EP1981842A2

EP1981842A2 - Sulfonamide derivatives, preparation and therapeutic application thereof

Info

Publication number: EP1981842A2
Application number: EP07730899A
Authority: EP
Inventors: Gilles Courtemanche; Pierre Despeyroux; Evelyne Fontaine; Pierrick Rochard; Claudine Serradeil-Le Gal; Erich Von Roedern
Original assignee: Sanofi Aventis France
Current assignee: Sanofi SA
Priority date: 2006-02-02
Filing date: 2007-02-01
Publication date: 2008-10-22
Also published as: US20090054439A1; WO2007088276A3; FR2896799A1; FR2896799B1; WO2007088276A2; JP2009525312A

Abstract

The invention concerns sulfonamide derivatives of general formula (I), wherein: Ar1 represents an aryl optionally substituted by one or several groups, an optionally substituted heterocyclyl group; T represents a -(CH2)n or a group (A); Ar2 represents an aryl optionally substituted by one or several groups, an optionally substituted heterocyclyl group; Ar3 represents an aryl optionally substituted by one or several groups, an optionally substituted heterocyclyl; R represents a hydrogen or a (C1-C4) alkyl; R' represents an optionally substituted (C1-C4) alkyl; a carboxylic acid, a (C1-C4) carboxylate, an optionally substituted carboxamide; in base, acid addition salt, hydrate or solvate form, or in enantiomeric, diastereoisomeric, rotameric, atropoisomeric forms or mixtures thereof. The invention also concerns the preparation method as well as the therapeutic use of the compounds of formula (I).

Description

SULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION

The present invention relates to sulfonamide derivatives, process for their preparation and their use in therapy.

Orexins A and B (or hypocretins 1 and 2) are hypothalamic neuropeptides of 33 and 28 amino acids respectively, recently identified as the endogenous ligands of two receptors with seven transmembrane domains, called orexin 1 and orexin 2 receptors (Sakurai T. , CeII, Vol 92, 573-585, 1998; De Lecea L., Proc Natl Acad ScL, Vol 95, 322-327, 1998).

The orexin 2 receptor has the property of recognizing both forms of orexin A and B in an equivalent manner. On the other hand, the orexin 1 receptor, which has 64% homology with the orexin 2 receptor, is more selective and binds orexin A ten times better than orexin B (Sakurai T., CeII, Vol 92, 573- 585, 1998). Via these receptors, orexins control various central and peripheral functions, including food and drink intake, certain cardiovascular endocrine functions and the wake / sleep cycle (Sakurai T., Regulatory Peptides, Vol 85, 25-30, 1999). ).

It has now been found that certain sulfonamide derivatives have a high affinity for orexin 2 receptors and are potent antagonists of these receptors. Thus, the subject of the present invention is compounds corresponding to the general formula (I)

0) in which "R represents:

a hydrogen atom;

a (C ₁ -C ₄ ) alkyl; - R "represents:

a (C ₁ -C ₄ ) alkyl optionally substituted with one or more groups chosen from a group:

. hydroxyl,

. halogen,

. (C ₁ -C ₄ ) alkoxy,

. an aryloxy, said aryl may be substituted with one or more groups selected from: a halogen atom, a (C ₁ -C ₄ ) alkyl, a (C 1 -C ₄ ) alkoxy;

. an aryl, said aryl may be substituted with one or more groups selected from: a halogen atom, a (CrC ₄ ) alkyl, a (C 1 -C ₄ ) alkoxy;

. a group -NH (COO) R _a , wherein R ₃ represents a (C ₁ -C ₄ ) alkyl;

. an NH (CO) R _{b group} , wherein R _b represents a (C ₁ -C ₄ ) alkyl, an aryl group, said aryl group being optionally substituted by one or more groups chosen from: a halogen atom, a C _r C ₄ ) alkyl, a

(C _r C ₄ ) alkoxy, a carboxylic acid;

. a group -NR _c R _d , in which R _c and R _d represent, independently of each other: a hydrogen atom, a (C ₁ -C ₄ ) alkyl, or form with the nitrogen atom which connects them to a heterocyclyl;

. an ammonium group -NR _f R ₉ R ₁ , in which R _f , R ₉ and R _h represent a

(C ₁ -C ₄ ) alkyl;

. a heterocyclyl group;

. a COOR ₈ group, in which R _e may represent a hydrogen, a (C ₁ -C ₄ ) alkyl;

. a group CONR _c R _d ; a COOH; a COO (C _r C ₄ ) alkyl or a CONR _G R _d ; • An represents

an aryl group, optionally substituted with one or more groups chosen independently of each other from the following groups: a halogen atom, a cyano, a (C ₁ -C ₄ ) alkyl, a fluoro (C ₁ -C ₄ ) alkyl, a (C ₁ -C ₄ ) alkoxy; a heterocyclyl group optionally substituted by a halogen atom, a (C ₁ -C ₄ ) alkyl or a (C ₁ -C ₄ ) alkoxy;

- T represents

- a group - (CHa) _n - with n ≈1 or 2; - a group :

\

C OH

/ H

• Ar ₂ represents

an aryl group, optionally substituted with one or more groups chosen independently of one another from the following groups: a halogen atom, a (C _r C ₄ ) alkyl, a (C ₁ -C ₄ ) alkoxy, a fluoro (Ci-C ₄₎ alkyl, fluoro (Ci-C ₄₎ alkoxy;

a heterocyclyl group, optionally substituted with a halogen atom, a (CrC ₄ ) alkyl, a (C ₁ -C ₄ ) alkoxy;

"Ar ₃ represents

an aryl group, optionally substituted with one or more groups chosen independently of one another from the following groups: a halogen atom, a hydroxyl group, a (C ₁ -C ₄ ) alkyl, a (C ₁ -C ₄₎ alkoxy; a heterocyclyl group, optionally substituted with a hydroxyl group, a (C ₁ -C ₄ ) alkyl, a (C ₁ -C ₄ ) alkoxy, a fluoro (C ₁ -C ₄ ) alkyl, a fluoro (C ₁ -C ₄ ) alkoxy; base, acid addition salt, hydrate or solvate, as enantiomers, diastereoisomers, rotamers, atropoisomers or mixtures thereof. Among the compounds that are subjects of the invention, there may be mentioned a second group of compounds of general formula (I), in which:

- R represents:

a hydrogen atom; a (C ₁ -C ₄ ) alkyl;

R 'represents:

. hydroxyl, halogen,

. (C ₁ -C ₄ ) alkoxy,

. an aryloxy, said aryl may be substituted with one or more groups selected from: a halogen atom, a (C ₁ -C ₄ ) alkyl, a (C ₁ -C ₄ ) alkoxy;

. an aryl, said aryl may be substituted with one or more groups; selected from: a halogen atom, a (CrC ₄ ) alkyl, a (CrC ₄ ) alkoxy;

. a group -NH (COO) R ₉ , in which R ₃ represents a (C ₁ -C ₄ ) alkyl

. an NH (CO) R _{b group} , in which R _b represents an aryl group, said aryl group being optionally substituted by one or more groups chosen from: a halogen atom, a (CrC ₄ ) alkyl, a (CiC ₄ ) alkoxy, a carboxylic acid;

. a group -NR ₀ R _d , in which R ₀ and R _d represent, independently of each other: a hydrogen atom or a (C ₁ -C ₄ ) alkyl, or form with the nitrogen atom which connects them to a heterocyclyl;

. an ammonium group -NR _f R _g R _h , wherein R _f , R ₉ and R _h are (C ₁ -C ₄ ) alkyl;

. a heterocyclyl group;

. a group COOR _e in which R _θ may represent a hydrogen, a (C ₁ -C ₄ ) alkyl;

. a group CONR _c Rd, a COO (CrC ₄ ) alkyl, a CONR _c R _d ;

- Ari represents

a phenyl or a naphthyl, optionally substituted by one or more groups chosen independently of one another from the following groups: a halogen atom, a (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy; a heterocyclyl group, especially pyridinyl or pyrimidinyl, said heterocycle group being optionally substituted by a halogen atom, a (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy; ^"T is

a group -CH ₂ -;

"Ar ₂ represents

a phenyl or a naphthyl, optionally substituted with one or more groups chosen independently of one another from the following groups: a halogen atom, a (CrC ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy;

a heterocyclyl group, especially pyridinyl, optionally substituted by a halogen atom, a (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy;

Ar ₃ represents a phenyl or a naphthyl, optionally substituted by one or more groups chosen independently of each other from the following groups: a halogen atom, a hydroxyl group, a (CrC ₄ ) alkyl, (CrC ₄ ) alkoxy;

a heterocyclyl group, especially pyridinyl or furanyl, optionally substituted with a hydroxyl group, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group; base, acid addition salt, hydrate or solvate, enantiomers, diastereoisomers, rotamers, atropoisomers or mixtures thereof.

Among the compounds that are the subject of the invention, there may be mentioned a third group of compounds of general formula (I), in which

• R represents:

a hydrogen atom;

a (C ₁ -C ₄ ) alkyl;

- R "represents: - a (C ₁ -C ₄ ) alkyl optionally substituted with one or more groups chosen from a group:

. hydroxyl,

. (C ₁ -C ₄ ) alkoxy,

. an aryloxy, said aryl may be substituted by one or more groups selected from: a halogen atom, a (CrC ₄ ) alkyl, a (CrC ₄ ) alkoxy;

. an aryl, said aryl may be substituted by one or more groups selected from: a halogen atom, a (CrC ₄ ) alkyl, a (CrC ₄ ) alkoxy;

. an NH (CO) Rb group, wherein R _b is an aryl group optionally substituted with one or more carboxylic acid groups; . a group -NR ₀ Rd, in which R _c and R _d represent, independently of each other: a hydrogen atom, a (C ₁ -C ₄ ) alkyl, or form with the nitrogen atom which connects a heterocyclyl; . a heterocyclyl group;

. a COOR group _e , in which R ₆ may represent a hydrogen, a (C ₁ -C ₄ ) alkyl;

. a group CONR ₀ Rd; _; a COO (C 1 -C 4) alkyl; a CONR _c R _d;

• An represents

a phenyl group, optionally substituted by one or more groups chosen independently of each other from the following groups: a halogen atom, a (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy; a pyridinyl group, said pyridinyl group being optionally substituted with a (C ₁ -C ₄ ) alkyl;

• T represents

- a group -CH ₂ -

Ar ₂ represents a phenyl group optionally substituted by one or more groups chosen independently of each other from the following groups: a halogen atom, a (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy ;

a pyridinyl group, optionally substituted by a halogen atom, a (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy; • Ar ₃ represents

a phenyl group optionally substituted by one or more groups chosen independently of one another from the following groups: a halogen atom, a hydroxyl group, (C ₁ -C ₄ ) alkyl group or (C ₁ -C ₄ ) alkoxy group;

a pyridinyl or furanyl group, said groups optionally being substituted with a hydroxyl, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group; base, acid addition salt, hydrate or solvate, enantiomers, diastereoisomers, rotamers, atropoisomers or mixtures thereof.

When Ar ₂ is an optionally substituted phenyl group, the T-Ar ₂ bonds on the one hand and Ar ₂ -N on the other hand are in the ortho position. In other words, the nitrogen atom and the substituent T are on two adjacent carbon atoms. In the context of the invention, the following terms mean:

a (C ₁ -C ₄ ) alkyl: a saturated, linear or branched aliphatic group comprising from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl; an optionally substituted (CrC ₄ ) alkyl: an alkyl group as defined above in which one or more hydrogen atoms have been substituted with a substituent; when several hydrogen atoms are replaced by fluors, a perfluoroalkyl such as -CF ₃ or C ₂ F ₅ ;

- a (C ₁ -C ₄₎ alkoxy: a radical (CrC ₄₎ alkyl-O- where the (Ci-C ₄₎ alkyl is as defined above, e.g., methoxy, ethoxy, propoxy, l isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy;

a halogen atom: a fluorine atom, a chlorine atom, a bromine atom or an iodine atom;

an aryl group: a monocyclic or bicyclic aromatic group comprising between 6 and 10 carbon atoms, for example phenyl or naphthyl. The aryl group may optionally be substituted with 1, 2, 3 or 4 substituents;

a heterocyclyl group: a saturated, unsaturated or aromatic monocyclic group comprising between 4 and 7 atoms and comprising from 1 to 2 heteroatoms chosen from nitrogen, oxygen or sulfur. By way of example, azetidine, piperidinyl, pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, thienyl and pyrimidinyl may be mentioned; furanyl; morpholine.

The compounds of general formula (I) may comprise one or more asymmetric carbons. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention. By their structure, the compounds of general formula (I) can also exist in the form of rotamers. In the context of the invention, rotamers are understood to mean compounds which have identical developed formulas but different fixed spatial conformations. These differences in the fixed spatial conformations of these compounds may give them different physicochemical properties and, even in some cases, different biological activities.

The compounds of general formula (I) may still exist in the form of atropoisomers. The atropoisomers are compounds of identical developed formulas, but which have a particular spatial configuration, resulting from a restricted rotation around a single bond, due to a steric hindrance important on both sides of this simple link. Atropioisomerism is independent of the presence of stereogenic elements, such as asymmetric carbon.

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 example, for the purification or separation of the compounds of general formula (I) are also part of the invention.

The compounds of general formula (I) may, in addition, be in the form of hydrates or solvates, namely in the form of combinations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.

The present invention also relates to the process for preparing the compounds of general formula (I).

Thus, the compounds of general formula (I) can be prepared by the process illustrated in Scheme 1. According to this scheme, the compounds of formula (I) can be obtained by condensation in basic medium of an epoxide of formula (X ) on the compounds of formula (II).

Diagram 1

The base used may be a phosphazene, for example 1- [N- (tert-butyl) -P, P-dipyrrolidin-1-ylphosphorimidoyl] pyrrolidine; This reaction is an adaptation of the method described by KARAT.L.D. and coll

J.Appl.Chem.USSR; EN; 65; 6.2; 1992; 1130-1133. The compounds of formula (II) are obtained beforehand according to Scheme 2, by the sulphonylation of the compound of formula (III) with sulphonyl chlorides of formula (V) in the presence of a base chosen from tertiary amines such as pyridine according to the method described by Stauffer et al., Bioorg. Med. Chem., 2000, EN 8, 6, 1293-1316. Tertiary amines also include triethylamine or diisopropylethylamine or, in some cases, a mixture of tertiary amines. When the compounds of formula (II) are obtained by reaction of the compounds of formula (IIIf) with the sulphonyl chlorides of formula (V), the ketone function of the compound obtained is then reduced, according to methods known to those skilled in the art. to yield compounds of formula (II).

Compounds of formula (V) are commercially available or can be obtained by adaptation of the methods described, for example, by A. J. Prinsen et al., Red. Trav. Chim. Netherlands 1965, EN 84, 24.

In the compounds of formula (III) and (V), Ar ₁ , Ar ₂ , Ar ₃ , and T are as defined in formula (I).

Diagram 2 T '= T or CO o base 11

Ar ₁ -T - ^ r ₂ NH ₂ '- Ar ₁ -T ^ r ₂ -NH -S -Ar ₃

Cl -SO ₂ → O, O

(II, ^ (II)

(HIa) = T ¹ = -CH ₂

QlJb): T '= ^ jC -O H

(IIIf): T '= ^> = O QlIg): T' = - (CH ₂ ) ₂ -

Compounds of formula (HIa), (HIb) and (HIf) are prepared according to Schemes 3 to 5.

According to Scheme 3, the 2-nitro benzaldehyde derivatives of formula (VT) react with organometallic compounds of formula (VTI) in which M represents a MgBr, MgI ₁ ZnI or Li group to give compounds of formula (VTII). The nitro function of the compounds of formula (VIII) is then reduced by hydrogenation, for example, under the action of tin metal and concentrated hydrochloric acid in ethanol, to give the compounds of formula (IIIb). The derivatives of formula (IUb) are reduced by the action of hydrides, for example by a mixture of triethylsilane and trifluoroacetic acid in dichloromethane to give derivatives of formula

The organometallic compounds of formula (VII) are commercial, or formed according to the conventional methods described in the literature.

The nitrobenzaldehydes of formula (VI) are commercially available or may be prepared, for example, according to an adaptation of the method described by J. Kenneth Horner et al., J. Med. Chem., 1968, 11; 5; 946.

Figure 3

H ₅

(HIa) (jπb)

Other possibilities for synthesizing the compounds of general formulas (HIb) and (HIf) are presented in scheme 4. Figure 4

PhBCI ₂ , NEt ₃ / Ar ₁ - CHO (XHI)

A NH ₉

1) Ar ₁ - M

(VII)

2) H ⁺

According to scheme 4, the anilines of formula (IX) are condensed with benzonitriles of formula (XII), in the presence of Lewis acid, for example boron trichloride with aluminum trichloride or with gallium trichloride for give the compounds of formula (UIf) ₃ according to the method described by T. Sugasawa et al JACS1978; 100; 4842. The compounds of formula (IIIf) can also be obtained by condensation of aminobenzonitriles (XI) with organometallic derivatives (VII) followed by acid hydrolysis, according to the method described by R. Fryer et al., J. Heterocycl . Chem, 1991, EN 28; 7, 1661 or from intermediate (XIV) according to an adaptation of the method described by D. Lednicer, J. Heterocyclic. Chem, 1971; 903. The carbonyl function of the compounds (III) can be reduced by the action of a hydride, for example sodium borohydride in ethanol, to give the compounds of formula (HIb).

Another method for preparing the compounds of formula (HIb) consists in condensing anilines of formula (IX) on benzaldehyde derivatives of formula (XIII) in the presence of phenyl-dichloroborane and triethylamine according to the process described by T. Toyoda et al., Tel Lett, 1980, 21, 173. It should be noted that the compounds of formula (IIIf) under the action of triethylsilane and trifluoroacetic acid, for example, can lead to compounds of formula (HIa).

Another possibility for synthesizing the compounds of general formulas (HIa), in which Ar ₁ represents a heteroaryl, is shown in Scheme 5.

Figure 5

Ar ₁ CH ₂ CI

(XVm) / ^

Ar ₂ -NO ₂ ^Ar i Ar ₂ -NO ₂

(XVH) Base _(χκ)

(IIIa)

The nitrophenyls of formula (XVII) are condensed on aromatic chloro methyl heterocyclyls of formula (XVIII) in the presence of a base, for example potassium tert-butoxide, to give derivatives (XIX) according to the process described by Florio. S et al., Eur.J.Org.Chem.2004, 2118, which are reduced for example by the action of metal tin in the presence of 12M hydrochloric acid, to yield derivatives of formula (HIa).

The compounds of formula (HIg) are prepared according to scheme 6. The nitrobenzaldehydes (VI), by condensation with the derivatives (XV) according to a wittig reaction lead to the compounds (XVI). These derivatives are reduced for example by catalytic hydrogenation with palladium to give the compounds of formula (HIg). Figure 6

Ar ₁ CH ₂ (Ph) ₃ Cl (XV)

OHC-Ar-NO ₂ -Ar ₂ - NO ₂ (XVI)

(VI)

H

Ar ₁ CH ₂ CH ₂ Ar ₂ -NH ₂

(IIIg)

In all the schemes and for all the compounds of formulas (II) to (XIX), the meanings of Ar-1, T, Ar ₂ , Ar ₃ , R 1 are as defined for the compounds of general formula (I).

In Schemes 1 to 6, the starting compounds and reagents, when their method of preparation is not described, are commercially available or described in the literature, or may be prepared by methods described therein or are known to those skilled in the art.

When a compound has a reactive function, for example a hydroxyl group, it may require prior protection before reaction. Those skilled in the art may determine the need for prior protection.

The compounds of formula (II) to (XIX) are useful as synthetic intermediates for the preparation of the compounds of general formula (I) and form an integral part of the present invention.

The following examples describe the preparation of the compounds according to the invention. These examples are not limiting and only illustrate the invention. The numbers of the exemplified compounds refer to those given in the table. Elemental microanalyses, mass spectra, and NMR spectra confirm the structures of the compounds obtained. The conditions for analysis by liquid chromatography coupled with LC / MS mass spectrometry are as follows:

• for the liquid chromatography part: Symmetry column C18 (2.1x 50mm) 3-

5 .mu.m. Eluent A = H ₂ O + 0.005% TFA, pH = 3.14; Eluent B = CH ₃ CN + 0.005% TFA, with a gradient from 100% A to 90% B in 10 minutes, then 5 minutes to 90% B

• for the mass spectrometry part: positive electrospray ionization mode.

When the ¹ H NMR spectrum shows rotamers, only the interpretation corresponding to the rotamer majority is described.

Example 1: N- [2- (2,6-Difluoro-benzyl) -6-methoxy-phenyl] -N- (2,3-dihydroxy-propyl) -3,4-dimethoxy-benzenesulfonamide (Compound No. 1)

To 224 mg of N- [2- (2,6-difluorobenzyl) -6-methoxy-phenyl] -3,4-dimethoxybenzenesulfonamide, 234 mg of 1- [N- (tert-butyl) -P, Β-dipyrrolidin-1-ylphosphorimidoyl] pyrrolidine dissolved in 5 ml of tetrahydrofuran is added 74 mg of oxiran-2-ylmethanol. After 72 hours at room temperature, the medium is directly chromatographed on a column of silica gel eluting with a water + 0.05% trifluoroacetic acid / acetonitrile + 0.05% trifluoroacetic acid mixture to obtain 102 mg of expected product.

¹ H NMR δ in ppm (DMSO d ⁶ ): 3.20 (3H, 2-OMe), 3.41 (2H, 14-H ₂ ), 3.80 (1H, 13-H), 3.72 (3H, 17-OMe), 3 , 84 / 3.03 (2H, 12-H ₂ ), 3.86 (3H, 18-OMe), 4.50 / 4.39 (2H, 7-H ₂ ), 4.60 (1H, 14-OH), 4.62 (1H, 13-OH), OH), 6.16 (1H, 5-H), 6.81 (1 H, 3-H) ₁ 7.03 (1 H, 16-H), 7.14 (2H, 10/10 ^'-H), 7.14 (1H, 19- H) ₁ 7.15 (1H, 4-H), 7.25 (1 H, 20-H), 7.42 (1 H, 11-H).

In the following table:

- MH ⁺ represents the peak mass of the ionized product

- The retention time is expressed in minutes

- n.d. means "not determined".

- Me represents a methyl group

- (R) and (S) represents indicates the asymmetry of carbon

* trifluoroacetic acid salt

The compounds of the invention have been the subject of pharmacological studies which have shown their interest as active substances in therapeutics.

In particular, they have been tested for their effects. More particularly, the affinity of the compounds of the invention for the orexin receptors 2 was determined in an in vitro binding assay according to the technique described below. This method consists of studying the displacement of radioiodinated orexin A bound to human orexin 2 receptors expressed in CHO cells. The test is carried out on membranes in an incubation buffer HEPES 50 mM, MgCl ₂ 1 mM, CaCl ₂ 25 mM, NaN ₃ 0.025% bovine serum albumin (BSA) 1% and 100 pM ligand for 30 minutes at 25 ⁰ C. The reaction was terminated by filtration and washing on filter Whatman GF / C. Nonspecific binding is measured in the presence of 10 ⁶ M human orexin B. Cl ₅₀ (inhibitory concentration of 50% of the binding of radioiodinated orexin A to its receptors) are low, less than 300 nM, in particular less than 100 nM and more particularly less than 30 nM. The following table illustrates the affinity of some compounds according to the invention for the orexin receptor

The biological results show that the compounds according to the invention are indeed antagonists of the orexin 2 receptors.

Thus, the compounds of the present invention, as orexin 2 receptor antagonists, can be used in the prophylaxis and treatment of any diseases involving a dysfunction related to these receptors.

The compounds of the invention can be used for the preparation of a medicament for the prophylaxis or the treatment of any diseases involving a dysfunction related to the orexin 2 receptor, and more particularly in the prophylaxis or treatment of pathologies in which an antagonist orexin 2 receptor provides therapeutic benefit. Such pathologies are, for example, obesity, disturbances of appetite or taste including cachexia, anorexia, bulimia (Smart et al., Eur J Pharmacol., 2002, 440, 2-3, 199-212), diabetes (Ouedraogo et al., Diabetes, 2002, 52, 111-117), metabolic syndromes (Sakurai, Curr, Opin Nutr.Matab.Care, 2003, 6, 353-360), vomiting and nausea (US 6, 506, 774), depression, and anxiety (Salomon et al., Biol Psychiatry, 2003, 54, 96-104, Jaszberenyi et al., J. Neuroendocrinol., 2000, 12 , 1174-1178), addictions (Georgescu et al., J. Neurosci., 2003, 23, 8, 3106-3111, Kane et al., Endocrinology, 2000, 141, 10, 3623-3629), mood and behavior, schizophrenia (Nishino et al., Psychiatry Res., 2002, 110, 1-7), sleep disorders (Sakurai, Neuroreport, 2002, 13, 8, 987- 995), the disease restless legs (Allen et al., Neurology, 2002, 59, 4, 639- 641), memory learning disorders (van den P OI et al., 2002, J. Physiol., 541 (1), 169-185; Jaeger et al., Peptides, 2003, 23, 1683-1688; Telegdy and Adamik, Regul. Pept, 2002, 104, 105-110), sexual and psychosexual dysfunctions (Gulia et al., Neuroscience, 2003, 116, 921-923), pain, visceral or neuropathic pain, hyperalgesia, Pallodynia (US 6,506,774 ; Suyama et al., In vivo, 2004, 18, 2, 119-123), digestive disorders (Takakashi et al., Biochem Biophys Res, Comm., 1999, 254, 623-627, Matsuo et al. Eur J. Pharmacol., 2002, 105-109), irritated bowel syndrome (US 6,506,774), neuronal degeneration (van den PoI, Neuron, 2000, 27, 415-418), ischemic or hemorrhagic attacks (Irving et al. et al., Neurosci Lett, 2002, 324, 53-56), Cushing's disease, Guillain-Barré syndrome (Kanbayashi et al., Psychiatry Clin Neurosci., 2002, 56, 3, 273-274). , myotonic dystrophy (Martinez-Rodriguez et al., Sleep, 2003, 26, 3, 287-290), urinary incontinence (Blackstone et al., AGS Annual Meeting, poster P491,2002), hyperthyroidism (Malendowicz et al., Biomed Res., 2001, 22, 5, 229-233), disorders of pituitary function (Voisin et al., Mol Life ScL, 2003, 60, 72-78), hypertension or hypotension (Samson et al., Brain Res., 1999, 831, 1-2, 248-253).

The use of the compounds according to the invention for the preparation of a medicament for preventing or treating the pathologies mentioned above is an integral part of the invention.

The invention also relates to medicaments which comprise a compound of formula (I). These drugs find their use in therapy, especially in the prophylaxis or treatment of the aforementioned pathologies.

According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active ingredient, at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of a compound according to the invention and optionally one or more pharmaceutically acceptable excipients.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its salt, solvate or hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases. Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, oral, Intratracheal, intraocular, intranasal, inhalation, subcutaneous, intramuscular or intravenous administration forms and rectal or vaginal administration forms. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.

For example, when preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic. or the like. The tablets may be coated with sucrose, a cellulosic derivative, or other materials. The tablets can be made by different techniques, direct compression, dry granulation, wet granulation or hot melt.

In order to obtain the desired prophylactic or therapeutic effect, the dose of active principle may vary between 0.1 mg and 200 mg per kg of body weight per day. Although these assays are examples of average conditions, there may be special cases where higher or lower dosages are appropriate, such assays also belong to 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.

Each unit dose may contain from 0.1 to 1000 mg, preferably from 0.1 to 500 mg, of active ingredient in combination with one or more pharmaceutical excipients. This unit dose can be administered 1 to 5 times per day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 0.5 to 2500 mg.

The present invention, according to another of its aspects, also relates to a method for preventing or treating the pathologies indicated above which comprises the administration of a compound according to the invention, a pharmaceutically acceptable salt, a solvate or a hydrate of said compound.

Claims

claims

1. Compound corresponding to general formula (I):

G ⁾ in which "R represents:

a hydrogen atom;

a (C ₁ -C ₄ ) alkyl; ^"R 'represents: - a (Ci-C ₄₎ alkyl optionally substituted with one or more groups selected from a group:

. hydroxyl,

. halogen,

. (CrC ₄ ) alkoxy,. an aryloxy, said aryl may be substituted with one or more groups selected from: a halogen atom, a (CrC ₄ ) alkyl, a (C _r C ₄ ) alkoxy;

. an aryl, said aryl may be substituted by one or more groups selected from: a halogen atom, a (C ₁ -C ₄ ) alkyl, a (C ₁ -C ₄ ) alkoxy;

. a group -NH (COO) R _a , wherein R _a represents a (C ₁ -C ₄ ) alkyl; . an NH (CO) R _{b group} , in which R _b represents a (C ₁ -C ₄ ) alkyl, an aryl group, said aryl group being optionally substituted with one or more groups chosen from: a halogen atom, a (CrC ₄ ) alkyl, a

(Ci-C ₄₎ alkoxy, a carboxylic acid;

. a group -NR _c R _d , in which R ₀ and R _d represent, independently of one another: a hydrogen atom, a (C _r C ₄ ) alkyl, or form with the nitrogen atom which connects them with a heterocyclyl;

. an ammonium group -NR _f R _g R _h , in which R _f , R ₉ and R _h represent a

(CrC ₄ ) alkyl;

. a heterocyclyl group; . a group COOR _e , in which R _e may represent a hydrogen, a (C ₁ -

C ₄ ) alkyl;

. a group CONR _c Rd; a COOH; a COO (CrC ₄ ) alkyl or a CONR _c Rd; ^"Ar ₁ represents

an aryl group, optionally substituted with one or more groups chosen independently of each other from the following groups: a halogen atom, a cyano, a (C ₁ -C ₄ ) alkyl, a fluoro (dC ₄ ) alkyl, a (CrC ₄ ) alkoxy; a heterocyclyl group, optionally substituted by a halogen atom, a (C ₁ -C ₄ ) alkyl, a (CrC ₄ ) alkoxy;

• T represents

- a group - (CHa) _n - with n = 1 or 2;

- a group :

C OH ^{/ H} ;

^" Ar ₂ represents

an aryl group, optionally substituted by one or more groups chosen independently of one another from the following groups: a halogen atom, a (C ₁ -C ₄ ) alkyl, a (C ₁ -C ₄ ) alkoxy, a fluoro (C ₁ -C ₄ ) alkyl, fluoro (C ₁ -C ₄ ) alkoxy;

- Ar ₃ represents

an aryl group, optionally substituted with one or more groups chosen independently of one another from the following groups: a halogen atom, a hydroxyl group, a (C ₁ -C ₄ ) alkyl, a (CrC ₄ ) alkoxy;

a heterocyclyl group, optionally substituted by a hydroxyl group, a (C ₁ -C ₄ ) alkyl, a (C ₁ -C ₄ ) alkoxy, a fluoro (C ₁ -C ₄ ) alkyl, a fluoro (C ₁ -C ₄ ) alkoxy; in the form of a base, an acid addition salt, a hydrate or a solvate.

2. Compound of general formula (I) according to claim 1, in which ^» R represents:

a hydrogen atom;

a (CrC ₄ ) alkyl; • R "represents:

a (CrC ₄ ) alkyl optionally substituted with one or more groups chosen from a group:

. hydroxyl,

. halogen,. (C ₁ -C ₄ ) alkoxy,

. an aryloxy, said aryl may be substituted by one or more groups selected from: a halogen atom, a (CrC ₄ ) alkyl, a (C _r C ₄ ) alkoxy;

. an aryl, said aryl may be substituted by one or more groups selected from: a halogen atom, a (CrC ₄ ) alkyl, a (CrC ₄ ) alkoxy; . a group -NH (COO) R ₃ , wherein R _a represents a (CrC ₄ ) alkyl;

. an NH (CO) R _{b group} , in which R _b represents an aryl group, said aryl group being optionally substituted by one or more groups chosen from: a halogen atom, a (CrC ₄ ) alkyl, a (CrC ₄ ) alkoxy, a carboxylic acid; . a group -NR _c R _d , in which R ₀ and R _d represent, independently of each other: a hydrogen atom, a (C ₁ -C ₄ ) alkyl, or form with the nitrogen atom that connects them a heterocyclyl;

. an ammonium group -NR _f R ₉ R _h , in which R _f , R ₉ and R _h represent a

(C ₁ -C ₄ ) alkyl; . a heterocyclyl group;

. a group COOR _e in which R _e may represent a hydrogen, a (C ₁ -C ₄ ) alkyl;

. a group CONR ₀ Rd;

a COO (C _r C ₄ ) alkyl; a CONR ₀ R; Ari represents

a phenyl or a naphthyl, optionally substituted by one or more groups chosen independently of one another from the following groups: a halogen atom, a (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy;

a heterocyclyl group, especially pyridinyl or pyrimidinyl, said heterocycle group being optionally substituted by a halogen atom, a (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy; • T represents

a group -CH ₂ -;

• Ar ₂ represents

a phenyl or a naphthyl, optionally substituted with one or more groups chosen independently of each other from the following groups: a halogen atom, a (C ₁ -C ₄ ) alkyl, (CrC ₄ ) alkoxy;

a heterocyclyl group, especially pyridinyl, optionally substituted by a halogen atom, a (CrC ₄ ) alkyl, (CrC ₄ ) alkoxy;

- Ar ₃ represents - a phenyl or a naphthyl, optionally substituted with one or more groups chosen independently of each other from the following groups: a halogen atom, a hydroxyl group, a (CrC ₄ ) alkyl, (C ₁ - C ₄ ) alkoxy;

a heterocyclyl group, especially pyridinyl or furanyl, optionally substituted with a hydroxyl, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group; in the form of a base, an acid addition salt, a hydrate or a solvate.

3. Compound of general formula (I) according to one of claims 1 or 2 wherein

R represents: a hydrogen atom;

a (C ₁ -C ₄ ) alkyl; "R ¹ represents:

a (C ₁ -C ₄ ) alkyl optionally substituted with one or more groups chosen from a group: hydroxyl,

. (C ₁ -C ₄ ) alkoxy,

. an aryloxy, said aryl may be substituted by one or more groups selected from: a halogen atom, a (CrC ₄ ) alkyl, a (CrC ₄ ) alkoxy; . an aryl, said aryl may be substituted by one or more groups selected from: a halogen atom, a (CrC ₄ ) alkyl, a (CrC ₄ ) alkoxy;

. an NH (CO) R _{b group} , wherein R _b is an aryl group optionally substituted with one or more carboxylic acid groups; . a group -NR ₀ Rd, in which R ₀ and R _d represent, independently of each other: a hydrogen atom or a (C ₁ -C ₄ ) alkyl, or form with the nitrogen atom which connects a heterocyclyl;

. a heterocyclyl group;

. a group COOR ₈ , in which R _θ can represent a hydrogen, a (C1-

C4) alkyl;

. a group CONR ₀ Rd; _;

a COO (C 1 -C 4) alkyl; a C0NR _c R _d; Ar-i represents

a phenyl group, optionally substituted with one or more groups chosen independently of one another from the following groups: a halogen atom, a (CrC ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy;

a pyridinyl group, said pyridinyl group being optionally substituted with a (CrC ₄ ) alkyl;

T represents

- a group -CH ₂ -

Ar ₂ represents

a phenyl group optionally substituted with one or more groups chosen independently of one another from the following groups: a halogen atom, a (CrC ₄ ) alkyl, (CrC ₄ ) alkoxy;

a pyridinyl group, optionally substituted by a halogen atom, a (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy;

Ar ₃ represents a phenyl group optionally substituted by one or more groups chosen independently of one another from the following groups: a halogen atom, a hydroxyl group, (C ₁ -C ₄ ) alkyl group, or a C ₁ -C ₄ ) alkoxy;

a pyridinyl or furanyl group, said groups optionally being substituted by a hydroxyl, (CrC ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group; in the form of a base, an acid addition salt, a hydrate or a solvate.

4. Process for the preparation of a compound of formula (I) according to any one of Claims 1 to 3, characterized in that condensation is carried out in a medium

in the compounds of formula (I), (II) and (X): Ar ₁ , Ar ₂ , Ar ₃ , T, R, and R 'are as defined in formula (I).

5. Preparation process according to claim 5, characterized in that the compound of formula (II) is obtained by the sulphonylation of compound of formula (III) with sulphonyl chlorides of formula (V), in the presence of a base: T '= T = or CO

o base 11

Ar ₁ - T -Ar ₂ NH ₂ Ar ₁ -T -Ar ₂ -NH -S -Ar ₃

Cl -SO ₂ - ^ r ₃ O

(IID ^ (H)

(II): T '= - CH ₂

(HIb): T '= ^ C -O H

(Ff): T '= ^> = O

(IHg): T '= - (CH ₂ ) ₂ - in the compounds of formula (III) and (V): Ar-1, Ar ₂ , Ar ₃ and T are as defined in formula (I).

6. Use of a compound of formula (I) according to any one of claims 1 to 3, for the preparation of a medicament for the prophylaxis or treatment of any diseases involving a dysfunction linked to the orexin 2 receptor.

7. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament for the prophylaxis or treatment of pathologies such as obesity, appetite disturbances or taste including cachexia, anorexia, bulimia, diabetes, metabolic syndromes, vomiting and nausea, depression and anxiety, addictions, mood and behavioral disorders, schizophrenia, sleep disorders, restless leg disease, memory learning disorders, sexual and psychosexual dysfunctions, pain, visceral or neuropathic pain, hyperalgesia, allodynia, digestive disorders, irritable bowel syndrome, neuronal degeneration, ischemic or hemorrhagic attacks, Cushing's disease, Guillain-Barré syndrome, myotonic dystrophy, urinary incontinence, hyperthyroidism, e pituitary function, hypertension or hypotension.

8. Medicinal product characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3.

9. Pharmaceutical composition containing at least one compound of formula (I) according to any one of claims 1 to 3 and optionally one or more pharmaceutically acceptable excipients.