FR2838438A1 - DIPHENYLPYRIDINE DERIVATIVES, THEIR PREPARATION, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME - Google Patents

Abstract

The invention relates to diphenylpyridine derivatives of formula: as well as to their preparation and to the pharmaceutical compositions containing them. These compounds exhibit antagonistic activity of the CB1 cannabinoid receptors.

Description

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

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

 New derivatives of 5,6-diphenyl-2-pyridine carboxamide have now been found which have antagonistic properties of the CB 1 cannabinoid receptors.

dans laquelle :

- RI représente l'hydrogène ou un (C l-C4)alkyle ; - R2 représente : . un groupe NR9R10, . un groupe (CH2)nR11, . un radical carbocyclique non aromatique en C3-C12, non substitué ou substitué une ou plusieurs fois par un groupe méthyle ; - R3, R4, R5, R6, R7, R8 représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (CI-C6)alkyle, (CI-C6)alcoxy ou trifluorométhyle ; - R9 et R10 ensemble avec l'atome d'azote auquel ils sont liés constituent un radical hétérocyclique, saturé ou insaturé, de 5 à 10 atomes, contenant ou non un deuxième hétéroatome choisi parmi 0 ou N, ledit radical étant non substitué ou substitué une ou plusieurs fois par un groupe méthyle ; - R11représente un radical hétéroaryle de 6 à 10 atomes contenant un ou plusieurs atomes d'azote ; - n représente 1, 2 ou 3 ; ainsi que leurs sels, leurs solvats et leurs hydrates. The subject of the present invention is therefore compounds of formula:

in which :

- RI represents hydrogen or a (C1-C4) alkyl; - R2 represents:. an NR9R10 group,. a group (CH2) nR11,. a non-aromatic C3-C12 carbocyclic radical, unsubstituted or substituted one or more times with a methyl group; - R3, R4, R5, R6, R7, R8 each independently of one another represent a hydrogen or halogen atom, a (CI-C6) alkyl, (CI-C6) alkoxy or trifluoromethyl group; - R9 and R10 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 0 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.

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 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 (C1-C6) alkyl group is meant a linear or branched radical, such as in particular: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, npentyl, isopentyl, n-hexyl, isohexyl, the group methyl being preferred.

 By (CI-C6) 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-C12 carbocyclic radicals include mono or polycyclic, condensed or bridged radicals. Monocyclic radicals include cycloalkyls, for example cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; cyclohexyl and cyclopentyl being preferred. The condensed, bridged or spiranic di- or tricyclic radicals include, for example, the norbomyl, bomyl, isobomyl, noradamantyl, adamantyl, spiro [5.5] undecanyl, bicyclo [2.2.1] heptanyl radicals; adamantyle, spiro [5.5] undecanyl, bicyclo [2.2.2] octanyl preferred.

 By heterocyclic radical, saturated or unsaturated, of 5 to 10 atoms, containing or not a second heteroatom such as 0 or N, one understands radicals such as morpholin-4yle, pipéridin-1-yle, pipérazin-1-yle, pyrrolidin- 1-yl, 3,6-dihydro-pyridin-1-yl, the radicals pyrrolidin-1-yl, piperidin-1-yl and morpholin-4-yl 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.

 Among the compounds which are the subject of the invention, there may be mentioned the preferred compounds which are defined by the following values of the substituents: - R1 represents a hydrogen atom; - And / or R2 represents a group chosen from: piperidinyl, pyrrodinyl, cyclohexyl, spiro [5.5] undecanyl, 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 R6, R7, R8 represents a halogen atom, preferably chlorine.

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 The present invention also relates to a process for the preparation of the compounds according to the invention.

dans laquelle R3, R4, R5, R6, R7, Rg sont tels que définis pour (I) avec une amine de formule HNR1R2 (III) dans laquelle RI et R2 sont tels que définis pour (I). This process is characterized in that a functional derivative of 5,6-diphenyl-2-pyridinecarboxylic acid of formula:

in which R3, R4, R5, R6, 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, for example, can be used. 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 (for example tetrahydrofuran, dioxane), or an amide (N, N-dimethylformamide for example) under an inert atmosphere, to a temperature between 0 C and temperature, in the presence of a tertiary amine such as triethylamine, Nmethylmorpholine 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.

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 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 R6 represent a halogen atom and R4, R5, R7, Rg represent a hydrogen atom.

 In step a1, a diketone of formula (IV) is reacted with an alkyl 2-amino-2hydrazinoacetate (described in Org. Synth., 1987, 66, 142) in a protic solvent such as ethanol.

 In step b2, the triazine derivative (V) 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.

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 This process is preferably applied for the preparation of compounds of formula (VI) in which the substituents R3, R4, R5 are similar to the substituents R6, R7, Rg. In fact, in the opposite case, step a1 leads to a mixture of (V) and (V ′) isomers which must be separated later.

DIAGRAM 2

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.

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 In step c2, the compound of formula (IX) is transformed into the ester derivative of 2pyridinecarboxylate (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.

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

dans laquelle :
R représente un atome d'hydrogène ou un groupe (C1-C4)alkyle et R3, R4, R5, R6, R7, Rg sont tels que définis pour (I), à la condition que lorsque l'un des substituants R3, R4, R5 est un (C1-C4)alcoxy et l'un des substituants R6, R7, Rg est un (C1-C4)alcoxy, R soit différent de l'hydrogène. Thus the subject of the present invention is also the compounds of formula:

in which :
R represents a hydrogen atom or a (C1-C4) alkyl group and R3, R4, R5, R6, R7, Rg are as defined for (I), provided that when one of the substituents R3, R4 , R5 is a (C1-C4) alkoxy and one of the substituents R6, R7, Rg is a (C1-C4) alkoxy, R is different from 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 in vitro affinity (IC50 <10-7M) for the cannabinoid receptors CB1, under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240-2424).

 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 salts, solvates or hydrates

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 pharmaceutically acceptable, for the preparation of medicaments intended to treat diseases involving the CB 1 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 trauma and the treatment of neurodegenerative diseases: 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, appetite (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, cirrhosis

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 chronic liver, asthma, Raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena, diseases of the immune system, in particular autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases resulting in demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, stroke 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 unit.

 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 method of administration, age, weight and response of said patient.

 In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular administration,

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 intravenous, transdermal, local or rectal, the active principle can be administered in unit administration form, in mixture with conventional pharmaceutical carriers, to 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, forms of subcutaneous, intramuscular, intravenous, intranasal or intraocular administration 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.

Preparation 1 (process B)
5- (4-chlorophenyl) -6- (2,4-dichlorophenyl) -2-pyridinecarboxylic acid.

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

 43 ml of tert-butylamine are introduced under nitrogen, at a temperature between 0 ° C. and 5 ° C., then 30 ml of acetaldehyde dropwise. 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 LDA solution 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 TMSiCI are added over the course of 1 hour and a half, the mixture is again stirred for 5 hours at -60 ° C. and 29 ml of TMSiCI are added. Let return to TA then filter on Celite # and concentrate to dryness under vacuum

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 before performing 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 and then 31.5 g of the compound of the preceding step, diluted in 60 ml of anhydrous THF, are added and the mixture is 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 with ether (2 times) then dried over MgSO4 and concentrated 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, F = 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 is 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 MgSO 4 and concentrated to dryness under vacuum. 23 g of the expected compound are obtained in the form of an oil.

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

 A sodium ethylate solution is prepared by the action of 5.3 g of sodium 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 thereto. 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 into 250 ml of water saturated with NaCl. The precipitate formed is filtered and then it is suspended in a water / DCM mixture. It is filtered and decanted, then the organic phase is dried over MgS04 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, F = 152 C.

G) ethyl 5- (4-Chlorophenyl) -6- (2,4-dichlorophenyl) -2-pyridinecarboxylate.

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 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 chromatography 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 previous step are placed in 15 ml of methanol, a solution of 1.36 g of potassium hydroxide in 15 ml of water is added, then the mixture is 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, F = 172 C.

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

A) Ethyl 5,6-bis (4-chlorophenyl) -1,2,4-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 the mixture is 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, F = 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, F = 185-190 C.

5-(4-Chlorophényl)-6-(2,4-dichlorophényl)-N-(1-pipéridinyl)-2-pyridine carboxamide. EXAMPLE 1

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

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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 it 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 the preceding step is added dropwise between 0 ° C. and 5 ° C. 15 ml DCM. After a night at 5 ° C., pour onto iced and decanted water. 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, F = 158 C.

EXAMPLE 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 5.6bis (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 for 16 hours. at TA. The mixture is poured into 30 ml of ice water and then extracted with DCM. The organic phase is washed with water, a 5% Na2CO3 solution, a saturated NaCl solution. After crystallization from isopropyl ether, 0.40 g of the expected compound is obtained, F = 158 C.

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

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TABLE 1

Exemples R6 R F C 3 H C-1 196 (exo) 4 H r1 194 5 H -(CH 2)2TI - 177 N H 185 -N 7 Cl /\ 148 8 Cl r 183

Examples R6 RFC 3 H C-1 196 (exo) 4 H r1 194 5 H - (CH 2) 2TI - 177 NH 185 -N 7 Cl / \ 148 8 Cl r 183

Claims (7)

 in which: - R1 represents hydrogen or a (C1-C4) alkyl; - R2 represents:. a group NR9R 10,. a group (CH2) nR11,. a non-aromatic C3-C12 carbocyclic radical, unsubstituted or substituted one or more times with a methyl group; - R3, R4, R5, R6, R7, R8 each independently of one another represent a hydrogen or halogen atom, a (C1-C6) alkyl, (CI-C6) alkoxy or trifluoromethyl group; - R9 and R10 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 0 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.

 CLAIMS 1. Compounds of formula: 2. Compounds according to claims 1 of formula (I) in which: - R1 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 R6, R7, Rg represents a halogen atom. <Desc / CRUD Page number 15> 3. Process for the preparation of a compound of formula (I) according to claim 1 or claim 2 characterized in that a functional derivative of 5,6-diphenyl-2-pyridinecarboxylic acid of formula is treated:

 in which R3, R4, R5, R6, R7, Rg are as defined for compound of formula (I) in claim 1 with an amine of formula HNR1R2 (III) in which R1 and R2 are as defined for a compound of formula (I) in claim 1. 4. Formula compounds:

 in which : R represents a hydrogen atom or a (CI-C4) alkyl group and R3, R4, R5, R6, R7, Rg are as defined for a compound of formula (I) in claim 1, provided that when one of the substituents R3, R4, R5 is an (CI-C4) alkoxy and one of substituents R6, R7, Rg is a (C1-C4) alkoxy, R is different from hydrogen. 5. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 or 2, or one of its pharmaceutically acceptable salts, hydrates or solvates. <Desc / Clms Page number 16> 6. Pharmaceutical composition characterized in that it comprises a compound of formula (I) according to any one of claims 1 or 2, or one of its pharmaceutically acceptable salts, hydrates or solvates as well as at least one pharmaceutically acceptable excipient. 7. Use of a compound of formula (I) according to any one of claims 1 or 2 for the preparation of a medicament intended for the treatment of any disease in which the cannabinoid receptor CB1 is involved.