FR2845385A1 - 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 or its precursor, 3-5C alkoxyalkyl or (CH2)p-Ar; p = 0 or 1; Ar = phenyl or pyridinyl (both optionally substituted by at least one halo, OH, NO2, CN, 1-3C alkoxy, carboxy, 1-4C alkoxycarbonyl, methylthio, methylenedioxy or a group of formula (i)); X = CH or N; R5 = H, halo, 1-3C alkoxy or OH, and R3, R4 = H or 1-4C alkyl, provided that at least one of R1 and R2 contains two aromatic rings (phenyl or pyridinyl). 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 2-thiohydantoin (or 2-thioxo-imidazolidin-4-one), to a process for their manufacture and to their use as active ingredients for the preparation of medicaments intended in particular 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.

des composés de type 1-(phénylsulfonyl)-2-thiohydantôine ; Il Farmaco, Ed. Bull, 1982, Vol. 30, No. 9, p. 3244-3254 describes the inhibition of aldose reductases by

1- (phenylsulfonyl) -2-thiohydantoin compounds; He 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-phenylthiohydantoins 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; Chem. 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 : # R1 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 C2-C3 , ou l'un de ses précurseurs, tels que le

groupe (tétrahydro-2H-pyran-2-yl)oxy(C2-C3)alkyle, - un groupe alcoxyalkyle en C3-C5, - un groupe (CH2)p-Ar, dans lequel p représente 0 ou 1, et Description
According to the invention, novel compounds are proposed comprising the 2-thioxo-imidazolidin-4-one (or 2-thiohydantoin) ring of formula (I):

in which: # R1 and R2, independently of each other, represent - a C1-C5 alkyl group, - a C3-C4 alkenyl group, - a C2-C3 hydroxyalkyl group, or one of its precursors, such as

(tetrahydro-2H-pyran-2-yl) oxy (C 2 -C 3) alkyl group, - a C 3 -C 5 alkoxyalkyl group, - a (CH 2) p -Ar group, in which p represents 0 or 1, and

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alcoxy(Ci-C4)carbonyl, méthylthio, méthylènedioxy ou

dans lequel
X représente CH ou N,
R5représente un atome d'hydrogène, un atome d'halogène, un groupe alcoxy en Cl-C3, ou un groupe hydroxy, # R3 et R4 représentent, chacun indépendamment, un atome d'hydrogène ou un groupe alkyle en C1-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. Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms selected from halogen, hydroxy, nitro, cyano, C1-C3 alkoxy, carboxyl,

(C1-C4) alkoxycarbonyl, methylthio, methylenedioxy or

in which
X represents CH or N,
R5 represents a hydrogen atom, a halogen atom, a C1-C3 alkoxy group, or a hydroxy group, # R3 and R4 represent, each independently, a hydrogen atom or a C1-C4 alkyl group, with the condition that at least one of the substituents R 1 and R 2 comprises in its structure 2 aromatic rings selected from phenyl or pyridinyl groups.

dans laquelle : ' Ri représente - un groupe alcènyle en C3-C4, - un groupe (CH2)n-Ar dans lequel n représente 0 ou 1, et
Ar représente un noyau aromatique phényle, non substitué ou substitué par un ou plusieurs atomes ou groupes d'atomes choisi (s) parmiles halogènes, les groupes alcoxy en C1-C3, nitro, ou le groupe

A family of preferred compounds according to the invention are the compounds of formula 1:

in which: R1 represents - a C3-C4 alkenyl group, a (CH2) n-Ar group in which n represents 0 or 1, and
Ar represents a phenyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms selected from halogen, C 1 -C 3 alkoxy, nitro, or the group

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' R3 et R4 représentent, chacun indépendamment, un atome d'hydrogène ou un groupe alkyle en Cl-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. in which
X represents CH or N,
R5 represents a hydrogen atom, a halogen atom, a C1-C3 alkoxy group, or a hydroxyl group, # R2 represents a C1-C5 alkyl group, a C3-C4 alkenyl group, a C2-C3 hydroxyalkyl group, or one of its precursors, such as the (tetrahydro-2H-pyran-2-yl) oxy (C2-C3) alkyl group, - a C3-C5 alkoxyalkyl group, a group (CH 2) p-Ar, 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, hydroxy, nitro, cyano, C 1 -C 3 alkoxy, carboxyl, alkoxy (C 1 -C 3) C4) carbonyl, methylthio, methylenedioxy or

R 3 and R 4 each independently represent a hydrogen atom or a C 1 -C 4 alkyl group, with the proviso that at least one of R 1 and R 2 comprises in its structure 2 aromatic rings selected from phenyl groups or pyridinyl.

 Particularly preferred compounds according to the invention are the compounds of formula (I) in which one of the groups R 1 or R 2 represents the (phenylmethyl) phenyl group, R 3 and R 4 and the other group R 1 or R 2 are as defined above .

 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.

 The invention also includes the salts of the compounds of formula (I) when they comprise in their structure a basic salifiable function, such as for example a pyridine group. These salts can be obtained with

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 non-toxic and therapeutically acceptable inorganic or organic acids, especially hydrochloric, sulfuric, phosphoric, methanesulfonic, 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 "C1-C4 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. 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 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.

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

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dans laquelle R1, R3 et R4 sont tels que définis précédemment pour les composés de formule (I), avec un isothiocyanate de formule

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, Rz, R3 et R4 conservent la même signification que dans les produits de départ ; b) si nécessaire, lorsque le composé de formule (I) obtenu ci-dessus comporte une fonction salifiable basique, telle que par exemple une amine, faire réagir ledit composé avec un acide minéral ou organique, dans un solvant anhydre, pour obtenir le sel du composé de formule (I).

in which R 1, R 3 and R 4 are as defined above for the compounds of formula (I), with an isothiocyanate of formula

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 boiling point of 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 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 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).

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)

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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 le composé avec un acide pour obtenir le sel correspondant. Ce procédé sera dénommé ci-après procédé E. in which R 1, R 3 and R 4 are as defined in the preceding process 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),

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, the compound is reacted with an acid to obtain the salt corresponding. This process will be called hereinafter process E.

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 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 base

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 as for example sodium bicarbonate and at a temperature between 60 and 150 C, for 0.5 to 10 hours.

 Preferably, an α-brominated acid is used.

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. 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) Ri-NH 2 (V) in which R 1 is as defined above, with a halogenated ester of formula (VII)

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.

1, l'-thiocarbonyldiimidazole. 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 R 2 -NH 2 with thiophosgene in the presence of a tertiary amine or with the

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. Melting points are measured at the Kofler bench and the spectral values of Magnetic Resonance

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 Nuclear are characterized by the chemical shift 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.

PREPARATION 1 1-Isothiocyanato-4- (phenylmethyl) benzene
A solution of 5 g (27 mmol) of 4- (phenylmethyl) aniline in 20 ml of dimethylformamide is prepared and a solution of 5.7 g (29 mmol) of ethyl acetate is added at 0 ° C. with stirring. Thiocarbonyldiimidazole in 20 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 100 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 thus obtained in the form of an oil which crystallises in the refrigerator (yield = 88%).

F <50 C PREPARATION II N- [4- (phenylmethyl) phenyl] alanine, ethyl ester
3 g (16.4 mmol) of 4- (phenylmethyl) aniline and 4.3 ml (32.7 mmol) of ethyl 2-bromopropanoate are mixed and 2.06 g (24.6 mmol) of bicarbonate are added. sodium. The mixture is stirred for 5 h at 140 ° C., then cooled and taken up in 50 ml of water and 100 ml of ethyl ether. After decantation, the aqueous phase is extracted again with 50 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). There is thus obtained 4.5 g of the expected product in the form of a yellow-orange oil (yield = 97%).

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 1 H NMR (300 MHz, DMSO): (m, 5H); 6.91 (d, 2H); 6.45 (d, 2H); 5.80 (d, 1H); 4.07 (q, 2H); (q, 1H); (s, 2H); (d, 3H); (t, 3H).

PREPARATION III N- [4- (phenylmethyl) phenyl] alanine
2 g (7 mmol) of the ester obtained according to Preparation II are dissolved in 60 ml of dimethoxyethane and 14 ml (14 mmol) of a normal solution of sodium hydroxide are added. The mixture is stirred for 18 hours at room temperature and then partially concentrated under reduced pressure. The residue is taken up in 25 ml of water and then acidified with hydrochloric acid diluted to pH4. The precipitated white solid is separated by filtration, washed with water and then dried under reduced pressure. The expected product is thus obtained in the form of a beige powder (yield = 64%).

F = 119 C PREPARATION IV N- [4-phenylmethyl) phenyl] glycine
A solution of 18.3 g (0.1 mole) of 4-benzylaniline in 150 ml of dimethylformamide is prepared and 20.5 g (0.12 mole) of bromoacetic acid and then 14 ml of triethylamine are added. The reaction mixture is stirred for 24 hours at 100 ° C. and then cooled and poured into 200 ml of ice water. The mixture is extracted twice with 200 ml of ethyl acetate and the combined organic phases are washed and then dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel, eluting with a cyclohexane / ethyl acetate mixture (95/5, v / v). The expected compound is thus obtained in the form of beige crystals (yield = 43%).

Mp = 148 ° C PREPARATION V 2-methyl-N- [4- (phenylmethyl) phenyl] alanine
183 g (1 mole) of 4-benzylaniline and 294 g (3.5 moles) of sodium bicarbonate are intimately mixed in a mortar. The mixture is placed in a reactor equipped with a robust stirrer and 600 g (3 moles) of 2-bromo-2-methylpropanoic acid are added. The mixture is stirred for one hour at 90 ° C., then cooled and poured into 2 liters of cold water. The hydrolysis medium is acidified slowly to pH 4 with concentrated hydrochloric acid. The formed precipitate is separated

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 by filtration, washed with water and dried in a vacuum oven. The expected compound is thus obtained in the form of pale pink crystals (yield = 83%).

Mp = 130 ° C. PREPARATION VI 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 VII N- [4- (4-hydroxyphenylmethyl) phenyl] glycine, ethyl ester A solution of 340 mg (1.71 mmol) of 4 - [(4-aminophenyl) methyl] phenol and 0.28 ml (2) is prepared. 55 mmol) of ethyl bromoacetate in 10 ml of 1,2-dimethoxyethane and 0.36 ml (2.55 mmol) of triethylamine are added.

The reaction mixture is brought to gentle reflux for 1.5 hours and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel, eluting with a toluene / ethyl acetate mixture (9/1, v / v). The expected product is thus obtained in the form of a colorless oil (yield = 62%).

1H NMR: (CDCl3, 300 MHz): (t, 3H); (s, 2H); (s, 2H); (q, 2H); 6.57 (d, 2H); (d, 2H); 7.03 (t, 4H).

PREPARATION VIII N- [4- (4-pyridinylmethyl) phenyl] alanine By following a procedure analogous to Preparation V, starting from 4- (4-pyridinylmethyl) aniline and 2-bromopropanoic acid, the expected product is obtained under oil form (Yield = 17%) 1 H NMR: (DMSO d 6.300 MHz): 1.34 (d, 3H); 3.79 (s, 2H); 3.88 (q, 1H); 6.48 (d, 2H); 6.95 (d, 2H); 7.21 (d, 2H); 8.43 (d, 2H).

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5-méthyl-1-phényl-3-[4-(phénylméthyl)phényl]-2-thioxo-4- imidazolidinone
On prépare un mélange de 165 g (1 mole) de N-phénylalanine et 153 ml de triéthylamine dans 2 1 d'éthanol. La solution obtenue est filtrée sur verre fritté et on ajoute 247,5 g (1,1 mole) du composé obtenu selon la préparation I. Le mélange est agité pendant 18 heures à température ambiante. Le précipité obtenu est séparé par filtration, puis repris en solution dans un mélange dichlorométhane/éthanol. La solution est traitée au charbon actif puis filtrée et partiellement concentrée à l'évaporateur rotatif. Le produit précipité est filtré, lavé à l'éthanol et séché. On obtient ainsi le produit attendu avec un rendement de 36 %. Example 1

5-methyl-1-phenyl-3- [4- (phenylmethyl) phenyl] -2-thioxo-4-imidazolidinone
A mixture of 165 g (1 mole) of N-phenylalanine and 153 ml of triethylamine in 2 l of ethanol is prepared. The solution obtained is filtered on sintered glass and 247.5 g (1.1 moles) of the compound obtained according to Preparation I are added. The mixture is stirred for 18 hours at room temperature. The precipitate obtained is separated by filtration and then taken up in solution in a dichloromethane / ethanol mixture. The solution is treated with activated charcoal, then filtered and partially concentrated on a rotary evaporator. The precipitated product is filtered, washed with ethanol and dried. The expected product is thus obtained with a yield of 36%.

Mp = 123-125 ° C Example 2 5-methyl-3- (2-propenyl) -1- [4- (phenylmethyl) phenyl) -2-thioxo-4-imidazolidinone
A solution of 0.2 g (0.71 mmol) of the ester obtained according to Preparation II in 3 ml of toluene is prepared and 0.6 ml of acetic acid and 0.07 g (0.71 mmol) are added. ) of allyl isothiocyanate. The reaction mixture is maintained at the reflux temperature of the solvent, with stirring, for 5 h and then concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with a cyclohexane / ethyl acetate mixture (95/5, v / v). 160 mg of the expected product are thus obtained in the form of a light yellow solid (yield = 67%).

Mp = 62-64C.

5-méthyl-3-(phényl)-1-[4-(phénylméthyl)phényl]-2-thioxo-4- imidazolidinone
En opérant de façon analogue à l'exemple 1, mais en utilisant comme produit de départ l'acide obtenu selon la préparation III, on obtient le produit attendu sous forme d'un solide fin et léger blanc (rendement = 21 %). Example 3

5-methyl-3- (phenyl) -1- [4- (phenylmethyl) 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 fine, light white solid (yield = 21%).

M.p. 164-166 ° C .;

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Example 4 5-Methyl-3- (4-nitrophenyl) -1- [4- (phenylmethyl) phenyl] -2-thioxo-4-imidazolidinone
A mixture of 0.51 g (2 mmol) of the acid obtained according to Preparation III in 15 ml of acetonitrile is prepared. 0.45 ml (3.3 mmol) of triethylamine and then 0.55 g (3 mmol) of 4-nitrophenylisothiocyanate are added. The reaction mixture is stirred for 15 hours at room temperature and then concentrated 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 thus obtained in the form of a yellow powder (yield = 46%).

Mp = 200 ° C. EXAMPLE 5 3- (4-Chlorophenyl) -5-methyl-1- [4- (phenylmethyl) phenyl] -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 4, but using as starting material 4-chlorophenylisothiocyanate, the expected product is obtained in the form of a yellow solid (yield = 51%).

3-[4-(phénylméthyl)phényl]-1-(2-propényl)-2-thioxo-4-imidazolidinone
On prépare une solution de 2,40 (2 mmoles) d'ester éthylique de la N-(alkyl)glycine dans 25 ml de toluène et on ajoute 0,5 g (2,2 mmoles) d'isothiocyanate obtenu selon la préparation I, et 2,2 ml d'acide acétique. Le mélange réactionnel est chauffé sous agitation à léger reflux du solvant pendant 2 heures, puis concentré sous pression réduite. Le résidu est purifié par chromatographie sur gel de silice en éluant avec du dichlorométhane. On obtient ainsi le produit attendu sous forme d'une poudre beige (rendement = 65 %). F = 144 C Example 6

3- [4- (phenylmethyl) phenyl] -1- (2-propenyl) -2-thioxo-4-imidazolidinone
A solution of 2.40 (2 mmol) of N- (alkyl) glycine ethyl ester in 25 ml of toluene is prepared and 0.5 g (2.2 mmol) of isothiocyanate obtained according to Preparation I is added. and 2.2 ml of acetic acid. The reaction mixture is heated with stirring at light reflux of the solvent for 2 hours and then concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with dichloromethane. The expected product is thus obtained in the form of a beige powder (yield = 65%).

3-phényl-l- [ 4-(phénylméthyl)phényl] - 2-th ioxo-4-imidazolid inone
En opérant de façon analogue à l'exemple 4, mais en utilisant comme produits de départ l'acide obtenu selon la préparation IV et l'isothiocyanate de F = 108 C Example 7

3-phenyl-1- [4- (phenylmethyl) phenyl] -2-thioxo-4-imidazolidone
By following a procedure analogous to Example 4, but using as starting materials the acid obtained according to Preparation IV and the isothiocyanate of

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 phenyl, in ethanol, the expected product is obtained in the form of cream crystals (yield = 20%).

1-[4-(phénylméthyl)phényl]-3-(2-propényl)-2-thioxo-4-imidazolidinone
En opérant de façon analogue à l'exemple 4, mais en utilisant comme produits de départ l'acide obtenu selon la préparation IV et l'isothiocyanate d'allyle on obtient le produit attendu sous forme de poudre blanche (rendement = 85 %). F = 182 C Example 8

1- [4- (phenylmethyl) phenyl] -3- (2-propenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 4, but using as starting materials the acid obtained according to Preparation IV and Allyl isothiocyanate, the expected product is obtained in the form of a white powder (yield = 85%).

3-(4-nitrophényl)-1-[4-(phénylméthyl)phényl]-2-thioxo-4- imidazolidinone
En opérant de façon analogue à l'exemple 4, mais en utilisant comme produits de départ l'acide obtenu selon la préparation IV et l'isothiocyanate de 4-nitrophényle, on obtient le produit attendu sous forme d'une poudre jaune pâle (rendement = 30 %). F = 132 C Example 9

3- (4-nitrophenyl) -1- [4- (phenylmethyl) phenyl] -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 4, but using as starting materials the acid obtained according to Preparation IV and 4-nitrophenylisothiocyanate, the expected product is obtained in the form of a pale yellow powder (yield = 30%).

3-(phénylméthyl)-1-[4-(phénylméthyl)phényl]-2-thioxo-4- imidazolidinone
En opérant de façon analogue à l'exemple 9, mais en utilisant comme produit de départ l'isothiocyanate de benzyle, on obtient le produit attendu sous forme de cristaux blancs (rendement = 57 %). F = 209 C Exempt 10

3- (phenylmethyl) -1- [4- (phenylmethyl) phenyl] -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 9, but using as starting material benzyl isothiocyanate, the expected product is obtained in the form of white crystals (yield = 57%).

3-(4-méthoxyphényl)-i-[4-(phénylméthyl)phényl]-2-thioxo-4- imidazolidinone
En opérant de façon analogue à l'exemple 9, mais en utilisant comme produit de départ l'isothiocyanate de 4-méthoxyphényle, on obtient le produit attendu sous forme de paillettes orange (rendement = 65 %). F = 107 C Example 11

3- (4-methoxyphenyl) -i- [4- (phenylmethyl) phenyl] -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 9, but using as starting material 4-methoxyphenyl isothiocyanate, the expected product is obtained in the form of orange flakes (yield = 65%).

 Mp = 164 ° C

<Desc / Clms Page number 15>

1-[4-(phénylméthyl)phényl]-3-(2-propényl)-2-thioxo-4-imidazolidinone
En opérant de façon analogue à l'exemple 9, mais en utilisant comme produit de départ l'isothiocyanate de 2-propényle, on obtient le produit attendu sous forme d'une poudre blanche (rendement = 27 %). Example 12

1- [4- (phenylmethyl) phenyl] -3- (2-propenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 9, but using as starting material 2-propenyl isothiocyanate, the expected product is obtained in the form of a white powder (yield = 27%).

Mp = 162 C EXAMPLE 13 1-Phenyl-3- [4- (phenylmethyl) phenyl] -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 6, but using as starting material the ethyl ester of N- (phenyl) glycine, the expected product is obtained in the form of a pale yellow powder (yield = 67%). .

Mp = 194 ° C. EXAMPLE 14 1- (4-Chlorophenyl) -3- [4- (phenylmethyl) phenyl] -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 13, but using as starting material the ethyl ester of N- (4-chlorophenyl) glycine, the expected product is obtained in the form of orange crystals (yield = 63% ).

5-méthyl-3-[4-(phénylméthyl)phényl]-1-(2-propényl)-2-thioxo-4- imidazolidinone
En opérant de façon analogue à l'exemple 6, mais en utilisant comme produit de départ l'isothiocyanate de 4-(phénylméthyl)phényle, on obtient le produit attendu sous forme d'une poudre légère blanche (rendement = 78%). F = 153 C Example 15

5-methyl-3- [4- (phenylmethyl) phenyl] -1- (2-propenyl) -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 6, but using 4- (phenylmethyl) phenyl isothiocyanate as starting material, the expected product is obtained in the form of a white light powder (yield = 78%).

3-(4-méthoxyphényl)-5-méthyl-1-[4-(phénylméthyl)phényl]-2-thioxo-4- imidazolidinone
En opérant de façon analogue à l'exemple 2, mais en utilisant comme produit de départ l'isothiocyanate de 4-méthoxyphényle, on obtient le produit attendu sous forme de cristaux blancs (rendement = 75 %). F = 135 C Example 16

3- (4-Methoxyphenyl) -5-methyl-1- [4- (phenylmethyl) phenyl] -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 2, but using as starting material 4-methoxyphenylisothiocyanate, the expected product is obtained in the form of white crystals (yield = 75%).

<Desc / Clms Page number 16>

5,5-diméthyl-3-(4-méthoxyphényl)-l-[4-(phénylméthy!)phényl]-2- thioxo-4-imidazolidinone
En opérant de façon analogue à l'exemple 1, mais en utilisant comme produits de départ l'acide obtenu selon la préparation V et l'isothiocyanate de 4-méthoxy-phényle, on obtient le produit attendu sous forme de cristaux blancs (rendement = 27 %). F = 122 C Example 17

5,5-dimethyl-3- (4-methoxyphenyl) -1- [4- (phenylmethyl) phenyl] -2-thioxo-4-imidazolidinone
By following a procedure analogous to Example 1, but using as starting materials the acid obtained according to Preparation V and 4-methoxyphenylisothiocyanate, the expected product is obtained in the form of white crystals (yield = 27%).

Mp = 162 ° C
The chemical structures of the compounds described above are summarized in Table I below.

 Table II gathers other compounds according to the invention, obtained by preparation methods similar to those described above; in this table are given the melting points (F C), the yields of the preparation as well as the synthesis method used (A by analogy with Example 1, E by analogy with Example 2).

<Desc / Clms Page number 17>

TABLE I

<Tb>
<Tb>
<Tb>

1 <> -<}CH> H3 V 7CHJV / CH2 CH=CH2 CH3 H CHz H3 H 4 < >-CH >- rro2 CH, 7 5 < >-CH >- -o-C1 H3 6 CHfcH-CH2 \ /CHr\ / H H CH.... f\CKJ~\ -CH2CH=CH2 CH # CHrCH=CH2 H \3" chO" No2

## STR1 ## CHr / HH CH .... f \ CKJ ~ \ -CH2CH = CH2 CH # CHrCH = CH2 H \ 3 "chO" No2

<Desc / Clms Page number 18>

C>CH2- -CHz 10 "\#/ \~/ / \ CHZ / \ ##''\-. oMe O CHo- -0-OMe 12 / \ CHz / # -CH2 CH=CHz H H 13 <> -:>CH2 -0 H H 14 c il C>CH2 -e- H H 15 CH, CH-CH, ### C>-CH 2-e>- C"I3 H 16 < }-C}- \ pMe CH3 H 17 / \ CH2 \ -0-ome CH3 CH3

## STR5 ## CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 ## STR2 ## ## STR2 ## ## STR2 ## ### ## ###################################################################################### 17 / \ CH2 \ -0-ome CH3 CH3

<Desc / Clms Page number 19>

Ex Rl R2 R3 R4 F C Aspect Rdt Méth.

Table II

Ex R1 R2 R3 R4 FC Aspect Rdt Meth.

<Tb>
<tb> 18 <SEP>###<SEP>#<SEP>#<SEP>#<SEP> 184 <SEP> Powder <SEP> 56 <SEP> A
<Tb>

\J KJ\ XJ c H,c blanche

\ J KJ \ XJ c H, white c

<Tb>
<tb> 19 <SEP>#<SEP>###<SEP> H <SEP> H <SEP> 232 <SEP> Powder <SEP> 89 <SEP> A
<Tb>

\\ /K? V blanche 20 I "::: l "::: / / 98 Poudre 95 E xc I V H,C H,C blanche 21 A c/ H3C RMN Solide 29 A KJ kA blanc 22 ()Q"': l "': , 185 Poudre 62 A I I /I jaune 23 I w I w , H H 78 Cristaux 58 A J KJ\ /'J blancs 24 /\yv cH3 H / RMN Huile 67 A

\\ / K? V white 20 I ::: I ::: // 98 Powder 95 E xc IVH, CH, C white 21 A c / H3C Solid NMR 29 A KJ kA white 22 () Q "': l"':, 185 Powder 62 AII / I yellow 23 I w I w, HH 78 Crystals 58 AJ KJ / J white 24 / v H3 H / NMR Oil 67 A

<Tb>
<tb>#<SEP>#<SEP> H3C <SEP> yellow
<tb> @ <SEP> pale <SEP> ~ <SEP>
<tb> 25 <SEP>###<SEP> CH3 <SEP>#<SEP>#<SEP> NMR <SEP> Oil <SEP> 52 <SEP> A
<tb>#<SEP>#<SEP>#<SEP> H3C <SEP> H3C <SEP> yellow
<tb> pale
<Tb>

26 I "': "': n# / / 188 Coton 66 A I C c blanc 27 H,c I c/ c/ 233 Poudre 40 A k U blanche 28 I I ('YCN H / 154 Poudre 52 A

AIC c white 27 H, c I c / c / 233 Powder 40 A k U white 28 II (YCN H / 154 Powder 52 A

<Tb>
<tb>#<SEP>#<SEP>#<SEP> H3C <SEP> white
<tb> broken
<Tb>

29 w w 'Y1 / / 130 Poudre 58 A

29 ww 'Y1 / / 130 Powder 58 A

<Tb>
<tb>#<SEP>#<SEP>#<SEP> H3C '<SEP> H3C <SEP> white
<Tb>

30 (YCN H H 186 Poudre 49 A L LA J\ jaune

30 (YCN HH 186 Powder 49 AL LA J \ Yellow

<Tb>
<tb> pale
<tb> 31 <SEP>###<SEP># C1 <SEP> H <SEP> H <SEP> 160 <SEP> Solid <SEP> 71 <SEP> A <SEP>
<tb>#<SEP>#<SEP>#<SEP> beige
<Tb>

32 w w ('Y CI / / 167 Poudre 73 A k blanche

32 ww ('Y CI / / 167 Powder 73 A white

<Desc / Clms Page number 20>

33 YY f1 H / 50 Cristaux 95 A

33 YY f1 H / 50 Crystals 95 A

<Tb>
<tb>#<SEP>#<SEP>#<SEP> H3C <SEP> green
<tb> 34 <SEP>#<SEP>###<SEP> H <SEP> H <SEP> 153 <SEP> Powder <SEP> 82 <SEP> A
<tb>#<SEP>#<SEP>#<SEP> white
<Tb>

35 H3C,......o1 '-':: ifYVl H / 202 Cristaux 76 A I V blancs 36 H / 140 Poudre 21 A Cl'Q 140 blanche 1 L J blanche 37 fTT HC / / 129 Poudre 79 A i 1 Ó 1 Ó c H3C blanche 38 I w I w I w H / 118 Poudre 57 A

35 H3C, ...... o1 '-' :: ifYVl H / 202 Crystals 76 AIV white 36 H / 140 Powder 21 A Cl'Q 140 white 1 LJ white 37 fTT HC / / 129 Powder 79 A i 1 Ó 1 Ó c H3C white 38 I w I w I w H / 118 Powder 57 A

<Tb>
<tb>#<SEP>#<SEP>#<SEP> H3C '<SEP> white
<Tb>

39 o}l1 w w H / 147 Cristaux 17 A -. zJ L Hc jaune

39 o} l1 ww H / 147 Crystals 17 A -. zJ L Hc yellow

<Tb>
<tb> clear
<tb> 40 <SEP>###<SEP>#F<SEP> H <SEP> H <SEP> 157 <SEP> Crystals <SEP> 56 <SEP> E
<tb>#<SEP>#<SEP>#SEP> white
<tb> 41 <SEP>###<SEP>#<SEP> H <SEP> H <SEP> 185 <SEP> Crystals <SEP> 80 <SEP> E
<tb>#<SEP>#<SEP>#N<SEP> yellow
<tb> clear
<tb> 42 <SEP>###<SEP>#<SEP> H <SEP> H <SEP> 142 <SEP> Crystals <SEP> 75 <SEP> E
<tb>#<SEP>#<SEP>#Cl<SEP> orange
<tb> pale
<tb> 43 <SEP>###<SEP>#<SEP> H <SEP> H <SEP> 172 <SEP> Crystals <SEP> 72 <SEP> E
<tb>#<SEP>#<SEP>#F<SEP> white
<tb> 44 <SEP>###<SEP>#<SEP> H <SEP> H <SEP> 130 <SEP> Crystals <SEP> 76 <SEP> E <SEP>
<tb>#<SEP>#<SEP># C # CH3 <SEP> beige
<tb> clear
<tb> 45 <SEP>###<SEP>#OH<SEP> H <SEP> H <SEP> 88 <SEP> Crystals <SEP> 35 <SEP> (*)
<tb>#<SEP>#<SEP>#<SEP> orange
<tb> clear
<tb> 46 <SEP>###<SEP>#<SEP> H <SEP> H <SEP> 146 <SEP> Sequins <SEP> 41 <SEP> E
<tb> 46 <SEP>#<SEP>#<SEP>#<SEP>#<SEP> orange
<tb> 47 <SEP>###<SEP>#OME<SEP> H <SEP> H <SEP> 160 <SEP> Crystals <SEP> 65 <SEP> E <SEP>
<tb>#<SEP>#<SEP>#OMeOMe<SEP> cream
<tb>#OMe
<Tb>

48 I ":: ":: iVX 205 Cristaux 71 E

48 I "::" :: iVX 205 Crystals 71 E

<Tb>
<tb>#<SEP>#<SEP>#<SEP>#<SEP> beiges
<Tb>

<Desc / Clms Page number 21>

<Tb>
<tb> 49 <SEP>###<SEP> H3C # OMe <SEP> H <SEP> H <SEP> 132 <SEP> Crystals <SEP> 63 <SEP> E
<tb>#<SEP>#<SEP>#<SEP> pink
<tb>#<SEP> pale
<tb> 50 <SEP>###<SEP> H <SEP> H <SEP> 132 <SEP> Crystals <SEP> 69 <SEP> (**)
<tb>#<SEP>#<SEP>#OH<SEP> white
<Tb>

51 w I w H H RMN Gomme 100 (***)

51 w I w HH NMR Gum 100 (***)

<Tb>
<tb> 52 <SEP>###<SEP>#OMe<SEP> H <SEP> H <SEP> 174 <SEP> Powder <SEP> 60 <SEP> E <SEP>
<tb> HO # <SEP>#<SEP>#<SEP> white
<Tb>

53 F F H H 135 Cristaux 89 E

53 FFHH 135 Crystals 89 E

<Tb>
<tb>#<SEP>#<SEP>#<SEP> red
<tb>#<SEP> clear
<tb> 54 <SEP>#<SEP>###<SEP> H <SE> H3C # <SEP> 143 <SEP> Crystals <SEP> 64 <SEP> A
<tb>#<SEP>#<SEP>#SEP> white
<Tb>

55 yni 0 H E:1y 155 Cristaux 25 E

55 yni 0 HE: 1y 155 Crystals 25 E

<Tb>
<tb>#<SEP>#<SEP>#<SEP> orange
<tb> ass
<tb> 56 <SEP>###<SEP>#<SEP> H <SEP> H3C # <SEP> 60 <SEP> Foam <SEP> 79 <SEP> E
<Tb>

crème F crime 57 #"'s rVYi H H3G 150 Cristaux 27 E

F crime cream 57 # "'s rVYi H H3G 150 Crystals 27 E

<Tb>
<tb>#<SEP>#<SEP>#SEP> white
<tb> 58 <SEP>###<SEP>#<SEP> H <SEP>#<SEP> 220 <SEP> Powder <SEP> 27 <SEP> A
<Tb>

H3C beige N X 1 H)C beige 59 /YVl (PS " /\/ 102 Solide 22 E P J 1 i 0 102 beige COOH beige "\ COOH 60 F H / 112 Solide 60 E l 1 'Yl 112 jaune Solide y, f "H /X/ Solide "8Ô~"Ê

H3C beige NX 1H) C beige 59 / YV1 (PS "/ \ / 102 Solid 22 EPJ 1 i 0 102 beige COOH beige" \ COOH 60 FH / 112 Solid 60 E l 1 'Yl 112 yellow Solid y, f "H / X / Solid "8Ô ~" Ê

<Tb>
<tb>#<SEP>#<SEP>#<SEP> H3C '<SEP> january
<tb> 62 <SEP>###<SEP>#COOH<SEP> H <SEP>#<SEP> 230 <SEP> Solid <SEP> 40 <SEP> E <SEP>
<tb>#<SEP>#<SEP>#<SEP> H3C <SEP> white
<Tb>

63 F / / 131 Solide 15 E I J 1 ))F / H3<: 131 jaune

63 E / 131 Solid 15 EIJ 1)) F / H3 <: 131 yellow

<Desc / Clms Page number 22>

<Tb>
<tb> 64 <SEP>###<SEP> 120 <SEP> Solid <SEP> 45 <SEP> E
<Tb>

(li: 1 1 i 1 / H3C 120 rose

(li: 1 1 i 1 / H3C 120 pink

<Tb>
<tb> F
<Tb>

65 r(YCOOH / / 245 Solide 7 E

65 (YCOOH / / 245 Solid 7 E

<Tb>
<tb>#<SEP>#<SEP>#<SEP> white
<Tb>
(*) Example 45: This compound is obtained by the action of 3-aminopropanol (1.1 equivalent) and 1,1-thiocarbonyldiimidazole (1.1 equivalent) on the acid obtained according to Preparation IV, in a dichloromethane mixture / methanol, for 1 hour at 45 ° C.

(**) Example 50: This compound is obtained by hydrolysis of the compound of Example 51, using paratoluenesulfonic acid (0.05 equivalents) in methanol at 45 ° C. for 2 hours.

(***) Example 51: This compound is obtained according to a process analogous to that of Example 45, from 2 - [(tetrahydro-2H-pyran-2-yl) oxy] ethanamine.

NMR: Example 21: 1 H NMR: (DMSO d6, 300 MHz): (s, 6H); (s, 2H); (2d, 2H); (m, 2H); (m, 1H); 7.30 (m, 9H).

Example 24: 1H NMR: (CDCl3, 300 MHz): (t, 3H); (m, 5H); 1.71 (m, 2H); 3.89 (t, 2H); 4.02 (s, 2H); 4.40 (q, 1H); (m, 9H).

Example 25: 1 H NMR: (DMSO d6, 250 MHz): (t, 3H); (m, 8H); 1.61 (m, 2H); (t, 2H); 4.01 (s, 2H); (m, 9H).

Example 51: 1H NMR: (CDCl3, 250 MHz): (m, 6H); 3.50 (m, 1H); 3.81 (m, 2H); (m, 4H); 4.18 (m, 1H); (s, 2H); (m, 1H); 7.26 (m, 7H); (d, 2H).

<Desc / Clms Page number 23>

 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).

 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 a dose below 200 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 CO2 / O2 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) within one hour of collection. 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 glucose and triglyceride levels after treatment are calculated and the results are expressed as a percentage change.

<Desc / Clms Page number 24>

 of these averages compared 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 -63% for blood glucose and -58% for triglycerides. It has also been observed that the treatment with the compounds according to the invention is 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 the treatment of diseases caused by microvascular or macrovascular complications in diabetics, particularly in the renal or central nervous system, said complications being generally associated with the metabolic syndrome X.

The compounds of the invention are also useful for treating cerebral ischemia or cerebrovascular accident.

 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. We will be able to present

<Desc / Clms Page number 25>

 the drug in the form of oral syrup, or in injectable form, preferably subcutaneously or intramuscularly.

Claims (12)

R5 represents a hydrogen atom, a halogen atom, a C1-C3 alkoxy group, or a hydroxyl group, # R3 and R4 represent, each independently, a hydrogen atom or a C1-C4 alkyl group, X represents CH or N,  in which

 (C1-C4) alkoxycarbonyl, methylthio, methylenedioxy or

Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms selected from halogen groups, hydroxy, nitro, cyano, C 1 -C 3 alkoxy, carboxyl,  (tetrahydro-2H-pyran-2-yl) oxy (C 2 -C 3) alkyl group, - a C 3 -C 5 alkoxyalkyl group, - a (CH 2) p -Ar group, in which p represents 0 or 1, and

 wherein # R1 and R2, independently of each other, represent - a C1-C5 alkyl group, - a C3-C4 alkenyl group, - a C2-C3 hydroxyalkyl group, or one of its precursors, such as

 1. Compound derived from 2-thiohydantoin, characterized in that it is chosen from: a) compounds of formula <Desc / Clms Page number 27>  with the proviso that at least one of the substituents R 1 and R 2 comprises in its structure 2 aromatic rings selected from phenyl or pyridinyl groups, b) the addition salts of the compounds of formula (I) with a nontoxic acid when said Compounds of formula (I) include a basic salifiable function. 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 (CH2) n-Ar group in which n represents 0 or 1, and Ar represents a phenyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms selected from halogen, C 1 -C 3 alkoxy, nitro, or the group

 in which X represents CH or N, R5 represents a hydrogen atom, a halogen atom, a C1-C3 alkoxy group, or a hydroxyl group, ## STR2 ## represents - a C1-C5 alkyl group, - a C3-C4 alkenyl group, <Desc / Clms Page number 28>  # R3 and R4 represent, each independently, a hydrogen atom or a C1-C4 alkyl group, 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 groups or pyridinyl, 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.

 (C1-C4) alkoxycarbonyl, methylthio, methylenedioxy or

Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms selected from halogen groups, hydroxy, nitro, cyano, C 1 -C 3 alkoxy, carboxyl,  a C2-C3 hydroxyalkyl group, or one of its precursors, such as the (tetrahydro-2H-pyran-2-yl) oxy (C2-C3) alkyl group, a C3-C5 alkoxyalkyl group; a group (CH 2) p-Ar, in which p represents 0 or 1, and 3. Compound according to one of claims 1 or 2, characterized in that one of the groups R 1 or R 2 represents the (phenylmethyl) phenyl group, R 3 and R 4 and the other group R 1 or R 2 are as defined in US Pat. one of claims 1 or 2. 4. Compound of formula (I) according to any one of claims 1 to 3, 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, R 1 R 4 are as defined in claim 1, with an isothiocyanate of formula (III) <Desc / Clms Page number 29>  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 salifiable basic function, reacting said compound with a mineral acid or organic, in an anhydrous solvent, to obtain the salt of the compound of formula (I).

 wherein R2 represents a group as defined 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 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 ester of formula (IV)

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

 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) <Desc / Clms Page number 30>  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.

7. Pharmaceutical composition characterized in that it contains, in combination with at least one physiologically acceptable excipient, at least one compound of formula (I) or one of its addition salts with a pharmaceutically acceptable acid according to one of the following: any 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 to 4 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 according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of hypertriglyceridemia and dyslipidemias. 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. 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 stroke.