WO2003084930A1

WO2003084930A1 - Diphenylpyridine derivatives, the preparation thereof, and pharmaceutical compositions containing said derivatives

Info

Publication number: WO2003084930A1
Application number: PCT/FR2003/001133
Authority: WO
Inventors: Francis Barth; Serge Martinez; Murielle Rinaldi-Carmona
Original assignee: Sanofi-Synthelabo
Priority date: 2002-04-11
Filing date: 2003-04-10
Publication date: 2003-10-16
Also published as: FR2838438A1; AU2003246810A1

Abstract

The invention relates to diphenylpyridine derivatives of formula (I), the preparation thereof, and pharmaceutical compositions containing said derivatives. Said compounds have an antagonistic activity of CB1 receptors to cannabinoids.

Description

DIPHENYLPYRIDINE DERIVATIVES, THEIR PREPARATION, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.

The subject of the present invention is derivatives of 5,6-diphenyl-2-pyridine carboxamide, their preparation and the pharmaceutical compositions containing them.

5,6-diphenyl-2-pyridine derivatives are described in the international patent application published under the number WO 92/02513. These compounds are presented as having an antithrombotic, vasodilatory, anti-inflammatory activity.

Novel derivatives of 5,6-diphenyl-2-pyridine carboxamide have now been found which have antagonistic properties of the CB ^ cannabinoid receptors.

The subject of the present invention is therefore compounds of formula:

in which :

- Rj represents hydrogen or a (Cι-C4) alkyl;

- R2 represents:. a group (C3-C7) al yle,

. an indan-1-yl or 1,2,3,4-tetrahydronaphthalen-1-yl group, said groups being unsubstituted or substituted by a halogen atom and / or a methyl group;

. a saturated monoazotated heterocyclic radical of 5 to 7 atoms, the nitrogen atom being substituted by a (Cι-C4) alkyl, benzyl, (Cι-C3) alkoxycarbonyl or (Cj-C ^ alkanoyl) group;

. an NR9R10 group;

. a group (CH ₂ ) _n Rll. CH (CH ₃ ) R _n ,

;

. a non-aromatic C3-C12 carbocyclic radical, unsubstituted or substituted one or more times with a methyl group;

- or Ri and R2 together with the nitrogen atom to which they are linked constitute either a piperazin-1-yl radical substituted in -4 by a phenyl or benzyl group, or a piperidin-1-yl radical disubstituted in -4 by a phenyl or benzyl group and by a (Cι-C4) alkyl or (Cι-C3) alkanoyl group; the phenyl or benzyl groups substituting the piperazin-1-yl radical or the piperidin-1-yl radical being unsubstituted or substituted by a halogen atom and / or a methyl group;

- R3, R4, R5, R, R7, Rg each independently of one another represent a hydrogen or halogen atom, a (Cι -Cβ) alkyl, (Cι-Cg) alkoxy or trifluoromethyl group;

- R9 and Rio together with the nitrogen atom to which they are linked constitute a heterocyclic radical, saturated or unsaturated, of 5 to 10 atoms, containing or not a second heteroatom chosen from O or N, said radical being unsubstituted or substituted one or more times with a (C -C4) alkyl, hydroxyl, or (C -

C4) alkoxy;

R l represents:. phenyl unsubstituted or substituted by one or more substituents chosen from a halogen atom or a methyl group; . a heteroaryl radical of 6 to 10 atoms containing one or more nitrogen atoms;

- n represents 1, 2 or 3;

- m represents 0, 2 or 3; as well as their salts, their solvates and their hydrates. The compounds of formula (I) can exist in the form of bases or of addition salts with acids. These salts are advantageously prepared with pharmaceutically acceptable salts but the salts of other acids useful, for example, for the purification or the isolation of the compounds of formula (I) also form part of the invention. By alkyl group is meant a linear or branched radical, such as in particular: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, the methyl group being preferred. for a (C1-C4) alkyl, the tert-butyl, 2-methylbutyl-2, 3,3-dimethylbutyl-2 groups being preferred for a (C3-C7) alkyl. By (C -Cg) alkoxy group is meant a linear or branched radical containing 1 to

6 carbon atoms, the methoxy group being preferred.

By halogen atom is meant a fluorine, chlorine, bromine or iodine atom; fluorine, chlorine or bromine atoms being preferred.

Non-aromatic C3-C 2 carbocyclic radicals include mono or polycyclic, condensed or bridged radicals. Monocyclic radicals include cycloalkyls, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyle, cyclooctyle; cyclohexyl and cyclopentyl being preferred. The condensed, bridged or spiranic di- or tricyclic radicals include, for example, the norbornyl, bornyl, isobornyl, noradamantyl, adamantyl, spiro [5.5] undecanyl, bicyclo [2.2.1] heptanyl radicals; adamantyle, spiro [5.5] undecanyl, bicyclo [2.2.2] octanyl being preferred.

By heterocyclic radical, saturated or unsaturated, of 5 to 10 atoms, containing or not containing a second heteroatom such as O or N, is meant radicals such as morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yle, 3,6-dihydropyridin-l-yle, octahydrocyclopenta [c] pyrrol-2-yle, the radicals pyrrolidin-1-yle, piperidin-1-yle and morpholin-4-yle being preferred.

By saturated monoazotated heterocyclic radical of 5 to 7 atoms is meant a radical such as piperidin-4-yl or pyrrolidin-3yle _y, the piperidin-4-yl radical being preferred.

By heteroaryl radical of 6 to 10 atoms containing one or more nitrogen atoms is meant radicals such as pyridyl, indolyl, quinolyl; Indolyl being preferred.

According to the present invention, the compounds of formula (I) are preferred in which:

- Ri represents hydrogen or a (Cι-C4) alkyl; R ₂ represents:. an NR9R10 group,

. a group (CH2) _n Rll>. a non-aromatic C3-C12 carbocyclic radical, unsubstituted or substituted one or more times with a methyl group;

- R3, R4, R5, Rg, R7, Rg each independently of one another represent a hydrogen or halogen atom, a group (Ci-C aD-yl, (C -C _ç alco y or trifluoromethyl; - R9 and Rio together with the nitrogen atom to which they are linked constitute a heterocyclic radical, saturated or unsaturated, of 5 to 10 atoms, containing or not a second heteroatom chosen from O or N, said radical being unsubstituted or substituted one or more times with a methyl group;

- Ru represents a heteroaryl radical of 6 to 10 atoms containing one or more nitrogen atoms; n represents 1, 2 or 3; as well as their salts, their solvates and their hydrates.

Among the compounds which are subject of the invention, there may be mentioned the preferred compounds which are defined by the following values of the substituents: - R represents a hydrogen atom; - And / or R2 represents a group chosen from: piperidinyl, pyrrodinyl, cyclohexyl, spiro [5.5] undecanyl, bicyclo [2.2.2] octan-2-yl, adamantyl, 2- (1H-indol-3-yl) ethyl;

- And / or at least one of the substituents R3, R4, R5 represents a halogen atom, preferably chlorine;

- And / or at least one of the substituents Rg, R7, Rg represents a halogen atom, preferably chlorine.

The present invention also relates to a process for the preparation of the compounds according to the invention. This process is characterized in that a functional derivative of 5,6-diphenyl-2-pyridinecarboxylic acid of formula:

in which R3, R4, R5, Rg, R7, Rg are as defined for (I) with an amine of formula HNR1R2 (III) in which Ri and R2 are as defined for (I). Optionally, the compound thus obtained is transformed into one of its salts or solvates.

As functional derivative of acid (II), acid chloride, anhydride, a mixed anhydride, a C1-C4 alkyl ester in which the alkyl is straight or branched, an activated ester can be used, for example p-nitrophenyl ester, or free acid suitably activated, for example, with N, N-dicyclohexylcarbodiimide or with benzotriazol hexafluorophosphate-N-yloxotris (dimethylamino) phosphonium (BOP).

Thus in the process according to the invention, it is possible to react the chloride of pyrazole-3-carboxylic acid, obtained by reaction of thionyl chloride on the acid of formula (II), with an amine HNR1R2, in a solvent inert, such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N, N-dimethylformamide for example) under an inert atmosphere, to an temperature between 0 ° C and temperature, in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine. A variant consists in preparing the mixed anhydride of the acid of formula (II) by reaction of ethyl chloroformate with the acid of formula (II), in the presence of a base such as triethylamine, and in doing so react with an amine HNR1R2, in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.

The compounds of formula (II) can be prepared by various methods known from the literature.

DIAGRAM 1

(IN)

The process in Scheme 1 called process A has been described in Aust. J. Chem., 1972, 25, 865 for compounds in which the substituents R3 and Rg represent a halogen atom and R4, R5, R7, Rg represent a hydrogen atom. In step ai, a diketone of formula (IN) is reacted with an alkyl 2-amino-2-hydrazinoacetate (described in Org. Synth., 1987, 66, 142) in a protic solvent such as ethanol.

In step b2, the triazine derivative (N) thus obtained is treated with bicyclo [2.2.1] hepta-2,5-diene) in a solvent such as benzene, dioxane or acetonitrile, at a temperature between room temperature and the reflux temperature of the solvent.

This process is preferably applied for the preparation of compounds of formula (NI) in which the substituents R3, R4, R5 are similar to the substituents Rg, R7, Rg. In fact, in the opposite case, step ai leads to a mixture of (N) and (N ') isomers which must be separated later.

DIAGRAM 2

Alk = (C.-C) alkyl Scheme 2 describes another process (called process B) for the preparation of the compounds of formula (II).

In step a2, a cinnamic aldehyde derivative (VII) is made to act with ethyl azidoacetate, in the presence of a base such as sodium ethylate, according to Tetrahedron Letters, 1979, 1717.

In step b2, the azidoester of formula (VIII) thus obtained is transformed into a phosphazene derivative (IX) by reaction with triphenylphosphine.

In step C2, the compound of formula (IX) is transformed into the 2-pyridinecarboxylate ester derivative (VI) by the action of a correctly substituted benzaldehyde derivative.

Steps b2 and C2 are carried out as described in J. Chem. Soc. Perkin Trans 1, 1990, 2193.

The acids of formula (II) and their esters of formula (VI) are generally new.

The Aust publication. J. Chem., 1972, 25 (4), 865-874 describes esters of formula (II) in which all of the substituents R3 to Rg are hydrogen.

International patent application WO 92/02513 describes 5,6-bis (4-methoxyphenyl) -2-pyridinecarboxylic acid.

Thus, the subject of the present invention is also the compounds of formula:

(Three)

in which :

R represents a hydrogen atom or a (Cι-C4) alkyl group and R3, R4, R5, Rg, R7, Rg are as defined for (I), provided that R3, R4, R5, Rg, R7 , Rg are not simultaneously hydrogen and on the condition that when one of the substituents R3 and Rg each represent a group (Cι-C4) alkoxy, R4, R5, R7, Rg are not simultaneously hydrogen.

More particularly, the compounds of formula (Ilbis) are preferred in which:

- R3 is in position -4 and represents a halogen atom;

- Rg is in position -2 and represents a hydrogen or halogen atom; - R7 is in position -4 and represents a halogen atom or a methyl group;

- R4, R5 and Rg are hydrogen.

The HNR1R2 amines are known or prepared by known methods such as those described in Chem. Ber., 1986, 119, 1413-1423. The compounds of formula (I) have a very good affinity in vitro (IC50 ≤

10 M) for the cannabinoid CBi receptors, under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240-244).

The antagonistic nature of the compounds of formula (I) has been demonstrated by the results obtained in the models of the inhibition of adenylate cyclase as described in M. Rinaldi-Carmona et al, J. Pharmacol. Exp. Ther., 1996, 278, 871-878.

The toxicity of the compounds of formula (I) is compatible with their use as a medicament.

According to another of its aspects, the present invention relates to the use of a compound of formula (I), or of one of its pharmaceutically acceptable salts, solvates or hydrates, for the preparation of medicaments intended for treating diseases involving CBi cannabinoid receptors.

For example and without limitation, the compounds of formula (I) are useful as psychotropic drugs, in particular for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive-compulsive disorder, psychosis in general, schizophrenia, as well as for the treatment of disorders linked to the use of psychotropic substances, in particular in the case of substance abuse and / or dependence on a substance, including alcohol dependence and nicotine dependence.

The compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, diseases of psychosomatic origin, attacks of panic attacks, epilepsy, movement disorders , especially dyskinesia or Parkinson's disease, tremors and dystonia.

The compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, of Alzheimer's disease, as well as in the treatment of attention or alertness disturbances. In addition, the compounds of formula (I) can be useful as neuroprotectors, in the treatment of ischemia, head injuries and the treatment of diseases neurodegenerative: including chorea, Huntington's chorea, Tourrette syndrome.

The compounds of formula (I) according to the invention can be used as medicaments in the treatment of pain: neuropathic pain, acute peripheral pain, chronic pain of inflammatory origin.

The compounds of formula (I) according to the invention can be used as medicaments in the treatment of appetite disorders, palatability (for sugars, carbohydrates, drugs, alcohols or any appetizing substance) and / or conduct food, especially as appetite suppressants or for the treatment of obesity or bulimia as well as for the treatment of type II diabetes or non-insulin dependent diabetes. In addition, the compounds of formula (I) according to the invention can be used as medicaments in the treatment of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, disorders of endocrine origin , cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, chronic cirrhosis of the liver, asthma, Raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena, immune system diseases, in particular autoimmune and neuroinflammatory diseases such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, cerebrovascular accidents as well as '' as drugs for cancer chemotherapy and for the treatment of Guillain-Barré syndrome.

According to the present invention, the compounds of formula (I) are very particularly useful for the treatment of psychotic disorders, in particular schizophrenia; for the treatment of appetite disorders and obesity for the treatment of memory and cognitive disorders; for the treatment of alcohol dependence, nicotine dependence, that is to say for alcohol withdrawal and for smoking cessation.

According to one of its aspects, the present invention relates to the use of a compound of formula (I), its pharmaceutically acceptable salts and their solvates or hydrates for the treatment of the disorders and diseases indicated above. The compound according to the invention is generally administered in dosage units. Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient. Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I), one of its pharmaceutically acceptable salts or one of their solvates.

The compound of formula (I) above and its pharmaceutically acceptable salts or solvates can be used in daily doses of 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably in daily doses of 0, 02 to

50 mg / kg. In humans, the dose may preferably vary from 0.05 to 4000 mg per day, more particularly from 0.1 to 1000 mg per day depending on the age of the subject to be treated or the type of treatment, namely prophylactic or curative. Although these dosages are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the mode of administration, the age, the weight and the response of said patient. In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle can be administered in unit administration form, in admixture with carriers conventional pharmaceuticals, animals and humans. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, administration forms topical, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and forms of rectal administration. In the pharmaceutical compositions of the present invention, the active ingredient is generally formulated in dosage units containing from 0.05 to 1000 mg, advantageously from 0.1 to 500 mg, preferably from 1 to 200 mg of said active ingredient per unit of dosage for daily administrations.

In the present description, the following abbreviations are used: DCM: dichloromethane

LDA: lithium diisopropylamide

THF: tetrahydrofuran

TMSiCl: trimethylchlorosilane

Ether: ethyl ether AcOEt: ethyl acetate

RT: room temperature F: melting point.

The compounds according to the invention are analyzed by LC / UV / MS coupling (liquid chromatography / UV detection / mass spectrometry). The molecular peak (M) and the retention time (t) in minutes are measured. An Xterra Waters MS C18 column, sold by Waters, of

2.1 x 30 mm, 3.5 μm, at room temperature, flow rate 1 mlJminute.

The eluent is composed as follows:

- solvent A: 0.025% trifluoroacetic acid (TFA) in water

- solvent B: 0.025% TFA in acetonitrile. Gradient: The percentage of solvent B varies from 0 to 100% in 2 minutes with a tray at 100% B for 1 minute.

UN detection is carried out between 210 nm and 400 nm and mass detection in chemical ionization mode at atmospheric pressure. Preparation 1 (method B) 5- (4-chlorophenyl) -6- (2,4-dichlorophenyl) -2-pyridinecarboxylic acid.

A) Ν- (tert-butyl) -Ν- (ethylidene) amine.

43 ml of tert-butylamine are introduced under nitrogen, at a temperature between 0 ° C. and 5 ° C., then dropwise 30 ml of acetaldehyde. The mixture is left stirring for 30 minutes at this temperature and then 500 mg of finely ground potassium hydroxide are added. After decantation, the organic phase is distilled under vacuum over barium oxide. 31 g of the expected compound are obtained in liquid form.

B) N- (2,2'-bis (trimethylsilyl) ethylidene) -N- (tert-butyl) amine.

300 ml of a 1.5 M solution of LDA in cyclohexane, 200 ml of anhydrous THF and then 23 g of the compound of the preceding step are introduced under nitrogen at -60 ° C. The mixture is left stirring at this temperature for 18 hours, then 29 ml of TMSiCl is added over 1 hour and a half, the mixture is again stirred for 5 hours at -60 ° C. and 29 ml of

TMSiCl. The mixture is left to return to TA then filtered through Celite and concentrated to dryness under vacuum before carrying out 2 successive distillations to obtain 31.5 g of the expected compound in liquid form. C) 3- (4-Chlorophenyl) -2-propenal.

Under nitrogen, at a temperature between 15 ° C and 20 ° C, a mixture is prepared containing 16.5 g of 4-chlorobenzaldehyde in 117 ml of anhydrous THF; 2.63 g of zinc bromide are added, then 31.5 g of the compound of the previous step diluted in 60 ml of anhydrous THF and left to stir overnight. A mixture containing 26 g of zinc chloride dissolved in 260 ml of water and 300 ml of ether is added and the mixture is left stirring for 2 hours. The medium is filtered on Celite, extracted at ether (2 times) then dry over MgS04 and concentrate in vacuo. The residue is chromatographed on silica, eluting with a toluene / AcOEt mixture (95/5; v / v). 11.5 g of the expected compound are obtained, which crystallizes, mp = 54 ° C.

D) Ethyl azidoacetate. To a solution of 23.6 ml of ethyl chloroacetate in 100 ml of acetonitrile, 14.2 g of sodium azide are added, then the mixture is refluxed for 4 days. After cooling, the white solid is filtered and then the solution is concentrated in vacuo. The oil obtained is diluted in 500 ml of ethyl acetate, then washed with water (2 times), dried over MgSθ4 and concentrated to dryness under vacuum. 23 g of the expected compound are obtained in the form of an oil.

E) Ethyl 5- (4-Chlorophenyl) -2-azido-2,4-pentanedioate.

A solution of sodium ethylate as action of 5.3 g of sodium is prepared on 141 ml of ethanol. This solution is cooled to -10 ° C and a mixture containing 11 g of 4-chlorophenyl-2-propenal and 29.83 g of ethyl azidoacetate in 100 ml of ethanol is added to it. After the end of the addition, the temperature is maintained at -10 ° C for 3 hours then allowed to return to RT and the reaction medium is poured onto 250 ml of water saturated with NaCl. The precipitate formed is filtered and then it is suspended in a DCM water mixture. It is filtered and decanted, then the organic phase is dried over MgSθ4 and evaporated. 4.6 g of the expected compound are obtained in the form of an oil. F) ethyl 5- (4-Chlorophenylphosphine) -2- (triphenylphosphoranylidene) amino-2,4-pentanedioate.

A mixture containing 4.24 g of triphenylphosphine in solution in 20 ml of DCM is prepared and 4.55 g of the compound of the preceding step is added at RT in solution in 34 ml of DCM. The mixture is left stirring at RT for 2 days and then concentrated under vacuum. The residue is taken up in isopropyl ether, filtered, rinsed and dried under vacuum to obtain 7.3 g of the expected compound in solid form, mp = 152 ° C. G) ethyl 5- (4-Chlorophenyl) -6- (2,4-dichlorophenyl) -2-pyridinecarboxylate.

7.3 g of the compound obtained in the preceding step are placed in 220 ml of acetonitrile with 2.5 g of 2,4-dichlorobenzaldehyde and the mixture is heated at 60 ° C for 26 hours. After returning to RT, the mixture is concentrated and then the residue is taken up in toluene and chromatographed on silica, eluting with a toluene / AcOEt mixture (90/10; v / v). 3.83 g of the expected compound are obtained. H) 5- (4-Chlorophenyl) -6- (2,4-dichlorophenyl) -2-pyridinecarboxylic acid.

3.8 g of the compound from the preceding step are placed in 15 ml of methanol, a solution of 1.36 g of potassium hydroxide in 15 ml of water is added and the mixture is then heated at reflux overnight. After returning to RT, the reaction medium is poured into 100 ml of ice water and then acidified to pH = 1 with 10% HCl. It is extracted with AcOEt and then washed with a saturated NaCl solution. 3.1 g of the expected compound are obtained, which crystallizes from iso ether, mp = 172 ° C. Preparation 2 (method A) 5,6-bis (4-chlorophenyl) -2-pyridinecarboxylic acid.

A) Ethyl 5, 6-bis (4-chlorophenyl) -1,4,4-triazine-3-carboxylate.

A suspension of 11.9 g of 1,2-bis (4-chlorophenyl) -1,2-ethanedione and 5.60 g of ethyl 2-amino-2-hydrozinoacetate is placed in 230 ml and heated to reflux. for 16 hours. After cooling, the crystals formed are filtered and washed with ethanol. After recrystallization from ethanol, they are purified by chromatography on silica, eluting with an AcOEt / toluene mixture (5/100; v / v to 12/100; v / v). 11.9 g of the expected compound are obtained.

B) 5,6-bis- (4-chlorophenyl) -2-ethyl pyridinecarboxylate.

1.50 g of the compound of the preceding step and 1 ml of bicyclo [2.2.1] hepta-2,5-diene are placed under a nitrogen atmosphere, in 50 ml of benzene and the mixture is heated at reflux for 4 hours. . By evaporation of the solvent, an oil is obtained which is purified by crystallization from isopropyl ether, mp 103 ° C.

C) 5,6-bis (4-chlorophenyl) -2-pyridinecarboxylic acid.

0.87 g of ester obtained in the previous step is suspended in a mixture of 5 ml of methanol, 5 ml of water and 0.33 g of potassium hydroxide and then heated under reflux for

4 hours. After cooling, acidification to pH = 1 with 10% HCl. The solid formed is filtered, washed with water and then with pentane and dried under vacuum. 0.76 g of the expected compound is obtained, M = 185-190 ° C.

Following method A described above, the intermediate compounds in the table below were also prepared:

TABLE 1

NMR: Preparation 3: 7.1 ppm: 2H; 7.2-7.4 ppm: mt: 4H; 7.45 ppm: d: 2H; 7.9-8.1 ppm: dd: 2H. NMR: Preparation 4: 2.2 ppm: 3H; 6.9-7.2 ppm: mt: 6H; 7.25 ppm: d: 2H 7.8-8 ppm: dd: 2H. EXAMPLE 1: Compound 1

5- (4-Chlorophenyl) -6- (2,4-dichlorophenyl) -N- (1-piperidinyl) -2-pyridine carboxamide.

A) 5- (4-Chlorophenyl) -6- (2,4-dichlorophenyl) -2-pyridine carboxylic acid chloride.

0.8 g of the acid obtained in Preparation 1 is placed in 8 ml of toluene in the presence of 0.46 ml of SOCI2 and the mixture is heated at reflux for 2.5 hours. After cooling, the solution is concentrated to dryness under vacuum then taken up in toluene and re-evaporated (2 times). 0.76 g of the expected compound is obtained, used as is in the following step.

B) 5- (4-Chlorophenyl) -6- (2,4-dichlorophenyl) -N- (1-piperidinyl) -2-pyridine carboxamide.

To a solution containing 0.27 ml of 1-aminopiperidine and 0.35 ml of triethylamine in 15 ml of DCM, the acid chloride obtained in step is added dropwise between 0 ° C and 5 ° C previous in 15 ml of DCM. After a night at 5 ° C, pour on ice water and decant. Extraction is carried out with DCM and then the organic phase is washed with a 5% Na2CO3 solution with a saturated NaCl solution. It is dried and evaporated, then the residue is chromatographed on silica, eluting with a toluene / AcOEt mixture (70/30; v / v). 0.6 g of the expected compound is obtained which crystallizes from iso ether, mp = 158 ° C.

EXAMPLE 2 Compound 2 5,6-bis- (4-chlorophenyl) -N-cyclohexyl-2-pyridinecarboxamide.

A) 5,6-bis (4-chlorophenyl) -2-pyridinecarboxylic acid chloride.

A mixture containing 0.76 g of 5.6-bis (4-chlorophenyl) -2-pyridinecarboxylic acid and 0.48 ml of thionyl chloride in 8 ml of toluene is heated at reflux for 4 hours. After cooling, the solvent is evaporated and the residue is taken up in 15 ml of toluene and evaporated to dryness. The oil obtained is used directly in the next step.

B) 5,6-bis- (4-chlorophenyl) -N-cyclohexyl-2-pyridinecarboxamide. A solution of 0.28 ml of cyclohexylamine and 0.68 ml of triethylamine in 10 ml of DCM is cooled to 0 ° C. and the acid chloride obtained in the preceding step is added dropwise, followed by stirring 16 hours at RT. The mixture is poured into 30 ml of ice water and then extracted with DCM. The organic phase is washed with water, a 5% Na Cθ3 solution, a saturated NaCl solution. After crystallization from isopropyl ether, 0.40 g of the expected compound is obtained, mp = 158 ° C.

By proceeding according to the examples described above, the compounds according to the invention prepared in the following table were prepared.

TABLE 2

Claims

1. Compounds of formula:

in which :

- Ri represents hydrogen or a (Cι-C4) alkyl;

- R2 represents:. an (C3-C7) alkyl group,

. a saturated monoazotated heterocyclic radical of 5 to 7 atoms, the nitrogen atom being substituted by a (Cι-C4) alkyl, benzyl, (Cι-C3) alkoxycarbonyl or (Cι-C4) alkanoyl group;

. an NR9R10 group;

. a group (CH ₂ ) _n Rι 1, CH (CH ₃ ) Rι _h (CH ₂ ) _m N (CH ₃ ) Rι 1;

- R3, R4, R5, Rg, R7, Rg each independently of one another represent a hydrogen or halogen atom, a (C -Cg) alkyl, (Cι-Cg) alkoxy or trifluoromethyl group;

- R9 and Rio together with the nitrogen atom to which they are linked constitute a heterocyclic radical, saturated or unsaturated, of 5 to 10 atoms, containing or not a second heteroatom chosen from O or N, said radical being unsubstituted or substituted one or more times by a (Cι-C4) alkyl, hydroxyl, or (C1-C4) alkoxy group;

- Rl l represents:. phenyl unsubstituted or substituted by one or more substituents chosen from a halogen atom or a methyl group;

. a heteroaryl radical of 6 to 10 atoms containing one or more nitrogen atoms;

- n represents 1, 2 or 3;

- m represents 0, 2 or 3; as well as their salts, their solvates and their hydrates.

2. Compounds according to claim 1 of formula (I) in which:

- Ri represents hydrogen or a (C -C4) alkyl;

- R2 represents:. an NR9R10 group,

. a group (CH2) _n Rn; . a non-aromatic C3-C 2 carbocyclic radical, unsubstituted or substituted one or more times with a methyl group;

- R3, R4, R5, Rg, R7, Rg each independently of one another represent a hydrogen or halogen atom, a (Cι-Cg) alkyl, (Cι-Cg) alkoxy or trifluoromethyl group;

- R9 and Rio together with the nitrogen atom to which they are linked constitute a heterocyclic radical, saturated or unsaturated, of 5 to 10 atoms, containing or not a second heteroatom chosen from O or N, said radical being unsubstituted or substituted one or more times with a methyl group; - R11 represents a heteroaryl radical of 6 to 10 atoms containing one or more nitrogen atoms;

- n represents 1, 2 or 3; as well as their salts, their solvates and their hydrates.

3. Compounds according to claim 1 or claim 2 of formula (I) in which:

- Ri represents a hydrogen atom;

- And / or R2 represents a group chosen from: piperidinyl, pyrrodinyl, cyclohexyl, spiro [5.5] undecanyl, bicyclo [2.2.2] octan-2-yl, adamantyl, 2- (1H-indol-3-yl) ethyl; - And / or at least one of the substituents R3, R4, R5 represents a halogen atom;

- And / or at least one of the substituents Rg, R7, Rg represents a halogen atom. Process for the preparation of a compound of formula (I) according to any one of Claims 1 to 3, characterized in that a functional derivative of 5,6-diphenyl-2-pyridinecarboxylic acid of the formula:

in which R3, R4, R5, Rg, R7, Rg are as defined for compound of formula (I) in claim 1 with an amine of formula HNR1R2 (III) in which Ri and R are as defined for a compound of formula (I) in claim 1. 5. Compounds of formula:

(Llbis)

in which :

R represents a hydrogen atom or a group (Cι-C4) alkyl and R3, R4, R5, Rg, R7, Rg are as defined for a compound of formula (I) in claim 1, provided that R3 , R4, R5, Rg, R7, Rg are not simultaneously hydrogen and on the condition that when R3 and Rg each represent an (Cι-Cg) alkoxy group, R4, R5, R7 and Rg are not simultaneously the hydrogen. 6. Compound according to claim 5 of formula (Ilbis) in which:

- R3 is in position -4 and represents a halogen atom;

- Rg is in position -2 and represents a hydrogen or halogen atom;

- R7 is in position -4 and represents a halogen atom or a methyl group;

- R4, R5 and Rg are hydrogen.

7. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, or one of its pharmaceutically acceptable salts, hydrates or solvates.

8. Pharmaceutical composition characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, or one of its pharmaceutically acceptable salts, hydrates or solvates as well as at least one pharmaceutically acceptable excipient.

9. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament intended for the treatment of any disease in which the cannabinoid receptor CB i is involved.

10. Use according to claim 9 for the preparation of a medicament intended for the treatment of psychotic disorders, memory and cognitive disorders, appetite disorders and obesity, or for smoking cessation or alcohol withdrawal.