EP1472208A1

EP1472208A1 - Novel 3-aryl-2,5-dihydroxy-1,4-benzoquinone derivatives, their preparation method and pharmaceutical compositions containing same

Info

Publication number: EP1472208A1
Application number: EP03737340A
Authority: EP
Inventors: Alexandra Dassonville; Anne Breteche; Muriel Route de Nantes DUFLOS; Guillaume Le Baut; Bruno Pfeiffer; Pierre Renard; Nigel Villa des Mioches LEVENS; Bernadette Husson-Robert
Original assignee: Laboratoires Servier SAS
Current assignee: Laboratoires Servier SAS
Priority date: 2002-02-06
Filing date: 2003-02-04
Publication date: 2004-11-03
Also published as: HK1078566A1; KR20040086352A; FR2835523A1; FR2835523B1; CN1274655C; BR0307465A; AU2003226860B2; EA200400992A1; AR038397A1; CN1628088A; NO20043532L; MA27103A1; AU2003226860A1; US20050085644A1; GEP20063900B; CA2474533A1; UA79448C2; EA006775B1; JP2005517001A; WO2003066561A1

Abstract

The invention concerns a compound of formula (I), wherein: R1 and R2, identical or different, represent each a hydrogen atom or an acyl or alkyl group; Ar represents an aryl or heteroaryl group; A represents a group selected from formula (II); R4 represents a hydrogen atom or an alkyl group; R5 represents a hydrogen atom or a group selected among alkyl, aryl and heteroaryl; R3 represents an aryl, heteroaryl, dicyclopropylmethyl or benzhydryl group, or A-R3 represents an optionally substituted naphthyl group, excluding 2,5-dihydroxy-3-(4-methoxyphenyl)-6-(2-phenylethenyl)-1,4-benzoquinone, 2,5-dihydroxy-3-(4-methoxyphenyl)-6-(2-naphthyl)-1,4-benzoquinone, and 2,5-dihydroxy-3-(2-naphthyl)-6-phenyl-1,4-benzoquinone. The inventive compound is useful for preparing medicines.

Description

NOVEL 3-ARYL-2,5-DIHYDROXY-1,4,4-BENZOQUINONES DERIVATIVES,

THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to new derivatives of 3-aryl-2,5-dihydroxy-1,4-benzoquinones, their preparation process, the pharmaceutical compositions which contain them as well as their use as anti-diabetics.

A 3-aryl-2,5-dihydroxy-6- (2-phenylethenyl) -1,4-benzoquinone has been described in the journal Liebigs Ann. Chem. 1986, 195-204 for its potential anti-tumor activity and its antioxidant activity.

The derivatives of the present invention, on the other hand, exhibit insulinomimetic properties such as an increase in the autophosphorylation of the insulin receptor and of protein kinase B.

Insulin resistance is a very complex syndrome with defects at different levels of the intracellular signaling cascade of insulin. In addition to a decrease in the number of insulin receptors (Kahn et al., Mechanism of action of hormones that act at the cell surface, 8 ^th edition, WB 91-134, Saunders, Philadelphia, 1992), there are clearly an alteration in the kinase activity of the insulin receptor. This post-receptor defect is located on the one hand on the tyrosine phosphorylation of 1TRS1 and on the other hand on the IRS1 / PI3 kinase interaction (Y. Le Marchand-Brustel, Exp. Clin. Endocrinol. Diabetes, 1999, 107, 126-132), thereby limiting the activation of protein kinase

B, a key enzyme in the use of glucose (Burgering et al., Nature, 1995, 376 (6541), 599-602) and apoptosis (Franke T.F., Cell, 1997, 88, 435-437).

The properties of the compounds of the present invention on the insulin receptor and protein kinase B therefore make them extremely advantageous for the treatment of diseases associated with deregulation of glycemia. They may in particular be used in the treatment of diabetes (type I or type II diabetes).

More specifically, the present invention relates to the compounds of formula (I):

in which :

VR _Ï and R ₂ , identical or different, each represent a hydrogen atom or a linear or branched (Ci-C ₆ ) acyl group, or linear or branched (CrC ₆ ) alkyl, Ar represents an aryl or heteroaryl group, A represents a group chosen from:

R ₄ substitutes the carbon atom linked to the benzoquinone ring and represents a hydrogen atom or a linear or branched (CrC ₆ ) alkyl group,

4 R ₅ substitutes the carbon atom linked to the residue R ₃ and represents a hydrogen atom or a group chosen from linear or branched (-C ₆ ) alkyl, aryl and heteroaryl,

VR ₃ represents an aryl, heteroaryl, dicyclopropylmethyl or benzhydryl group, or AR ₃ represents an optionally substituted naphthyl group, and in this case Ar represents an aryl group,

and their stereoisomers when they exist, as well as their addition salts with a pharmaceutically acceptable acid or base, excluding 2,5-dihydroxy-3- (4-methoxyphenyl) -6- (2-phenylethenyl) -1,4-benzoquinone, 2,5-dihydroxy-3- (4-methoxyphenyl) - 6- (2-naphthyl) -1,4-benzoquinone, and 2,5-dihydroxy-3- (2-naphthyl) -6-phenyl-1,4-benzoquinone.

The term “aryl group” is understood to mean phenyl, biphenylyl, naphthyl or tetrahydronaphthyl, each of these groups being optionally substituted by one or more atoms or groups, identical or different, chosen from halogen atoms and alkyl groups (Cι-C ₆ ) linear or branched, hydroxy, alkoxy (dC ₆₎ linear or branched polyhaloalkyl (C _i -C ₆₎ linear or branched, amino (optionally substituted by one or more alkyl (Ci-Ce) linear or branched), nitro, linear or branched (Ci-C ₆ ) acyl, alkylenedioxy (Ci-C ₂ ) or phenyloxy.

The expression “optionally substituted naphthyl group” means a naphthyl group which is unsubstituted or substituted by one or more atoms or groups, identical or different, chosen from halogen atoms and linear or branched (C ₁ -C ₆ ) alkyl groups, hydroxy, linear or branched alkoxy (Ci-Ce), linear or branched polyhaloalkyl (Ci-C ₆ ), amino (optionally substituted by one or more alkyl groups (Ci-C ₆ ) linear or branched), nitro, acyl (Ci-C ₆ ) linear or branched, alkylenedioxy (Ci-C ₂ ) or phenyloxy.

By heteroaryl group is meant a 5 to 12-membered mono- or bicyclic aromatic group containing one, two or three heteroatoms chosen from oxygen, nitrogen or sulfur, it being understood that the heteroaryl may be optionally substituted by one or more atoms or groups , identical or different, chosen from halogen atoms and linear or branched (Ci-Ce) alkyl, hydroxy, linear or branched (Ci-C ₆ ) alkoxy, linear or branched polyhaloalkyl (CrC ₆ ), amino (substituted optionally with one or more alkyl (Ci -This) linear or branched), nitro, acyl (Q-Ce) linear or branched alkylenedioxy (Ci-C _2), or phenyloxy. Among the heteroaryl groups, non-limiting mention may be made of thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl and pyrimidinyl groups. By stereoisomer is meant a geometric double bond isomer or an optical isomer.

An advantageous variant according to the invention relates to the compounds of formula (I)

in which :

V Ri and R _2, identical or different, each represents a hydrogen atom or an acyl group (Ci-C ₆₎ linear or branched alkyl or (Ci-C ₆₎ linear or branched,

VR ₃ represents an aryl, heteroaryl, dicyclopropylmethyl or benzhydryl group,

V Ar represents an aryl or heteroaryl group,

V A represents a group chosen from:

R substitutes the carbon atom linked to the benzoquinone ring and represents a hydrogen atom or a linear or branched (Ci-C ₆ ) alkyl group,

R ₅ substitutes the carbon atom linked to the residue R ₃ and represents a hydrogen atom or a group chosen from linear or branched (Ci-C ₆ ) alkyl, aryl and heteroaryl,

and their stereoisomers when they exist, as well as their addition salts with a pharmaceutically acceptable acid or base,

excluding 2,5-dihydroxy-3- (4-methoxyphenyl) -6- (2-phenylethenyl) -1,4-benzoquinone. Another variant according to the invention relates to the compounds of formula (I)

in which

V Ri and R, identical or different, each represent a hydrogen atom or an acyl group (Cι-C ₆ ) linear or branched, or alkyl (Ci-C ₆ ) linear or branched, Ar represents an aryl group, AR ₃ represents an optionally substituted naphthyl group,

excluding 2,5-dihydroxy-3- (4-methoxyphenyl) -6- (2-naphthyl) -1,4-benzoquinone, and 2,5-dihydroxy-3- (2-naphthyl) -6-phenyl-l, 4-benzoquinone.

The preferred Ri and R groups are the hydrogen atom.

Ar advantageously represents an aryl group and more particularly the phenyl or naphthyl groups, unsubstituted or substituted.

Even more preferably, Ar represents a phenyl or naphthyl group, these groups being unsubstituted or substituted by a halogen atom such as chlorine or bromine for example.

The preferred AR ₃ groups are the unsubstituted or substituted naphthyl group and the arylethenyl group and more particularly the non-phenylethenyl group. substituted or substituted. The substitutions of these naphthyl and phenylethenyl groups are preferably halogen atoms such as chlorine, bromine or fluorine.

Even more preferably, the invention relates to the compounds of formula (I) which are:

- 2- (4-chlorophenyl) -3,6-dihydroxy-5- (2-naphthyl) -1,4-benzoquinone, - 2- (4-bromophenyl) -3,6-dihydroxy-5- (2 -naphthyl) -1,4-benzoquinone, 2 - [(E) -2- (4-fluorophenyl) ethenyl] -3,6-dihydroxy-5-phenyl-1,4-benzoquinone,

- 2- (4-chlorophenyl) -3,6-dihydroxy-5 - [(E) -2-phenylethenyl] -1,4-benzoquinone,

2,5-dihydroxy-3-phenyl-6 - [(E) -2-phenylethenyl] -1,4-benzoquinone,

- 2- (4-bromophenyl) -3,6-dihydroxy-5 - [(E) -2-phenylethenyl] -1,4-benzoquinone, - 2,5-dihydroxy-3 - [(E) -1 -methyl-2-phenylethenyl] -6-phenyl-1,4-benzoquinone, and 2- (3-chlorophenyl) -3,6-dihydroxy-5 - [(E) -2-phenylethenyl] - 1, 4- benzoquinone.

The stereoisomers as well as the addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention.

Among the pharmaceutically acceptable bases, non-limiting mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine.

Among the pharmaceutically acceptable acids, non-limiting mention may be made of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulfonic, camphoric acids. , oxalic.

The invention also relates to a novel derivative of 3-aryl-2,5-dihydroxy-1,4-benzoquinone which is 2- (4-bromophenyl) -3,6-dihydroxy-5-phenyl-1,4-benzoquinone , as well as its addition salts with a pharmaceutically acceptable base. The invention also extends to a process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is reacted:

Ar "OH (D)

O

in which Ar is as defined in formula (I), with a compound of formula (III)

in which R represents a linear or branched (Ci-C ₆ ) alkyl group,

to lead to the compound of formula (IV):

in which Ar and R are as defined above, which are cyclized under basic conditions, then, when desired, with an acylation or alkylation reagent, to yield the compound of formula (V) :

in which Ar is as defined above, and Ri is as defined in formula (I),

which is reacted with a compound of formula (NI):

in which A and R ₃ are as defined in formula (I),

to lead to the compound of formula (Nile):

in which A, Ar, Ri and R ₃ are as defined above,

which are subjected to basic conditions, then, when desired, to an acylation or alkylation reagent, to yield the compound of formula (I),

which is purified according to a conventional purification technique, and from which the stereoisomers are separated, where appropriate, according to a conventional separation technique.

The compounds of formula (II) can be obtained, either by reaction of the compound of formula (VIII):

in which Ar is as defined in formula (I),

with tris (trimethylsilyloxy) -ethylene, in the presence of a Lewis acid,

either by reaction of the compound of formula (IX):

(IX)

in which Ar is as defined in formula (I) with peracetic acid in the presence of osmium trichloride.

The compounds of the present invention, in addition to the fact that they are new, exhibit advantageous pharmacological properties. They have insulin-like properties that make them useful in the treatment of diseases associated with blood sugar dysregulation, such as type I or IL diabetes

The invention also extends to pharmaceutical compositions containing as active principle at least one compound of formula (I) with one or more inert, non-toxic and suitable excipients. Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), nasal administration, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments, dermal gels, injections, oral suspensions, etc.

The useful dosage is adaptable according to the nature and severity of the condition, the route of administration as well as the age and weight of the patient and any associated treatments. This dosage varies from 0.5 mg to 2 g per 24 hours in one or more doses.

The following examples illustrate the invention and do not limit it in any way. The starting materials used are known products or prepared according to known preparatory methods.

The structures of the compounds described in the examples were determined according to the usual spectrometric techniques (infrared, NMR, mass spectrometry).

EXAMPLE 1: 2,5-Dihydroxy-3-phenyl-6 - [(E) - 2-phenylethenyl] -1 _? 4-benzoq none:

Stage A: 1-Hydroxy-3-phenylacetone

To 0.3 mmol of allylbenzene in solution in a mixture of acetonitrile, of dichloromethane and of water are added 0.3 mmol of hydrated osmium trichloride, then, slowly, 20 mmol of a solution of 30% peracetic acid in ethyl acetate. After addition, the stirring is continued for 3 hours at room temperature, then the reaction mixture is poured onto an aqueous solution of sodium bisulfite at 5%. After extraction with dichloromethane, the organic phases are combined, washed, dried and evaporated. The residue obtained is purified by chromatography on silica (eluent: hexane / ethyl acetate 7/3) to yield the expected product.

Melting point: 42-43 ° C

Stage B: Ethyl (2-oxo-3-phenylpropyl) oxalate

To 10 mmol of the compound obtained in the preceding stage in solution in tetrahydrofuran are added, at 0 ° C., 11.6 mmol of triethylamine, then 10.4 mmol of ethyl oxalate chloride. After 3 hours of stirring, the medium is extracted with ethyl acetate, then the organic phase is washed, dried and evaporated to yield the expected product in the form of an oil. Stage C: 3-Hydroxy-4-phenylpyran-2,5-dione

To 20.5 mmol of 1,8-diazabicyclo [5.4.0] undec-7-ene in solution in dimethylformamide at -20 ° C are added, slowly dropwise, 10 mmol of the compound obtained in the preceding stage in solution in dimethylformamide. After 2.5 hours of stirring at -15 ° C, the reaction mixture is poured slowly over a 1 M hydrochloric acid solution at 0 ° C. The precipitate formed is filtered, washed and then dried to yield the expected product.

Melting point: 175-176 ° C.

Stage D: 3-Hydroxy-6-phenylpropenylidene-4-phenylpyran-2,5-dione

To 10 mmol of the compound obtained in the preceding stage in glacial acetic acid are added 10 mmol of cinnamaldehyde. The reaction mixture is then heated to 60 ° C until dissolution, then a few drops of concentrated hydrochloric acid are added, and the temperature is brought to 90 ° C. After 2 hours of stirring, the medium is cooled to 0 ° C and a mixture of 1/1 ether and hexane is added. The precipitate obtained is filtered and then dried to yield the expected product.

Melting point: 231-232 ° C.

Stage Ej 2,5-Dihydroxy-3-phenyl-6 - [(E) - 2-phenylethenyl] -1,4-benzoquinone:

To 10 mmol of the compound obtained in the preceding stage suspended in methanol is added, at room temperature, 100 ml of a 30% by weight solution of sodium methanolate in methanol. After 15 minutes of stirring, the reaction mixture is slowly poured onto a 1 M hydrochloric acid solution at 0 ° C. The precipitate is filtered, then washed and dried to yield the expected product.

Melting point: 259-260 ° C.

Mass Svectrometry: SMm / z (%) = 318.20 (100), 199.15 (40), 115.10 (36). EXAMPLE 2: 2,5-Dihydroxy-3-phenyl-6 - [( _J E) -2- (4-chloropheny - ethenyl-1,4-benzoquinone:

The expected product is obtained according to the process described in Example 1, replacing, in stage D, the cinnamaldehyde with 4-chloro-cinnamaldehyde.

Melting point: 244-245 ° C.

Mass Svectrometry: SMm / z (%) = 325, 7 (22), 351, 7 (100), 235.86 (8), 323.87 (32).

EXAMPLE 3: 2,5-Dihydroxy-3-phenyl-6 - [(E) -2- (4-bromophenyl) - etheny!] - 1,4-benzoquinone:

The expected product is obtained according to the process described in Example 1, replacing, in stage D, cinnamaldehyde with 4-bromo-cinnamaldehyde.

Melting point: 240-241 ° C.

Mass spectrometry: SMm / z (%) = 397.35 (100), 396.95 (46)

EXAMPLE 4: 2 5-Dihydroxy-3-phenyl-6- (phenylethynyl) -1,4-benzoquinone:

The expected product is obtained according to the process described in Example 1, replacing, in stage D, cinnamaldehyde with 3-phenyl-2-propynal.

EXAMPLE 5: 2 - [(lE) -3,3-DicyclopropyI-l-propenyl] -3,6-dihydroxy- 5-phenyl-1,4-benzoquinone:

The expected product is obtained according to the process described in Example 1, replacing, in stage D, the cinnamaldehyde with (2E) -4,4-dicyclopropyl-2-butenal. EXAMPLE 6 2- (2,2-Diphenylvinyl) -3,6-dihydroxy-5-phenyl-1,4-benzoquinone:

The expected product is obtained according to the process described in Example 1 by replacing, in stage D, the cinnamaldehyde with 3,3-diphenylacrylaldehyde.

Melting point: 212-213 ° C.

EXAMPLE 7 2,5-Dihydroxy-3 - [(E) -2- (2-naphthyl) -ethenyl] -6-phenyl 1,4,4-benzoquinone;

The expected product is obtained according to the process described in Example 1 by replacing, in stage D, the cinnamaldehyde with (2E) -3- (2-naphthyl) -2-propenal.

Melting point: 263-264 ° C.

EXAMPLE 8 2,5-Dihydroxy-3-phenyl ~ 6- (2-pheιιylcycIopropyl) -1,4-benzoquinone:

The expected product is obtained according to the process described in Example 1, replacing, in Stage D, cinnamaldehyde with 2-phenylcyclopropane carbaldehyde.

EXAMPLE 9 2,5-Dihydroxy-3-phenyl-6 - [(Z) -2-phenylethenyl] -1,4-benzoquinone:

The expected product is obtained according to the process described in Example 1, replacing, in stage D, cinnamaldehyde with (2Z) -3-phenyl-2-propenal.

EXAMPLE 10: 2,5-Dihydroxy-3 - [(JJ) -1-methyl-2-phenylphenyl-6-phenyl-1 _s 4-> benzoquinone:

The expected product is obtained according to the process described in Example 1, replacing, in Stage D, cinnamaldehyde with (2 £) -2-methyl-3-phenyl-2-propenal. Melting point: 205-206 ° C

EXAMPLE 11 2,5-Dιhydroxy-3-phenyl-6 - [(1J5 ') - 2-phenyl-l-propényI] - 1,4-benzoquinone:

The expected product is obtained according to the process described in Example 1 by replacing, in stage D, the cinnamaldehyde with (2E) -3-phenyl-2-butenal.

Melting point: 227 -228 ° C

EXAMPLE 12: 2,5-Diacetoxy-3-phenyl-6 - [(£) -2-phenylethenyl] -1 _? 4- benzoqumone:

To 10 mmol of the compound of Example 1 in solution in pyridine are added, dropwise at 0 ° C., 100 mmol of acetic anhydride, then the reaction mixture is brought to room temperature. After one hour of stirring, the reaction mixture is poured onto ice and then extracted with dichloromethane. The organic phase is washed, dried, filtered and then evaporated and the residue obtained is purified by chromatography on silica (dichloromethane / ethanol 98/2) to yield the expected product.

EXAMPLE 13; 2- (4-Chlorophenyl) -3,6-dihydroxy-5 - [(E) -2-phenylethenyl] -1,4-benzoquinone:

Stage A: 1- (4-Chlorophenyl) -3-hydroxyacetone

To 10 mmol of (4-chlorophenyl) -acetyl chloride are slowly added 25 mmol of tris (trimethylsilyloxy) -ethylene, then a few drops of TiCl ₄ . After 3 hours of stirring at room temperature, 14.5 ml of a 3/7 mixture of 0.6M hydrochloric acid and dioxane are added. The reaction medium is then heated at 90 ° C for 10 min, then it is brought to room temperature. After extraction, the combined organic phases are washed, dried and then evaporated, and the residue obtained is purified by chromatography on silica (eluent: ether / petroleum ether 6/4), then recrystallized, to yield the expected product.

Stage B: 2- (4-Chlorophenyl) -3,6-dihydroxy ~ 5 - [(E) -2-phenylethenyl] -1,4-benzoquinone

The expected product is obtained according to the process described in stages B to D of Example 1, from the compound obtained in the preceding stage.

Melting point: 258-259 ° C.

EXAMPLE 14 2,5-Dihydroxy-3- (4-phenoxyphéπyl) -6 - [( _J E) -2-phenyléthéιιyl] -l, 4-benzoquinone:

The expected product is obtained according to the process described in Example 13 by replacing, in stage A, (4-chlorophenyl) -acetyl chloride with (4-phenoxyphenyl) -acetyl chloride.

EXAMPLE 15 2,5-Dihydroxy-3 - [(^) - 2-phenylethenylJ-6- (2-pyridyI) -1,4-benzoquinone;

The expected product is obtained according to the process described in Example 13 by replacing, in Stage A, (4-chlorophenyl) -acetyl chloride with 2-pyridylacetyl chloride.

EXAMPLE 1 2- (4-Chlorophenyl) -3,6-d ydroxy-5- (2-naphthyl) -1,4-benzoqumone

Stage A: 4- (4-Chlorophenyl) -3-hydroxy-pyrane-2,5-dione

The procedure is carried out as in stages B and C of Example 1, taking as starting material the compound obtained in Stage A of Example 13. Stage B: 4- (4-Chlorophenyl) -3-hydroxy-6- (2-naphthylmethylene) -pyran-2,5-dione

A solution of 0.922 mmol of the compound obtained in stage A and 0.922 mmol of 2-naphthaldehyde in 2.45 ml of glacial acetic acid is heated to 60 ° C until dissolution. A few drops of concentrated hydrochloric acid are added, the temperature is brought to 90 ° C. and the reaction medium is stirred for 6 hours.

After cooling to room temperature, the flask is immersed in an ice bath and 10 ml of a mixture of diethyl ether and hexane (1/1) are added. The title product is obtained in the form of a yellow powder after filtration.

Melting point: 274-275 ° C.

Stage C: 2- (4-Chlorophenyl) -3,6-dihydroxy-5- (2-tιaphtyl) -1,4-benzoquinone

To a suspension of 0.66 mmol of the compound obtained in Stage B in a minimum of anhydrous methanol are added at room temperature 6 ml of a 30% by weight solution of sodium methylate in methanol. After 1 hour of stirring, the reaction mixture is slowly poured into 40 ml of a 1 M hydrochloric acid solution previously cooled to 0 ° C. The precipitate obtained is filtered, washed with water and dried in a desiccator overnight. The title product is obtained in the form of a brown powder after recrystallization from a tetrahydrofuran / hexane mixture.

Melting point: 302-303 ° C.

EXAMPLE 17 2.5-Dihydroxy-3,6-di- (2-naphthyl) -1.4-benzoquinone

Stage A: (Napht-2-yl) acetyl chloride

A mixture of 30 mmol of naphth-2-ylacetic acid and 5 ml of thionyl chloride is heated to reflux, under an argon atmosphere for 12 hours. After cooling the reaction medium and evaporation, the residue obtained is taken up in anhydrous methylene chloride until elimination of the excess thionyl chloride to yield the title product in the form of a yellow oil. Stage B: 1-Hydroxy-3- (2-naphthyl) acetone

At room temperature, under a stream of argon, 71.45 mmol of tris (trimethylsilyloxy) ethylene are slowly added to 28.58 mmol of (napht-2-yl) acetyl chloride (obtained in stage A). After 5 hours of stirring at 90 ° C., the mixture is cooled and then a mixture consisting of 12 ml of 0.6 M hydrochloric acid and 30 ml of dioxane is added slowly. The reaction medium is heated at 90 ° C for 10 minutes, then cooled and extracted several times with diethyl ether. The organic phases are combined and washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue obtained is chromatographed on silica gel, eluting with an ethyl acetate / hexane mixture in the proportions 6/4. The title product is obtained after recrystallization from hexane.

Melting point: 109-110 ° C

Stage C: 3-Hydroxy-4- (2-naphthyl) -pyrane-2,5-dione

The procedure is as in stages B and C of Example 1, starting from the compound obtained in stage B.

The title compound is obtained in the form of a yellow powder after recrystallization from a CH ₂ C1 ₂ / Hexane mixture.

Melting point: 196-197 ° C

Stage D: 2,5-Dihydroxy-3,6-di (2-naphthyl) -1,4-benzoquinone

The procedure is as in stages B and C of Example 16, starting from the compound obtained in stage C. The title compound is obtained in the form of a dark pink powder after recrystallization from a tetrahydrofuran / hexane mixture.

Melting point: 328-329 ° C.

EXAMPLE 18; 2- (4-Fluorophenyl) -3,6-hydroxy-5- (2-naphthyl) -1,4-benzoquinone

The procedure is as in Example 13 starting from (4-fluorophenyl) acetyl chloride and naphthaldehyde.

Brown powder.

Melting point: 300-301 ° C.

EXAMPLE 19; 2- (4-Bromophenyl) -3,6-dihydroxy-5- (2-naphthyl) -1,4-benzoquinone

The procedure is as in Example 13 starting from (4-bromophenyl) acetyl chloride and naphthaldehyde.

Brown powder.

Melting point: 312-313 ° C.

EXAMPLE 20 2- (2-Chlorophenyl) -3,6-dihydroxy-5- (2-ttaphtyl) -1,4-benzoquinone

The procedure is as in Example 13 starting from (2-chlorophenyl) acetyl chloride and naphthaldehyde. Brown powder.

Melting point: 242-243 ° C. EXAMPLE 21 2- (6-Bromo-2-naphthy) -3,6-dihydroxy-5-phenyl-1,4-benzoquinone

The procedure is as in Example 1 starting from allylbenzene and (6-bromo) -2-naphthaldehyde.

EXAMPLE 22; 2,5-Dihydroxy-3- (2-naphthyl) -6- [3- (trifluoromethyl) phenyl] -1,4-benzoquinone

The procedure is as in Example 13 starting from (3-trifluoromethylphenyl) acetyl chloride and naphthaldehyde.

EXAMPLE 23 2,5-Dihydroxy-3- (2-naphthyl) -6- (4-nitrophéιιyl) -l, 4-benzoqumone

The procedure is as in Example 13 starting from (4-nitrophenyl) acetyl chloride and naphthaldehyde.

EXAMPLE 24 2- (4-Bromophenyl) -3,6-dihydroxy-5- (6-methoxy-2-Biaphthyl) benzo-1,4-quinone

The procedure is as in Example 13 starting from (4-bromophenyl) acetyl chloride and (6-methoxy) -2-naphthaldehyde.

EXAMPLE 25 2,5-Diacetoxy-3- (4-Bromophenyl) -6- (2-naphthyl) -1,4-benzoquinone

The procedure is as in Example 12 starting from the compound obtained in Example 19. EXAMPLE 26: 2- (3-Chlorophenyl) -3 _? 6-dihydroxy-5- (2-naphthyl) -1,4-benzoquinone

The procedure is as in Example 13 starting from (3-chlorophenyl) acetyl chloride and naphthaldehyde.

Melting point: 258-259 ° C.

EXAMPLE 27; 2 - [(E) -2- (4-Fluorophenyl) ethenyIl-3,6-dihydroxy-5-phenyl-l, 4-benzoquinone

The procedure is as in Example 1, replacing cinnamaldehyde in stage D with 4-fluoro-cinnamaldehyde.

Melting point: 250-251 ° C.

EXAMPLE 28; 2- (4-Bromophenyl) -3.6-dihydroxy-5 - [(£) -2-phéιιyléthényIl-l, 4- benzoquinone

The procedure is as in Example 13, taking as starting material (4-bromophenyl) acetyl chloride.

Melting point: 262-263 ° C.

EXAMPLE 29 2- (2-ChlorophênyI) -3,6-dihydroxy-5 - [( _J B) -2-phenylethéιιyl] -l, 4-benzoquinone

The procedure is as in Example 13, taking as starting material (2-chlorophenyl) acetyl chloride.

Melting point: 266-268 ° C EXAMPLE 30 2- (3-Chlorophenyl) -3,6-dihydroxy-5 - [(E) -2-phenylethenyl] -1,4-benzoquinone

The procedure is as in Example 13, taking as starting material (3-chlorophenyl) acetyl chloride.

Melting point: 210-211 ° C.

EXAMPLE 31: 2 _? 5-Dihydroxy-3 - [(E) -l-methyl-2-phenylethenyll-6- (2-naphthyl) - 1, 4-benzoquinone

The procedure is carried out as in stages D and E of Example 1 starting from the compound obtained in stage C of Example 17 and replacing cinnamaldehyde in stage D by (2E) -2-methyl-3-phenyl-2 -propénal.

Melting point: 217-218 ° C.

EXAMPLE 32 2,5-Dihydroxy-3- (2-naphthyl) -6 - [(E) -2-phenylphenyl] -1,4-benzoquinone

The procedure is as in stages D and E of Example 1 starting from the compound obtained in stage C of Example 17.

Melting point: 247 -248 ° C.

EXAMPLE 33 2- (4-Chlorophenyl) -5- (2,2-diphenylvmyl) -3,6-dihydroxy-1,4-benzoquinone

The procedure is as in Example 13 starting from (4-chlorophenyl) acetyl chloride and 3,3-diphenylacrylaldehyde.

Melting point: 253-254 ° C. EXAMPLE 34 2- (4-fluorophenyl) -3,6-dihydroxy-5 - [(E) -2-phenylethênyH, 4-benzoquinone

The procedure is as in Example 13, taking as starting material (4-fluorophenyl) acetyl chloride.

Melting point: 259-260 ° C.

EXAMPLE 35: 2.5-Dihydroxy-3- (3-methylphenyl) -6 - [(£) -2-phenylphenyl] -1,4-benzoquinone

The procedure is as in Example 13, taking as starting material (3-methylphenyl) acetyl chloride.

EXAMPLE 36 2- (4-Ethylphenyl) -5 - [(E) -2- (4-fluorophenyl) ethenyl] -3,6- dihydroxy-l _» 4-benzoquinone

The procedure is as in Example 13 starting from (4-ethylphenyl) acetyl chloride and 4-fluoro-cinnamaldehyde.

EXAMPLE 37; 2,5-Dihydroxy-3 - [(E) -2- (4-methylphenyl) ethenyl] -6- (4-nîtro phenyI) ~ 1,4 »benzoqumone

The procedure is as in Example 13 from (4-nitrophenyl) acetyl chloride and 4-methyl-ciιmamaldehyde.

EXAMPLE 38 2- (4-Fluorophenyl) -3,6-dihydroxy-5 - [(E) -2- (3-propoxyphenyl) ethenyl] -1,4-benzoqumone

The procedure is as in Example 13 starting from (4-fluorophenyl) acetyl chloride and

3 -propoxy-cinnamaldehyde. EXAMPLE 39 2,5-Dihydroxy-3-phenyl-6 - {(E) -2- [4- (trifluoromethyl) phenyl] ethenyl} -1,4-benzoqumone

The procedure is as in Example 1, replacing cinnamaldehyde in stage D with 4-trifluoromethyl-cinnamaldehyde.

EXAMPLE 40; 2- [4-Bromophenyl] -θ _» 6-dihydroxy-5-phenyM _» 4-benzoquinone

The procedure is as in Example 1, replacing cinnamaldehyde in stage D with 4-bromobenzaldehyde.

Melting point: 250-251 ° C.

PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION

EXAMPLE A Activation of the insulin receptors (IR) and of protein kinase B

(PKB);

The pharmacological effect of the compounds of the invention on cell signaling is evaluated in vitro on hamster ovary cells transfected with human insulin receptors (CHO-HIR). The techniques used come from TA V ARE and DENTON (1988, BIOCHEM. J., 250, 509-519) and TAVARE et al. (1988, Biochem. J.,

253, 783-788) modified by ISSAD et al. (1991, Biochem. J., 275, 15-21) and COMBETTES-SOUVERALN et al. (1997, Diabetologia, 40, 533-540).

The products are studied at 10 ^"5 M in incubation for two hours at 37 ° C on CHO-HIR in culture. A negative control (solvent) and positive control (50 nM insulin, 5 min incubation) were introduced in parallel in the same test At the end of the incubations, the enzymatic reactions are immediately stopped by a mixture of protease inhibitors (aprotinin, pepstatin, antipain, leuleptin, AEBSF) and the samples are immersed in ice at 4 ° C. The insulin receptor (IR) and protein kinase B phosphorylations are evaluated by immunoblotting as follows.

The IRs are extracted from wheat germ lectin; the samples are then deposited by electrophoresis on 7.5% polyacrylamide gel and undergo an electrotransfer on a PDVF membrane in a semi-dry system. After blocking, the membranes are incubated with an antiphosphotyrosine antibody (p-tyr (PY99), ref SC7020, Santa Cruz) and the chemiluminescence associated with a conjugated antibody is detected by a LAS 1000 camera (Fujifilm). After dehybridization then rehybridization with an anti-insulin receptor β-subunit antibody (βsubunit, ref 06492, Upstate biotechnology), the amount of total IR deposited on blot is evaluated by chemiluminescence and the rate of phosphorylation of the receptors is reduced. to the amount of total receptor deposited.

Likewise, the determination of the protein kinase B phosphorylation state following an electrophoresis of the samples on 10% polyacrylamide gel is carried out by chemiluminescence after immunoblotting with anti-phospho protein kinase B (phospho Akt (Ser473) antibody) antibodies. , ref 9271, Cell Signaling) then related to the amount of total protein kinase B (AKT antibody, ref 9272, Cell signaling).

The phosphorylation induced by the compounds of the invention is expressed as a percentage relative to the insulin at 50 nM, fixed at 100% activation.

The compounds of the invention activate either predominantly insulin receptors, predominantly protein kinase B, or both, which demonstrates their potential activity as insulinomimetic compounds.

For example, the compound of Example 27 to 10 ^"5 M, has an activation percentage

87.7% (n = 1) on insulin receptors, and 48.9% (n = 1) on protein kinase B.

The compound of Example 10, at 10 ^"5 M, has an activation percentage of 91% (n = 3) on protein kinase B. The compound of Example 30, at 10 ^{" 5} M, has a activation percentage of

134.4% (n = 2) on insulin receptors. EXAMPLE B; In vivo chronic study

11-week-old female C57BL / 6 ob / ob mice, randomized to basal glycemia in fed animals, are treated for 9 days with the test compound at 10 or 20 mg / kg ^ o and compared to a control group receiving HEC 1%. Laboratory tests (blood glucose, insulin, triglycerides) is the 10 ^th day of fed animals, the latest treatment that occurred the day before. The results are expressed in the form of percentages of variation compared to D0 (glycemia, body weight) compared to the control group. The results obtained show that the body weight is significantly reduced after treatment with the compounds of the invention. In particular, the compound of Example 16 shows a decrease of -26.9% while the result obtained for the control group is

+ 4.9%. It should be noted that the effect observed is dose-dependent.

The glycemia as well as the insulinemia are also greatly reduced during the treatment with the compounds of the invention. Thus, for the compound of Example 16, a result of -60.7% was recorded, compared to + 4.5% for the controls for glycemia, and -84.2% compared to the controls for insulinemia.

The results obtained also show a decrease in triglycerides during treatment with the compounds of the invention: by way of example, the compound of Example 1 shows a reduction of -37.8% compared to the control.

These results attest to the excellent in vivo activity of the compounds according to the invention as insulinomimetic agents, useful in this respect for the treatment of diabetes.

EXAMPLE C Pharmaceutical composition

Preparation formula for 1000 tablets containing 10 mg

Compound of example 1 10 g

Hydroxypropylcellulose 2 g Wheat starch 10 g

Lactose 100 g

Magnesium stearate 3 g

Talc 3 g

Claims

1. Compound of formula (I)

in which

Ri and R ₂ , identical or different, each represent a hydrogen atom or an acyl group (Cι-C ₆ ) linear or branched, or linear or branched alkyl (dC ₆ ), Ar represents an aryl or heteroaryl group, A represents a group chosen from:

_t substitutes the carbon atom linked to the benzoquinone ring and represents a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group,

R ₅ substitutes the carbon atom linked to the residue R ₃ and represents a hydrogen atom or a group chosen from linear or branched (Ci-Ce) alkyl, aryl and heteroaryl,

R ₃ represents an aryl, heteroaryl, dicyclopropylmethyl or benzhydryl group, or AR ₃ represents an optionally substituted naphthyl group, and in this case Ar represents an aryl group,

and its stereoisomers when they exist, as well as its addition salts with a pharmaceutically acceptable acid or base, excluding 2,5-dihydroxy-3- (4-methoxyphenyl) -6- (2-phenylethenyl) -1,4-benzoquinone, 2,5-dihydroxy-3- (4-methoxyphenyl) - 6- (2-naphthyl) -1,4-benzoquinone, and 2,5-dihydroxy-3- (2-naphthyl) -6-phenyl-1,4-benzoquinone,

it being understood that: - by aryl group is meant phenyl, biphenylyl, naphthyl, or tetrahydronaphthyl, each of these groups being optionally substituted by one or more atoms or groups, identical or different, chosen from halogen atoms and alkyl groups (dC ₆ ) linear or branched, hydroxy, alkoxy (Cι-C ₆ ) linear or branched, polyhaloalkyl (dC ₆ ) linear or branched, amino (optionally substituted by one or more alkyl groups (dC ₆ ) linear or branched), nitro , linear or branched acyl (dC ₆ ), alkylenedioxy (Cι-C ₂ ) or phenyloxy,

- optionally substituted naphthyl group means a naphthyl group unsubstituted or substituted by one or more atoms or groups, identical or different, chosen from halogen atoms and linear or branched (dC ₆ ) alkyl groups, hydroxy, alkoxy (dC ₆ ) linear or branched, polyhaloalkyl

(Ci-Ce) linear or branched, amino (optionally substituted by one or more alkyl (dC ₆ ) linear or branched), nitro, acyl (dC ₆ ) linear or branched, alkylenedioxy (dC ₂ ) or phenyloxy,

- And by heteroaryl group, is meant a mono- or bicyclic aromatic group of 5 to 12 members containing one, two or three heteroatoms chosen from oxygen, nitrogen or sulfur, it being understood that the heteroaryl can be optionally substituted by one or more atoms or groups, identical or different, chosen from halogen atoms and linear or branched (dC ₆ ) alkyl, hydroxy, linear or branched (C1-C6) alkoxy, linear or branched polyhaloalkyl (dC ₆ ), amino (substituted optionally by one or more alkyl groups (Ci-

Ce) linear or branched), nitro, acyl (dC ₆ ) linear or branched, alkylenedioxy (Cι-C ₂ ) or phenyloxy.

2. Compound of formula (I) according to claim 1

in which :

Ri and R ₂ , identical or different, each represent a hydrogen atom or a linear or branched acyl (dC ₆ ) or linear or branched alkyl (dC ₆ ) group, R ₃ represents an aryl, heteroaryl, dicyclopropylmethyl or benzhydryl group, Ar represents an aryl or heteroaryl group, A represents a group chosen from:

R ₄ substitutes the carbon atom linked to the benzoquinone ring and represents a hydrogen atom or a linear or branched (dC ₆ ) alkyl group,

4 R ₅ substitutes the carbon atom linked to the residue R ₃ and represents a hydrogen atom or a group chosen from linear or branched (Ci-Ce) alkyl, aryl and heteroaryl,

and its stereoisomers when they exist, as well as its addition salts with a pharmaceutically acceptable acid or base,

excluding 2,5-dihydroxy-3- (4-methoxyphenyl) -6- (2-phenylethenyl) -1,4-benzoquinone.

3. Compound of formula (I) according to claim 1:

in which :

V Ri and R ₂ , identical or different, each represent a hydrogen atom or a linear or branched acyl (dC ₆ ) group, or linear or branched alkyl (dC ₆ ), Ar represents an aryl group, AR ₃ represents a group optionally substituted naphthyl,

4. Compound of formula (I) according to claim 1 for which R _Î and R represent a hydrogen atom, its stereoisomers as well as its addition salts with a pharmaceutically acceptable acid or base.

5. Compound of formula (I) according to claim 1 for which Ar represents an aryl group, its stereoisomers as well as its addition salts with a pharmaceutically acceptable acid or base.

6. Compound of formula (I) according to claim 1 for which AR ₃ represents an arylethenyl group, its stereoisomers as well as its addition salts with a pharmaceutically acceptable acid or base.

7. Compound of formula (I) according to claim 1 which is 2- (4-chlorophenyl) -3,6- dihydroxy-5- (2-naphthyl) -1,4-benzoquinone, as well as its addition salts to a pharmaceutically acceptable acid or base.

8. Compound of formula (I) according to claim 1 which is 2- (4-bromophenyl) -3,6- dihydroxy-5- (2-naphthyl) -1,4-benzoquinone, as well as its addition salts to a pharmaceutically acceptable acid or base.

9. Compound of formula (I) according to claim 1 which is 2 - [(E) -2- (4-fluorophenyl) ethenyl] -3,6-dihydroxy-5-phenyl-1,4-benzoquinone, as well as its addition salts with a pharmaceutically acceptable acid or base.

10, Compound of formula (I) according to claim 1 which is 2- (4-chlorophenyl) -3,6- dihydroxy-5 - [(E) -2-phenylethenyl] -1,4-benzoquinone, as well as its addition salts with a pharmaceutically acceptable acid or base.

11. Compound of formula (I) according to claim 1 which is 2,5-dihydroxy-3-phenyl-6- [(E) -2-phenylethenyl] -1,4-benzoquinone, as well as its addition salts to a pharmaceutically acceptable acid or base.

12. Compound of formula (I) according to claim 1 which is 2- (4-bromophenyl) -3,6- dihydroxy-5 - [(E) -2-phenylethenyl] -1,4-benzoquinone, as well as its addition salts with a pharmaceutically acceptable acid or base.

13. Compound of formula (I) according to claim 1 which is 2,5-dihydroxy-3 - [(E) -l - methyl-2-phenylethenyl] -6-phenyl-1,4-benzoquinone, as well as its addition salts with a pharmaceutically acceptable acid or base.

14. Compound of formula (I) according to claim 1 which is 2- (3-chlorophenyl) -3,6- dihydroxy-5 - [(E) -2-phenylethenyl] -1,4-benzoquinone, as well as its addition salts with a pharmaceutically acceptable acid or base. , Compound which is 2- (4-bromophenyl) -3,6-dihydroxy-5-phenyl-1,4-benzoquinone, as well as its addition salts with a pharmaceutically acceptable base.

, Process for preparing the compounds of formula (I) according to claim 1, characterized in that a compound of formula (II) is reacted:

Ar 'J OH (D)

O in which Ar is as defined in formula (I), with a compound of formula

(III):

in which R represents a linear or branched (Cι-C ₆ ) alkyl group,

to lead to the compound of formula (IN):

in which Ar is as defined above, and Ri is as defined in formula (I),

which is reacted with a compound of formula (NI):

in which A and R ₃ are as defined in formula (I),

to lead to the compound of formula (Nile):

in which A, Ar, Ri and R are as defined above,

17. Pharmaceutical composition containing as active ingredient a compound according to any one of claims 1 to 15, in combination with one or more inert, non-toxic and pharmaceutically acceptable vehicles.

18. Pharmaceutical composition according to claim 17 useful as a medicament in the treatment of diseases associated with a deregulation of the glycemia.

9. Pharmaceutical composition according to claim 18 useful as an anti-diabetic drug.