amyloid (B-A4) peptide. The compounds of the invention satisfy this aim.

A first subject of the present invention is compounds corresponding to the general formula (I): s a

Ar 0 R, 0 in which

R, represents: either a Ci.g alkyl optionally substituted with one to three substituents chosen from a halogen, a trifluoromethyl, a hydroxyl, a Ci ¢ alkoxy, a Cis thioalkyl, a thiophene or a phenyl; or a Csz.; cycloalkyl, a thiophene, a benzothiophene, a pyridyl, a furyl or a phenyl; the said phenyl groups being optionally substituted with one to three substituents chosen from a halogen atom, a Ci-¢ alkyl, a Cig alkoxy, a hydroxyl, a methylenedioxy, a phenoxy, a benzyloxy or a trifluoromethyl;

R, and R’, represent, independently of each other, a hydrogen atom, a halogen atom, a hydroxyl, a Ci-3 alkoxy, a Ci-3 alkyl, a Cs-7 cycloalkyl, an 0-C(0O)-Ci-¢ alkyl group, or Ry, and R’; together form an oxo group;

Rs; represents a hydrogen atom, a Cis alkyl optionally substituted with a hydroxyl, a Cj.s cycloalkyl or a Cis alkoxy; one or other of R, and Rs represents a group 2 2

B

A,

Y ac” and one or other of Ry and Rs represents a group -C(X)Re;

G represents a single bond or a -CH;- group;

Y represents a single bond, an oxygen or sulphur atom, a Ci. alkylene group or -N(W)-, the -Ci alkylene- group being optionally substituted with a hydroxyl or Cis alkoxy group;

W represents either a hydrcgen atom, a Ci-3 alkyl optionally substituted with a phenyl, or a phenyl;

A and B represent, independently of each other, a hydrogen or halogen atom, a hydroxyl, Cis alkyl, Cis alkoxy, trifluoromethyl, trifluoromethoxy or ~-0-CHF> group; on condition that if Y is a single bond or an oxygen atom and if the group Z is of the type xg

B od,

Y a” then A is other than a hydrogen atom;

X represents an oxygen atom or a sulphur atom;

Re represents a Cy_¢ alkoxy, hydroxyl or —-NR;Rg group; the Ci. alkoxy group being optionally substituted with a phenyl;

R; and Rg represent, independently of each other: either a hydrogen atom; or a Cig alkyl group optionally substituted with a Cz; cycloalkyl, a Cz. cycloalkenyl, a

Ci.3 alkoxy, a phenyl, a morpholinyl or a pyridyl; or a

Cs.7 cycloalkyl, Ci-¢ alkoxy or phenyl group; the said Ci cycloalkyl and phenyl groups being optionally substituted with one or two groups chosen from a halogen atom, a hydroxyl group, a Ci-3 alkyl and a Ci-3 alkoxy group; or

R; and Rg, with the nitrogen atom that bears them, form an aziridine, azetidine, pyrrolidine, piperidine, morpholine or benzopiperidine ring.

Among the compounds of general formula (I), a first subgroup of compounds consists of the compounds for which R; represents a Ci-.s alkyl or a phenyl optionally substituted with one to three halogen atoms.

Among the compounds of general formula (I), a second subgroup of compounds consists of the compounds for which R, and R’, represent, independently of each other, a hydrogen atom or a hydroxyl, or R; and R’; together form an 0x0 group.

Among the compounds of general formula (I), a third subgroup of compounds consists of the compounds for which Rj; represents a Cig alkyl.

Among the compounds of general formula (I), a fourth subgroup of compounds consists of the compounds for which: one or other of R; and Rs represents a group 7% aD

B

2,

Y a” and one or other of R; and Rs represents a group -—

C(X) Reg:

GCG represents a single bond;

Y represents a single bond, an oxygen or sulphur atom, or a Ci-4 alkylene group, more particularly methylene;

A and B represent, independently of each other, a hydrogen atom, a halogen atom, more particularly fluorine, or a trifluoromethyl or trifluocromethoxy group; on condition that if Y is a single bond or an oxygen atom and if the group Z is of the type a

B

(Z) £2

SZ sc then A is other than a hydrogen atom;

X represents an oxygen atom or a sulphur atom; 5 Rg represents a Cj-g alkoxy group, more particularly a methoxy or an ethoxy.

The compounds for which A, B, W, X, Y, 2Z, Ri,

R,, R’,, Ri, Rs, Rs, Rg, R; and Rg are as defined in the subgroups of compounds above, form a fifth subgroup.

Among the compounds of general formula (I) and of the above subgroups, a sixth subgroup of compounds consists of the compounds for which:

R, represents a Cj-q alkyl, preferably an isopropyl or a tert-butyl, or a phenyl substituted with two fluorine atoms; and/or

R; represents a hydrogen atom or a hydroxyl and R’; represents a hydrogen atom; and/or

R; represents a Cj-4 alkyl, preferably a methyl, ethyl or propyl; and/or

X represents an oxygen atom.

In the context of the present invention, the following definitions apply: - C:., in which t and z may take the values from 1 to 7, a carbon-based chain which may contain from t to z

REPLACEMENT SHEET (RULE 26)

carbon atoms, for example C;_.3 a carbon-based chain which mey contain from 1 to 3 carbon atoms, Ci: a carbon-based chain which may contain from 3 toc 6 carbon atoms, etc.; - alkyl, a saturated, linear or branched aliphatic group; for example, a Ci-¢ alkyl group represents a linear or branched carbon-based chain of 1 to 6 carbon atoms, more particularly a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc., preferably a methyl, ethyl, propyl or isopropyl: - alkylene, a saturated, linear or branched divalent alkyl group, for example a Cj -z3—alkylene group represents a linear or branched divalent carbon-based chain of 1 to 3 carbon atoms, more particularly a methylene, ethylene, isopropylene or propylene; - cycloalkyl, a cyclic alkyl group, for example a

Cs-7 cycloalkyl represents a cyclic carbon-based chain of 3 to 7 carbon atoms, more particularly a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably a cyclopentyl or cyclohexyl; - cycloalkenyl, a mono- or polyunsaturated cyclic alkyl group, for example a Cs; cycloalkenyl group represents a mono- or polyunsaturated cyclic carbon-based chain of : 3 to 7 carbon atoms, more particularly a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, preferably a cyclopentenyl or

REPLACEMENT SHEET (RULE 26)

cyclohexenyl; - thiocalkyl, an S-alkyl group containing a saturated, linear cor branched aliphatic chain; - alkoxy, an -O-alkyl group containing & saturated, linear or branched aliphatic chain; - halogen atom, a fluorine, a chlorine, a bromine or an iodine; - “R, and R’, together form an oxo group” the group such that:

ENE i 2d and - in the group Z, the aromatic group is such that one of the carbon atoms of the aromatic ring may be replaced with a nitrogen atom in the position in which there is no substituent A or B.

The compounds of general formula (I) may comprise one or more asymmetric carbons. They may thus exist in the form of enantiomers or diastereocisomers.

These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention. When the carbon bearing R, and R': and/or the carbon bearing Rs; are asymmetric, the preferred compounds are those of general formula (I) for which the carbon bearing R; and R’; is of (8S)

REPLACEMENT SHEET (RULE 26)

configuration and/or the carbon bearing R3 is of (5S) configuration.

The compounds of formula (I) may exist in the form of bases or of acid-addition salts. Such addition salts form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other useful acids, for example for the purification or isolation of the compounds of formula (1), also form part of the invention.

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

A second subject of the present invention is processes for preparing the compounds of formula (I).

Thus, these compounds may be prepared via processes, illustrated in the schemes that follow, the operating conditions of which are standard for those skilled in the art.

The term “protecting group” means a group that prevents the reactivity of a function or position, during chemical reaction that could affect it, and which restores the molecule after cleavage according to methods known to those skilled in the art. Examples of protecting groups and protection and deprotection methods are given, inter alia, in Protective groups in

Organic Synthesis, Greene et al., 2%¢ Ed. (John Wiley &

Sons, Inc., New York).

The meanings of A, B, W, X, Y, Z, Ri, Rp, R'y,

Rs, Rs, Rs, Rg, Ry; and Rg in the compounds of formulae (IT) to (XVIII) below are as defined for the compounds of formula (I), unless another definition is specified.

According to scheme 1 below, the compound of formula (I) may be obtained by peptide coupling of the 2-aminothiazole of formula (III) with the acylamino acid of formula (II) according to conditions known to those skilled in the art, for example in the presence of benzotriazol-1l-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) or benzotriazol-1l- vyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and N-ethylmorpholine or N-methylmorpholine in an inert solvent such as N,N-dimethylformamide, acetonitrile or dichloromethane, at a temperature that can range from 0°C to room temperature.

The compound of formula (II) may be obtained by peptide coupling of the compound of formula (IV) with the protected acid of formula (V), in which Pg represents a protecting group, for example a benzyl, according to methods known to those skilled in the art, as described above. The compound thus obtained is then deprotected. In the case where the protection is a benzyl, the compound is hydrogenated beforehand in the presence of palladium-on-charcoal in absolute ethanol under an atmospheric pressure of hydrogen, at room temperature, to give the compound of formula (IT).

Scheme 1 rR, KR + H,N_ _CO,Pg con YT

R; R, (Iv) | Vv)

H

N._ _CO,H a \ +

Ar hi HN k 0 R, 8 Rs (1 an peptide|coupling

R .

Re ] 0 N ’

NP

R N

1 H Ss R, 0} R, "

Alternatively, the compound of formula (I) may be prepared according to scheme 2.

According to scheme 2 below, the compound of formula (I) may be obtained by peptide coupling of the compound of formula (IV) with the amine of formula (VI), according to methods known to those skilled in the art, for instance in the presence of hydroxybenzotriazole hydrate (HOBt) and l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDAC

HCl).

Scheme 2

O s— Ns \ + PgHN

HN OH

R

4

R, (111) | (Vi)

R, R> 9 R

HN

N—4&

R OH H

1 2 R N R, 3 (IV) . (Vi) peptide coupling

R, R', 0 R

H S— 5

N \

R; N—\

H NT OR

O R, 4

U)

The compound of formula (VI) may be obtained by peptide coupling of the 2-aminothiazole of formula (III) with the protected amine of formula (VII) in which Pg represents a protecting group, for example an

N-tert-butoxycarbonyl (Boc), according to methods known to those skilled in the art, as described above. The compound thus obtained is then deprotected. In the case where the protection is a Boc, the deprotection is performed by acidic hydrolysis, in the presence of gaseous hydrogen chloride dissolved in an anhydrous solvent, or of trifluorcacetic acid, to give the compound of formula (VI).

The compounds of formula (I) in which R; and

R’, form an oxo group may be obtained by oxidation of a compound of formula (I) in which R, or R’, represents a hydroxyl group. The reaction may be performed according to the conditions known to those skilled in the art, for example with the Dess-Martin reagent. These compounds may also be obtained by direct coupling of a keto acid of formula (IV), in which R, and R’, together form an oxo group, with an amine of formula (VI) according to the conditions known to those skilled in the art. The methods for preparing such keto acids are known to those skilled in the art.

The compound of formula (III) in which Ry = ~C(0)-Rg, Rg representing a C;.¢ alkoxy group, may be obtained according to scheme 3 below.

Scheme 3

CI,CHCOR, | ¢ Nes, NH SSR

Rs H (IX) on Ae Ren 2 2 gd 5

T NaOCH, S68 04 ROH 2 " COR, ab (X) XH (i)

According to scheme 3, the compound of formula (III) may be obtained by reacting an aldehyde of formula (VIII) in which Rs is as defined above with the methyldichloroacetate of formula (IX) in which Rg represents a Ci-¢ alkoxy optionally substituted with a phenyl, and, for example, sodium methoxide or ethoxide, at 0°C, according to an adaptation of the process described by Takeda (Bull. Chem. Soc. Jp, 1970, p. 2997). The mixture of products (X) and (XI) obtained is treated with thiourea in the presence, for example, of methanol or ethanol at reflux for 4 or 8 hours to give the compound of formula (III).

The compound of formula (III) in which Rg = -C (0) ~-Rg, Rg representing a hydroxyl, may be obtained by hydrolysis of the above compounds for which Rg represents a Cj_g alkoxy group optionally substituted with a phenyl, according to the conditions known to those skilled in the art.

The compound of formula (III) in which Rs = -C(0)-Rg, Rg representing a C;-¢ alkoxy group, may be obtained according to scheme 4 below.

Scheme 4

COR), i id -

XVi Br,, H,0

R, CH, xn ) ry COS : ~Y : (x) hil NaH, THF, e) 0]

Oo Jay 6) 0 (XIV) (X11) NH,CSNH,

ROH, & = oH 1) CDI, THF, a

Nr 2) R.COCH,COLK (XVia), HN— SCOR,

S MgCl,, THF 0 Va

N—\ (XV) R, (im

According to scheme 4, the compound of formula (III) may be obtained by bromination of P-keto ester of formula (XIII), in which Rg represents a

Cy-¢ alkoxy optionally substituted with a phenyl, to give the compound of formula (XII), followed by a reaction with thiourea, according to an adaptation of the process described by A. Barton et al. (J.C.S Perkin

I, 1982, p. 159).

The B-keto ester of formula (XIII) may be obtained by reacting a ketone of formula (XIV) with a dialkyl carbonate of formula (XVI) in which Re represents a Cig alkoxy optionally substituted with a phenyl, according to an adaptation of the process described by L. Crombie et al. (J.C.S Perkin Trans I, 1987, p. 323). The P-keto ester of formula (XIII) may also be obtained by reacting an acid of formula (XV) activated with carbonvldiimidazole (CDI) with a malonate of formula (XVIa) in which Rg represents a

Ci-¢ alkoxy optionally substituted with a phenyl, according to an adaptation of the process described, for example, by D.W. Brooks et al. (Angew. Chem. Int.

Ed., 1979, p. 72).

The compound of formula (III) in which R; = -C(0)-Rg, Rg representing a hydroxyl, may be obtained by hydrolysis of the above compounds for which Rg represents a Cj. alkoxy group, according to the conditions known to those skilled in the art.

The compound of formula (III) in which Rg or

Rs represents a group -C(0)-NR;R; may be obtained according to scheme 5.

Scheme 5

Ss Ror COH R, 7

PgHN—L, + "No (XVII)

N COH or R, 7 (XVI) 1) peptide coupling 2) deprotection

S Ror CONR,R,

NH,

N CONR,R, or R, (11)

According to scheme 5, the compound of formula (III) is obtained by peptide coupling of the compound of formula (XVII), in which Rs or Rs represents a carboxylic group and Pg a protecting group such as a

Boc, with a compound of formula (XVIII) in the presence, for example, of HOBt and (EDAC HCl). The compound thus obtained is then deprotected according to the conditions known to those skilled in the art. The compound of formula (XVII), in which Pg represents a

Boc, may be obtained by protecting a compound of formula (III) in which Rs or Rs; represents a group -C(O)Ry and Ry is a Ci-s alkoxy optionally substituted with a phenyl, via the action of di-tert-butyl dicarbonate in anhydrous tetrahydrofuran in the presence of dimethylaminopyridine at room temperature, followed by hydrolysis of the carboxylate under the conditions known to those skilled in the art, for example with lithium hydroxide in a 7/3 (v/v) tetrahydrofuran/water mixture at a temperature of 60°C.

The compounds of general formula (I), in which Rs; or Rs represents a group -C(X)Rg and X=S, may be prepared from corresponding compounds of general formula (I) or (III), in which Rs or Rs represents a group -C(X)Rg and X=0, by conversion of the C(O) group into a C(S) group, for example using Lawesson’s reagent according to a method similar to that described by M.P.

Cava et al. in Tetrahedron 1985, p. 5061.

In schemes 1 to 5, the starting compounds and the reagents, especially the compounds of formula (III), (IV), (V), (VII), (VIII), (IX), (XIV), (XV), (XVI), (XVIa), (XVII) and (XVIII), when their mode of preparation is not described, are commercially available or described in the literature, or may be prepared via methods described therein or known to those skilled in the art.

For example, the compounds of formula (IV) in which R; or R’; represents a hydroxyl may be prepared by addition of trimethylsilyl cyanide to an aldehyde according to an adaptation of the process described by

D.A. Evans et al. (J.C.S., Chem. Comm. 1973, p. 55) or via the action of sodium nitrite on an a-amino acid according to an adaptation of the process described by

I. Shinn et al. (J. Org. Chem., 2000, p. 7667).

For example, the compounds of formula (XV) in which Y = 0 may be prepared according to an adaptation of the process described by Sindel et al. (Collect. csech. chim. Tchecosl., 1982, p. 72) or by Atkinson et al. (J. Med. Chem., 1983, p. 1353).

For example, the compounds of formula (XV) in which Y is of the -C;-4 alkylene- type may be prepared, for example, according to an adaptation of the process described by Crow et al. (Austral. J. Chem. , 1881, p. 1037) or alternatively via a Suzuki reaction according to an adaptation of the process described by

Chahen et al. (Synlett, 2003, p. 1668).

For example, the compounds of formula (XV) in which Y = S may be prepared according to the process described by Goldberg (Chem. Ber., 19%4, p. 4526).

For example, the compounds of formula (XV) in which Y = N(W) may be prepared according to the process described by Chane et al. (Tetrahedron Letters, 1998, p. 2933) or Chamain (Tetrahedron Letters, 1998,

p. 4179) or Huwe et al. (Tetrahedron Letters, 1559, p. 683).

For example, the compounds of formula (XV) in which Y is a single bond may be prepared via a Suzuki reaction according to the conditions known to those skilled in the art, for example according to the process described by Deng et al., Synthesis, 2003, p. 337 or Meier et al., Synthesis, 2003, p. 551.

For example, the compounds of formula (VITI) may be obtained by reduction of the compounds of formula (XV) according to the conditions known to those skilled in the art.

When a function of a compound is reactive, for example when R; comprises a hydroxyl, it may be necessary to protect it before reaction. A person skilled in the art can readily determine the need for prior protection.

The examples that follow describe the preparation of certain compounds in accordance with the invention. These compounds are not limiting and serve merely to illustrate the invention.

The numbers of the compounds given as examples refer to those given in the table hereinbelow.

The elemental micrcanalyses and the NMR, IR or LC-MS (liguid chromatography coupled to mass spectrometry) analyses confirm the structures of the compounds obtained.

Example 1: methyl 2-{2-(S)-[2-(3,5-difluocrophenyl)acetylamino]- pentanoyl}amino-5-[2- (4-fluorophenoxy)phenyl] thiazole- 4-~carboxylate (compound 13) + Ho 0

F PL ne 100 S = fo) : N CO,CH, h

Example 1.1: 2-(4-fluorophenoxy)benzoic acid 0 OH

AT

100 g of potassium carbonate are added slowly to a mixture of 120 g of 2-iodobenzoic acid, 1 g of copper powder and 54.4 g of 4-fluorophenol in 200 ml of

N,N-dimethylformamide. The mixture is heated at 160°C for 4 hours and is then allowed to cool before evaporating. The residue is taken up in distilled water, acidified with aqueous 1N hydrochloric acid solution and then extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulphate and then concentrated. The desired product crystallizes from a diethyl ether/pentane mixture. 50 g of a white solid are obtained.

LC/MS: MH™ = 233

Example 1.2: 2-(4-fluorophenoxy)-0,N-dimethylbenzamide oN.

OMe

JT

29.7 g of hydroxybenzotriazole hydrate are added to a solution of 50 g of 2-(4- fluorophenoxy)benzoic acid, obtained in step 1.1, in 450 ml of N,N-dimethylformamide, followed by addition of 37 g of (EDAC HCl), 19 g of (O,N- dimethylhydroxylamine HCl) and 19.4 g of

N-methylmorpholine. The mixture is stirred at room temperature for 16 hours. The solvent is evaporated off, the residue is taken up in ethyl acetate and the organic phase is washed twice with saturated aqueous sodium chloride solution, once with distilled water, once with aqueous 1M potassium hydrogen sulphate solution and then with saturated aqueous sodium chloride solution. The resulting solution is dried over anhydrous sodium sulphate and then concentrated. 49 g of a coloured oil are obtained, and are used without further purification in the following synthesis.

LC/MS: MH™ = 276

Example 1.3: 2- (4-fluorophenoxy)benzaldehyde

CHO

©

AT

48.5 g of 2-(4-fluorophenoxy)-0, N- dimethylbenzamide, obtained in step 1.2, in 300 ml of anhydrous tetrahydrofuran are added dropwise to 100 ml of a 1M solution of lithium aluminium hydride in tetrahydrofuran at 0°C. The mixture is stirred at 0°C for 1 hour and then hydrolysed dropwise with 40 ml of aqueous 1M potassium hydrogen sulphate solution. The resulting mixture is evaporated and the residue is taken up in ethyl acetate and washed twice with aqueous 1M potassium hydrogen sulphate solution and then with saturated aqueous sodium chloride solution. The resulting solution is dried over anhydrous sodium sulphate and then concentrated. 35 g of a coloured oil are obtained.

LC/MS: MH = 217

NMR 300 MHz (CDCls3) & ppm: 6.70~7.00 (m, 4H); 7.20-7.35 (m, 2H); 7.55 (t, 1H); 7.95 (d, 1H); 10.43 (s, 1H).

Example 1.4: methyl 2-amino-5-[2-(4-fluorophenoxy) - phenyl] thiazocle-4-carboxylate r—~ Ho

S an—

N CO,CH, 30 g of methyl dichloroacetate are added, at 0°C, to 35 g of 2-(4-fluorophenoxy)benzaldehyde, obtained in step 1.3, dissolved in 400 ml of diethyl ether, followed by dropwise addition of 325 ml of a solution (0.5 M) of sodium methoxide in methanol. After 1 hour at 0°C, the diethyl ether only is evaporated off, while retaining the methanol, 11 g of thiourea are added and the mixture is refluned for 6 hours. The reaction medium is evaporated to dryness and the residue is taken up in ethyl acetate and washed with aqueous 10% ammonium hydroxide solution and then with saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulphate and then concentrated. The residue is taken up in 100 ml of diethyl ether and filtered through a sinter funnel. 30 g of a white solid are obtained.

LC/MS: MH" = 345

NMR 300 MHz (CDCls3) & ppm: 3.70 (s, 3H); 5.55 (broad s, 2H); 6.55-6.80 (m, 4H); 7.00 (d, 1H); 7.20 (t, 1H): 7.35-7.45 (m, 2H).

Example 1.5: methyl 2-[2- (8S) -pentanoylamino]amino-5-[2- (4-fluorophenoxy) phenyl] thiazole-4-carboxylate

Pass . _ *'™ N—4 i: H NT “co,cH,

MN

2.75 g of N-methylmorpholine, 14.30 g of

PyBOP and then 5.97 g of (S)-BocNorvaline are added to 8.6 g of methyl 2-amino-5-[2-(4- fluorophenoxy)phenyllthiazole-4-carboxylate, obtained in step 1.4, dissolved in 200 ml of N,N- dimethylformamide at 0°C. The reaction medium is allowed to return to room temperature and is then stirred for 16 hours. After evaporation, the residue is taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution, twice with water, once with aqueous 1M potassium hydrogen sulphate solution and then with saturated aqueous N sodium chloride solution. The organic phase is dried over anhydrous sodium sulphate and then concentrated.

The residue is chromatographed on a column of silica gel, eluting with a 3/7 (v/v) mixture of ethyl acetate and petroleum ether. 8.5 g of a white solid are obtained.

LC/MS: MH' = 544

NMR 300 MHz (CDCls) 8 ppm: 0.88 (t, 3H); 1.38 (s, 9H);

1.39-1.55 (2m, 2H); 1.75 (m, 2H); 3.35 (broad s, 1H); 3.68 (s, 3H); 4.28 (m, 1H); 5.65 (d, 1H); 6.80-6.90 (m, 5H); 7.10 (t, 1H); 7.20-7.32 (m, 2H). 6.5 g of product obtained above dissolved in 60 ml of trifluoroacetic acid are stirred at room temperature for 30 minutes, and the solution is then evaporated. The residue is taken up in ethyl acetate and washed twice with saturated aqueous sodium carbonate solution, and then with saturated agueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulphate and then evaporated to give 3.9 g of a white solid.

LC/MS: MH' = 444

Example 1.6: methyl 2-{2-(S)-[2-(3,5-difluorophenyl)acetylamino]- pentanoyllamino-5-[2-(4-fluorophenoxy) phenyl] thiazole- 4-carboxylate 0.20 g of N-methylmorpholine, 0.99 g of PyBOP and then 0.33 g of 3,5-difluorophenylacetic acid are added to 0.7 g of methyl 2-amino-2-[2-(S)- pentanoylamino]-5-[2-(4-fluorophenoxy)phenyl]thiazole- 4-carboxylate, obtained in Example 1.5, dissolved in ml of N,N-dimethylformamide at 0°C. The mixture is allowed to warm to room temperature and 1s stirred for

Claims

1. Compound corresponding to the general formula (I): R, R, . 0] N R, A R; N H S R; Oo R, (h in which R, represents: either a Ci-¢ alkyl optionally substituted with one to three substituents chosen from a halogen, a trifluoromethyl, a hydroxyl, a Ci.¢ alkoxy, a Cig thioalkyl, a thiophene or a phenyl; or a Cs. cycloalkyl, a thiophene, a benzothiophene, a pyridyl, a furyl or a phenyl; the said phenyl groups being optionally substituted with one to three substituents chosen from a halogen atom, a Ci-s alkyl, a Ci-s alkoxy, a “hydroxyl, a methylenedioxy, a phenoxy, a benzyloxy or a trifluoromethyl; : R, and R’, represent, independently of each other, a hydrogen atom, a halogen atom, a hydroxyl, a

C,.3 alkoxy, a Ci-3 alkyl, a Cs; cycloalkyl, an 0-C(O)- Ci-¢ alkyl group, or R, and R’, together form an Oxo group; R; represents a hydrogen atom, a Cis alkyl optionally substituted with a hydroxyl, a Ci.g cycloalkyl or a

Ci-3 alkoxy; one or other of Rs. and Rs represents a group Z aD B Y a” and one or other of Ry, and Rs represents a group -C(X) Re: G represents a single bond or a —-CHp;- group; Y represents a single bond, an oxygen or sulphur atom, a Cis alkylene group or -N(W)-, the -C;4 alkylene- group being optionally substituted with a hydroxyl or Ci-3 alkoxy group; W represents either a hydrogen atom, a C;-3 alkyl optionally substituted with a phenyl, or a phenyl; A and B represent, independently of each other, a hydrogen or halogen atom, a hydroxyl, C;-3 alkyl,

Ci.3 alkoxy, trifluoromethyl, trifluoromethoxy or -O-CHF, group; on condition that if ¥ is a single bond or an oxygen atom and 1f the group Z is of the type a B y £0 (2) zc” then A is other than a hydrogen atom; X represents an oxygen atom or a sulphur atom; Rg represents a Cig alkoxy, hydroxyl or -NR;Rg group;

the Ci.¢ alkoxy group being optionally substituted with a phenyl; R, and Rg represent, independently of each other: either a hydrogen atom; or a Cig alkyl group optionally substituted with a Cs.7 cycloalkyl, a Cs; cycloalkenyl, a C,-3 alkoxy, a phenyl, a morpholinyl or a pyridyl; or a Cs3-7 cycloalkyl, Cis alkoxy or phenyl group; the said C3-7 cycloalkyl and phenyl groups being optionally substituted with one or two groups chosen from a halogen atom, a hydroxyl group, a C;-; alkyl and a Ci-3 alkoxy group; or R; and Rg, with the nitrogen atom that bears them, form an aziridine, azetidine, pyrrolidine, piperidine, morpholine or benzopiperidine ring; in the form of base, acid-addition salt, hydrate or solvate.

2. Compound according to Claim 1, characterized in that R; represents a C;-5 alkyl or a phenyl optionally substituted with one to three halogen atoms; in the form of base, acid-addition salt, hydrate or solvate.

3. Compound of formula (I) according to Claim 1 or 2, characterized in that R; and R’; represent, independently of each other, a hydrogen atom or a hydroxyl or R; and R’, together form an oxo group; in the form of base, acid-addition salt, hydrate or solvate.

4. Compound of formula (I) according to any one of Claims 1 to 3, characterized in that Rj represents a C;-g alkyl; in the form of base, acid- addition salt, hydrate or solvate.

5. Compound of formula (I) according to any one of Claims 1 to 4, characterized in that one or other of Ry, and Rs represents a group Z “Le B 2, Y Gc" and one or other of R, and Rs represents a group —C (X) Rg; G represents a single bond; Y represents a single bond, an oxygen or sulphur atom, or a Cj-4 alkylene group; A and B represent, independently of each other, a hydrogen atom, a halogen atom, or a trifluoromethyl or Lrifluoromethoxy group; on condition that if Y is a single bond or an oxygen atom and if the group Z is of the type ag] B £2, Y a” then A is other than a hydrogen atom; X represents an oxygen atom or a sulphur atom;

Rg represents a Cg alkoxy group; in the form of base, acid-addition salt, hydrate or solvate.

6. Process for preparing a compound of formula (I) according to any one of Claims 1 to 5, comprising the step consisting in forming a peptide coupling of the 2-aminothiazole of formula (III) N Re IT (1 H,N S Rg with the acylamino acid of formula (II) R, R) Pe COH (ID

2

R. he 0 R, in which Ry, Rs, R’,, R3, Ry and Rs are as defined in formula (I) according to any one of Claims 1 to 5.

7. Process for preparing a compound of formula (I) according to any one of Claims 1 to 5, comprising the step consisting in performing a peptide coupling of the compound of formula (IV) R, rR, X Vv R; O,H with the amine of formula (VI)

- ? R N—4& Lv R, H N R, in which Ri, Ry, R’,, Riz, Ry and Rs are as defined in formula (I) according to any one of Claims 1 to 5.

8. Medicament, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 5, in the form of base or of pharmaceutically acceptable salt, hydrate or solvate.

9. Pharmaceutical composition containing at least one compound of formula (I) according to any one of Claims 1 to 5, in the form of base or of pharmaceutically acceptable salt, hydrate or solvate, and optionally one or more pharmaceutically acceptable excipients.

10. Use of a compound of formula (I) according to any one of Claims 1 to 5, in the form of base or of pharmaceutically acceptable salt, hydrate or solvate, for the preparation of a medicament for treating a pathology in which an inhibitor of the formation of the P-amyloid (P-A4) peptide provides a therapeutic benefit.

11. Use of a compound of formula (I) according to any one of Claims 1 to 5, in the form of base or of pharmaceutically acceptable salt, hydrate or solvate, for the preparation of a medicament for v treating senile dementia, Alzheimer’s disease, Down's syndrome, Parkinson's disease, amyloid angiopathy, cerebrovascular disorders, frontotemporal dementia and Pick’s disease, post-traumatic dementia, pathologies associated with neuroinflammatory processes, Huntington’s disease and/or Korsakov’s syndrome.