FR2845384A1 - New 2-thiohydantoin derivatives used for treating diabetes, hyperglycemic disorders, obesity, cerebral ischemia and cerebral vascular accidents - Google Patents

Abstract

2-Thiohydantoin derivatives (I) are new. 2-Thiohydantoin derivatives (I) and their acid addition salts, are new. R1, R2 = 1-5C alkyl, 3-4C alkenyl, 2-3C hydroxyalkyl, 3-5C alkoxyalkyl, CH2-COOCH3, N,N-dialkylaminoalkyl, a group of formula (i), dibenzofuranyl or (CH2)p-Ar; m = 2 or 3; Y = O or N-CH3; p = 0 or 1; Ar = phenyl or pyridinyl (both optionally substituted by at least one halo, 1-4C alkyl, OH, NO2, 1-3C alkoxy, methylenedioxy, ester, CF3, CF3O, CN, morpholinyl or a group of formula (ii)); A = O or S; X = C or N; R5 = H, halo, N,N-dialkylamino, 1-3C alkoxy or OH optionally esterified with an amino acid; R3 = H, halo, 1-4C alkyl, 1-4C alkoxy, OH, phenyl or benzyl, and R4 = H, halo or 1-4C alkyl, provided that at least one of R1 and R2 contains two aromatic rings (phenyl or pyridinyl) or is dibenzofuranyl. An Independent claim is also included for the preparation of (I).

Description

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 The present invention relates to novel compounds derived from 2thiohydantoin (or 2-thioxo-imidazolidin-4-one), their method of manufacture and their use as active ingredients for the preparation of medicaments intended especially for the treatment of diabetes.

Prior art
The chemistry of thiohydantoin compounds has been known for many years. Certain derivatives of this heterocycle have been used in the field of photography, as described for example in US Pat. Nos. 2,551,134 or JP 81,111,847, or in the field of pesticides, essentially herbicides or fungicides, as described for example in US 3,798,233, US 4,473,393 or Indian J. Chem., 1982, Vol 21B, p. 162-164, J. Indian Chem. Soc., 1981, Vol 58 (10), p. 994-995, Chem. Abst. 67, 82381v and Indian J. Chem., 1979, vol. 18B, p 257-261. More recently, compounds comprising the thiohydantoin ring have been prepared in order to provide therapeutically active products: for example, US 3,923,994 discloses the use of 3-aryl-2-thiohydantoins for their anti-arthritic activity; US 3,984,430 proposes new thiohydantoins for treating ulcers; Indian J. Chem., 1978, Vol 16B, p. 71-72 describes coumaryl-thiohydantoins active against tuberculosis; US 4,312,881 claims acids and esters comprising the 2-thiohydantoin ring and having prostaglandin-like activity; Chem. Pharm. Bull, 1982, Vol. 30, No. 9, p. 3244-3254 discloses the inhibition of aldose reductases by 1- (phenylsulfonyl) -2-thiohydantoin compounds; Il Farmaco, Ed. Scientifico, 1983, Vol. 38, No. 6, p. 383-390 proposes 3-dialkylaminopropyl-2-thiohydantoins as anti-arrhythmic agents; WO 96/04248 discloses amide or sulfonamide derivatives of 2-thiohydantoin antagonists of angiotensin II; WO 97/19932 claims the use of 2-thiohydantoin derivatives to increase HDL levels; WO 98/33776 cites a library of compounds obtained by combinatorial chemistry and tested for their antimicrobial or analgesic properties; WO 93/18057 and EP 584 694 describe acids or esters comprising a 2-thiohydantoin ring and inhibitors of platelet aggregation; EP 580,459 and WO 97/00071 disclose N-phenyl-thiohydantoins having anti-androgenic activity.

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 Other publications, such as for example J. Prakt. Chem., Vol 333 (2), p. 261-266; Indian J. Chem., 1974, vol. 12, No. 6, p. 577-579; Abstr 68, (1968) 87240d and Organic Magn. Resonance, vol. 19 (1), p. 27-30 cite preparations of compounds including the 2-thiohydantoin ring without indicating the industrial utility.

 The publication J. Pharm. Sc., Vol. 70, No. 8, p. 952-956 mentions cyclic derivatives of sulfonylthiourea, among which thiourea can be represented by a thiohydantoin ring, said derivatives having antidiabetic activity at a dose of about 100 mg / kg.

Object of the invention
The present invention relates to novel compounds comprising in their structure the heterocycle 2-thiohydantoin (or 2-thioxo-imidazolidin-4-one) as well as their method of preparation and their therapeutic use, in particular for the preparation of a medicinal product intended for treatment of diabetes, diseases caused by hyperglycemia, hypertriglyceridemia, dyslipidemia or obesity.

dans laquelle ' R] et R2, indépendamment l'un de l'autre représentent - un groupe alkyle en C1-C5, - un groupe alcènyle en C3-C4 , - un groupe hydroxyalkyle en CZ-C3 , - un groupe alcoxyalkyle en C3-C5, - un groupe CH2-COOCH3, - un groupe N,N-dialkylaminoalkyle, - un groupe Description
According to the invention, novel compounds containing the 2thioxo-imidazolidin-4-one (or 2-thiohydantoin) ring of formula (I) are proposed:

wherein R 1 and R 2, independently of each other, represent a C 1 -C 5 alkyl group, a C 3 -C 4 alkenyl group, a C 3 -C 3 hydroxyalkyl group, a C 3 alkoxyalkyl group, -C5, - a CH2-COOCH3 group, - an N, N-dialkylaminoalkyl group, - a group

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(CH 2)m 1\ (CH2)m# -(CH2)m-N "--1 dans lequel m représente 2 ou 3, et
Y représente 0 ou N-CH3, - un groupe dibenzofuranyle, - un groupe (CH2)p-Ar, dans lequel - p représente 0 ou l,et - Ar représente un noyau aromatique phényle ou pyridinyle, non substitué ou substitué par un ou plusieurs atomes ou groupes d'atomes choisi (s) les halogènes, les groupes alkyl en C1-C4, hydroxy, nitro, alcoxy en C1-C3, méthylènedioxy, ester, trifluorométhyl, trifluorométhoxy, cyano, morpholinyle ou le groupe

dans lequel - A représente 0 ou S, - X représente C ou N et, - R5 représente un atome d'hydrogène, un atome d'halogène, un groupe N,N- dialkylamino, un groupe alcoxy en C1-C3, ou un groupe hydroxy libre ou estérifié par un aminoacide, # R3 représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle en C1-
C4, un groupe alcoxy en C1-C4, un groupe hydroxy, un groupe phényle ou un groupe benzyle, # R4 représente un atome d'hydrogène, un atome d'halogène ou un groupe alkyle en
C1-C4, avec la condition que l'un au moins des substituants R1 et R2 comprenne dans sa structure 2 noyaux aromatiques choisis parmi les groupes phényle ou pyridinyle, ou représente le groupe dibenzofuranyle ; et les sels d'addition des composés de formule (I) avec un acide non toxique lorsque lesdits composés de formule (I) comprennent une fonction salifiable basique.

(CH 2) m 1 (CH 2) m # - (CH 2) m N "- 1 wherein m is 2 or 3, and
Y represents 0 or N-CH3, - a dibenzofuranyl group, - a (CH2) p -Ar group, in which - p represents 0 or 1, and - Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted with one or a plurality of atoms or groups of atoms selected from halogen, C1-C4 alkyl, hydroxy, nitro, C1-C3 alkoxy, methylenedioxy, ester, trifluoromethyl, trifluoromethoxy, cyano, morpholinyl or the group

wherein - A is O or S, - X is C or N and - R5 is hydrogen, halogen, N, N-dialkylamino, C1-C3 alkoxy, or free hydroxy group or esterified with an amino acid, # R3 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group,
C4, C1-C4 alkoxy, hydroxy, phenyl or benzyl, # R4 is hydrogen, halogen, or alkyl.
C1-C4, with the proviso that at least one of the substituents R1 and R2 comprises in its structure 2 aromatic rings selected from phenyl or pyridinyl groups, or represents the dibenzofuranyl group; and the addition salts of the compounds of formula (I) with a nontoxic acid when said compounds of formula (I) comprise a basic salifiable function.

 In the present description, the dibenzofuranyl group is considered to comprise 2 aromatic rings.

 A family of preferred compounds according to the invention are the compounds of formula (I):

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dans laquelle : # R1 représente - un groupe alcényle en C3-C4, - un groupe dibenzofuranyle, - un groupe (CH2)n-Ar dans lequel n représente 0 ou 1, et
Ar représente un noyau aromatique phényle ou pyridinyle, non substitué ou substitué par un ou plusieurs des atomes ou groupes d'atomes choisis parmi : les halogènes, les groupes alkyle en C1-C4, nitro, alcoxy en CI-C3, alcoxyalkyle en C3-C4, ou le groupe

dans lequel
A représente 0 ou S,
X représente C ou N et,
R5 représente un atome d'hydrogène, un atome d'halogène, un groupe N,N- di(Ci-C3)alkylamino, un groupe alcoxy en C1-C3, ou un groupe hydroxy libre ou estérifié par un aminoacide, # R2 représente - un groupe alkyle en C1-C5, - un groupe alcènyle en C3-C4, - un groupe hydroxyalkyle en C2-C3, - un groupe alcoxyalkyle en C3-CS , - un groupe CH2-COOCH3, - un groupe N,N-di(Ci-C3)alkylamino(Ci-C3)alkyl, - un groupe

in which: # R1 represents - a C3-C4 alkenyl group, - a dibenzofuranyl group, - a (CH2) n-Ar group in which n represents 0 or 1, and
Ar represents a phenyl or pyridinyl aromatic ring unsubstituted or substituted with one or more of the atoms or groups of atoms selected from: halogens, C 1 -C 4 alkyl, nitro, C 1 -C 3 alkoxy, C 3 alkoxyalkyl C4, or the group

in which
A represents 0 or S,
X represents C or N and,
R5 represents a hydrogen atom, a halogen atom, an N, N-di (C1-C3) alkylamino group, a C1-C3 alkoxy group, or a free hydroxy group or esterified by an amino acid, # R2 represents a C 1 -C 5 alkyl group, a C 3 -C 4 alkenyl group, a C 2 -C 3 hydroxyalkyl group, a C 3 -C 4 alkoxyalkyl group, a CH 2 -COOCH 3 group, an N, N-C group; di (C 1 -C 3) alkylamino (C 1 -C 3) alkyl, - a group

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(CH2)m N Y (CH m\---/ dans lequel m représente 2 ou 3, et
Y représente 0 ou N-CH3, - un groupe (CH2)p-Ar, dans lequel p représente 0 ou l,et
Ar représente un noyau aromatique phényle ou pyridinyle, non substitué ou substitué par un ou plusieurs atomes ou groupes d'atomes choisi (s) les halogènes, les groupes alkyl en C1-C4, hydroxy, nitro, alcoxy en C1-C3 , méthylènedioxy, ester, trifluorométhyl, trifluorométhoxy, cyano, morpholinyle ou le groupe

dans lequel
B représente 0 ou S ; @ R3 représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle en Ci-
C4, un groupe alcoxy en C1-C4, un groupe hydroxy, un groupe phényle ou un groupe benzyle, @ R4 représente un atome d'hydrogène, un atome d'halogène ou un groupe alkyle en C]-C4, avec la condition que l'un au moins des substituants RI et R2 comprenne dans sa structure 2 noyaux aromatiques choisis parmi les groupes phényle ou pyridinyle ou que RI représente le groupe dibenzofuranyle.

(CH2) m NY (CH m \ --- / wherein m is 2 or 3, and
Y represents 0 or N-CH3; a (CH2) p-Ar group, in which p represents 0 or 1, and
Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms selected from halogen, C1-C4 alkyl, hydroxy, nitro, C1-C3 alkoxy, methylenedioxy, ester, trifluoromethyl, trifluoromethoxy, cyano, morpholinyl or group

in which
B represents 0 or S; R 3 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group,
C4, C1-C4 alkoxy, hydroxy, phenyl or benzyl, R4 is hydrogen, halogen or C₁-C alkyle alkyl, with the proviso that at least one of the substituents R 1 and R 2 comprises in its structure 2 aromatic rings chosen from phenyl or pyridinyl groups or that R 1 represents the dibenzofuranyl group.

 Particularly preferred compounds according to the invention are the compounds of formula (I) in which one of the radicals R 1 or R 2 represents the phenoxyphenyl or phenylthiophenyl group, the radicals R 3 and R 4 and the other radical R 1 or R 2 are such that previously defined.

 The invention also comprises, when the substituents R3 and R4 are different, the compounds of configuration R, the compounds of configuration S and mixtures thereof.

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 The invention also comprises the salts of the compounds of formula (I) when they comprise in their structure a basic salifiable function, such as for example an amine function, a pyridine group or a morpholine group. These salts can be obtained with non-toxic and therapeutically acceptable inorganic or organic acids, in particular hydrochloric, sulfuric, phosphoric, methanesulphonic, citric, maleic, fumaric, oxalic and trifluoroacetic acids.

 The invention also relates to compounds of formula (I) for use as a pharmacologically active substance.

 In particular, the invention relates to the use of at least one compound according to formula (I) above as an active principle for the preparation of a medicinal product intended for use in therapy, in particular for combating diseases hyperglycemia, diabetes, hypertriglyceridemia, dyslipidemia or obesity.

detailed description
In the formula (I) representing the compounds according to the invention, the term "(C 1 -C 4) alkyl group" means a hydrocarbon chain containing from 1 to 4 carbon atoms, linear or branched, or even cyclic. Examples of C 1 -C 4 alkyl groups include methyl, ethyl, propyl, butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl groups. By C1-C5 alkyl group is meant a hydrocarbon chain having from 1 to 5 carbon atoms, linear or branched, or even cyclic. Examples of C1-C5 alkyl groups include the aforementioned groups as well as pentyl, isopentyl and cyclopentyl groups. When a phenyl group is substituted, the substituent may be in the ortho, meta or para position, the para position being preferred. By linear or branched C1-C3 alkoxy group is meant the methoxy, ethoxy, propoxy and 1-methylethoxy groups.

 Halogen atom includes fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.

 By N, N-di (C 1 -C 3) alkylamino group, denotes in particular the dimethylamino, diethylamino, dipropylamino and diisopropylamino groups.

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 By N, N-di (C1-C3) alkylamino (C1-C3) alkyl, denotes in particular the dimethylaminoethyl, diethylaminoethyl and dimethylaminopropyl groups.

 By C3-C4 alkenyl group is meant a hydrocarbon chain comprising 3 or 4 carbon atoms comprising in its structure an ethylenic bond between 2 carbons.

 By C3-C4 alkoxyalkyl group is meant a hydrocarbon chain having 3 or 4 carbon atoms interrupted by an oxygen atom, in particular the methoxyethyl and ethoxyethyl groups.

dans laquelle RI est tel que défini précédemment pour les composés de formule (I), R3 représente H, alkyle en CI-C4 , phényle ou benzyle et R4 représente H ou alkyle, avec un isothiocyanate de formule
R -N=C=S
R2 -N=C=S (III) dans laquelle R2 représente un groupe tel que défini précédemment pour les composés de formule (I), dans un solvant tel que par exemple l'éthanol, à une température comprise entre 20 C et la température d'ébullition du solvant, en présence d'une base aprotique telle que par exemple la triéthylamine et pendant 1 à 20 heures, pour obtenir le composé de formule (I)

dans laquelle RI, R2, R3 et R4 conservent la même signification que dans les produits de départ ; The compounds of formula (I) may be prepared according to a first general method A comprising the steps of:
1) reacting an acid of formula

in which R 1 is as defined above for the compounds of formula (I), R 3 represents H, C 1 -C 4 alkyl, phenyl or benzyl and R 4 represents H or alkyl, with an isothiocyanate of formula
R -N = C = S
R2 -N = C = S (III) in which R2 represents a group as defined above for the compounds of formula (I), in a solvent such as, for example, ethanol, at a temperature of between 20 ° C. and the temperature boiling the solvent, in the presence of an aprotic base such as for example triethylamine and for 1 to 20 hours, to obtain the compound of formula (I)

wherein R1, R2, R3 and R4 retain the same meaning as in the starting materials;

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 b) if necessary, when the compound of formula (I) obtained above comprises a basic salifiable function, such as for example an amine, reacting said compound with an inorganic or organic acid, in an anhydrous solvent, to obtain the salt of the compound of formula (I).

dans laquelle R1, R3 et R4 sont tels que définis dans le procédé A et R représente un groupe alkyle en C1-C4, préférentiellement un groupe méthyle, éthyle ou isopropyle, que l'on fait réagir avec un isothiocyanate de formule (III),
R2-N=C=S (III) la réaction étant alors conduite dans un solvant, tel que le toluène ou le xylène, en présence d'un acide faible organique, tel que l'acide acétique, à une température comprise entre 80 C et la température d'ébullition du solvant, pendant 0,5 à 5 heures, pour obtenir le composé de formule (I)

dans laquelle R1, R2 , R3 et R4 conservent la même signification que dans les composés de départ et si nécessaire, dans le cas où le composé de formule (I) comprend une fonction salifiable basique, on fait réagir ledit composé avec un acide pour obtenir le sel correspondant. Ce procédé sera dénommé ci-après procédé E. According to a variant of this process, it is possible to use, in place of the acid of formula (II), an ester of formula (IV)

in which R 1, R 3 and R 4 are as defined in process A and R represents a C 1 -C 4 alkyl group, preferentially a methyl, ethyl or isopropyl group, which is reacted with an isothiocyanate of formula (III),
R2-N = C = S (III) the reaction then being carried out in a solvent, such as toluene or xylene, in the presence of a weak organic acid, such as acetic acid, at a temperature of between 80 ° C. and the boiling point of the solvent, for 0.5 to 5 hours, to obtain the compound of formula (I)

in which R1, R2, R3 and R4 retain the same meaning as in the starting compounds and if necessary, in the case where the compound of formula (I) comprises a basic salifiable function, said compound is reacted with an acid to obtain the corresponding salt. This process will be called hereinafter process E.

 The compounds of formula (I) in which R 3 represents a halogen atom, especially the fluorine atom can be obtained from compounds of formula (I) in which R 3 is a hydrogen atom by successive action of a halogenating agent, such as N-bromosuccinimide, water (which makes it possible to obtain the compound of formula (I) in which R3 represents a hydroxyl group) and then of a

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 halogenating agent, such as N, N-diethylamino-sulfur trifluoride which leads to the compound of formula (I) wherein R3 represents a fluorine atom.

 The compounds of formula (I) in which R 3 represents a C 1 -C 4 alkoxy group may be obtained from compounds of formula (I) in which R 3 is a hydrogen atom, by the action of a halogenating agent, such as N-bromo succinimide, followed by the action of a C 1 -C 4 aliphatic alcohol.

dans laquelle Hal représente un atome d'halogène, et R3 et R4 sont tels que définis précédemment, de préférence en l'absence de solvant , en présence d'une base faible comme par exemple le bicarbonate de sodium et à une température comprise entre 60 et 150 C, pendant 0,5 à 10 heures. The compounds of formula (II) are generally known products or can be prepared according to methods known to those skilled in the art, for example by reaction of an aliphatic or aromatic primary amine of formula (V):
R 1 -NH 2 (V) in which R 1 is as defined above, with a halogenated acid of formula (VI)

in which Hal represents a halogen atom, and R3 and R4 are as defined above, preferably in the absence of a solvent, in the presence of a weak base such as, for example, sodium bicarbonate and at a temperature of between 60.degree. and 150 C, for 0.5 to 10 hours.

 Preferably, an α-brominated acid is used.

The compounds of formula (IV) are generally known products or can be prepared according to methods known to those skilled in the art, for example by reaction of an aliphatic or aromatic primary amine of formula (V):
R 1 -NH 2 (V) in which R 1 is as defined above, with a halogenated ester of formula (VII)

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dans laquelle Hal représente un atome d'halogène, R3 et R4 sont tels que définis précédemment et R représente un groupe alkyle, notamment méthyle ou éthyle, de préférence en l'absence de solvant, en présence d'une base faible comme par exemple le bicarbonate de sodium ou une amine tertiaire, et à une température comprise entre 60 et 150 C, pendant 0,5 à 10 heures.

in which Hal represents a halogen atom, R3 and R4 are as defined above and R represents an alkyl group, in particular methyl or ethyl, preferably in the absence of a solvent, in the presence of a weak base such as, for example, sodium bicarbonate or a tertiary amine, and at a temperature between 60 and 150 C for 0.5 to 10 hours.

 Preferably, an α-brominated ester is used.

 The compounds of formula (III) are generally known products or can be prepared according to methods known to those skilled in the art, for example by reaction of an aliphatic or aromatic primary amine of formula R 2 NH 2 with thiophosgene in the presence of a tertiary amine or with 1,1'-thiocarbonyldiimidazole.

 The following examples of preparation of compounds according to formula (I) will allow a better understanding of the invention.

 In these examples, the term "preparation" means the examples describing the synthesis of intermediate compounds and, for example, those describing the synthesis of compounds of formula (I) according to the invention. The melting points are measured on the Kofler bench and the Nuclear Magnetic Resonance spectral values are characterized by the chemical displacement calculated with respect to the TMS, by the number of protons associated with the signal and by the shape of the signal (s for singlet, d for doublet, t for triplet, q for quadruplet, m for multiplet). The working frequency and the solvent used are indicated for each compound.

 If the compounds comprise an asymmetric carbon, the absence of any particular indication means that the compound is in its racemic form, and the presence of the sign of chirality (R or S) means that the compound is in its chiral form.

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PREPARATION 1 N- (4-phenoxyphenyl) alanine
203.7 g (1.1 moles) of 4- (phenoxy) aniline and 323 g (3.84 moles) of sodium bicarbonate are intimately mixed by grinding in a mortar. The mixture is then placed in a reactor of 21, equipped with robust agitation, and 306 ml (3.3 moles) of 2-bromopropanoic acid are added. The mixture is heated with stirring at 90 ° C. for 1 hour, then cooled and poured over 21 ml of cold water. The hydrolysis medium is then acidified slowly to pH 4 with concentrated hydrochloric acid. The precipitate formed is separated by filtration, washed with water several times on the filter and then dried in a vacuum oven.

 This gives 178.5 g of the expected product in the form of a white solid (yield = 63%).

Mp = 160 ° C PREPARATION II 1- (Isothiocyanato) -4- (phenylthio) benzene
A solution of 10 g (50 mmol) of 4- (phenylthio) aniline in 40 ml of dimethylformamide is prepared and a solution of 10.8 g (55 mmol) of 1.1 ml is added at 0 ° C. with stirring. Thiocarbonyldiimidazole in 35 ml of dimethylformamide. The reaction medium is stirred for 5 h at 5 ° C. and then poured into ice water. The mixture obtained is extracted twice with 180 ml of dichloromethane and the combined organic phases are washed with water and then dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography eluting with cyclohexane. The expected product is obtained in the form of a colorless oil (yield = 96%).

PREPARATION III N- [4- (4-fluorophenoxy) phenyl] alanine
By following a procedure analogous to Preparation I, but using 4- (4-fluorophenoxy) aniline as starting material, the expected product is obtained, used subsequently without additional purification (yield = 88%).

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PREPARATION IV N- [4- (4-hydroxyphenoxy) phenyl] alanine
By following a procedure analogous to Preparation I, but using 4- (4-aminophenoxy) phenol as starting material, the expected product is obtained in the form of a fine white solid (yield = 75%).

Mp = 188 ° C PREPARATION V N- [4- (phenylthio) phenyl] alanine
By following a procedure analogous to Preparation I, but using 4- (phenylthio) aniline as starting material, the expected product is obtained in the form of a light yellow oil (yield = 81%).

1 H NMR (300 MHz, DMSO): 7.24 (m, 4H); 7.11 (t, 1H); 7.03 (d, 2H); 6.61 (d, 2H); 3.98 (q, 1H); 1.39 (d, 3H).

PREPARATION VI 2 - [(4-Phenoxyphenyl) amino] butanoic acid, ethyl ester
5 g (27 mmol) of 4- (phenoxy) aniline and 10.72 g (55 mmol) of ethyl 2-bromobutanoate are added and 3.36 g (40 mmol) of sodium bicarbonate are added.

The mixture is stirred for 5 hours at 140 ° C., then cooled and taken up in 70 ml of water and 150 ml of ethyl ether. After decantation, the aqueous phase is again extracted with 75 ml of ethyl ether. The combined organic phases are washed with water and then dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with a methylcyclohexane / ethyl acetate mixture (8/2; v / v). The expected product is obtained in the form of a yellow oil (yield = 80%).

1 H NMR (300 MHz, DMSO): 7.29 (m, 2H); 7.01 (t, 1H); 6.83 (m, 4H); 6.59 (d, 2H); 5.91 (d, 1H); 4.11 (m, 2H); 3.86 (q, 1H); 1.78 (m, 2H); 1.17 (t, 3H); 0.97 (t, 3H).

PREPARATION VII 2-methyl-N- (4-phenoxyphenyl) alanine
A solution of 15 g (67.7 mmol) of 4- (phenoxy) aniline hydrochloride in 200 ml of dimethylformamide is prepared and 13.7 g (82 mmol) of 2-bromo-2-methylpropanoic acid are added, followed by 9 5 ml (67.7 mmol) of triethylamine.

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 The reaction mixture is stirred for 24 h at 100 ° C., then cooled and poured into 250 ml of ice water. The mixture is extracted twice with 250 ml of ethyl acetate and the combined organic phases are washed with water and then dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel. The expected product is obtained in the form of white crystals (yield = 75%).

M.p. 192 C PREPARATION VIII 2-methyl-N- (2-propenyl) -alanine, methyl ester
15 ml of allylamine and 12 g of methyl 2-bromo-2-methylpropanoate are mixed and the mixture is heated at 80 ° C. overnight. The excess of amine is removed under reduced pressure and the residue is purified by chromatography on silica gel, eluting with a cyclohexane / ethyl acetate mixture (7/3, v / v). The expected product is thus obtained in the form of a pale yellow oil (yield = 11%).

 1 H NMR: (DMSO d6, 300 MHz) 1.20 (s, 6H); (s, 2H); (s, 3H); (d, 1H); 5.11 (d, 1H); 5.79 (m, 1H).

PREPARATION IX N- (4-phenoxyphenyl) -phenylalanine
A mixture of 2.17 g (7.3 mmol) of 4-phenoxyiodobenzene, 1.02 g (6.2 mmol) of phenylalanine, 0.48 g of bis (tri-o-tolyl palladium) dichloride is prepared. 125 mg of cuprous iodide, 240 mg of benzyltriethylammonium chloride and 876 mg of potassium carbonate in 12 ml of dimethylformamide, 1.2 ml of water and 2.4 ml of triethylamine. This reaction medium is stirred at 100 ° C. for 24 h and then cooled. 50 ml of toluene are added and concentrated under reduced pressure. The residue is taken up in 40 ml of ethyl acetate and 40 ml of water and the mixture is acidified to pH 2. The precipitate formed is separated by filtration and washed with 10 ml of water and 5 ml of water. ethyl acetate and then dried.

640 mg of the expected product are thus obtained in the form of a fine gray solid (yield = 30%).

F = 194 C

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PREPARATION X N- [4- (4-fluorophenoxy) phenyl] alanine, ethyl ester
By following a procedure analogous to Preparation VII, but using as starting materials 4- (4-fluorophenoxy) aniline and ethyl 2-bromopropanoate, in ethanol and in the presence of sodium acetate, the following are obtained: the expected product in the form of a beige oily liquid, subsequently used without further purification (yield = 80%).

PREPARATION XI N- [4- (3-chlorophenoxy) phenyl] alanine
A solution of 0.8 g (3.64 mmol) of 4- (3-chlorophenoxy) aniline in 10 ml of dimethoxyethane is prepared and 0.328 ml (3.64 mmol) of 2-bromopropanoic acid and 0.5 ml of triethylamine. The reaction medium is stirred for 24 h at 50 ° C., then cooled and poured into 50 ml of water. The mixture is brought to basic pH by adding a solution of sodium hydroxide and extracted with 50 ml of ethyl acetate. The aqueous phase is then acidified with a hydrochloric acid solution to pH 4 and extracted twice with 70 ml of ethyl ether. The combined organic phases are washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. 0.75 g of the expected product is thus obtained in the form of a beige solid, used subsequently without additional purification (yield = 70%).

Mp = 138-140 ° C PREPARATION XII N- [4- (2-chlorophenoxy) phenyl] alanine
By following a procedure analogous to Preparation XI, but using 4- (2-chlorophenoxy) aniline as starting material, the expected product is obtained in the form of an oil (yield = 70%). This compound is used later without further purification.

PREPARATION XIII N- [4- [3- (dimethylamino) phenoxy] phenyl] alanine, ethyl ester
By following a procedure analogous to Preparation VII, but using 4- [3- (dimethylamino) phenoxy] aniline as starting material, the expected product is obtained in the form of a brown oil (yield = 64%).

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 1 H NMR (300 MHz, CDCl 3): 7.18 (t, 1H); 6.89 (q, 2H); (q, 2H); (m, 2H); 6.23 (2d, 1H); 4.21 (q, 2H); (q, 1H); 2.91 (s, 6H); (d, 3H); (t, 3H).

PREPARATION XIV N- [4-phenoxyphenyl) methyl] alanine, ethyl ester
By following a procedure analogous to Preparation VII, but using 4-phenoxy-benzenemethanamine and ethyl 2-bromopropanoate as starting material in dioxane, the expected product is obtained in the form of a beige oil (yield = 37%).

1 H NMR (300 MHz, DMSO): 7.37 (m, 4H); 7.12 (t, 1H); 6.97 (m, 4H); 4.09 (q, 2H); 3.63 (2d, 2H); (q, 1H); 1.20 (m, 6H).

PREPARATION XV N- [2-Phenoxy-5-pyridinyl] alanine
By following a procedure analogous to Preparation I, but using as starting products 5-amino-2-phenoxypyridine and 2-bromopropanoic acid, the expected product is obtained in the form of a poorly crystallized solid, which is subsequently used without complementary purification.

PREPARATION XVI N- [4- (4-chlorophenoxy) phenyl] alanine, ethyl ester
By following a procedure analogous to Preparation X, starting from 4- (4-chlorophenoxy) aniline, the expected product is obtained in the form of a white solid (yield = 78%).

PREPARATION XVII N- [4- (phenylthio) phenyl] glycin
By following a procedure analogous to Preparation I, starting from 4- (phenylthio) aniline and bromoacetic acid, the expected product is obtained in the form of an oil (yield = 93%).

 1H NMR (DMSO d6, 250 MHz) 4.13 (s, 2H); 6.61 (d, 2H); 7.09 (d, 2H); 7.30 (m, 5H)

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PREPARATION XVIII
By following a procedure analogous to Preparation XVII, starting from 2-bromo-2-methylpropanoic acid, the expected product is obtained in the form of an oil (yield = 99%).

 1 H NMR (DMSO of 300 MHz) 1.40 (s, 6H); 6.57 (d, 2H); 7.02 (d, 2H); 7.18 (m, 5H).

PREPARATION XIX N- (4-phenoxyphenyl) -2-phenylglycine
By following a procedure analogous to Preparation XI, the expected product is obtained in the form of a white solid (yield = 67%).

F = 145 C PREPARATION XX 2- [4-Phenoxyphenyl] amino] pentanoic acid
By following a procedure analogous to Preparation I, the expected product is obtained in the form of a paste (yield = 70%).

 1H NMR (DMSO d6, 300 MHz): 0.91 (t, 3H); 1.43 (m, 2H); (m, 2H); 3.81 (t, 1H); 6.59 (d, 2H); 6.83 (m, 4H); 6.99 (t, 1H); 7.29 (t, 2H).

PREPARATION XXI 1 - [(4-Phenoxyphenyl) amino] cyclopropanecarboxylic acid, ethyl ester a) A suspension of 6.15 g of 1-aminocyclopropane carboxylic acid in 100 ml of ethanol is prepared and 6.5 ml of thionyl chloride. The reaction mixture is heated at gentle reflux for 8 hours and then concentrated under reduced pressure, adding toluene to drive off the ethanol. There is thus obtained 10 g of the hydrochloride of the ethyl ester of the starting acid. b) 1.25 g of the hydrochloride of the ester obtained above are mixed with 6.25 g of diacetyl-tri (4-phenoxyphenyl) bismuth in 20 ml of dichloromethane and 1.1 ml of triethylamine and 22 mg are added. of copper powder. The reaction mixture is stirred at ambient temperature overnight and then chromatographed on silica gel, eluting with a dichloromethane / cyclohexane (8/2; v / v) mixture. 0.47 g of the expected product is thus obtained (yield = 24%).

 F = 80C

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PREPARATION XXII 1 - [(4-Phenoxyphenyl) amino] cyclopropanecarboxylic acid
0.35 g of the ester obtained according to Preparation XXI, 1 ml of a 10% sodium hydroxide solution, 20 ml of dimethoxyethane and 20 ml of methanol are mixed and this reaction mixture is stirred at room temperature overnight. This mixture is then concentrated under reduced pressure and taken up in 20 ml of water. The solution obtained is filtered and acidified with a solution N of hydrochloric acid. The precipitate is extracted with dichloromethane and the organic phase obtained is dried over magnesium sulfate and concentrated. The expected acid is thus obtained in the form of white crystals (yield = 97%).

F = 163 C PREPARATION XXIII 2 - [(4-Phenoxyphenyl) amino] -4-methylpentanoic acid
By following a procedure analogous to Preparation I, starting from 2-bromo-4-methylpentanoic acid, the expected product is obtained in the form of a paste (yield = 10%).

1 H NMR (CDCl 3, 250 MHz): (m, 6H); (m, 2H); 1.8 (m, 1H); 3.8 (t, 1H); 6.6 (d, 2H); (m, 4H); (t, 1H); 7.3 (t, 1H).

PREPARATION XXIV N- (2,6-dimethylphenyl) -2-methylalamine
By following a procedure analogous to Preparation XI, the expected product is obtained in the form of beige crystals (yield = 53%).

Mp = 148 ° C Example 1 5-methyl-1- (4-phenoxyphenyl) -3-phenyl-2-thioxo-4-imidazolidinone
A mixture of 175 g (0.68 mol) of the compound obtained according to the preceding step and 104 ml of triethylamine in 21 of ethanol is prepared. The resulting solution is filtered on sintered glass and 89.5 ml (0.75 mole) of phenylisothiocyanate are added. The reaction mixture is stirred at room temperature for 18 hours. The white precipitate formed is separated by filtration and then taken up in solution in a dichloromethane / ethanol mixture. The solution is treated with activated carbon,

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 filtered and partially reconcentrated to the evaporator under reduced pressure. The white precipitate obtained is separated by filtration, washed with ethanol and dried. 228.3 g of the expected product are thus obtained in the form of white crystals (yield = 89%).

F = 141 C Examples 2 and 3 (S) -methyl-1- (4-phenoxyphenyl) -3-phenyl-2-thioxo-4-imidazolidinone (Example 2) (R) -methyl-1- (4- phenoxyphenyl) -3-phenyl-2-thioxo-4-imidazolidinone (Example 3)
A solution of 50 mg of the racemic compound obtained according to Example 1 is prepared in 1 ml of a hexane / dichloromethane mixture. This solution is injected into a preparative high pressure chromatography device equipped with a 250x20 mm column, CHIRALPACK AD 10 m (supplied by DAICEL).

The eluent is a 75/25 hexane / isopropanol mixture with a flow rate of 10 ml / min. The configuration compound (S) has a retention time of the order of 21 to 26 min and the configuration compound (R) has a retention time of about 32 to 37 min. The separated compounds, recovered in solution after chromatography, are obtained by evaporation of the solvent at low temperature. There is thus obtained approximately 9 mg of each of the two enantiomers: Example 2: (S enantiomer): [alpha] D23 = +8 (C = 1.24, CH2Cl2) Example 3: (R enantiomer): [alpha] D23 = - 6 (C = 1.02, CH 2 Cl 2).

The proof of the configuration of the two enantiomers has been established by unambiguous synthesis, starting from (R) alanine and (S) alanine.

Example 4 5-methyl-1,3-bis (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1, but using 4-phenoxyphenylisothiocyanate instead of phenylisothiocyanate, the expected product is obtained in the form of an off-white solid (yield = 74%). .

3-(4-méthoxyphényl)-5-méthyl-1-(4-phénoxyphényl)-2-thioxo-4-imidazolidinone
En opérant de façon analogue à l'exemple 1 mais en utilisant l'isothiocyanate de 4-méthoxyphényle à la place de l'isothiocyanate de phényle, et en utilisant M = 184-186 C Example 5

3- (4-methoxyphenyl) -5-methyl-1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1 but using 4-methoxyphenylisothiocyanate instead of phenyl isothiocyanate, and using

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 acetonitrile as a solvent medium, the expected product is obtained in the form of white crystals (yield = 84%).

Mp = 170 ° C Example 6 5-methyl-3- (4-nitrophenyl) -1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1, but using 4-nitrophenyl isothiocyanate in place of phenyl isothiocyanate, the expected product is obtained in the form of an orange powder (yield = 70%).

3-(4-hydroxyphényl)-5-méthyl-1-(4-phénoxyphényl)-2-thioxo-4-imidazolidinone
En opérant de façon analogue à l'exemple 1 mais en utilisant l'isothiocyanate de 4-hydroxyphényle à la place de l'isothiocyanate de phényle, et en utilisant comme solvant l'acétonitrile, on obtient le produit attendu sous forme d'un solide fin blanc (rendement = 71 %). F = 210-212 C Example 7

3- (4-hydroxyphenyl) -5-methyl-1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1 but using 4-hydroxyphenyl isothiocyanate instead of phenyl isothiocyanate, and using acetonitrile as the solvent, the expected product is obtained in the form of a solid. fine white (yield = 71%).

Mp = 202-204 C Example 8 3-ethyl-5-methyl-1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1 but using ethyl isothiocyanate instead of phenylisothiocyanate, the expected product is obtained in the form of a white solid (yield = 64%).

EXAMPLE 9 5-Methyl-1- (4-phenoxyphenyl) -3- (2-propenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1, but using allylisothiocyanate in place of phenylisothiocyanate, the expected product is obtained in the form of a beige solid (yield = 58%).

F = 77C

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Example 10 5-Methyl-3- (4-phenoxyphenyl) -1-phenyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1, but using as starting products N-phenylalanine and 4-phenoxyphenyl isothiocyanate, the expected product is obtained in the form of a white powder (yield = 83%).

Mp = 132 ° C Example 11 5-methyl-1-phenyl-3- [4- (phenylthio) phenyl] -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 10, but using the isothiocyanate obtained according to Preparation II as starting material, the expected product is obtained in the form of a white powder (yield = 42%).

Mp = 136-138 ° C Example 12 1- (4-Methoxyphenyl) -5-methyl-3- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1, but using N- (4-methoxyphenyl) alanine and 4-phenoxyphenyl isothiocyanate as starting products, the expected product is obtained in the form of white crystals (yield = 92%). .

Mp: 208-210 ° C Example 13 1- [4- (4-Fluorophenoxy) phenyl] -5-methyl-3-phenyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1, but using as starting material the acid obtained according to Preparation III, the expected product is obtained in the form of a white powder (yield = 15%).

Mp = 145 ° C. EXAMPLE 14 1- [4- (4-Hydroxyphenoxy) phenyl] -5-methyl-3-phenyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1, but using as starting material the compound obtained according to Preparation IV, the expected product is obtained in the form of a white powder (yield = 53%).

F = 106-108 ° C

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Example 15 1- [4- (4-Hydroxyphenoxy) phenyl] -3- (4-methoxyphenyl) -5-methyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 14, but using 4-methoxyphenyl isothiocyanate instead of phenyl isothiocyanate, the expected product is obtained in the form of a fine white solid (yield = 15%). .

Mp = 196-198 ° C Example 16 5-Methyl-3-phenyl-1- [4- (phenylthio) phenyl] -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1, but using as starting material the compound obtained according to Preparation V, the expected product is obtained in the form of light yellow crystals (yield = 47%).

Mp = 84 ° C Example 17 1- (4-Phenoxyphenyl) -3- (2-propenyl) -2-thioxo-4-imidazolidinone
A solution of 2.71 g (10 mmol) of N- [4- (phenoxy) phenyl] glycine ethyl ester in 30 ml of xylene is prepared and 1.2 g (12 mmol) of isothiocyanate are added. allyl and 10 ml of acetic acid. The reaction mixture is heated with stirring for 2 h at 110 ° C. and then concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with dichloromethane. The pure fraction is crystallized from ethyl ether, filtered and dried. The expected product is thus obtained in the form of yellow crystals (yield = 33%).

Mp = 158-160 ° C Example 18 5-Ethyl-1- (4-phenoxyphenyl) -3-phenyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 17, but using as starting material the compound obtained according to Preparation VI, the expected product is obtained in the form of a white powder (yield = 43%).

F = 158-159 ° C

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Example 19 3- (4-Fluorophenyl) -5-methyl-1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
A mixture of 1.29 g (5 mmol) of the acid obtained according to Preparation 1 in 40 ml of acetonitrile is prepared. Triethylamine (1.14 ml, 8.4 mmol) was added (a solution was obtained), followed by the addition of 1.15 g (7.5 mmol) of 4-fluorophenyl isothiocyanate. The reaction mixture is stirred for 15 h at room temperature and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel, eluting with a cyclohexane / ethyl acetate mixture (9/1, v / v). The expected product is obtained in the form of a powder (yield = 16%).

Mp = 150 ° C Example 20 3- (3-Fluorophenyl) -5-methyl-1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using as starting material 3-fluorophenyl isothiocyanate, in dichloromethane, the expected product is obtained in the form of white crystals (yield = 65%).

3-(3,4-diméthoxyphényl)-5-méthyl-1 -(4-phénoxyphényl)-2-thioxo-4-imidazolidinone
En opérant de façon analogue à l'exemple 19, mais en utilisant comme produit de départ l'isothiocyanate de 3,4-diméthoxyphényle dans le dichlorométhane, on obtient le produit attendu sous forme d'un solide blanc (rendement = 74 %). F = 116 C Example21

3- (3,4-Dimethoxyphenyl) -5-methyl-1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using as starting material 3,4-dimethoxyphenyl isothiocyanate in dichloromethane, the expected product is obtained in the form of a white solid (yield = 74%).

Mp = 156 ° C Example 22 3- (3,4-Methylenedioxyphenyl) -5-methyl-1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, starting from 3,4-methylenedioxyphenyl isothiocyanate, in dichloromethane, the expected product is obtained in the form of a white powder (yield = 73%).

 F = 185 C

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Example 23 3- (Cyclopentyl) -5-methyl-1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
Operating in a similar manner to Example 19, but using as starting material cyclopentyl isothiocyanate, the expected product is obtained in the form of white crystals (yield = 35%).

Mp = 99 ° C Example 24 3- (2-Methoxyethyl) -5-methyl-1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using as starting material 2-methoxyethylisothiocyanate, in ethanol, the expected compound is obtained in the form of an orange gummy product (yield = 76%). .

 1 H NMR (300 MHz, CHCl 3): 7.4 (m, 2H); 7.33 (m, 2H); 7.19 (m, 1H); 7.08 (m, 4H); 4.42 (q, 1H); 4.13 (t, 2H); (t, 2H); (s, 3H); (d, 3H).

Example 25 3- (2-hydroxyethyl) -5-methyl-1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
A solution of 1.5 g (4.21 mmol) of the compound obtained according to Example 24 is prepared in 75 ml of dichloromethane. The mixture is cooled to -70 ° C. and 16.8 ml (16.8 mmol) of a standard solution of boron tribromide in dichloromethane are added. The reaction medium is stirred at -70 ° C. for 15 min and then at 0 ° C. for 2 h, and then poured into 500 ml of water. The mixture obtained is extracted with 500 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with a dichloromethane / diethyl ether mixture (80/20; v / v). The expected product is obtained in the form of white crystals (yield = 29%).

Mp = 120 ° C Example 26 to 5-methyl-3- [2- (4-morpholinyl) ethyl] -1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using as starting material 2- (4-morpholinyl) ethylisothiocyanate, the expected product is obtained in the form of a white foam (yield = 58%).

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 1 H NMR (300 MHz, DMSO): 7.47 (m, 4H); 7.14 (m, 5H); 4.90 (q, 1H); 3.90 (t, 2H); 3.5 (m, 4H); 2.54 (m, 6H); 1.25 (d, 3H).

Example 26b 5-methyl-3- [2- (4-morpholinyl) ethyl] -1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone hydrochloride
A solution of 0.27 g (0.656 mmol) of the compound obtained according to Example 26a in 20 ml of diethyl ether and 2 ml of ethanol is prepared and 0.7 ml of a normal solution of hydrogen chloride in ethyl ether. A white precipitate forms. 25 ml of ethyl ether are added and the precipitate is then isolated by filtration. The solid is washed on the filter with 2 times 5 ml of ethyl ether and then dried.

0.27 g of the expected product is thus obtained in the form of fine white crystals (yield = 94%).

Mp = 246 ° C Example 27 a 5-methyl-3- [3- (4-morpholinyl) propyl] -1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using as starting material 3- (4-morpholinyl) propyl isothiocyanate, the expected product is obtained in the form of a pale yellow oil (yield = 61%). .

1 H NMR (300 MHz, DMSO): 7.45 (m, 4H); 7.08 (m, 5H); 4.86 (q, 1H); 3.82 (t, 2H); 3.68 (m, 4H); 2.33 (m, 6H); (m, 2H); 1.26 (d, 3H).

Example 27b 5-methyl-3- [3- (4-morpholinyl) propyl] -1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone hydrochloride
By following a procedure analogous to Example 26b, but using as starting material the compound obtained according to Example 27a, the expected product is obtained in the form of white crystals (yield = 84%).

F = 140 ° C

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Example 28 5-methyl-1- (4-phenoxyphenyl) -3- (pyridinyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using 3-pyridinyl isothiocyanate as starting material, the expected product is obtained in the form of a white foam (yield = 68%).

1 H NMR (300 MHz, DMSO): 8.63 (m, 2H); 7.88 (m, 1H); 7.50 (2m, 5H); 7.17 (2m, 5H); 5.07 (q, 1H); 1.39 (d, 3H).

Example 28b 5-Methyl-1- (4-phenoxyphenyl) -3 - (- pyridinyl) -2-thioxo-4-imidazolidinone hydrochloride
By following a procedure analogous to Example 26b, but using as starting material the compound obtained according to Example 28a, the expected product is obtained in the form of white crystals (yield = 96%).

Mp = 140 ° C Example 29 5-methyl-1- (4-phenoxyphenyl) -3- (phenylmethyl) -2-thioxo-4-imidazolidinone
Operating in a similar manner to Example 19, but using as starting material benzyl isothiocyanate, the expected product is obtained in the form of an oil which then crystallizes (yield = 57%).

Mp = 62 ° C Example 5,5-dimethyl-3- (4-methoxyphenyl) -1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using as starting materials the acid obtained according to Preparation VII and 4-methoxyphenylisothiocyanate, the expected product is obtained in the form of white crystals (yield = 32%).

Mp = 144 ° C Example 31 1- (4-Phenoxyphenyl) -3-phenyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 17, but using as starting materials the ethyl ester of N- (4-phenoxyphenyl) glycine, and

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 phenyl isothiocyanate, the expected product is obtained in the form of a white powder (yield = 84%).

Mp = 213 ° C Example 32 5-Methoxy-1- (4-phenoxyphenyl) -3-phenyl-2-thioxo-4-imidazolidinone
A solution of 0.4 g (1.1 mmol) of the compound obtained according to Example 31 in 60 ml of carbon tetrachloride is prepared and 0.22 g (1.22 mmol) of N-bromosuccinimide is added. The reaction medium is then stirred for 1 hour under reflux of the solvent. After cooling to room temperature, 50 ml of methanol are added, the mixture is stirred for 15 min and then concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with dichloromethane. The product obtained is crystallized from ethyl ether, filtered and dried. The expected product is obtained in the form of light orange crystals (yield = 87%).

Mp = 164 C Example 33 5-Fluoro-1- (4-phenoxyphenyl) -3-phenyl-2-thioxo-4-imidazolidinone
A solution of 0.5 g (1.33 mmol) of the compound obtained according to Example 47 in 10 ml of dichloromethane is prepared and 0.53 ml of (diethylamino) sulfur trifluoride are added. The reaction mixture is stirred for 10 min and then concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel, eluting with a dichloromethane / cyclohexane (6/4, v / v) mixture. The expected product is obtained in the form of beige crystals (yield = 63%).

Mp = 126 C Example 34 3,5-Diphenyl-1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using as starting products α - [(4-phenoxyphenyl) amino] benzeneacetic acid and phenylisothiocyanate, the expected product is obtained in the form of a white powder ( yield = 20%).

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F = 100 C Example 35 1- (4-Phenoxyphenyl) -3-phenyl-5-phenylmethyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using as starting material the acid obtained according to Preparation IX and phenyl isothiocyanate, the expected product is obtained in the form of a fine white solid (yield = 30%). %).

Mp = 36 ° C Example 36 1- [4- (4-Fluorophenoxy) phenyl] -3- (4-hydroxyphenyl) -5-methyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 17, but using as starting materials the compound obtained according to Preparation X and 4-hydroxyphenylisothiocyanate in toluene, the expected product is obtained in the form of white crystals (yield = 30%). ).

Mp = 148 ° C Example 37 1- [4- (4-Fluorophenoxy) phenyl] -3- (4-methoxyphenyl) -5-methyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 36, but using as starting material 4-methoxyphenylisothiocyanate, the expected product is obtained in the form of white crystals (yield = 40%).

Mp 38 ° C Example 38 1- [4- (3-Chlorophenoxy) phenyl] -5-methyl-3-phenyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1, but using as starting material the acid obtained according to Preparation XI, the expected product is obtained in the form of a white fluffy solid (yield = 70%).

 F = 156 C

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Example 39 1- [4- (2-Chlorophenoxy) phenyl] -5-methyl-3-phenyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using as starting material the compound obtained according to Preparation XII and phenyl isothiocyanate, the expected product is obtained in the form of a white powder (yield = 25%).

Mp = 108 C Example 40a 1- [4- [3- (Dimethylamino) phenoxy] phenyl] -5-methyl-3-phenyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 17, using as starting products the ester obtained according to Preparation XIII and phenyl isothiocyanate in toluene, the expected product is obtained in the form of a beige powder (yield = 33 %).

Mp = 135 ° C Example 40b 1- [4- [3- (dimethylamino) phenoxy] phenyl] -5-methyl-3-phenyl-2-thioxo-4-imidazolidinone, hydrochloride
0.32 g (0.76 mmol) of the compound obtained according to Example 40a are dissolved in 5 ml of a standard solution of hydrogen chloride in ethanol at 0 ° C. The solution obtained is then poured slowly. on 30 ml of ethyl ether cooled to 0 C. The precipitate formed is separated by filtration and then dried under vacuum. The expected product is obtained in the form of a white powder (yield = 91%).

41-41 ° C. EXAMPLE 41 1- [4- [4- [2- (Diethylamino) -1-oxoethoxy] phenoxy] phenyl] -3- (4-methoxyphenyl) -5-methyl-2-thioxo-4-imidazolidinone , hydrochloride
A mixture of 1 g (2.38 mmol) of the compound obtained according to Example 15.0.24 g of triethylamine and 0.23 g of ethyl chloroformate in
100 ml of dichloromethane. The mixture is stirred for 30 min at room temperature and then 0.28 g of N, N-diethylglycine is added. After 24 hours stirring at room temperature, the reaction mixture is poured into 50 ml of water. The organic phase is separated and the aqueous phase is extracted with 40 ml of dichloromethane.

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 The combined organic phases are washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The semi-solid residue is taken up in 25 ml of ethyl acetate and 2.5 ml of a normal solution of hydrogen chloride in ethyl ether are added. The precipitate obtained is separated by filtration, rinsed with 4 ml of ethyl ether and dried under vacuum. The expected product is thus obtained in the form of pale yellow crystals (yield = 96%).

Mp = 120 ° C Example 42 5-methyl-1- (4-phenoxyphenyl) methyl-3-phenyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 40a, but using as starting material the ester obtained according to Preparation XIV, the expected product is obtained in the form of white crystals (yield = 86%).

Mp = 122 C EXAMPLE 43 5-Methyl-1- (2-phenoxy-5-pyridinyl) -3-phenyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using as starting materials the acid obtained according to Preparation XV and phenyl isothiocyanate, the expected product is obtained in the form of white crystals (yield = 25%).

Mp = 156 ° C Example 44 5-methyl-3- (4-phenoxyphenyl) -1-phenylmethyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using as starting material N- (phenylmethyl) alanine and 4-phenoxyphenyl isothiocyanate, the expected product is obtained in the form of an off-white powder (yield = 50%). ).

Mp = 138 ° C Example 45 5-methyl-3- (3-phenoxyphenyl) -1- (2-propenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 17, but using as starting products the ethyl ester of N- (2-propenyl) alanine and 3-phenoxyphenyl isothiocyanate, the expected product is obtained in the form of crystals. white (yield = 77%).

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Mp. 46 ° C Example 46 3- (4-Nitrophenyl) -1- (4-phenoxyphenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 19, but using as starting material N- (4-phenoxyphenyl) glycine and 4-nitrophenylisothiocyanate, the expected product is obtained in the form of a beige powder (yield = 40%). .

Mp = 204 ° C Example 47 5-hydroxy-1- (4-phenoxyphenyl) -3-phenyl-2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 32, but treating the brominated derivative with water to replace methanol, the expected product is obtained in the form of pale orange crystals (yield = 61%).

F = 160 C
The chemical structures of the compounds described above are summarized in Table 1 below.

 Table 1 groups together Examples 1 to 47 previously described.

 Table II groups together other examples of compounds 48 to 137, obtained according to methods of preparation similar to those used to obtain examples 1 to 48. The letters A and E indicating the method of preparation respectively correspond to the methods of the examples. 1 (from an acid) and 18 (from an ester).

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TABLE I

EX Ri R2 R3 R4 \# / \# / \ # / CH3 H (S) CH 3 H \# / \# / \/ CH3H \ # / \ / ~ CH3 H 0- CH3 H 0- --- 0-CH, CH3 H Q CH3 H /~\o~/~\. ~TA 0H -0-OH CH3 H \ / \ / C2Hs CH3 H \~~/ \~~/ CH2 CH-CHZ CH3 H

## STR2 ## CH, CH3 HQ CH3 H / ~ \ o ~ / ~ \. ~ TA 0H -0-OH CH3 H \ / \ / C2Hs CH3 H \ ~~ / \ ~~ / CH2 CH-CHZ CH3 H

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~~1 -f0r\ CH3 \~/ \~/ \~/ CH3 (l- -C>S-o CH3 CHb H3 0 y./'"\ Bzz3 12 3 \~/ \ / CH3 H 13 F-0-- -y CH3 13 H / \ bzz \~/ CHa 14 H0 \ / \ / \ / CH3 H 15 Ho o o-cH3 CH3 H 16 \ / s \ / CH3 H 17 \ / \ / CHz CH-CH2 H H 18 0- -0 - 7 19 / \ o F CH3 H CH3 20 \ # / \# / -c CH3

~~ 1 -f0r \ CH3 \ ~ / \ ~ / \ ~ / CH3 (l- -C> So CH3 CHb H3 0 y ./ '"\ Bzz3 12 3 \ ~ / \ / CH3 H 13 F-0-- CH 3 H 15 CH 3 H 16 CH 3 H 16 CH 3 H 17 CH 3 H 17 CH 3 CH 2 CH 2 - -0 - 7 19 / \ o F CH3 H CH3 20 \ # / \ # / -c CH3

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f\0Jr\ o-cH3 CH3 0- CH3 CH3 H -CH3 22 W/ 0 \=/ ~7 CH3 H 23 \~/ \~/~ ######( CH3 H 24 \~/ \~/ CHz CH2 0-CH3 CH3 H 25 \ / \ / CHZ CH2 O-H CH3 H 26b / \ o (CH2# il P CH3 H (HC1) 27b \,)" '(,J' ( cH2 > 3 CH3 H (HC1) <Y -)77 28b 28b '='~~~~~~~'=' (HCl) 29 / \ CH2--e CH3 30 / \ o / \ / \ o-cH3 CH3 CH3

f \ 0Jr \ o-cH3 CH3 0- CH3 CH3 H -CH3 22 W / 0 \ = / ~ 7 CH3 H 23 \ ~ / \ ~ / ~ ###### (CH3 H24 \ ~ / \ ~ / ## STR5 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## EQU1 ##

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~~~\ / \ -J~\ 31 \ / \ / ~/ H H 32 / \ OCH3 H 7 f\0Jr\ -0 34 f~\0\ -ry ç*\ T CH2 36 F / \ o oH CH3 H 37 F / \ o o-cH3 CH3 cl 38 y~\~ ~jf~\ \=y CH3 H 39 0 \ # / CH3 H

~~~ \ / \ -J ~ \ 31 \ / \ / ~ / HH 32 / \ OCH3 H 7 f \ 0Jr \ -0 34 f ~ \ 0 \ -ry ç * \ T CH2 36 F / \ o oH CH3 ## EQU1 ## where ## STR2 ##

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40a (CH3) QO-C> 2 ~/ CH3 H N ( CH3 ) 2 40b 0 CH3 N (CH3) 2 (HC1) 0 41 S# ≤ .# 'W. /; ~~~ CH H o-v / \ / OMe (HC1) f\0Jr\Cîl - CH3 42 2 \~/ CH3 H <A-0~A~ #f~\ CH3 N # / / ~ CH3 44 / \ CH2 \~/ \~/ CH3 H 45 ch=ch-ch# \~/ \~/ CH3 H 46 /yo~\~ ~~/~\ N0 H H 47 \~/~0~\~/ -0 HO H

40a (CH3) QO-C> 2 ~ / CH3 HN (CH3) 2 40b 0 CH3 N (CH3) 2 (HCI) O 41 S # ≤. # 'W. /; ## EQU1 ## where ## STR2 ## ~ / \ ~ / CH3 H 45 ch = ch-ch # \ ~ / \ ~ / CH3 H 46 / yo ~ \ ~ ~ ~ / ~ \ N0 HH 47 \ ~ / ~ 0 ~ \ ~ / -0 HO H

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Ex. RI R2 R3 R4 F C aspect rdt méthode 48 0 fi H H'c / 168 blanche 62 ci blanche 49 0 I 1 H, c '\ c""'- 195 poudre 30 E blanche i i "-'-t-' 50 (r 'Q H,c:y H c' 204 poudre blanc- 40 cassé 51 c I 0 H '\C.....- 130 poudre 51 E blanche 52 >11 0 -' '\ c""'- '\ c""'- 113 poudre blanc- 12 -\ cassé 53 '## JT T) H H . 148 poudre blanc- 148 cassé 0 H,CX? .....- .....- poudre CI% 238 blanche 55 çcCR, 1 .;-:; CHs 0 I '3C/ '3C/ 78 cristaux blancs 83 CH, TABLE II

Ex. R1 R2 R3 R4 FC aspect rdt method 48 0 fi H H'c / 168 white 62 ci white 49 0 I 1 H, c '''' - 195 powder 30 E white ii "-'- t- ' 50 white powder broken 51 white powder 51 white powder 52 white powder white powder broken white powder broken white 0 H, CX? .....- .....- powder CI% 238 white 55 cc, 1 CH 3 CH 3 C / 78 white crystals 83 CH,

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Ex. R, R2 R3 R4 F C aspect rdt méthode 56 çcc " \ 0 \ H,c / 157 blanche 75 A N blanche CH, C- MS(] H H,c )00 poudre jaune 77 clair 58 aS'Q CHZ H xjc/ .os solide jaune 28 \ pale 59 I 0 I H H,c/ 144 Poudre 86 A -- -\ J≤ #. blanche 60 l 0 CH2 H 3 RMN huile incolore 41 A 60 61 CY Yl H,C H tc/ 174 poudre}aune 50 A \ claIr clair 62 c fTT) H H 128 poudre 67 E / %/ blanche 63 i XTU H H 181 Poudre 19 blanche CH,

Ex. R, R2 R3 R4 FC aspect rdt method 56 white, white 75 AN white CH, C-MS (] HH, c) 00 yellow powder 77 light 58 aS'Q CHZ H xjc / yellow solid 28 HH, c / 144 Powder 86 A white 60 l 0 CH 2 H 3 NMR colorless oil 41 A 60 61 CY Yl H, CH tc / 174 powder 50 A clear crystal 62 c (TT) HH 128 powder 67 E /% / white 63 i XTU HH 181 Powder 19 white CH,

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Ex. R, R2 R3 R4 FOC aspect rdt méthode 64 N V H H 155 moussejaune 71 A 65 Q ÀfS'O H,c H,o 193 poudre 50 blanche 66 Cl"Q Àf 'O H H, c 141 poudre blanc- 59 141 cassé ,anc- casse Y') i 67 I I H H 192 poudre beige 57 A 68 (ï Uk \ I ci H c 120 Poudre 49 \ > blanche 69 - N V c oc 65 solide blanc 62 E 70 s f") "' c./ 174 paillettes 30 V /0 174 blanches 71 0 \ CN C/ / 168 Poudre 71 \ blanche 72 s 165 poudre rouge- cf /0 165 marron

Ex. R, R2 R3 R4 FOC aspect method 64 NVHH 155 foam yellow 71 A 65 Q AO H, c H, o 193 powder 50 white 66 Cl "Q A 'OHH, c 141 powder white-59 141 broken, anc Y ') Y IIHH 192 beige powder 57 A 68 HK 120 Powder 49 white 69 NV white 65 solid white 62 70 70 70 70 V / 0 174 white 71 0 \ CN C / / 168 Powder 71 \ white 72 s 165 red powder-cf / 0 165 brown

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Ex. RI R2 R1 R4 F C aspect rdt méthode 73 I 0 I 1 154 poudre 82 A A. HiJ blanche -- CfX} 100 poudre 85 E N V H,c 100 blanche 73 1 1 1 H C 150 poudre 47 A blanche 76 nr'n I NO, c- H, c./ 212 Poudre 86 - " /5> blanche 77 I 0 I # t-t3c 77 poudre jaune 69 A 78 / 'Q jQfY) 242 blanahe 51 '\ blanche f1 Yi) RMN 79 j oN H H 79 mousse jaune 96 A 80 Ok "0 H c/ RMN mousse 93 A s/v 0- 80 blanche 81 CL I I c c RMN ""pair"6 40 A

Ex. R1 R2 R1 R4 FC aspect method 73 I 0 I 1 154 powder 82 A A. HiJ white - CfX} 100 powder 85 ENVH, c 100 white 73 1 1 1 HC 150 powder 47 A white 76 nr'n I NO, c-H, c / 212 Powder 86 - "/ 5> white 77 I 0 I # t-t3c 77 yellow powder 69 A 78 / 'Q jQfY) 242 white 51' white f1 Yi) RMN 79 jON HH 79 foam yellow 96 A 80 Ok "0 H c / NMR foam 93 A s / v 0- 80 white 81 CL II cc RMN""pair" 6 40 A

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Ex. Ri RZ R3 R4 F C aspect rdt méthode 82 c/ 'Q 1 H,c H,c 202 poudre ' blanche fi( 'f') r01( '-#, cristaux 83 V N H H 184 floconneux 60 A oranges 84 0 / C1 H ./' 185 solide blanc- 68 casse Cl f'( Yj1 164 solide blanc 85 ""fl rï0X) H H .64 cotonneux 64 A // / cotonneux 0 /\ X\ 86 # / H H 96 coton blanc 50 A 87 I 0 I /0 H H 194,5 poudre beige 33 A 0 # v ^ 206 colle blanche 88 kJ kA. 01 H'C 206 colle blanche 50 A 89 Lj Li 0 H H 148 coton beige 50 A 90 a 'Ov \ 0 \' 5C/ ,34 Poudre 78 / /\/ yy blanche

Ex. R1 R3 R3 R4 FC Aspect Method 82 C / H, C H, C 202 White Powder, Crystals 83 VNHH 184 Flaky 60 A Oranges 84 0 / C1 H. 185 white solid-68 case C1 white solid white 85 cm HH .64 cottony 64 A // / cottony 0 / \ X \ 86 # / HH 96 white cotton 50 A 87 I 0 I / 0 HH 194.5 beige powder 33 A 0 # v ^ 206 white glue 88 kJ kA 01 H'C 206 white glue 50 A 89 Lj Li 0 HH 148 beige cotton 50 A 90 a 'Ov \ 0 \' 5C /, 34 Powder 78 / / \ / yy white

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Ex. RI RZ R3 R4 F C aspect rdt méthode 91 f T T ÀYCI c/ H.c" 170 blanche 27 A k ' ' blanche CI NS'n 92 ci N V H Ilc 132 poudre blanc 50 A 165 poudre beige 93 ()'Q ÀYCI H H 165 poudre beige 38 A 94 cl i s Hr' Hf 154 poudre 45 Icc lac 154 blanche 95 / 'Q À)s'(J H /' 194 Poudre 53 \- blanche 96 ""Ck À) '(J 184 poudre 184 blanche "f") CH RMN 97 V H Il C 97 huile 92 98 H,c/o1 ""= y "0 H H 167 poudre j*aune 25 A \ \ pâle f f!) \-CH, RMN 99 o CHZ H Ilc/' RMN huile incolore 53 A 100 II, oN H C/ 59 poudre beige 40 A

Ex. RI RZ R3 R4 FC aspect method 91 f TT YYCI c / Hc "170 white 27 A white CI NS'n 92 ci NVH IIc 132 powder white 50 A 165 powder beige 93 () 'Q AYCI HH 165 powder beige 38 A 94 cl is Hr 'Hf 154 powder 45 Icc lac 154 white 95 /' Q A) s' (JH / '194 Powder 53 \ - white 96 "" Ck To)' (J 184 powder 184 white "f ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## colorless oil 53 A 100 II, oN HC / 59 beige powder 40 A

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Ex. RI R2 R3 R4 roc aspect rdt méthode 101 I o NCN ./' 184 blanche 102 Cl'Q H H ./' 141 poudre A 102 Ó blanche 0 103 'Y1 N 0 H H,c- 148 poudre beige 20 A 104 0 /0 HO./' I\C./' 176 poudre 104 176 blanche 105 0 H HjC/ RMN huile 35 105 HjC 105 huile 106 Ov (YsYil I\C./' . cristaux jaune 146 pale 64 107 oN H ""3 RMN 107 huile trouble 83 A

Ex. R1 R2 R3 R4 rd appearance method 101 I NCN. / '184 white 102 Cl'Q HH ./' 141 powder A 102 Ó white 0 103 'Y1 N 0 HH, c- 148 beige powder 20 A 104 0 H 2 O / H NMR (CDCl 3), H 2 O 5 HCl, O-H 2 O 5 HCl, O-HCl, O-HCl, O-HCl, O-HCl, O-HCl, O-HCl, O-HCl 3 NMR 107 cloudy oil 83A

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Ex. R, RZ R3 R4 F C aspect rdt méthode 108 F'C IIJL oN H,c 1\c '28 cristaux blancs 44 A 109 C# XXO H 1\c/ RMN huile 50 E 110 (T'Y)! H C/ 168 Poudre 92 A V N....... Cl\ (*) blanche 111 C X i / 234 poudre blanc 88 A 111 V /0 (*) casse 111 r N ill H S 205 poudre 90 112 U kA (*) blanche 90 113 CT XX jf h'c'X 240 poudre jaune 60 113 V /=5 240 pale 114 fT Yl! jcTl H , 189 poudre 55 114 \ \ /V 1\c 189 blanche 115 a r5*" 188 poudre c 188 blanche ti6 fT T"l. XTfC1 60 hUilT 63 E / Vx/ cristallise ('y 'Y') "RMN 1 17 \ \ fil H H,C Il? huile marron 81 A

Ex. R, RZ R3 R4 FC aspect method 108 F'C IIJL oN H, c 1 \ c '28 white crystals 44 A 109 C # XXO H 1 \ c / NMR oil 50 E 110 (T'Y)! HC / 168 Powder 92 AV N ....... Cl \ (*) white 111 CX i / 234 white powder 88 A 111 V / 0 (*) breakage 111 r N ill HS 205 powder 90 112 U kA (* ) White 90 113 XX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX White powder, white powder, white powder, white powder and white powder. XTfCl1 60HuILT 63 E / Vx / Crystallize ('Y' Y ') 1H NMR 1 HH, C, 81A brown oil

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Ex. R, R2 R3 R4 F C aspect rdt méthode 118 nr tl ÍLul\u- , H fiC/ 243 poudraesbéanc- 71 A V V\ Li (*) casse 119 I 0 I fX H fic/ 195 poudre blanc- 10 A s/ -\ /t/ casse 120 CYX1 d H fi c/ 236 blanche 39 A %/ %\ /> blanche 121 ry rx '[(0,- '" 50 mousse 63 a fi blanche 122 (T Ï1. \ F, H fic/ 128 poudre beige 100 A V V\ // rosée 0 123 LJJ LJ) N-.../ H fic/ 154 solide marron 34 A 124 Qr Xl jf! F 118 poudre bzz V V\ F 118 blanche MeOY'îl 125 V N H fi C 192 cristaux blancs 51 A 126 f J F II L JJ. H "3 175 cristaux blancs 72 A

Ex. R, R2 R3 R4 FC Aspect Method 118 ## EQU1 ## ## EQU1 ## ## ############################################################################################################### \ / t / breaks 120 CYX1 d H fi c / 236 white 39 A% /% \ /> white 121 ry rx '(0, -' 50 foam 63 a fi white 122 (T Ï1. \ F, H fic / 128 beige powder 100 AVV \ // dew 0 123 LJJ LJ) N -... / H fic / 154 solid brown 34 A 124 Qr Xl jf! F 118 powder bzz VV \ F 118 white MeOY'îl 125 VNH fi C 192 white crystals 51 A 126 f JF II L JJ. H "3 175 white crystals 72 A

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Ex. Ri R2 R3 R4 F C aspect rdt méthode 127 I N H IJ:.c"""" 76 cristaux blancs 70 A 128 V N H IJ:.c"""" 183 cristaux blancs 66 A 129 V M H IJ:.c"""" 160 cristaux blancs 66 A Chez fYoYil 130 CT XX, N H c 165 cristaux blancs 42 A 131 1 1 1 71 H ne 155 cristaux blancs 63 A ci fYOYil H,C 132 I I H IJ:.C 155 cristaux blancs 61 A 133 I 0 0 H x3c 143 .poudre 74 A 5t/ %/x ##'cf-, IJ:. jaunâtre O F 134 I I H H3 130 solide jaune 80 A 0 \. RMN 135 (j( Xj\ oH H IJ:.c 135 sirop pâteux 8,5 (***)

Ex. R1 R2 R3 R4 FC aspect rdt method 127 INH IJ: .c """" 76 white crystals 70 A 128 VNH IJ: .c """" 183 white crystals 66 A 129 VMH IJ: .c """" 160 white crystals 66 A In fYoYil 130 CT XX, NH c 165 white crystals 42 A 131 1 1 1 71 H ne 155 white crystals 63 A ci fYOYil H, C 132 IIH IJ: .C 155 white crystals 61 A 133 I 0 0 H x3c 143 .powder 74 A 5t /% / x ## 'cf-, IJ :. yellowish OF 134 IIH H3 130 yellow solid 80 A 0 \. NMR 135 (H): 135 pasty syrup 8.5 (***)

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Ex. R, Rz R3 R4 F C aspect rdt méthode 136 h i )Y 0 H C;!:\; 138 cristaux blancs 32 A 137 F L \ 0 q 114 cristaux blancs 73 E

Ex. R, Rz R3 R4 FC aspect rdt method 136 hi) Y 0 HC;!: \; 138 white crystals 32 A 137 FL \ 0 q 114 white crystals 73 E

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 (*) Hydrochloride (**) Ex 124: This compound is prepared starting from Example 31, in carbon tetrachloride, by the action of N-fluorobenzenesulphonimide (2 equivalents) and DAST (diethylaminosulfur trifluoride, 3 equivalents) to reflux of the solvent for 10 h, then purification of the crude product by chromatography on silica gel.

(***) Ex 135: This compound is prepared in dichloromethane by the action of thiocarbonyldiimidazole on 3-aminopropanol in the presence of the amino acid obtained according to Preparation 1 and triethylamine, for 24 hours at room temperature, and then purification of the product crude by chromatography on silica gel.

NMR 1 H NMR: (DMSO of 300 MHz): 1.3 (d, 3H); 4.37 (m, 2H); 4.70 (q, 1H); 5.11 (m, 2H); 5.81 (m, 1H); 6.96 (d, 1H); 7.05 (d, 2H); 7.18 (t, 1H); 7.25 (t, 1H); 7.38 (m, 3H); 7.53 (d, 1H).

1H NMR: 1H NMR (DMSO d6, 250 MHz): 4.80 (s, 2H); 4.99 (s, 2H); 6.98 (m, 4H); (t, 1H); 7.39 (m, 7H); 7.69 (d, 2H).

1 H NMR: 1H NMR (DMSO d6, 250 MHz): 1.26 (d, 3H); 4.99 (s, 2H); 5.03 (m, 1H); 6.99 (m, 4H); 7.14 (t, 1H); 7.42 (m, 7H); 7.53 (m, 2H).

NMR 81 MNH: (DMSO d6, 300 MHz): 1.37 (d, 6H); 5.02 (s, 2H); 7.00 (t, 4H); 7.15 (t, 1H); 7.38 (m, 6H); 7.53 (m, 3H).

1H NMR: 1H NMR (DMSO of 300 MHz): (d, 3H); (q, 1H); 4.36 (m, 2H); (d, 1H); 5.12 (dd, 2H); 5.23 (d, 1H); 5.83 (m, 1H); 6.99 (m, 4H); (t, 1H); 7.39 (m, 4H).

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1 H NMR: 1H NMR (DMSO d6, 300 MHz): 1.27 (d, 3H); 4.39 (d, 2H); 5.00 (q, 1H); 5.17 (m, 2H); 5.83 (m, 1H); 7.06 (m, 3H); 7.18 (t, 1H); 7.28 (m, 2H); 7.45 (m, 3H).

1H NMR: 1H NMR (DMSO d6, 300 MHz): 1.17 (d, 3H); (m, 2H); (t, 2H); (q, 1H); 7.08 (d, 4H); 7.31 (m, 6H); 7.46 (m, 4H).

1 H NMR: 1H NMR (DMSO d6, 250 MHz): 1.30 (d, 3H); 4.32 (q, 1H); 4.84 (d, 1H); 4.94 (s, 2H); 5.21 (d, 1H); 6.98 (t, 4H); (m, 1H); 7.32 (m, 9H).

1 H NMR 1 H NMR (DMSO of 300 MHz): (d, 3H); 4.18 (dd, 1H); 4.39 (q, 1H); 4.59 (dd, 1H); 4.90 (s, 2H); 5.27 (dd, 2H); 5.81 (m, 1H); 6.97 (m, 4H); 7.11 (t, 1H); 7.36 (m, 4H).

 1H NMR: 1H NMR (CDCl3, 250 MHz): 0.9 (dd, 6H); 1.83 (m, 3H); 4.66 (q, 1H); 7.09 (m, 4H); 7.12 (t, 1H); 7.38 (m, 6H); 7.50 (m, 3H).

1 H NMR: 1H NMR (CDCl3, 250 MHz): 1.43 (d, 3H); 1.96 (m, 2H); 2.67 (t, 1H); 3.63 (q, 2H); 4.10 (t, 2H); 4.43 (q, 1H); 7.07 (m, 4H); 7.18 (t, 1H); 7.29 (m, 2H); 7.38 (m, 2H).

 The compounds of formula (I) according to the invention have been subjected to pharmacological tests in order to evaluate their potential to reduce the level of blood glucose in the blood.

Experimental protocol
In vivo studies were performed in male C57BL / KsJ-db / db mice from CERJ (Dry Oak Road - BP 5 - 53940 Le Genest St Isle - France).

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 The animals are housed in cages with a filter cover and have free access to irradiated standard food and filtered drinking water. All equipment used (cages, bottles, pipettes and chips) is sterilized by autoclaving, irradiation or soaking in a disinfectant. The room temperature is maintained at 23 2 C. The light and dark cycle is 12 hours.

 During the acclimation period, each animal is marked with an electronic chip implanted under anesthesia by inhalation of a CO2 / O2 mixture.

 Groups of 8 to 10 mice are formed and treatments begin while the animals are 9 to 11 weeks old. The products are suspended in gum arabic at 3% and administered to the animals using a feeding cannula, for 10 days at a rate of two administrations per day, and the morning of the eleventh day. The products are tested at doses below 200 mg / kg, usually 10 mg / kg. The animals in the control group receive the administration vehicle only.

 A blood sample is taken before treatment, then four hours after the last administration of the product. The animals are anesthetized by inhalation of a C02 / 02 mixture, the blood is taken from the retroorbital sinus, collected in a dry tube and kept cold. The serum is separated by centrifugation at 2800 g (15 minutes, 4 C) in the hour following the sampling. Samples are stored at -20 C until analysis.

 The serum glucose and triglyceride levels are determined on Konélab 30 analyzer, using Konélab kits. Animals whose glycemia before treatment was less than 3 g / 1 are systematically excluded from the study.

 For each group, the average levels of glucose and triglycerides after treatment are calculated and the results are expressed as a percentage of variation of these averages with respect to the control group, after verification of the homogeneity of the averages before treatment.

 The experiments carried out on the compounds described in the invention generally show very significant drops in blood glucose and triglyceride levels, with values of up to 60% for blood glucose and 60% for blood glucose.

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 triglycerides. It has also been observed that the treatment with the compounds according to the invention was accompanied by a favorable modification of the lipid parameters.

 The compounds according to the invention can be used as the active principle of a medicament for the treatment of diabetes in mammals and, more particularly, in humans. They can be used to fight against hypertriglyceridemia and diseases caused by an excess of triglycerides in the blood, such as for example atherosclerosis.

 More generally, they may be useful for the prevention or treatment of diseases associated with hyperglycemia or hypertriglyceridemia such as for example type II diabetes, hypertension, dyslipidemia, cardiovascular disease, and obesity; they are also useful for treating diseases caused by microvascular or macrovascular complications in diabetics, in particular in the renal or central nervous system, said complications being generally associated with the metabolic syndrome X. The compounds according to the invention are also useful for treating cerebral ischemia or stroke.

 Pharmaceutical compositions incorporating the compounds according to the invention may be formulated in particular by combination of these compounds with usual non-toxic excipients according to methods well known to those skilled in the art, preferably so as to obtain orally administrable medicaments, for example capsules or tablets. In practice, in the case of administration of the compound orally, the daily dosage in humans will preferably be between 5 and 500 mg. Although formulations in the form of capsules or tablets are preferred for the sake of patient comfort, the compounds according to the invention may also be prescribed in other dosage forms, for example if the patient does not accept or is not in a position to accept solid oral formulations or if the treatment requires a very rapid bioavailability of the active ingredient. It will thus be possible to present the drug in the form of an oral syrup, or in injectable form, preferably subcutaneously or intramuscularly.

Claims (12)

Y represents 0 or N-CH3, - a dibenzofuranyl group, - a (CH2) p-Ar group, in which - p represents 0 or 1, and - Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted by one or a plurality of atoms or groups of atoms selected from halogen, C1-C4 alkyl, hydroxy, nitro, C1-C3 alkoxy, methylenedioxy, ester, trifluoromethyl, trifluoromethoxy, cyano, morpholinyl or the group  - (CH 2) -N m "-1 wherein m is 2 or 3, and

 wherein R1 and R2 independently of each other are - (C1-C5) alkyl, (C1-C4) alkenyl, (C2-C3) hydroxyalkyl, (C1-C3) alkoxyalkyl CS, - a CH2-COOCH3 group, - an N, N-dialkylaminoalkyl group, - a group

 1. Compound derived from 2-thiohydantoin, characterized in that it is chosen from: a) compounds of formula <Desc / Clms Page number 52> C1-C4, with the proviso that at least one of the substituents R1 and R2 comprises in its structure 2 aromatic rings chosen from phenyl or pyridinyl groups, or represents the dibenzofuranyl group and b) the addition salts of the compounds of formula (I) with a nontoxic acid when said compounds of formula (I) comprise a basic salifiable function. C4, C1-C4 alkoxy, hydroxy, phenyl or benzyl, # R4 is hydrogen, halogen, or alkyl.  wherein - A is O or S, - X is C or N and - R5 is hydrogen, halogen, N, N-dialkylamino, C1-C3 alkoxy, or hydroxyl group free or esterified with an amino acid, # R3 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or

 2. Compound according to claim 1, characterized in that it is chosen from: a) compounds of formula:

 in which: # R1 represents - a C3-C4 alkenyl group, - a dibenzofuranyl group, - a (CH2) n-Ar group in which <Desc / Clms Page number 53> Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms selected from halogen, C 1 -C 4 alkyl, hydroxy, nitro, C 1 -C 3 alkoxy, Y represents 0 or N-CH3; a (CH2) p-Ar group, in which p represents 0 or 1, and  (cl2) / - (y) (CH2) m # N Y \ - / in which m represents 2 or 3, and

R5 represents a hydrogen atom, a halogen atom, an N, N-di (C1-C3) alkylamino group, a C1-C3 alkoxy group or a free hydroxy group or esterified with an amino acid, # R2 represents - C1-C5 alkyl, - C3-C4 alkenyl, - C3-C3 hydroxyalkyl, - C3-C5 alkoxyalkyl, -CH2-COOCH3, -N, N-di (C] -C3) alkylamino (C] -C3) alkyl, - a group X represents C or N and, A represents 0 or S,  in which

 n represents 0 or 1, and Ar represents an aromatic phenyl or pyridinyl ring, unsubstituted or substituted by one or more of the atoms or groups of atoms chosen from: halogens, C1-C4 alkyl, nitro, C1-alkoxy groups; -C3, C3-C4 alkoxyalkyl, or the group <Desc / Clms Page number 54> C4, C1-C4 alkoxy, hydroxy, phenyl or benzyl; R4 is hydrogen, halogen or C1-C4 alkyl, with the proviso that at least one of the substituents R 1 and R 2 comprises in its structure 2 aromatic rings chosen from phenyl or pyridinyl groups or that R 1 represents the dibenzofuranyl group. B represents 0 or S; # R3 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group  in which

 methylenedioxy, ester, trifluoromethyl, trifluoromethoxy, cyano, morpholinyl or the group  3. Compound according to one of claims 1 or 2, characterized in that one of the radicals R1 or R2 represents the phenoxyphenyl or phenylthiophenyl group, the radicals R3 and R4 and the other radical R1 or R2 are as defined in one of claims 1 or 2.  4. Compound of formula (I) according to claim 1, characterized in that R3 represents a methyl group and R4 represents a hydrogen atom or a methyl group.  5. Process for preparing a compound of formula (I) according to any one of claims 1 to 4, characterized in that it comprises the steps of: a) reacting an acid of formula

 in which R 1 and R 4 are as defined above in claim 1 and R 3 represents H, C 1 -C 4 alkyl, phenyl or benzyl, with an isothiocyanate of formula (III), <Desc / Clms Page number 55>  in which R 1, R 2, R 3 and R 4 retain the same meaning as in the starting materials b) if necessary, when the compound of formula (I) obtained above has a basic salifiable function, such as for example an amine, reacting said compound with a mineral or organic acid in an anhydrous solvent to obtain the salt of the compound of formula (I).

 wherein R2 represents a group as defined above in claim 1, in a solvent, at a temperature between 20 C and the boiling point of the solvent, in the presence of an aprotic base and for 1 to 20 hours, to obtain the compound of formula (I)

 6. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 4, characterized in that it consists in: a) reacting an ester of formula (IV)

 in which R 1 and R 4 are as defined in claim 1, R 3 represents H, C 1 -C 4 alkyl, phenyl or benzyl and R represents a C 1 -C 4 alkyl group, preferably a methyl, ethyl or isopropyl group, with an isothiocyanate of formula (III),

<Desc / Clms Page number 56>  wherein R 1, R 2, R 3 and R 4 retain the same meaning as in the starting compounds; b) if necessary, in the case where the compound of formula (I) comprises a basic salifiable function, reacting said compound with an acid to obtain the corresponding salt.

 the reaction being carried out in a solvent, in the presence of a weak acid, at a temperature of between 80 ° C. and the boiling point of the solvent, for 0.5 to 5 hours, to obtain the compound of formula (I)  7. Pharmaceutical composition, characterized in that it contains, in combination with at least one physiologically acceptable excipient, at least one compound of formula (I) according to any one of claims 1 to 4.  A compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof according to any one of claims 1 or 2 as a pharmacologically active substance.  9. Use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of diabetes and diseases due to hyperglycemia.  Use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof as claimed in any one of claims 1 to 4 for the preparation of a medicament for the treatment of hypertriglyceridemia and dyslipidemia.  11. Use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of obesity. . <Desc / Clms Page number 57>  12. Use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of vascular accidents. brain.