WO2011033225A2

WO2011033225A2 - Substituted 3-amino-cinnolin-4(1h)-one derivatives, preparation thereof, and therapeutic use thereof

Info

Publication number: WO2011033225A2
Application number: PCT/FR2010/051927
Authority: WO
Inventors: Carole Legeay; Murielle Rinaldi-Carmona; Pascale Roux; Claude Vernhet
Original assignee: Sanofi-Aventis
Priority date: 2009-09-17
Filing date: 2010-09-16
Publication date: 2011-03-24
Also published as: FR2950055A1; WO2011033225A3

Abstract

The present invention relates to compounds having Formula (I): - R₁ is a hydrogen atom or a (C₁-C₄)alkyl; - R₂ is a substituted or unsubstituted (C₁-C₁₀)alkyl or a substituted or unsubstituted (C₃-C₁₂) non-aromatic carbocyclic radical; - or R₁ and R₂ together, with the nitrogen atom to which they are linked, form a heterocyclic radical selected from among azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, and piperazin-1-yl, said heterocyclic radical being substituted or unsubstituted; - R₃ is a -(CH₂)_n-R₅group; - R₄ is a hydrogen atom, a halogen atom, an Alk group, or an OAlk group; - R₅ is a halogen atom, a CF₃ group, or a group selected from among -S-Alk,, -SO-Alk, -SO₂-Alk, -N(R₆)SO₂-Alk; -R₆ is a hydrogen atom or a (C₁-C₄)alkyl; - Alk is a substituted or unsubstituted (C₁-C₄)alkyl; n is equal to an integer between 2 and 5. The invention also relates to a preparation method and to therapeutic use.

Description

SUBSTITUTED 3-AMINO-CINNOLIN-4 (7H) -ONE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF

The present invention relates to novel 3-amino-cinnolin-4 (H) -one derivatives, having an affinity for cannabinoid type 2 (CB2) receptors, to their preparation and to their therapeutic application.

Delta9-THC is the major active ingredient extracted from Cannabis sativa [Paton, Annual Review in Pharmacology (1975) 15: 191-220].

Numerous articles have described not only the psychotropic effects of cannabinoids, but also their influence on immune function [Klein et al, Immunology Today (1998) 19: 373-381], pain control [Pertwee, Progress in Neurobiology (2001) 63: 569-611], food intake [Cota et al. International Journal of Obesity (2003) 27: 289-301] and many other biological functions [Nahas et al. Marihuana and medicine (1999) Humana Press: Totowa, New Jersey, USA].

The effects of cannabinoids are due to an interaction with specific high affinity, G-protein coupled receptors present at the central and peripheral level [Howlett et al., Pharmacological Reviews (2002) 54: 161-2002].

The central effects of cannabinoids are of a first type of receptor (CBT) present mainly in the brain but also on the periphery [Matsuda et al, Nature (1990) 346: 561-564]. In addition, Munro et al. [Nature (1993) 365: 61-65] have cloned a second type of cannabinoid receptor called CB2 which is present at the periphery and in particular in the cells of the immune system, but also in the brain under certain pathological conditions.

Certain indole derivatives have been cited in the prior art as having affinity for CB2 receptors: patent applications US 5,532,237, EP 833,818, US 4,581,354, WO 2002/42269, WO2003 / 097597, WO 2006/069196, WO 2007/057 571.

Certain cinnolin-4 (1H) -one derivatives have been described in patent applications WO93 / 09098 and WO2009 / 053799.

Cinnoline derivatives have also been described by E. Stern et al. in J. Med. Chem, 2007, 50, 5471-5484, in particular the compound of formula:

Novel 3-amino-cinnolin-4 (H) -one derivatives have now been found which exhibit high affinity and selectivity for cannabinoid CB2 receptors. These compounds have a modulatory effect on the activity of CB2 receptors. By modulator effect is meant in particular agonist effects, antagonists and / or inverse agonists.

The subject of the present invention is compounds corresponding to formula (I):

in which :

R 1 represents a hydrogen atom or a (C 1 -C 4) alkyl;

- R-2 represents:

. a (Ci -Ci) alkyl unsubstituted or substituted one or more times with substituents independently selected from:

a) a fluorine atom;

b) a non-aromatic (C 3 -C 12) carbocyclic radical which is unsubstituted or substituted one or more times with substituents chosen independently from a halogen atom, an Alk group or an OAlk group;

c) phenyl which is unsubstituted or substituted one or more times with substituents independently chosen from a halogen atom, an Alk group and an OAlk group;

. a non-aromatic (C 3 -C 12) carbocyclic radical unsubstituted or substituted one or more times with substituents independently selected from a halogen atom, an Alk group, an OAlk group; or R 1 and R 2 together with the nitrogen atom to which they are bonded constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin- 4-yl, piperazin-1-yl, said heterocyclic radical being unsubstituted or substituted one or more times with substituents independently selected from a halogen atom, an Alk group, an OAlk group;

R3 represents:

. a group - (CH2 R5;

R4 represents a hydrogen atom, a halogen atom, an Alk group or an OAlk group;

R 5 represents a halogen atom, a CF 3 group or a group chosen from

-S-Alk, -SO-Alk, -SO ₂ -Alk,

-N (R ₆ ) S0 ₂ -Alk;

- R ₍ 5 represents a hydrogen atom or a (C 1 -C 4) alkyl;

Alk represents a (C 1 -C 4) alkyl which is unsubstituted or substituted one or more times with a fluorine atom;

n is equal to an integer between 2 and 5.

The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful for purifying or isolating the compounds of formula (I) are also part of the invention.

When the compounds of formula (I) comprise a sulfur atom, all optical isomers and their mixture in any proportions are objects of the invention.

By (C 1 -C 4) alkyl or (C 1 -C 4) alkyl, respectively, is meant a linear or branched alkyl radical of 1 to 4 carbon atoms or, respectively, of 1 to 10 carbon atoms, such as the methyl radical. ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl.

By (Ci -C 4) alkoxy is meant an oxygen atom linked to a linear or branched carbon radical of 1 to 4 carbon atoms such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert butoxy. By halogen atom is meant a bromine, chlorine, fluorine or iodine atom.

By (C 3 -C 5) cycloalkyl is meant a cyclic alkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

C3-C12 non-aromatic carbocyclic radicals include mono or polycyclic radicals, fused, bridged or spiranic. Monocyclic radicals include (C3-C7) cycloalkyls. The fused, bridged or spiro di- or tricyclic radicals include, for example, the norbornyl, bornyl, isobornyl, noradamantyl, adamantyl, spiro [5.5] undecyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, bicyclo radicals. [3.1.1] heptyl.

According to the present invention, the compounds of formula (I) in which: R 1 represents a hydrogen atom or a methyl;

R-2 represents:

. a (C 1 -C 10) alkyl unsubstituted or substituted by a substituent selected from: b) a non-aromatic (C 3 -C 12) carbocyclic radical which is unsubstituted or substituted one or more times with an Alk group;

c) phenyl substituted one or more times with an Alk group;

. a non-aromatic (C 3 -C 12) carbocyclic radical unsubstituted or substituted one or more times with an Alk group;

or R 1 and R 2 together with the nitrogen atom to which they are attached constitute the piperazin-1-yl radical substituted with an Alk group;

R3 represents:

. a group - (CH2 R5;

R4 represents a hydrogen atom or an OAlk group;

R5 is fluorine, CF3, -S-Alk, -SO-Alk, -SO2-Alk, -NHSC-Alk;

n is an integer of 2 to 5;

in the form of a base or an acid addition salt.

In particular, the compounds of formula (I) in which:

R 1 represents a hydrogen atom or a methyl;

R2 represents:

. 1,1,3,3-tetramethylbutyl, [4- (trifluoromethyl) cyclohexyl] methyl, a

(adamantan-1-yl) methyl, 2- (trifluoromethyl) benzyl;

. adamantan-1-yl, 3,5-dimethyladamantan-1-yl; or R 1 and together with the nitrogen atom to which they are attached constitute the 4-methylpiperazin-1-yl radical;

R3 represents a 4-fluorobutyl, a 5,5,5-trifluoropentyl, a 2- (ethylthio) ethyl, a 2- (ethylsulfmyl) ethyl, a 2- (ethylsulfonyl) ethyl, a 3 - [(methylsulfonyl) amino] propyl ;

P4 represents a hydrogen atom or a methoxy;

in the form of a base or an acid addition salt.

Among the compounds of formula (I) that are subjects of the invention, mention may be made especially of the following compounds:

3- (Adamantan-1-ylamino) -1- (4-fluoro-butyl) -1H-cinnolin-4-one;

3- (Adamantan-1-ylamino) -1- (5,5,5-trifluoropentyl) -1H-cinnolin-4-one;

3- (2-Trifluoromethyl-benzylamino) -1- (5,5,5-trifluoro-pentyl) -1H-cinnolin-4-one;

(3, 5-Dimethyl-adamantan-1-ylamino) -1- (4-fluoro-butyl) -1H-cinnolin-4-one;

(3, 5-Dimethyl-adamantan-1-ylamino) -1- (5,5,5-trifluorpentyl) -1H-cinnolin-4-one;

(1,1,3,3-tetramethyl-butylamino) -1- (5,5,5-trifluorpentyl) -1H-cinnolin-4-one;

3 - [(4-Trifluoromethylcyclohexylmethyl) amino] -1- (5,5,5-trifluoropentyl) -1H-cinnolin-4-one;

[(Adamantan-1-ylmethyl) amino] -1- (5,5,5-trifluoropentyl) -1H-cinnolin-4-one; 1- (2-Ethylsulfanyl-ethyl) -8-methoxy-3- (2-trifluoromethyl-benzylamino) -1H-cinnolin-4-one;

1- (4-Fluoro-butyl) -3- (2-trifluoromethyl-benzylamino) -1H-cinnolin-4-one;

1- (4-Fluoro-butyl) -8-methoxy-3- [methyl- (2-trifluoromethyl-benzyl) -amino] -1H-cinnolin-4-one;

1- (4-Fluoro-butyl) -8-methoxy-3- (2-trifluoromethyl-benzylamino) -1H-cinnolin-4-one;

1- (2-Ethanesulfonyl-ethyl) -8-methoxy-3- (2-trifluoromethyl-benzylamino) -1H-cinnolin-4-one;

1- (2-Ethanesulfinyl-ethyl) -8-methoxy-3- (2-trifluoromethyl-benzylamino) -1H-cinnolin-4-one;

N- {3- [4-Oxo-3- (2-trifluoromethyl-benzylamino) -4H-cinnolin-1-yl] -propyl} -methanesulfonamide;

3- (4-methylpiperazin-1-yl) -1- (5,5,5-trifluoropentyl) -1H-cinnolin-4-one;

in the form of a base or an acid addition salt.

In what follows, a protective group GP is understood to mean a group which makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, secondly, to regenerate the intact reactive function at the end of synthesis. Examples of protecting groups and methods of protection and deprotection are given in "Protective Group in Organic Synthesis", Green et al, 4 ^th Edition (John Wiley & Sons, Inc., New York), 2007.

By leaving group is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with departure from an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxy group such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups as well as references for their preparation are given in "Advanced Organic Chemistry", M. B. Smith and J. March, 6th Edition, Wiley Interscience, 2007, p. 496-501.

According to the invention, the compounds of formula (I) can be prepared according to a process which is characterized in that:

In the presence of a base, a compound of formula

in which R3 and R4 are as defined for a compound of formula (I), and Hal represents a halogen atom, with a compound of formula:

HNR1 R2 (m)

wherein R 1 and R 2 are as defined for a compound of formula (I).

The reaction can be carried out in the presence of a palladium catalyst such as, for example, tetrakis (triphenylphosphine) palladium, palladium (II) acetate or tris (dibenzylideneacetone) dipalladium (O), in the presence of a ligand. such as 2-dicyclohexyl-2 ', 6'-dimethoxybiphenylphosphine (S-Phos) or 2-dicyclohexyl-2', 4 ', 6'-triisopropylbiphenylphosphine (X-Phos) and in the presence of a base such that, for example, sodium tert-butylate or sodium carbonate, in a solvent such as, for example, toluene, 1,4-dioxane, methanol, ethanol or a mixture of these solvents and at a temperature between room temperature and the reflux temperature of the solvent. Preferably, Hal represents a bromine or iodine atom. Optionally, the compound of formula (I) is converted into one of its addition salts with mineral and / or organic acids.

The compounds of formula (I) thus obtained may subsequently be separated from the reaction medium and purified by conventional methods, for example by crystallization or chromatography.

The compounds of formula (I) thus obtained are isolated in free base or salt form, according to conventional techniques.

According to a variant of this process, it is also possible to prepare a compound of formula (I) in which R 3 represents a group - (CH 2) _n -R 5 in which R 5 = -S-Alk by reaction of a compound of formula:

in which n, R 1, R 2 and R 4 are as defined for a compound of formula (I) and Hal 'represents a halogen atom, with a sodium alkanethiolate derivative of formula:

NaS-Alk (V)

wherein Alk is as defined for a compound of formula (I).

The reaction is carried out in a solvent such as ethanol at a temperature between room temperature and the reflux temperature of the solvent.

According to another variant of the above processes, a compound of formula (I) in which R3 represents a - (CH2) _n -R5 group in which R5 = -SOAlk or -SO2Alk can be prepared by reaction of a compound of formula ( I) wherein R5 represents -SAlk with an oxidizing agent. As an oxidizing agent, for example hydrogen peroxide or 3-chloroperbenzoic acid can be used in a solvent such as dichloromethane or acetic acid and at a temperature of between 0 ° C. and room temperature.

Depending on the number of equivalents of oxidant used and on the temperature of the reaction, a sulfoxide (R 5 = -SOAlk) or a sulfone (R 5 = -SC 3 Alk) is obtained. It is also possible to obtain a mixture of the two compounds which are separated using methods known to those skilled in the art, for example by preparative chromatography. The compounds of formula (II) are prepared by reaction of a compound of formula:

in which R4 is as defined for a compound of formula (I) and Hal represents a halogen atom with a compound of formula:

Hal-R ₃ (VII)

wherein R3 is as defined for a compound of formula (I) and Hal represents a halogen atom.

The reaction is carried out in the presence of a strong base such as, for example, sodium hydride, in a solvent such as, for example, N, N-dimethylformamide and at a temperature of between 0 ° C. and the reflux temperature of solvent.

According to a variant of this process, it is also possible to prepare the compounds of formula (II) in which R3 represents a group - (CH2) _n -R5 in which R5 = -N (R ₍ 5) -SO2Alk with R = H, by reaction of a compound of formula:

in which n and R4 are as defined for a compound of formula (I) with a compound of formula:

Hal-S0 ₂ Alk (XX)

wherein Alk is as defined for a compound of formula (I) and Hal represents a halogen atom.

The reaction is carried out in the presence of a base such as, for example, triethylamine, in a solvent such as, for example, dichloromethane and at a temperature of between 0 ° C. and room temperature.

The compounds of formula (II) in which R 5 = -N (R 8) SO 2 Alk with R 6 different from H can be prepared by reaction of the compounds of formula (II) in which R 5 = - NHSO 2 Alk with an alkylating agent, in the presence of a based. As alkylating agent is used, for example, a dialkyl sulfate of formula SO 4 (R 2) 2 or a halide alkyl radicals of formula RgHa1, in which = (Ci -C4) alkyl and Hal represents a halogen atom, in the presence of a strong base such as, for example, sodium hydride.

The compounds of formula (III) are commercial, known or prepared according to methods known to those skilled in the art.

The compounds of formula (IV) are prepared by reaction of a compound of formula:

wherein n and R4 are as defined for a compound of formula (I) and Hal 'represents a halogen atom, with a compound of formula (III).

The reaction is carried out according to the conditions previously described for the reaction of a compound of formula (II) with a compound of formula (III).

The compounds of formula (V) are commercial, known or prepared according to methods known to those skilled in the art.

The compounds of formula (VI) are prepared from a compound of formula:

in which R 4 is as defined for a compound of formula (I), by reaction with bromine, in the presence of a base such as, for example, potassium ethoxide, in a solvent such as, for example, acetic acid and at a temperature between room temperature and the reflux temperature of the solvent. There is thus obtained a compound of formula (VI) in which Hal represents a bromine atom.

It is also possible to prepare a compound of formula (VI) in which Hal represents an iodine atom by reaction of a compound of formula (IX) with iodine, in the presence of a base such as, for example, pyridine and in the presence of bis (trifluoroacetate) phenyl iodide in a solvent such as, for example, dichloromethane and at a temperature between room temperature and the reflux temperature of the solvent. The compounds of formula (VII) are commercial, known or prepared according to methods known to those skilled in the art.

The compounds of formula (VIII) are prepared by reaction of a compound of formula (VI) wherein R4 is as defined for a compound of formula (I) with a compound of formula:

Hal- (CH ₂ ) _n -Hal ^* (X)

in which Hal and Hal 'represent a halogen atom and n is as defined for a compound of formula (I). The reaction is carried out in the presence of a strong base such as, for example, sodium hydride, in a solvent such as for example Ν, Ν-dimethylformamide at a temperature of between 0 ° C. and the reflux temperature of the solvent. .

The compounds of formula (IX) are prepared by cyclization of a compound of formula:

in which R 4 is as defined for a compound of formula (I), in the presence of sodium nitrite, in a solvent such as, for example, hydrochloric acid and water and at a temperature of between 0 ° C. and the temperature room.

The compounds of formula (X) are commercial, known or prepared according to methods known to those skilled in the art.

The compounds of formula (XI) in which R4 is as defined for a compound of formula (I) are prepared according to SCHEME I below.

SCHEME I

(XII) (XIII) (XIV)

In step a1 of SCHEME I, the reaction of a compound of formula (XII) with sulfonyl chloride is carried out at a temperature between room temperature and 100 ° C.

In step M, the compound of formula (XIII) thus obtained is reacted with diethyl malonate, in the presence of magnesium, in a solvent such as for example an ether (diethyl ether for example) at a temperature between the ambient temperature and the reflux temperature of the solvent.

The compound (XIV) thus obtained is reduced in step c1 in the presence of zinc, acetic acid in a solvent such as, for example, tetrahydrofuran and at a temperature of between 0 ° C. and room temperature.

The compound of formula (XII) is commercially known or prepared according to methods known to those skilled in the art.

According to a variant of this process, it is also possible to prepare a compound of formula (XI) in which R4 is as defined for a compound of formula (I) according to SCHEMA II.

(XV) (XVI) (XVII)

In step a2 of SCHEMA II, the compound of formula (XV) is reacted with N-methoxymethanamine, in the presence of a coupling agent used in peptide chemistry such as for example 1,3-dicyclohexylcarbodiimide (DCC ) or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP) or 2- (1H-benzotriazol-1-yl) tetrafluoroborate 1,1,3,3-tetramethyl uronium, in the presence of a base such as, for example, triethylamine, Ν, Ν-diisopropylethyl amine or 4-dimethylaminopyridine, in a solvent such as, for example, dichloromethane, dichloroethane, N, N-dimethylformamide or tetrahydrofuran at a temperature of between -10 ° C. and the reflux temperature of the solvent.

In step b2, the amine is protected from the compound of formula (XVI) thus obtained according to the methods known to those skilled in the art.

The compound (XVII) thus obtained is reacted in step c2 with an organometallic compound such as methyl magnesium bromide in a solvent such as an ether (tetrahydrofuran, dioxane for example) at a temperature of between -100 ° C. and the ambient temperature.

The compound (XVIII) thus obtained is deprotected in step d2.

The compounds (XIX) are prepared by reaction of a compound of formula:

wherein n and R4 are as defined for a compound of formula (I) with hydrazine monohydrate in a solvent such as for example methanol and at a temperature between room temperature and the reflux temperature of the solvent.

The compounds of formula (XX) are commercially known or prepared according to methods known to those skilled in the art.

The compounds of formula (XXI) are prepared by reaction of a compound of formula (VI) in which R4 is as defined for a compound of formula (I) with a compound of formula:

(XXII)

wherein n is as defined for a compound of formula (I) and Hal represents a halogen atom.

As an alternative to the compound (XXII), a compound of formula Hal- (CH2) _n -NHBOC may be used with the compound of formula (VI).

The reaction is carried out in the presence of a strong base such as, for example, sodium hydride, in a solvent such as for example Ν, Ν-dimethylformamide at a temperature of between 0 ° C. and the reflux temperature of the solvent. .

The compounds of formula (XXII) are commercial, known or prepared according to methods known to those skilled in the art.

The following EXAMPLES describe the preparation of certain compounds in accordance with the invention. These examples are not limiting and only illustrate the present invention. The numbers of the exemplified compounds refer to those given in TABLE I below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.

In Preparations and Examples the following abbreviations are used:

AcOEt: ethyl acetate,

AcONa: sodium acetate,

BOC: tert-butyloxycarbonyl,

HPLC: high performance liquid chromatography,

DCM: dichloromethane,

DIPEA: diisopropylethylamine,

DMF: N, N-dimethylformamide,

DMSO: dimethylsulfoxide,

ether: diethyl ether,

iso ether: diisopropyl ether,

F: melting point,

HBr: hydrobromic acid,

MeOH: methanol,

TA: room temperature,

Tetrakis: tetrakis (triphenylphosphine) palladium,

TFA: trifluoroacetic acid,

THF: tetrahydrofuran.

Proton nuclear magnetic resonance spectra (1H NMR) are recorded at 200 MHz in DMSO-dg. The chemical shifts δ are expressed in parts per million (ppm). For the interpretation of the spectra, we use the following abbreviations: s: singlet, d: doublet, t: triplet, qd: quadruplet, m: massive, mt: multiplet, se: expanded singlet, dd: doublet split.

The solvent mixtures are quantified in volumetric ratio.

The compounds according to the invention are analyzed by LC / UV / MS coupling (liquid chromatography / UV detection / mass spectrometry). The molecular peak (MH ⁺ ) and the retention time (tr) are measured in minutes.

The conditions used are as follows:

Conditions A

Column: Symmetry Ci g (2.1 x 50 mm) 3.5 μιη;

Eluent: A: H ₂ O + 0.005% TFA pH ~ 3;

B: acetonitrile / 0.005% TFA;

Flow rate: 0.4 ml / minute;

UV detection: λ = 210-220 nm;

Conditions B

An XTerra MS C \ g column (2.1 x 50 mm) 3.5 μιη is used;

Eluent: A: 10 mM AcONH ₄ pH ~ 7;

B: acetonitrile;

Flow rate: 0.4 ml / minute;

UV detection: λ = 220 nm;

Conditions C

An Acquity BEH C \ g column (2.1 x 50 mm) 1.7 μιη is used; Eluent: A: H ₂ O + 0.05% TFA pH ~ 3; acetonitrile (97/3);

B: acetonitrile / 0.035% TFA;

Gradient:

Flow rate: 1 ml / minute;

UV detection: λ = 220 nm;

The recording of the mass spectra is carried out in electrospray mode (ESI) positive, in order to observe the ions resulting from the protonation of the analyzed compounds (MH) or the formation of adducts with other cations such as N ⁺ , K ⁺ , etc ..

PREPARATIONS

1. Preparations of compounds of formula (XI)

Preparation 1.1

1- (2-Amino-3-methoxyphenyl) ethanone.

(XI): R4 = 3-OMe.

A-3-methoxy-2-nitrobenzoyl chloride.

A mixture of 10 g of 3-methoxy-2-nitrobenzoic acid in 60 ml of thionyl chloride is heated at 75 ° C. for 3 hours. The reaction mixture is concentrated under vacuum and gives 10.9 g of the expected compound which is used as such in the next step.

B-1- (3-Methoxy-2-nitrophenyl) ethanone.

To a mixture of 3.2 g of magnesium in 10 ml of ether is added dropwise and at RT, a solution of 20 ml of diethyl malonate in 12 ml of EtOH and then, dropwise, a solution of 10.9 g of the compound of the preceding step in 40 ml of ether and refluxed for 18 hours. The reaction mixture is poured into 50 ml of ether and the insoluble material is filtered off. The insoluble material is taken up with a saturated solution of NH 4 Cl, extracted with 100 ml of chloroform, the aqueous phase is acidified by addition of 20 ml of a 10% solution of HCl, the aqueous phase is re-extracted with 100 ml of chloroform, dried the organic phases joined on MgSO4 and evaporates the solvents under vacuum. The residue is taken up in a mixture of 10 ml of acetic acid, 1.5 ml of H 2 SO 4 and 7 ml of water and then refluxed for 5 hours. The acetic acid is concentrated under vacuum, the reaction mixture is taken up in 100 ml of water, the mixture is basified with aqueous phase by addition of NH 4 OH, extracted with 100 ml of chloroform, the organic phase washed with saturated NaCl solution, dried over MgSO 4 and the solvent evaporated in vacuo. The residue is chromatographed on silica gel, eluting with a gradient of cyclohexane / AcOEt from (80/20; v / v) to (20/80; v / v). 3.3 g of the expected compound are obtained.

C- 1- (2-Amino-3-methoxyphenyl) ethanone.

A solution of 3.3 g of the compound of the preceding step in 100 ml of THF is cooled to 0 ° C., 13.27 g of zinc and 15.7 ml of acetic acid are added and the mixture is then left stirring and allowed to rise. at RT and let stirring for 4 hours at RT. Filtering the reaction mixture through Celite ^® and the filtrate concentrated in vacuo. The residue is extracted with THF, the organic phase is washed with 100 ml of a 10% NaOH solution and with saturated NaCl solution, dried over MgSO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a gradient of cyclohexane / AcOEt from (80/20; v / v) to (60/40; v / v). 2 g of the expected compound are obtained.

This compound can also be prepared according to the procedures described in Preparation 1.1 bis below:

Preparation 1.1 bis

1- (2-Amino-3-methoxyphenyl) ethanone.

(XI) _: R4 = 3-OMe.

A-2-Amino-N, 3-dimethoxy-N-methylbenzamide.

To a suspension of 15.10 g of 2-amino-3-methoxybenzoic acid in 410 ml of DCM was added 54.1 ml of triethylamine, 9.69 g of N-methoxymethanamine and 51.70 g of PyBOP and left behind. stirring hours at RT. The reaction mixture is washed with a buffer solution pH = 2, with a solution of NaOH at 10%, with a saturated solution of NaCl, the organic phase is dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a gradient of cyclohexane / AcOEt from (70/30; v / v) to (40/60; v / v). 17.89 g of the expected compound are obtained in the form of an oil.

Tert-Butyl b- [2-methoxy-6- [methoxy (carboxy)] carbamoyl] phenyl] carbamate.

To a mixture of 2.3 g of the compound of the previous step in 20 ml of 1,4-dioxane was added 4.78 g of di-tert-butyldicarbonate and refluxed for 27 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in AcOEt / water, the organic phase is washed with saturated NaCl solution, dried over Na 2 SO 4 and the solvent is evaporated off under vacuum. The residue is chromatographed on a gel of silica eluting with a gradient of cyclohexane / AcOEt from (70/30; v / v) to (40/60; v / v). 3.43 g of the expected compound are obtained.

Tert-Butyl C- (2-acetyl-6-methoxyphenyl) carbamate.

A solution of 5.73 g of the compound of the preceding step in 170 ml of THF is cooled to -50 ° C., 18.5 ml of a 3 M bromide solution are added dropwise under a nitrogen atmosphere. of methylmagnesium in ether and left stirring overnight, allowing the temperature to rise to RT. The reaction mixture is poured into 150 ml of a 4% aqueous solution of HCl, extracted with AcOEt, the organic phase is washed with saturated NaCl solution, dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel eluting with cyclohexane and then with a cyclohexane / AcOEt mixture (70/30; v / v). 4.22 g of the expected compound are obtained.

D- 1- (2-Amino-3-methoxyphenyl) ethanone.

To a solution of 2.14 g of the compound of the preceding step in 60 ml of DCM is added, dropwise, 3.1 ml of trifluoroacetic acid and stirred for 22 hours at RT. The reaction mixture is diluted by adding 30 ml of DCM, poured into 50 ml of a 10% aqueous NaOH solution, the organic phase is washed with saturated NaCl solution and dried over Na 2 SO 4, and the solvent is evaporated under vacuum. 1.16 g of the expected compound is obtained.

2. Preparations of compounds of formula (IX)

Preparation 2.1

8-Méthoxycinnolin-4 (IH) -one.

(IX): R4 = 8-OMe.

A solution of 2 g of the compound of Preparation 1.1 in 8 ml of concentrated HCl is cooled to 0 ° C. and the solution is added dropwise while maintaining the temperature of the reaction mixture below 10 ° C. 25 g of NaNO 2 in 2.7 ml of water, left stirring for 2 hours at 0 ° C. and overnight at RT. The reaction mixture is concentrated under vacuum, 50 ml of a solution of AcONa is added, the precipitate formed is filtered off and washed with 20 ml of water. 1.95 g of the expected compound are obtained.

Preparation 2.2

Cinnolin-4 (lH) -one.

(IX): R4 = Η.

A solution of 20 g of 1- (2-aminophenyl) ethanone in 80 ml of conc. HCl is cooled to 0 ° C, the solution is added dropwise while maintaining the temperature of the reaction mixture below 5 ° C. 3 g of NaNO 2 in 40 ml of water are stirred for 2 hours at 0 ° C. and overnight at RT. We concentrate the mixture In a vacuum reaction, 50 ml of AcOK solution are added, the precipitate formed is filtered off and washed with water. 10.5 g of the expected compound are obtained.

3. Preparations of compounds of formula (VI)

Preparation 3.1

3-Bromo-8-méthoxycinnolin-4 (IH) -one.

(VI): R4 = 8-OMe; Hal = Br.

To a mixture of 1.95 g of the compound of Preparation 2.1 in 20 ml of AcOH was added 1.40 g EtOK and heated to reflux. A solution of 0.68 ml of bromine in 2 ml of AcOH is then added dropwise and refluxed for 1 hour and 30 minutes. The AcOH is concentrated under vacuum, the residue is taken up in water, the precipitate formed is wrung out, washed with water and dried. 2.8 g of the expected compound are obtained.

Preparation 3.2

3-Iodo-8-méthoxycinnolin-4 (IH) -one.

(VI): R4 = 8-OMe; Hal = I.

To a solution of 2.39 g of the compound of Preparation 2.1 in 55 ml of DCM, 2.27 g of iodine, 1.45 ml of pyridine and then, in small portions, 3.85 g of bis are successively added ( trifluoroacetate) phenyliodide and left stirring for 16 hours at RT. The precipitate formed is filtered off and washed with water. 2.56 g of the expected compound are obtained.

Preparation 3.3

3-Bromocinnolin-4 (IH) -one.

(VI): R4 = Η; Hal = Br.

Compound prepared according to the procedure described in Preparation 3.1 from the compound of Preparation 2.2.

Preparation 3.4

3-Iodocinnolin-4 (IH) -one.

(VI): R4 = Η; Hal = I.

Compound prepared according to the procedure described in Preparation 3.2 from the compound of Preparation 2.2.

4. Preparations of compounds of formula (II)

Preparation 4.1

3-Bromo-1- (5,5,5-trifluoropentyl) cinnolin-4 (1H) -one.

(II): R 3 = - (CH ₂₎ 4-CF _3; R ₄ = H; Hal = Br.

A suspension of 0.55 g of 60% NaH in oil is cooled to 0-5 ° C. in 20 ml of DMF, a solution of 2.0 g of the compound of Preparation 3.3 is added dropwise. 30 ml of DMF and then a solution of 2.8 g of 5-bromo-1,1,1-trifluoropentane in 10 ml of DMF and heated at 75 ° C for 3 hours. We pay reaction mixture in water, extracted with DCM, the organic phase washed with saturated NaCl solution, dried over MgSO 4) and the solvent evaporated in vacuo. The residue is chromatographed on silica gel, eluting with a gradient of cyclohexane / AcOEt from (80/20; v / v) to (50/50; v / v). 0.65 g of the expected compound is obtained.

Preparation 4.2

N- [3 - (3-Bromo-8-methoxy-4-oxocinnolin-1 (4H) -yl) propyl] methanesulfonamide.

(II): R ₃ = - (CH ₂ ) 3-NHS0 ₂ Me; R4 = 8-OMe; Hal = Br.

A- 2- [3- (3-Bromo-8-methoxy-4-oxocinnolin-1 (4H) -yl) propyl] -1H-isoindol-1, 3 (2H) -dione (XXI).

A suspension of 0.77 g of 60% NaH in oil is cooled to 0-5 ° C. in 15 ml of DMF is added dropwise a solution of 3.3 g of the compound of Preparation 3.1 in 50 ml of DMF and then a solution of 5.2 g of 2- (3-bromopropyl) -1H-isoindole-1,3 (2H) -dione in 20 ml of DMF and heated at 75 ° C. for 6 hours and allowed to come back at RT overnight.

The reaction mixture is poured into water and extracted with DCM, the organic phase is washed with saturated NaCl solution and dried over MgSO.sub.4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a gradient of cyclohexane / AcOEt from (90/10; v / v) to (40/60; v / v). 5 g of the expected compound are obtained.

B- 1- (3-Aminopropyl) -3-bromo-8-methoxycinnolin-4 (1H) -one (XIX).

To a solution of 3 g of the compound of the preceding step in 20 ml of MeOH is added 0.66 ml of hydrazine monohydrate and refluxed for 4 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in 10% NaOH solution and extracted with DCM, the organic phase is washed with a saturated solution of

NaCl, dried over MgSO4 and evaporated the solvent in vacuo. 1.87 g of the expected compound are obtained.

C- N- [3- (3-bromo-8-methoxy-4-oxocinnolin-1 (4H) -yl) propyl]

methanesulfonamide.

A mixture of 1.87 g of the compound of the preceding step, 1.84 ml of triethylamine and 0.51 ml of methanesulfonyl chloride in 75 ml of DCM is left stirring overnight at RT. The reaction mixture is washed with 10% HCl solution, 10% NaOH solution, the precipitate formed is filtered off and dried. 2 g of the expected compound are obtained.

Preparation 4.3

N- [3- (3-iodo-4-oxocinnolin-l (4H) -yl) propyl] methanesulfonamide. (II): R 3 = - (CH ₂₎ 3-NHS02Me; R4 = H; Hal = I.

A) 2- [3- (3-Iodo-4-oxocinolin-1 (4H) -yl) propyl] -1H-isoindole-1,3 (2H) -dione.

This compound is prepared according to the procedure described in Preparation 4.2 from the compound of Preparation 3.4.

B) 1- (3-Aminopropyl) -3-iodocinolin-4 (1H) -one trifluoroacetate.

To a suspension of 2 g of the compound of the preceding step in 20 ml of MeOH is added 0.42 ml of hydrazine monohydrate and heated at 85 ° C for 3 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is washed with 10% NaOH solution and with saturated NaCl solution and dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is taken up in ether, trifluoroacetic acid is added, the precipitate formed is filtered off and dried. 0.84 g of the expected compound is obtained.

C) N- [3- (3-iodo-4-oxocinnolin-1 (4H) -yl) propyl] methanesulfonamide.

To a suspension of 0.84 g of the compound of the preceding step in DCM, 1.1 ml of triethylamine and then 0.16 ml of methanesulfonyl chloride are successively added and the mixture is stirred for 21 hours at RT. The reaction mixture is washed with 2% HCl solution, saturated NaCl solution, dried over Na 2 SO 4 and the solvent evaporated in vacuo. 0.69 g of the expected compound is obtained.

5. Preparations of compounds of formula (VIII)

3-Bromo-1- (3-chloropropyl) cinnolin-4 (1H) -one.

(VIII): n = 3; R4 = Η; Hal = Br; Hal * = Cl.

A suspension of 1.06 g of 60% NaH in oil in 80 ml of DMF is cooled down to 5 ° C., a solution of 4 g of the compound of Preparation 3.3 in 50 ml of DMF is added dropwise. then a solution of 2.64 ml of 1-bromo-3-chloropropane in 50 ml of DMF and left stirring overnight, allowing the temperature to rise to RT. The reaction mixture is poured into water and extracted with DCM, the organic phase is washed with saturated NaCl solution and dried over MgSO 4, and the solvent is evaporated off under vacuum. 4.9 g of the expected compound are obtained.

EXAMPLE 1: Compound No. 3

3 - [[2- (Trifluoromethyl) benzyl] amino] -1- (5,5,5-trifluoropentyl) cinnolin-4 (1H) -one.

To a solution of 0.3 g of the compound of Preparation 4.1 in 5 ml of toluene is added, under nitrogen, 0.14 ml of 1- [2- (trifluoromethyl) phenyl] methanamine, 0.09 g. g of Pd2 (dba) 3, 0.05 g of S-Phos ligand then 0.25 g of sodium tert-butoxide and refluxed for 2 hours. The reaction mixture is filtered through Celite®, washed with DCM and then the filtrate is concentrated under vacuum. We the residue is chromatographed on silica gel, eluting with a gradient of cyclohexane / AcOEt from (100/0 v / v) to (90/10 v / v). 0.23 g of the expected compound is obtained, mp 82 ° -84 ° C.

EXAMPLE 2 Compound No. 14

1- (2-Ethanesulfinyl-ethyl) -8-methoxy-3- (2-trifluoromethyl-benzylamino) -1H-cinnolin-4-one.

A mixture of 0.38 g of Compound No. 9 in 9 ml of acetic acid is cooled to 5 ° C., 0.11 ml of a 30% hydrogen peroxide solution are added under nitrogen. water and leave stirring for 5 hours at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with saturated NaCl solution and dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is taken up in ether, the precipitate formed is filtered off and dried. 0.22 g of the expected compound is obtained.

EXAMPLE 3: Compound No. 13

1- (2-Ethanesulfonyl-ethyl) -8-methoxy-3- (2-trifluoromethyl-benzylamino) -1H-cinnolin-4-one.

A mixture of 0.4 g of Compound No. 9 in 10 ml of DCM is cooled to 5 ° C., 0.57 g of 3-chloroperbenzoic acid at 55% in 20 ml of DCM are added under a nitrogen atmosphere and the mixture is left behind. stirring hours at RT. The reaction mixture is washed with 10% aqueous NaOH solution, with saturated NaCl solution, the organic phase is dried over Na 2 SO 4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a cyclohexane / AcOEt mixture (60/40, v / v). 0.18 g of the expected compound is obtained.

The following table illustrates the chemical structures and the physical properties of some examples of compounds according to the invention, obtained following the procedures described in the Examples above. In this table, Me represents a methyl radical.

TABLE I

The compounds according to the invention have shown a very good in vitro affinity (IC 50 <500 nM) for the human and rodent EC-2 receptors. The binding affinity assays were performed according to the experimental conditions described by M. Rinaldi-Carmona in J. Pharmacol. Exp. Therap. 1998, 287, 644-650, with membranes from either rodent tissue or recombinant cell line in which human CB2 receptors were expressed (Munro et al, Nature 1993, 365, 61-65). The affinity of the compounds is expressed as IC 50 (concentration causing a 50% inhibition of the specific binding of the tritiated ligand used in vitro).

The compounds according to the invention have shown a modulatory effect on CB2 receptors. In particular, the compounds according to the invention exhibit properties of agonistic, inverse agonist and / or antagonistic nature.

The agonist nature of the compounds according to the invention has been demonstrated in the adenylate cyclase inhibition models (forskolin-stimulated) as described in M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther. 1996, 278, 871-878 and 1998, 284, 644-650 and M. Bouaboula et al., J. Biol Chem., 1997, 272, 22330-22339.

The antagonistic nature of the compounds according to the invention has been demonstrated in the models of reversion of the inhibition of the adenylate cyclase (forskolin-stimulated) induced by a CB2 receptor agonist as described in M. Rinaldi-Carmona and al, J. Pharmacol. Exp. Ther. 1996, 278, 871-878 and 1998, 284, 644-650.

The inverse agonist nature of the compounds according to the invention has been demonstrated in the adenylate cyclase activation models (forskolin-stimulated) as described in M. Portier et al., J. Pharmacol. Exp. Ther. 1999, 288, 582-589.

The compounds according to the invention also have a good in vivo affinity for the CB2 receptors present in the spleen of mice when they are administered orally. The tests were carried out according to the conditions experimental compounds described by Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther., 1998, 284, 644-650. The affinity of the compounds is expressed as ED50 (dose causing a 50% inhibition of the specific binding of the tritiated ligand used ex vivo).

The compounds of the present invention are in particular active principles compatible with their use as medicaments and / or pharmaceutical compositions.

According to one of its aspects, the present invention relates to the use of a compound of formula (I) or a salt thereof, which is pharmaceutically acceptable for the preparation of medicaments intended to prevent or treat any human pathology and / or to veterinary use. Thus the compounds according to the invention can be used in humans or animals (in particular in mammals including, but not limited to, dogs, cats, horses, cattle, sheep) for prevention or treatment. of diseases involving CB2 receptors.

For example, the following diseases or conditions can be mentioned:

- Disorders of the immune system: including autoimmune diseases including but not limited to: psoriasis, lupus erythematosus, connective tissue diseases or connective tissue diseases, Sjômer's syndrome, ankylosing spondylitis, rheumatoid arthritis, arthritis reactive, undifferentiated spondyloarthritis, Charcot's disease, Behcet's disease, autoimmune haemolytic anemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, transplant rejection, and diseases affecting the plasma cell line;

- Allergic diseases: especially delayed or immediate hypersensitivity, asthma, allergic rhinitis, contact dermatitis and allergic conjunctivitis;

- Parasitic, viral or bacterial infectious diseases including AIDS and meningitis;

- amyloidosis and diseases affecting the lines of the lympho-hematopoietic system;

- Chronic liver diseases of alcoholic origin, cirrhosis, viral and toxic as well as non-alcoholic steatohepatitis and primary cancer of the liver;

- Inflammatory diseases: in particular articular diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel disease, irritable bowel syndrome (in particular English IBD: inflammatory bowel disease and IBS: irritable bowel syndrome), ulcerative colitis and acute pancreatitis.

- Bone diseases and osteoporosis. - Pain: particularly chronic inflammatory pain, neuropathic pain and acute peripheral pain.

- Eye diseases: especially ocular hypertension and glaucoma.

- Pulmonary diseases: respiratory tract diseases, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), emphysema.

- diseases of the central nervous system and neurodegenerative diseases: Tourette's syndrome, Parkinson's disease, Alzheimer's disease, senile dementia, chorea, Huntington's disease, epilepsy, psychoses, depression and spinal cord injury.

The compound of formula (I) according to the invention can be used as a medicament for the treatment or prevention of migraine, stress, psychosomatic diseases, seizures, panic attacks, epilepsy, movement disorders, dizziness, vomiting, nausea especially those following chemotherapy.

- Migraine, stress, psychosomatic diseases, panic attacks (panic attacks or acute anxiety attacks), epilepsy, movement disorders, vertigo, vomiting, nausea especially those following chemotherapy.

- Cardiovascular diseases in particular hypertension, arteriosclerosis, heart attack, cardiac ischemia.

- Renal ischemia.

- Cancers: especially benign tumors of the skin, papillomas and cancerous tumors, prostate tumors, brain tumors (examples: glioblastomas, medullo-epitheliomas, medulloblastomas, neuroblastomas, tumors of embryonic origin, astrocytomas, astroblastomas, ependymomas , oligodendrogliomas, plexus tumors, neuroepitheliomas, epiphysis tumors, ependymoblastomas, neuroectodermal, malignant meningiomas, sarcomatoses, malignant melanomas, schwannomas).

- Gastrointestinal disorders, diarrhea disorders, ulcers, bladder and urinary disorders, nephritis, endocrine disorders, hemorrhagic shock, septic shock, Raynaud's disease and fertility disorders.

- obesity; type II diabetes, metabolic syndrome, insulin resistance and inflammation of adipose tissue.

- Fibrosis: pulmonary, renal, hepatic, and dermal. More particularly, the compounds of formula (I) according to the present invention will be useful for the preparation of medicaments for the prevention and / or treatment of pain, inflammatory diseases, autoimmune diseases, allergic diseases, infectious diseases , neurodegenerative diseases, cardiovascular diseases, cancers, gastrointestinal diseases, obesity, type II diabetes, insulin resistance, inflammation of adipose tissue and fibrositis.

The use of the compounds according to the invention for the prevention and / or treatment of the diseases mentioned above, as well as for the preparation of medicaments intended to treat these diseases forms an integral part of the invention.

The compounds of formula (I) above, or one of their pharmaceutically acceptable salts, may be used at daily doses of 0.01 to 100 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses. from 0.1 to 50 mg / kg. In humans, the dose may preferably vary from 0.1 to 4000 mg per day, more particularly from 0.5 to 1000 mg depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.

Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active ingredient, a compound of formula (I), or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. .

In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal, local or rectal administration, the active ingredients can be administered in forms administration units, in admixture with conventional pharmaceutical carriers, to animals and humans.

Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules, oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. , by inhalation, aerosols, topical, transdermal administration forms, implants, subcutaneous, intramuscular, intravenous administration forms and rectal administration forms. For topical administration the compounds according to the invention can be used in creams, ointments, gels, or lotions.

By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:

Compound according to the invention

mannitol

Croscarmellose sodium

Corn starch

Hydroxypropylmethylcellulose

Magnesium stearate

Orally, the dose of active ingredient administered per day can reach 0.01 to 100 mg / kg, in one or more doses, preferably 0.02 to 50 mg / kg.

There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.

The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or of a pharmaceutically acceptable salt thereof.

The compounds according to the invention may also be used for the preparation of compositions for veterinary use.

In addition, the compounds according to the invention, either as such or in radiolabeled form can be used as pharmacological tools in humans or animals for the detection and labeling of CB2 cannabinoid receptors.

Claims

1. Compound corresponding to formula (I):

in which :

R 1 represents a hydrogen atom or a (C 1 -C 4) alkyl;

R2 represents:

a) a fluorine atom;

b) a non-aromatic (C 3 -C 12) carbocyclic radical which is unsubstituted or substituted one or more times with substituents chosen independently from a halogen atom, an Alk group or an OAlk group; c) phenyl which is unsubstituted or substituted one or more times with substituents independently chosen from a halogen atom, an Alk group and an OAlk group;

. a non-aromatic (C 3 -C 12) carbocyclic radical unsubstituted or substituted one or more times with substituents independently selected from a halogen atom, an Alk group, an OAlk group;

or else R 1 and R 2 together with the nitrogen atom to which they are bonded constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin- 4-yl, piperazin-1-yl, said heterocyclic radical being unsubstituted or substituted one or more times with substituents independently selected from a halogen atom, an Alk group, an OAlk group;

R3 represents:

. a group - (CH2 R5;

R4 represents a hydrogen atom, a halogen atom, an Alk group or an OAlk group; R 5 represents a halogen atom, a CF 3 group or a group chosen from -S-Alk, -SO-Alk, -SO ₂ -Alk,

-N (R6) S0 ₂ -Alk;

- Rg represents a hydrogen atom or a (Ci -C4) alkyl;

n is an integer of 2 to 5;

in the form of a base or an acid addition salt.

Compound of formula (I) according to claim 1 wherein:

- R \ represents a hydrogen atom or a methyl;

- R ₂ represents:

c) phenyl substituted one or more times with an Alk group;

or else R 1 and R ₂ together with the nitrogen atom to which they are attached constitute the piperazin-1-yl radical substituted by a group Alk;

R3 represents:

. a group - (CH2 R5;

R 4 represents a hydrogen atom or an OAlk group;

R5 represents a fluorine atom, a CF3 group, a -S-Alk group, a SO-Alk group or a -SO2-Alk group;

-NHSO2Alk;

n is an integer of 2 to 5;

in the form of a base or an acid addition salt.

Compound of formula (I) according to claim 1 wherein:

- R \ represents a hydrogen atom or a methyl;

R2 represents:

. 1,1,3,3-tetramethylbutyl, [4- (trifluoromethyl) cyclohexyl] methyl, (adamantan-1-yl) methyl, 2- (trifluoromethyl) benzyl;

. adamantan-1-yl, 3,5-dimethyladamantan-1-yl; either K 1 and R 2 together with the nitrogen atom to which they are attached constitute the 4-methylpiperazin-1-yl radical;

R 3 represents a 4-fluorobutyl, a 5,5,5-trifluoropentyl, a 2- (ethylthio) ethyl, a 2- (ethylsulfmyl) ethyl, a 2- (ethylsulfonyl) ethyl, a 3 - [(methylsulfonyl) amino] propyl;

R4 represents a hydrogen atom or a methoxy;

in the form of a base or an acid addition salt.

Compound according to Claim 1 of formula (I) chosen from:

3- (Adamantan-1-ylamino) -1- (4-fluoro-butyl) -1H-cinnolin-4-one;

(Adamantan-1-ylamino) -1- (5,5,5-trifluoropentyl) -1H-cinnolin-4-one;

(3, 5-Dimethyl-adamantan-1-ylamino) -1- (4-fluoro-butyl) -1H-cinnolin-4-one;

(3, 5-Dimethyl-adamantan-1-ylamino) -1- (4,5,5-trifluoropentyl) -1H-cinnolin-4-one;

(1,1,3,3-tetramethyl-butylamino) -1- (4,5,5-trifluoro-pentyl) -1H-cinnolin-4-one;

[(Adamantan-1-ylmethyl) amino] -1- (5,5,5-trifluoropentyl) -1H-cinnolin-4-one;

1- (2-Ethylsulfanyl-ethyl) -8-methoxy-3- (2-trifluoromethyl-benzylamino) -1H-cinnolin-4-one;

1- (4-Fluoro-butyl) -3- (2-trifluoromethyl-benzylamino) -1H-cinnolin-4-one;

3- (4-Methyl-piperazin-1-yl) -1- (4,5,5-trifluoropentyl) -1H-cinnolin-4-one;

in the form of a base or an acid addition salt.

5. Process for the preparation of the compounds of formula (I) according to any one of claims 1 to 4, characterized in that:

In the presence of a base, a compound of formula

wherein R3 and R4 are as defined for a compound of formula (I) in claim 1, and Hal represents a halogen atom, with a compound of formula:

HNR1 R2 ( ^m )

wherein R 1 and R 2 are as defined for a compound of formula (I) in claim 1.

Medicinal product, characterized in that it contains a compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt of the compound of formula (I).

Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Use of a compound of formula (I) according to any one of claims 1 to 4 for the preparation of a medicament for the treatment and prevention of pain, inflammatory diseases, autoimmune diseases, diseases allergic diseases, infectious diseases, neurogenerative diseases, cardiovascular diseases, cancers, gastrointestinal diseases, obesity, type II diabetes, insulin resistance, inflammation of the adipose tissue and fibroses.