HK1192230B

HK1192230B - Indol-2-one derivatives disubstituted in the 3-position, preparation thereof and therapeutic use thereof

Info

Publication number: HK1192230B
Application number: HK14105500.6A
Authority: HK
Inventors: Letizia Puleo; Marco Baroni
Original assignee: 赛诺菲-安万特
Priority date: 2007-08-16
Filing date: 2008-08-14
Publication date: 2017-09-15

Description

Indol-2-one derivatives disubstituted in position 3, their preparation and their therapeutic application

The present invention relates to indol-2-one derivatives disubstituted in the 3-position, their preparation and their therapeutic use.

Growth hormone releasing hormone (ghreline) is a 28 amino acid peptide hormone produced following pre-pro-ghreline cleavage primarily in the stomach by post-translational (post-translational) processes (KojimaM., et al, Nature 1999; 402: 656-60). Growth hormone releasing hormone is an endogenous ligand for growth hormone secretagogue pituitary receptor (GHSR1 a).

GHS-R is encoded by two exons: exon 1 encodes transmembrane domains (TMs)1-5 and exon 2 encodes TM6 and 7 of G protein-coupled receptors (GPCRs).

These two transcripts have been identified in the pituitary and brain: one encoding the full-length GPCR (GHS-R1a) and the other encoding the truncated receptor lacking TM6 and 7 (GHS-R1 b). Only the GHS-R1a subclass is activated by growth hormone releasing hormone and growth hormone releasing hormone mimics. GHS-R1b is present in the liver and other peripheral tissues, but its function is unknown. (SmithR. G. et al, trends EndocrinologyandMetabolism, 2005, 16, No.9).

It is a rhodopsin-type receptor with seven transmembrane domains of family a coupled to Gq/phospholipase C. Receptors for growth hormone releasing hormone may also be coupled to the Gs/protein kinase A pathway in certain tissues (Ueno, N. et al, Endocrinology, 2004, 145, 4176-4184; Kim, M.S. et al, int.J.Obes.Relat.Metab.D., 2004, 28: 1264-1271). Interestingly, receptors for growth hormone releasing hormone have relatively rare characteristics: has significant ligand independent compositional activity (Barazzoni, r. et al, am.j. physiol.endocrinol.metab., 2004, 288: E228-E235).

Low growth hormone releasing hormone expression levels have been demonstrated in different tissues (e.g., intestine, pancreas, kidney, immune system, placenta, testis, pituitary tissue, and hypothalamus) (Horm. Res. 2003; 59 (3): 109-17).

It has been demonstrated that: growth hormone releasing hormone is involved in hunger at and during the beginning of a meal. As food is ingested, the circulating levels decrease and increase before meals to a concentration sufficient to stimulate hunger and ingest food. The intake of growth hormone releasing hormone stimulates rapid and transient ingestion of food, primarily by increasing the appetite feeding behavior and number of meals. Growth hormone releasing hormone stimulates short term food intake (other than neuropeptide Y) more effectively than any other molecule, and is about equivalent to neuropeptide Y (wrena.m. et al, j.clin.endocrinol.meta.2001; 86: 5992-5). However, growth hormone releasing hormone is unique in its ability to exert this effect, whether it be injected peripherally or centrally (centrale).

It is also the only mammalian substance that has been shown to increase appetite and food intake when administered to humans (drucem. r., et al, int.j.obes., 2005; 29: 1130-6; wynnek., et al, j.am.soc. nephrol., 2005; 16: 2111-8).

In addition to its role in initiating a meal, growth hormone releasing hormone meets established criteria for hormones associated with obesity, which are involved in regulating long-term body mass. The level of growth hormone releasing hormone cycles as a function of energy reserve and shows compensatory changes in response to changes in body mass.

Growth hormone releasing hormone crosses the blood-brain barrier and stimulates food intake through the action of traditional regulatory centers on certain body masses (such as the hypothalamic, hindbrain and mesolimbic compensatory systems).

Long-term administration of growth hormone releasing hormone increases body mass through different synergistic effects on food intake, energy expenditure and resource usage. Innate abscission of growth hormone releasing hormone or its receptor genes causes resistance to eating-induced obesity, and pharmacological blockade of growth hormone releasing hormone reduces food intake and body mass.

Existing evidence shows a role in favoring growth hormone releasing hormone in both short-term initiation of meals and long-term energy homeostasis, thus making it an attractive target for drugs for the treatment of obesity and/or abnormal weight loss.

Growth hormone releasing hormone also exerts both physiological and pharmacological effects on the endocrine pancreas. Acylated bioactive growth hormone releasing hormone produced in cells, recently described inIn pancreatatiques (Prado, c.l., et al, 2004, proc. natl acad. sci. usa, 101: 2924-.

Ghrelin release (ablution) in mice (ghrelin mouse-/-) increased glucose-dependent insulin secretion by pancreatic beta cells and improved sensitivity to peripheral insulin by decreasing Ucp2 expression (suny et al, 2006, CellMetabolism, 3: 379-.

Antagonists of receptors for growth hormone releasing hormone may thus modulate hunger, the intake of diet and its frequency, as well as, in the long term, modulate weight, particularly weight gain following diet or treatment regimen. Furthermore, in the context of anti-diabetic therapy, ghrelin antagonists may be used to maintain a balance between insulin and glucose to control diabetic bulimia. Growth hormone releasing hormone antagonists can therefore be used as anorectic and/or anti-obesity agents, or in the treatment of diabetes and its effects.

Patent application WO95/18105 describes 5-chloro-3- (2-chlorophenyl) -1, 3-dihydro-3- [2- (4-methylpiperazin-1-yl) acetamido ] indol-2-one and 5-chloro-3- (2-chloroacetylamino) -3- (2-chlorophenyl) -1, 3-indolin-2-one compounds as intermediates in the synthesis of 1, 3-indolin-2-one derivatives 3-substituted with nitrogen-containing groups and having affinity against diuretic and/or oxytocin.

One object of the present invention is a compound corresponding to general formula (I):

whereinRepresents a single or double bond, and is,

x represents-N < - > -CH < or

Y represents > N-or > CH-, with the understanding that at least one of X, Y represents N; (ii) a

Ar represents an aryl or heteroaryl group optionally substituted with one or more identical or different substituents selected from: a halogen atom, a (C1-6) alkyl group, a (C1-6) haloalkyl group, a perhalogenated (C1-3) alkyl group, a (C1-6) alkoxy group, a perhalogenated (C1-3) alkoxy group and an aryl group;

r1 represents a hydrogen atom or a (C1-6) alkyl, -C (═ O) (C1-6) alkyl or-C (═ O) aryl group;

r2, R3 and R4, which are the same or different, located at any available position of the phenyl ring, independently represent a hydrogen atom, a halogen atom, CN, OH, (C1-6) alkyl optionally substituted with a halogen atom or OH; perhalogenated (C1-3) alkyl, (C1-6) alkoxy, perhalogenated (C1-3) alkoxy, aminocarbonyl, (C1-6) alkylaminocarbonyl, di (C1-6) alkylaminocarbonyl, aryl, aryloxy; a heteroaryl group; the aryl, aryloxy or heteroaryl group may be optionally substituted with a halogen atom, CN, OH or (C1-6) alkyl, perhalo (C1-3) alkyl or (C1-6) alkoxy; it is understood that at least one of R2, R3, R4 is not H, and the aryl, aryloxy or heteroaryl group may be optionally substituted with a halogen atom, CN, OH or (C1-6) alkyl, perhalo (C1-3) alkyl or (C1-6) alkoxy;

r5 represents (C1-6) alkyl or (C2-6) alkenyl; and

n represents 1 or 2; but with the exception of 5-chloro-3- (2-chlorophenyl) -1, 3-dihydro-3- [2- (4-methylpiperazin-1-yl) acetylamino ] indol-2-one.

The compounds of formula (I) contain one or more asymmetric carbon atoms. They may therefore exist as enantiomers or diastereomers. These enantiomers, diastereomers and mixtures thereof, including racemic mixtures, form part of the present invention.

The compounds of formula (I) may exist in the form of a base or as an addition salt with an acid. Such addition salts form part of the present invention.

These salts may be prepared using pharmaceutically acceptable acids, but salts of other acids which may be used, for example, in the purification or isolation of the compounds of formula (I) also form part of the invention.

In the context of the present invention, the following are understood:

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

-an alkyl group: a straight or branched chain saturated aliphatic group. By way of example, mention may be made of (C1-6) alkyl containing from 1 to 6 carbon atoms, more particularly (C1-4) alkyl, which may represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

-alkenyl: a linear or branched, monounsaturated or polyunsaturated aliphatic radical comprising, for example, 1 or 2 unsaturations and comprising from 2 to 6 carbon atoms;

-haloalkyl groups: an alkyl group whose one or more hydrogen atoms have been substituted with a halogen atom; for example, fluoroalkyl groups: an alkyl group whose one or more hydrogen atoms have been substituted with a fluorine atom;

-perhaloalkyl groups: alkyl groups in which all hydrogen atoms have been substituted with halogen atoms; for example, perfluoroalkyl groups: alkyl groups in which all hydrogen atoms have been substituted with fluorine atoms;

alkoxy groups: -O-alkyl, wherein alkyl is as defined above;

-perhaloalkoxy: -O-perhaloalkyl, wherein perhaloalkyl is as defined above; as examples, trifluoromethoxy groups;

-aryl: cyclic aryl groups containing 6 to 10 carbon atoms. As examples of aryl groups, mention may be made of phenyl and naphthyl;

heteroaryl group: cyclic aryl groups containing 2 to 10 carbon atoms and containing 1 to 3 heteroatoms such as nitrogen, oxygen or sulfur. As examples of heteroaryl groups, mention may be made of furyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, oxadiazolyl, oxazolyl, isoxazolyl, furazanyl, thiadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and the corresponding groups resulting from the fusion with phenyl, such as benzothiophene, benzofuran, benzothiazole and the like.

Within the object of the present invention compounds of formula (I), a group of compounds consists of those for which:

ar represents aryl or heteroaryl, optionally substituted with one or more identical or different substituents selected from: a halogen atom, a (C1-6) alkyl group, a perhalogenated (C1-3) alkyl group, a (C1-6) alkoxy group, an aryl group;

r2, R3 and R4, identical or different, located in any of the available positions of the phenyl ring, independently represent a hydrogen atom, a halogen atom, CN, OH, (C1-6) alkyl, perhalo (C1-3) alkyl, (C1-6) alkoxy, perhalo (C1-3) alkoxy, aminocarbonyl, (C1-6) alkylaminocarbonyl, di (C1-6) alkylaminocarbonyl, aryl, aryloxy or heteroaryl, it being understood that at least one of R2, R3, R4 is not H;

r5 represents (C1-6) alkyl;

represents a single or double bond; and/or

X represents-N < - > -CH < orAnd/or

Y represents > N-or > CH-, and/or

It is understood that at least one of X, Y represents N; and/or

Ar represents an aryl group optionally substituted with one or more substituents selected from: a halogen atom, preferably chlorine or bromine, and (C1-6) alkoxy, (C1-6) alkyl, aryl, trifluoromethyl, trifluoromethoxy; and/or

R1 represents a hydrogen atom or-C (═ O) (C1-6) alkyl, -C (═ O) aryl or (C1-6) alkyl; and/or

R2, R3 and R4, identical or different, located in any of the available positions of the phenyl ring, independently represent a hydrogen atom, a halogen atom, preferably chlorine or bromine, or a (C1-6) alkyl or trifluoromethyl group, with the understanding that at least one of R2, R3, R4 is not H; and/or

R5 represents (C1-6) alkyl; and/or

n represents 1 or 2;

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

Within the object of the present invention, compounds of formula (I), another group of compounds consists of compounds for which:

represents a single or double bond; and/or

X represents-N < - > -CH < orAnd/or

Y represents > N-or > CH-, and/or

It is understood that at least one of X, Y represents N; and/or

Ar represents phenyl or naphthyl optionally substituted with one or more substituents selected from: halogen atoms, preferably chlorine or bromine, and methoxy, methyl, tert-butyl, phenyl, trifluoromethyl and trifluoromethoxy; and/or

R1 represents a hydrogen atom or — C (═ O) methyl, -C (═ O) phenyl, methyl; and/or

R2, R3 and R4, identical or different, located in any available position of the phenyl ring, independently represent a hydrogen atom, a halogen atom, preferably chlorine or bromine, or a methyl or trifluoromethyl group, with the understanding that at least one of R2, R3, R4 is not H; and/or

R5 represents methyl, ethyl or 2-propyl; and/or

n represents 1 or 2;

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

ar represents a heteroaryl group, optionally substituted with one or more identical or different substituents selected from: halogen atom and (C1-6) alkyl, perhalo (C1-3) alkyl, (C1-6) alkoxy and aryl.

Among the compounds of formula (I) object of the present invention, mention may in particular also be made of the following compounds:

(+) -N- [5, 6-dichloro-3- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (4-methylpiperazin-1-yl) acetamide

(+) -N- [4, 6-dichloro-3- (4-trifluoromethylphenyl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (1-ethylpiperidin-4-yl) acetamide

N- [4, 6-dichloro-3- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (4-methylpiperazin-1-yl) acetamide

N- [ 4-trifluoromethyl-6-cyano-3- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (4-ethylpiperazin-1-yl) acetamide

(+) -N- [ 1-benzoyl-5, 6-dichloro-3- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (4-methylpiperazin-1-yl) acetamide

3- (4-chlorophenyl) -3- [2- (4-ethylpiperazin-1-yl) acetylamino ] -2-oxo-4-trifluoromethyl-2, 3-dihydro-1H-indole-6-carboxamide

N- [ 6-chloro-3- (4-chlorophenyl) -1, 5-dimethyl-2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (4-methylpiperazin-1-yl) acetamide

(+) -N- [4, 6-dichloro-3- (4-trifluoromethylphenyl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (1-ethyl-1, 2,3, 6-tetrahydropyridin-4-yl) acetamide

N- [4, 6-dichloro-3- (3, 4-dichlorophenyl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (4-ethylpiperazin-1-yl) acetamide

N- [4, 6-dichloro-3- (3-fluoro-4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (4-ethylpiperazin-1-yl) acetamide

N- [4, 6-dichloro-3- (3-trifluoromethyl-4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (4-ethylpiperazin-1-yl) acetamide

N- [4, 6-dichloro-1-ethyl-3- (2-methylbenzo [ b ] thiophen-5-yl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (1-ethylpiperidin-4-yl) acetamide

N- [4, 6-dichloro-1-ethyl-3- (2-methyl-benzofuran-5-yl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (4-ethylpiperazin-1-yl) acetamide

N- [4, 6-dichloro-3- (4-trifluoromethoxyphenyl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (4-ethylpiperazin-1-yl) acetamide

In the form of a base or of an addition salt with an acid.

In the following, by "protecting group Gp" is understood a group which on the one hand can protect a reactive function (such as a hydroxyl group or an amine) during synthesis and on the other hand can regenerate the intact reactive function at the end of synthesis. Examples of protecting groups and examples of methods of protection and deprotection are given in "protective organic Synthesis" Green et al, 2 nd edition (John Wiley & Sons, in inc., New York).

Hereinafter, the term "leaving group" means a group which can be easily cleaved from a molecule by breaking an heterobond and taking away an electron pair. Such a group can thus be easily substituted with another group, for example during a substitution reaction. Such leaving groups are, for example, halogen or activated hydroxy groups such as methane sulfonate, benzene sulfonate, p-toluene sulfonate, trifluoromethyl sulfonate, acetate and the like. Examples of leaving groups and references for their preparation are given in advanced organic chemistry, J.March, 3 rd edition, Wiley Interscience, page 310-316.

According to the invention, the compounds of general formula (I) can be prepared according to the following procedure:

scheme 1：

A compound of formula (I) wherein R1 is other than H andr2, R3, R4, R5, Ar, X, Y and n are as defined in general formula (I), can be prepared by the reaction of a compound of formula (I) (wherein R1 ═ H) with a compound of formula (II):

R1-Hal(II)

wherein R1, is not H, which is as defined in formula (I) and Hal represents a halogen atom, for example chlorine, according to methods known to those skilled in the art, for example in the presence of a base (e.g. K)₂CO₃NaH or t-BuO^-K⁺) In a solvent such as Dimethylformamide (DMF), Tetrahydrofuran (THF), dimethoxyethane, Dimethylsulfoxide (DMSO) in the presence of water.

Compounds of general formula (I), wherein R1 ═ H, can be prepared according to one or other of the following variants:

compounds of formula (I) wherein R1 ═ H, i.e. compounds of formula (II), can be prepared by compounds of formula (III):

with a compound of general formula (IV):

wherein Y, R2, R3, R4, R5, Ar and n are as defined in formula (I). Such reactions typically employ organic or inorganic bases (e.g., K)₂CO₃、Na₂CO₃Pyridine or 4-dimethylaminopyridine) in the presence of NaI or KI in an inert solvent such as DMF, dichloromethane, THF, dimethoxyethane or toluene.

The compound of formula (III) may be prepared from a compound of formula (V):

and from compounds of the general formula (VI):

wherein R2, R3, R4, R5 and Ar are as defined in formula (I) and Hal' and Hal ", identical or different, independently represent a halogen atom, preferably chlorine.

This reaction is generally carried out using pyridine or 4-dimethylaminopyridine in a solvent such as toluene, benzene or dichloromethane, preferably at a temperature between room temperature and the reflux temperature of the solvent.

When X is-CH, -N < orCompounds of general formula (I), wherein R1 ═ H, can also be prepared from compounds of general formula (V):

and from compounds of the general formula (VII):

whereinR2, R3, R4, R5, Ar, X, Y and n are as defined in formula (I). Such reactions generally employ halogenating agents, such as chlorinating agents, for example phosphorus chloride, in particular PCl₅Or PCl₃Or POCl₃To proceed with. The reaction is usually carried out in the presence of pyridine or 4-dimethylaminopyridine in a solvent such as dichloromethane or DMF.

Intermediates of general formula (V) are known and can be prepared according to the methods illustrated in the following schemes:

scheme 2:

wherein R2, R3, R4 and Ar are as defined in formula (I) and Hal represents a halogen atom, for example chlorine.

In step c of scheme 2, the compound of formula (V) is prepared from the compound of formula (VIII) by ammonia bubbling, according to the method described in patent application FR 2714378.

The same compounds can also be prepared by reduction of the compounds of formula (X) according to methods known to those skilled in the art, for example with the aid of zinc in a solvent such as methanol. The preparation of the compound of formula (X) of this step is described in patent application FR 2714378.

Optically pure compounds of formula (V) can be synthesized according to scheme 3, steps d and e as described in patent application WO 03/008407.

Intermediates of general formula (VIII) can be prepared according to the method described in patent application WO03/008407 and illustrated by scheme 3:

scheme 3：

The compounds of formula (XIV) may also be prepared by applying or modifying the compounds described in journal of heterocyclic chemistry, 43(4), 1031-1035; the process in 2006 proceeds.

Thus, the compounds of formula (XIV) may be prepared by reduction of compounds of formula (XV):

wherein R2, R3, R4 and Ar are as defined in formula (I) and Alk represents an alkyl group, for example methyl, ethyl or butyl. This reaction is generally carried out in an acidic medium (for example using acetic acid) using iron.

The compound of formula (XV) can be prepared by reacting a compound of formula (XVI):

wherein R2, R3 and R4 are as defined in general formula (I), with a compound of formula (XVII):

wherein Ar is as defined in formula (I) and Alk represents an alkyl group, such as methyl, ethyl or butyl, according to reactions known to those skilled in the art and described in journal of heterocyclic chemistry, 43(4), 1031-1035; 2006, for example in the presence of a base such as t-BuOK or NaH.

The compounds of general formula (VII) can be prepared according to one or the other of the following methods illustrated by scheme 4:

scheme 4:

according to a first embodiment, when X ═ CH <, the compound of formula (VII) can be obtained by reacting a compound of formula (XX):

wherein R5 and Y are as defined in formula (I), in an acidic medium (for example using concentrated hydrochloric acid).

Compounds of general formula (XX) may be prepared by reduction (for example using magnesium) of a compound of formula (XIX):

wherein R5 and Y are as defined in formula (I). This reaction is usually carried out in a solvent such as methanol or ethanol.

The compounds of formula (XIX) can be prepared by Wittig-The reaction is prepared starting from a compound of general formula (XVIII):

wherein R5 and Y are as defined in formula (I). Typically, this reaction is carried out using a suitable phosphonate derivative, such as diethyl (cyanomethyl) phosphonate. The process is advantageously carried out in the presence of a base (e.g. K)₂CO₃) In the presence of a solvent such as THF or dimethoxyethane.

According to a second embodiment, when X ═ N <, the compound of formula (VII) can be prepared from the compound of formula (XXII):

wherein R5 and Y are as defined in formula (I), and Alk represents an alkyl group, for example methyl, ethyl or butyl. This reaction is generally carried out in an acidic medium (for example using concentrated hydrochloric acid).

The compound of formula (XXII) can be prepared by reacting a compound of formula (XXI):

wherein R5 and Y are as defined in formula (I), with corresponding halogen-containing compounds (e.g. Hal' -CH)₂COOAlk, in which Hal' "represents a halogen atom, such as chlorine, and Alk represents an alkyl group, such as ethyl). This reaction is advantageously carried out in a solvent such as toluene, benzene or dioxane.

According to the third embodiment, whenWhen the compound of formula (VII) is represented by the formula (XXIV):

The compounds of formula (XXIV) can be prepared by starting from compounds of formula (XVIII):

wherein R5 and Y are as defined in formula (I), using the reaction of a compound of formula (XXIII):

NC-CH₂COOH(XXIII)

typically, this reaction is carried out in a solvent (e.g., THF).

According to another embodiment, compounds of general formula (I), wherein R1 represents alkyl and R2, R3, R4, R5, Ar, X, Y and n are as defined in general formula (I), may also be prepared according to scheme 5 below:

scheme 5：

Compounds of general formula (XXV) may be prepared by reacting a compound of formula (XIII):

ALK-Hal(XIV)

in which ALK represents a linear or branched, saturated aliphatic radical comprising from 1 to 6 carbon atoms and Hal represents a halogen atom, for example chlorine, in a base (such as K) according to methods known to those skilled in the art₂CO₃NaH or t-BuO^-K⁺) In a solvent (such as DMF, THF, dimethoxyethane, DMSO) in the presence of a solvent.

The compound of formula (XXVIII) can be prepared according to a method similar to that described previously.

The compounds of general formula (XXVIII) can also be prepared according to scheme 6 below:

scheme 6:

according to this scheme, a compound of formula (V) is reacted with a protecting group PG to give a compound of formula (XXX). As amine-protecting groups PG, it is possible to use, for example, benzylimine (benzimine) and tert-butyl carbamate. According to methods known to the person skilled in the art, for example in the presence of a base (e.g.K)₂CO₃NaOH or triethylamine) in a solvent such as dioxane, THF or DMSO.

Compounds of general formula (XXXI) may be prepared by reacting a compound of formula (XXX) with a compound of formula (XIV):

ALK-Hal(XIV)

wherein ALK represents a linear or branched, saturated aliphatic group containing 1 to 6 carbon atoms and Hal represents a halogen atom, such as chlorine.

The compounds of general formula (XXVIII) are obtained from the compounds of formula (XXXI) by deprotection according to well-known methods, for example in an acidic medium using HCl or trifluoroacetic acid.

Then, by applying the procedures described above for the compounds of the formulae (XIII), (XIV), (X), (V), (III) and (I) of schemes 1,2 and 3, the compounds of the formulae (XXV), (XXVI), (XXVII), (XXVIII), (XXIX) and (I) are obtained.

Optionally, the compound of formula (I) is converted into an addition salt thereof with an acid.

The process according to the invention may optionally comprise a step which consists in isolating the desired product of general formula (I).

In schemes 1,2,3, 4, 5 and 6, the starting compounds and reagents, when their mode of preparation is not described, are commercially available or described in the literature, or can be prepared according to the methods described therein or known to those skilled in the art.

According to another of its aspects, the present invention also provides compounds of the formula (III) with the exception of 5-chloro-3- (2-chloroacetamido) -3- (2-chlorophenyl) -1, 3-indolin-2-one. These compounds are useful as synthetic intermediates for compounds of formula (I).

Within the object of the present invention compounds of formula (III), a group of compounds consists of those for which:

ar represents a heteroaryl group, optionally substituted with one or more identical or different substituents selected from: halogen atom, (C1-6) alkyl, perhalogenated (C1-3) alkyl, (C1-6) alkoxy, aryl.

According to another of its aspects, the invention also relates to compounds of the formulae (XXVIII) and (XXIX). These compounds are useful as synthetic intermediates for compounds of formula (I).

The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and serve only to illustrate the invention. The numbers of the exemplified compounds refer to the numbers given in the following table, which exemplify the chemical structures and physical properties of some compounds according to the invention.

The physico-chemical measurements were carried out in the following manner:

melting points were measured using BUCHIB-540 apparatus.

Proton nuclear magnetic resonance spectra (1HNMR) were recorded at 500MHz on a Bru ker instrument equipped with an AvanceIII console. Chemical shifts (in ppm) are given relative to the frequency of TMS.

All spectra were recorded at a temperature of 40 ℃.

Abbreviations used to characterize the signals are as follows:

s is singlet, bs is broad singlet, m is multiplet, d is doublet, t is triplet, q is quartet.

Due to interference with the broad peak due to water, it is not integrable.

It is not integratable due to interference with peaks generated by NMR solvents.

HPLC was performed using a thermionic electron surveyor system (syst emimetherm electron surveyor) equipped with an ion trap mass spectrometer detector and a diode array detector.

The analysis conditions by liquid chromatography coupled with mass spectrometry (LC/UV/MS) were as follows:

for the liquid chromatography part, three different chromatography systems were used:

chromatographic System A

-eluent a ═ H₂O+0.005％TFA

-eluent B ═ CH₃CN

Gradient from 95% a to 90% B over 17 min, then elution with 90% B for 5 min

Flow rate 0.3 ml/min

Injection of 2. mu.L in CH₃CN∶H₂0.1mg/ml solution in a 9: 1 mixture

-chromatographic system B

-eluent a ═ H₂O+0.01％TFA

-eluent B ═ CH₃CN

Gradient from 98% a to 95% B over 10 min, then elution with 95% B for 5 min

-a flow rate of 0.5 ml/min; the temperature is 40 DEG C

Injection of 2. mu.L in CH₃CN∶H₂0.1mg/ml solution in a 9: 1 mixture

-chromatographic system C

-eluent a ═ H₂O +0.005M ammonium acetate pH6.5

-eluent B ═ CH₃CN

Gradient from 95% a to 90% B over 17 min, then elution with 90% B for 5 min

Flow rate 0.3 ml/min

Injection of 2. mu.L in CH₃CN∶H₂0.1mg/ml solution in a 9: 1 mixture

The columns used were:

-WatersXTreraMSC182.1X 50mm3.5um column No.186000400

-Waters XBridgeC182.1X 50mm2.5 μm column No.186003085

-Phenomenex GeminiC182.1X 100mm510 μm column No.00D-4435-B0

WatersSunfireC182.1X 100mm3.5 μm column No.186002534.

The product was detected by UV at 220 nm.

For the mass spectroscopy part:

-ionization mode: positive electrospray (API-ES polarity +)

Scan from 100 to 1200 uma.

Thin layer chromatography was performed on silica gel thin layer chromatography (CCM) plates from Merck. Silica gel for flash column chromatography was sold by Biotage.

All solvents used were of "reagent grade" or "HPLC grade" purity.

The α D measurement was performed on a PerkinElmer PE341 type polarimeter using a cell (cell) with a 1dm optical length.

In the examples and preparations:

AcOH and AcOEt represent acetic acid and ethyl acetate, respectively.

MeOH, EtOH and t-BuOH represent methanol, ethanol and tert-butanol, respectively.

Pf denotes the melting point.

Preparation 1:

(1-methylpiperidin-4-yl) acetic acid

(i) (1-methylpiperidin-4-ylidene) acetonitrile

9.36gK in 12ml tetrahydrofuran₂CO₃And 8.89ml of diethyl (cyanomethyl) phosphonate were added to a round bottom flask equipped with a magnetic stirrer and under a nitrogen stream, allowed to react at room temperature for 15 minutes and then refluxed for 20 minutes. It was allowed to cool and 6.5ml of 1-methyl-4-piperidone were added dropwise. The mixture was refluxed for 16 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. Organic phase in Na₂SO₄Dried, filtered and evaporated under vacuum. 6.8g of an oil were obtained.

(ii) (1-methylpiperidin-4-yl) acetonitrile

1g of the product obtained in the preceding step in 70ml of methanol are added to a reactor equipped with a magnetic stirrerIn a round bottom flask of a stirrer. 7.2g of magnesium were added in small portions at 0 ℃. The mixture was stirred for 4 hours. Filtration to remove magnesium solid particles and evaporation of the filtered water (eauxdefiltraction). The residue was dissolved in a saturated solution of NaCl and extracted with dichloromethane. Organic phase in Na₂SO₄Dried, filtered and evaporated under vacuum. 450mg of oil are obtained.

CCM：AcOEt9/MeOH1，Rf＝0.2

(iii) (1-methyl-piperidin-4-yl) acetic acid

3.65g of the product obtained in step (ii) in 47ml of concentrated hydrochloric acid are introduced into a round-bottomed flask equipped with a magnetic stirrer. The mixture was refluxed for 20 hours. Diluted with water and extracted with dichloromethane to remove impurities. The aqueous phase was brought to pH5-6 and extracted with dichloromethane. The aqueous phase was evaporated under vacuum and a white solid was isolated. Dissolved with ethanol to separate the product from the salt. The filtered water was evaporated to isolate 3.6g of a pale yellow solid.

CCM：MeOH99/NH₄OH1，Rf＝0.2

Preparation 2:

(1-ethylpiperidin-4-yl) acetic acid

By working as described in preparation 1, but using 1-ethyl-4-piperidone instead of 1-methyl-4-piperidone, the title compound was obtained.

CCM：100％MeOH，Rf＝0.15；

Preparation 3:

(4-ethylpiperazin-1-yl) acetic acid

(i) (4-ethylpiperazin-1-yl) acetic acid ethyl ester

8.9ml of ethylpiperazine in 91.5ml of toluene were added to a round-bottom flask. A solution of 4.1ml of ethyl bromoacetate in 11.6ml of toluene was added dropwise. It was allowed to react at reflux at 110 ℃ for 1 hour, concentrated to a smaller volume and allowed to cool in the refrigerator for 3 hours. A white precipitate formed, which was filtered off and washed with dichloromethane. Evaporating the filtered water; 7g of the expected product are obtained.

CCM：AcOEt1/MeOH1，Rf＝0.45

(ii) (4-ethylpiperazin-1-yl) acetic acid

7g of the product obtained in the preceding step was added to 190ml of 6N HCl and reacted at reflux for 4 hours. Evaporate to dryness and wash with a mixture of AcOEt1/EtOH1 and dry the resulting white solid. 7g of the expected product are obtained.

CCM：100％MeOH，Rf＝0.2

Preparation 4:

(4-methylpiperazin-1-yl) acetic acid

By working as described in preparation 3, but using 1-methylpiperazine instead of 1-ethylpiperazine, the title compound was obtained.

CCM：100％MeOH，Rf＝0.25

Preparation 5:

(+) -3-amino-5, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

(i)5, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

A) (4-chlorophenyl) (4, 5-dichloro-2-nitrophenyl) acetic acid methyl ester

A solution of 5g of 1, 2-dichloro-4-fluoro-5-nitrobenzene and 4.4g of 4-chlorophenylacetic acid methyl ester in 70ml of DMF was added under a stream of nitrogen to a suspension of 2.85g of 60% NaH at-10 ℃ in 45ml of DMF and the temperature was maintained at-5 ℃. The reaction was allowed to proceed for 2 hours, and the temperature was returned to room temperature. Poured onto ice and 10% NH added₄Aqueous Cl and extracted with ethyl acetate. The organic phase was dried, filtered and concentrated. 30g of a brown oil are obtained which is purified on a column with hexane and then with 95/5 hexane/AcOEt mixture, giving 3.18g of an oil.

B)5, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

4.6g of the product from step A, 60ml of methanol, 15ml of acetic acid and 2.7g of iron are introduced into a round-bottomed flask equipped with a mechanical stirrer and under a stream of nitrogen and refluxed for 1 hour 30 minutes. It was poured onto ice and 10% NaHCO was added₃The solution was brought to alkaline pH. Ethyl acetate was added and filtered. The organic phase was separated and dried, filtered and concentrated. A solid was obtained, which was dissolved in isopropyl ether and filtered. 2.75g of a white solid was obtained.

Melting point: 214 ℃ and 215 DEG C

(ii)5, 6-dichloro- [ [ (1R) -2-hydroxy-1-phenylethyl ] amino ] -1, 3-dihydro-3- (4-chlorophenyl) indol-2-one isomers A and B

A) 3-bromo-5, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

2.75g of the product from step B above were dissolved in 100ml of dichloromethane under a stream of nitrogen. Cooled in an ice bath and 3.93g PhMe were added dropwise₃NBr₃Solution in 100ml dichloromethane. The reaction was allowed to react for 3 hours, and the temperature was gradually returned to room temperature. Washed with 1M hydrochloric acid and water. Dried, filtered and concentrated. 3.7g of an oil were obtained.

B)5, 6-dichloro- [ [ (1R) -2-hydroxy-1-phenylethyl ] amino ] -1, 3-dihydro-3- (4-chlorophenyl) indol-2-one isomers A and B

3.4g of the compound from the preceding step and 2.9 gR-phenylglycinol in 50ml of chloroform were mixed under a nitrogen flow. The reaction was allowed to proceed at room temperature for 2 hours, then 1.6ml of DIPEA was added and allowed to proceed at room temperature. The solid formed was filtered off and the filtered water was evaporated to dryness and purified on a column, eluting with 7/3 hexane/AcOEt.

1.8g of the less polar product are obtained, isomer A (melting point: 79.8-80.5 ℃) and 2.2g of the more polar isomer B (melting point: 213.2 ℃).

(iii) (+) -3-amino-5, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

1.8g of the product obtained in the preceding step are reacted in a mixture of 28ml of dichloromethane and 12ml of methanol. Adding 1.9g of Pb (OAc)₄And allowed to react at room temperature for 3 hours. Evaporated to dryness and dissolved in ethyl acetate and then with NaHCO₃Washing with saturated aqueous solution. The organic phase was dried, filtered and concentrated. The product obtained was dissolved in a mixture of 36ml of 3N hydrochloric acid and 3.7ml of methanol and stirred overnight. Concentrated and diluted with a mixture of water and dichloromethane. The organic phase is washed with a 1N hydrochloric acid solution. Combining the aqueous phases with NH₃The aqueous solution was brought to basic pH and extracted with dichloromethane. The organic phase was dried, filtered and concentrated to yield 540mg of product as a white solid.

Melting point 221 ℃; α D +32.5 °, c 0.5 wt% MeOH

Preparation 6:

(-) -3-amino-5, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

By working as described in preparation 5(iii) but replacing the isomer a of this same preparation with the more polar isomer B obtained in preparation 5(ii), the title compound is obtained.

α D ═ 23.6 °, c ═ 0.35% by weight MeOH

Preparation 7:

3-amino-4, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

(i)4, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

a) 4-chloro-O-acyl-mandelic chloride (4-chloro-O-acyl-mangelic-chlorore)

10g of 4-chloro-dl-mandelic acid, 88ml of dichloromethane and 4.2ml of acetyl chloride were added to a two-necked round-bottomed flask equipped with a magnetic stirrer. This was allowed to react at 50 ℃ for 3 hours. 7.8ml of thionyl chloride were then added. The reaction was refluxed for 2 hours. Evaporate under vacuum and obtain 13.7g of opaque liquid.

b) 4-chloro-N-3, 5-phenyl-mandelamide

4.04g of 3, 5-dichloroaniline and 50ml of toluene are introduced into a three-neck round-bottom flask equipped with a mechanical stirrer and under a nitrogen stream. Cooled to 0 ℃. Then 9.6g of potassium carbonate were added. 6.8g of the product obtained in the preceding step, diluted in 10ml of toluene, are slowly added. This was allowed to react at room temperature for 1 hour, and then 4.15ml of methanol was added. This was allowed to react at 80 ℃ for 2 hours, followed by pouring into a 1N hydrochloric acid solution and extraction with ethyl acetate. The organic phase was evaporated under vacuum. 5.7g of a solid are obtained.

c)4, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

22ml of 96% sulfuric acid and 5ml of oleum were added to a round bottom flask equipped with a magnetic stirrer. Cooled in an ice bath and 5.7g of the product obtained in the preceding step are added in small portions. Then allowed to react at room temperature for 4 hours. The reaction was poured into an ice bath and washed with NaHCO₃The solution is then brought to an alkaline pH with concentrated sodium hydroxide solution. Extracting with dichloromethane, separating organic phase, and purifying with Na₂SO₄Dried above, filtered and evaporated under vacuum to give 7.5g of a solid which was dissolved in ether. Filtration gave 4.2g of powder.

(ii) 3-azido-4, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

A) 3-bromo-4, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

The product was obtained by operating as described in point (ii) of preparation 5, but using the compound obtained in the previous step.

B) 3-azido-4, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

550mg of the compound obtained in the preceding step, 17ml of acetonitrile and 270mg of NaN₃Into a three-neck round-bottom flask equipped with a mechanical stirrer and under nitrogen flow. The mixture was refluxed for 2 hours and then dissolved in ethyl acetate and washed with a saturated solution of sodium chloride. The organic phase is separated off, which is over Na₂SO₄Dried, filtered and evaporated in vacuo to give 320mg of resin which was purified by flash chromatography eluting with 85/15 cyclohexane/ethyl acetate. The phase containing the product was evaporated to yield 220mg of a white solid.

(iii) 3-amino-4, 6-dichloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

220mg of the product obtained in the preceding step in 5ml of THF, 10ml of methanol, 170mg of NH₄Cl and 80mg zinc were added to a two-necked round bottom flask equipped with a mechanical stirrer. The reaction was allowed to proceed at room temperature for 3 hours. Filtered and evaporated under vacuum. It was dissolved in ethyl acetate and washed with a saturated solution of sodium chloride. Separating the organic phase, which is in Na₂SO₄Dried, filtered and evaporated under vacuum. 200mg of oil are obtained and the product is purified by flash chromatography, eluting with 8/2 cyclohexane/ethyl acetate. 74mg of the expected product are obtained.

CCM: cyclohexane 6/AcOEt4, Rf 0.3

Preparation 8:

(+) -3-amino-4, 6-dichloro-1, 3-dihydro-3- (4-trifluoromethylphenyl) indol-2-one

(i) 3-hydroxy-4, 6-dichloro-1, 3-dihydro-3- (4-trifluoromethylphenyl) indol-2-one

1.8g of Grignard magnesium (magnesium powder Grignard) in 19ml of anhydrous ether was added to a round bottom flask equipped with a mechanical stirrer and under nitrogen flow. A mixture of 8.9ml of 4-bromotrifluoromethylbenzene in 46ml of dry diethyl ether was then added. Stirring was allowed to proceed for 1 hour, followed by the addition of a solution of 5.7g4, 6-dichloro-1H-indole-2, 3-dione in 100ml anhydrous THF. Stirred at room temperature for 4 hours and 30 minutes. Water was added and extraction was performed using ethyl acetate. Is separated byThe organic phase was dried on top, filtered and evaporated under vacuum. The residue was dissolved in ethyl acetate and washed with 1N sodium hydroxide solution. Organic phase in Na₂SO₄Dried, filtered and evaporated under vacuum. The solid was dissolved in ether and filtered. 4.7g of the expected product are obtained.

(ii)3, 5, 6-trichloro-1, 3-dihydro-3- (4-trifluoromethylphenyl) indol-2-one

1.2g of the product from the preceding step in 8ml of dichloromethane are added to a round-bottom flask equipped with a magnetic stirrer and under nitrogen flow. 0.47ml pyridine and 0.34ml SOCl were added at 0 deg.C₂Mixture in 4ml dichloromethane. It was allowed to react at room temperature and then poured over NH₄Cl in saturated aqueous solution. The organic phase is separated and purified over Na₂SO₄Dried, filtered and evaporated under vacuum.

CCM: hexane 1/AcOEt1, Rf 0.85

(iii)4, 6-dichloro- [ [ (1S) -2-hydroxy-1-phenylethyl ] amino ] -1, 3-dihydro-3- (4-trifluoro-methylphenyl) indol-2-one isomers A and B

Operating as described for preparation 5, steps (ii) a and B, but using the compound from the previous step and (S) -phenylglycinol instead of (R) -phenylglycinol, the title compound is obtained.

CCM: AcOEt 4/cyclohexane 6, Rf ═ 0.5 (isomer a), Rf ═ 0.2 (isomer B)

(iv) (+) -3-amino-5, 6-dichloro-1, 3-dihydro-3- (4-trifluoromethylphenyl) indol-2-one

This compound was obtained by working as described in step (ii) B of preparation 5.

α D +60 °, c 0.25 wt.% in MeOH

Preparation 9:

3-amino-1, 5-dimethyl-6-chloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

(i) 6-chloro-3- (4-chlorophenyl) -3-hydroxy-1, 5-dimethyl-1, 3-indolin-2-one

This compound was prepared from 3-hydroxy-5-methyl-6-chloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one (compound obtained according to the method described in point (i) of preparation 8), and 1.2g thereof was dissolved in 8ml of Dimethylformamide (DMF). 167mg of 60% NaH was added under a nitrogen stream at 0 ℃. Then 260. mu. lCH was added₃I, and allowing to react for 30 minutes. Poured into water and extracted with dichloromethane. The organic phase was dried, filtered and concentrated. The product was purified on a column, eluting with 9/1 hexane/AcOEt.

CCM: AcOEt 1/Hexane 1, Rf 0.7

(ii) 6-chloro-3- (4-chlorophenyl) -1, 5-dimethyl-1, 3-indolin-2-one

1g of the product obtained in the preceding step in 4ml of TFA and 1.3ml of HSiEt₃Mixed and allowed to react at 80 ℃ for 1 hour. Pour it into water and use NH₃The aqueous solution is brought to an alkaline pH. Extraction was performed with ethyl acetate. The organic phase was dried, filtered and concentrated. Dissolved in ether and filtered. 688mg of a white solid was obtained.

CCM: AcOEt 4/hexane 6, Rf 0.7

(iii) 3-amino-1, 5-dimethyl-6-chloro-1, 3-dihydro-3- (4-chlorophenyl) indol-2-one

The title compound was obtained by operating as described in preparation 7, points (ii) and (iii), but using the product from the previous step instead of the product obtained in preparation 7, step (i).

CCM: AcOEt 1/Hexane 1, Rf 0.5

Preparation 10:

(1-Ethyl-1, 2,3, 6-tetrahydropyridin-4-yl) acetic acid

(i) (1-Ethyl-1, 2,3, 6-tetrahydropyridin-4-yl) acetonitrile

2.9g of 1-ethyl-4-piperidone, 3.3g of cyanoacetic acid and 36ml of toluene were added to a round-bottomed flask equipped with a magnetic stirrer and under a stream of nitrogen. Reflux was allowed to occur for 4 hours while removing water using a Markusson apparatus. The evaporation was carried out under vacuum. 4.2g of an oil are obtained.

(ii) (1-Ethyl-1, 2,3, 6-tetrahydropyridin-4-yl) acetic acid

The title compound was obtained by operating as described in point (iii) of preparation 1, but using the product from the previous step instead of the product of preparation 1 (ii).

CCM：MeOH99/NH₄OH1，Rf＝0.2

¹HNMR：(ppm，DMSO-d6)：1.09(t，J＝7.2Hz，3H)，2.18(m，2H)，2.62(q，J＝7.2Hz，2H)，2.68-2.76(m，2H)，2.92(s，2H)，3.11(bs，2H)，5.49(m，1H).

Preparation 53:

(+) -3-amino-1-isopropyl-4, 6-dichloro-1, 3-dihydro-3- (3, 4-dichlorophenyl) indol-2-one

(i) (+) -3-amino-4, 6-dichloro-1, 3-dihydro-3- (3, 4-dichlorophenyl) indol-2-one

This compound was obtained by working as described in preparation 5, but using 3, 4-dichloro-bromobenzene in step (i) instead of 4-bromo-trifluoromethylbenzene.

(ii) (+) -3-Benzimidyl-4, 6-dichloro-1, 3-dihydro-3- (3, 4-dichlorophenyl) indol-2-one

215mg of the product obtained in the preceding step and 120. mu.l of benzaldehyde were added to a round-bottom flask. Heated in a microwave reactor at 100 ℃ for 5 minutes. A solid was obtained which was dried under vacuum to remove benzaldehyde.

(iii) (+) -3-Benzimidyl-1-isopropyl-4, 6-dichloro-1, 3-dihydro-3- (3, 4-dichlorophenyl) indol-2-one

At K₂CO₃144mg of the product obtained in the previous step in DMF (800. mu.l) was added to a round bottom flask in the presence of (49mg) and isopropyl bromide (30. mu.l). Heated in a microwave reactor at 140 ℃ for 5 minutes. Filtered and the crude product was used in the following step.

(iv) (+) -3-amino-1-isopropyl-4, 6-dichloro-1, 3-dihydro-3- (3, 4-dichlorophenyl) indol-2-one

The product obtained in the previous step (157mg) was dissolved in methanol (550. mu.l) and 2.7ml of 3N HCl solution was added. After 5 hours at room temperature, it was neutralized with aqueous ammonia and extracted with ethyl acetate. Dried and evaporated. A semi-solid product (112mg) was obtained.

Intermediates of the following general formula (V), wherein R1, R2, R3, R4 and Ar are as defined in table 1, are also prepared by the methods used for the preparation of 5,6, 7, 8 and 9.

Table 1, which follows, illustrates the chemical structures and physical properties of some preparations according to the present invention. In this table:

in the column "isomers", racemic "represents a racemic mixture, (+) or (-) represents one or the other of the stereoisomers,

-Me, Et, n-Pr, i-Pr, n-Bu and i-Bu represent methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl, respectively, and

-Ph and Bn represent phenyl and benzyl, respectively.

Example 1：

(i) 2-chloro-N- [5, 6-dichloro-3- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] acetamide:

1.3g of the product obtained in preparation 5, 5.47ml of toluene, 0.32ml of pyridine and 0.31ml of chloroacetyl chloride are introduced into a round-bottomed flask equipped with a magnetic stirrer under nitrogen flow. It was allowed to react at 110 ℃ for 4 hours, then the reaction mixture was poured into water and extracted with ethyl acetate. Organic phase in Na₂SO₄Dried, filtered and evaporated under vacuum. 900 mg of a beige solid are obtained, which is purified on a column by flash chromatography using a cyclohexane 8/ethyl acetate 2 mixture to obtain 400 mg of the expected product.

CCM: hexane 1/AcOEt1, Rf 0.5

(ii) (+) -N- [5, 6-dichloro-3- (4-chlorophenyl) -2-oxo-2, 3-dihydro-1H-indol-3-yl ] -2- (4-methylpiperazin-1-yl) acetamide:

0.4g of the product from the previous step, 0.11ml of N-methylpiperazine (d0.903), 0.14g of potassium carbonate and 0.07g of sodium iodide (in 8ml of DMF) were added to a round-bottom flask equipped with a magnetic stirrer. The reaction was allowed to react at 60 ℃ for 4 hours, then the reaction mixture was poured into water and extracted with ethyl acetate. Organic phase in Na₂SO₄Dried, filtered and evaporated under vacuum. 240 mg of oil are obtained and the product is dissolved in diethyl ether to yield 140 mg of a white solid. The filtered water was purified by flash chromatography using ethyl acetate 9/methanol 1 followed by ethyl acetate 7/methanol 3 as eluent to isolate 40mg of a white solid.

Melting point 207.1-207.6 deg.C, [ α ℃_D]+141 ℃, c 0.25 wt% MeOH;¹HNMR(ppm，DMSO-d6)：2.37(bs，3H)，2.50-2.74(m，**)，2.94-3.16(m，2H)，7.08(s，1H)，7.31(m，2H)，7.48(m，2H)，7.52(s，1H)，8.71(s，1H)，10.70(s，1H).LCMS：(M+H)⁺＝m/z467uma

example 2：

1) Under a nitrogen stream, 172.84mgPCl was added₅To 4.4ml of anhydrous dichloromethane cooled in an ice bath was added and 142.13 mg of the acid of preparation 2 was slowly added. The reaction mixture was allowed to react at 0 ℃ for 10 minutes and then at room temperature for 3 hours.

2) In addition, 100mg of preparation 8 were suspended in 4.4ml of dichloromethane under a nitrogen stream, and then 0.1ml of pyridine was added. Cooled in an ice bath. The solution prepared in 1) was added dropwise and stirred at room temperature for 1 hour.

The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was saturated NaHCO₃Washing with a solution of Na₂SO₄Dried, filtered and evaporated under vacuum. 145 mg of orange solid was obtained and the product was purified by flash chromatography on a column eluting with ethyl acetate 1/methanol 1 to give 85 mg of product which was dissolved in isopropyl ether to give 75mg of white/pink solid product.

Melting point 158 ℃ -_D]+194 °, c-0.125 wt.% in MeOH;¹HNMR：(ppm，DMSO-d6)：0.97(t，J＝7.1Hz，3H)，1.07-1.23(m，2H)，1.47-1.67(m，3H)，1.71-1.85(m，2H)，2.07-2.22(m，2H)，2.27(q，J＝7.1Hz，2H)，2.78(m，2H)，6.90(bs，1H)，7.18(bs，1H)，7.47(m，2H)，7.78(m，2H)，9.15(s，1H)，10.74(bs，1H)；LCMS：(M+H)⁺＝m/z514uma

example 3：

The title compound was obtained by operating as described in example 2, but using the compound of preparation 4 instead of the compound of preparation 2 and the compound of preparation 7 instead of the compound of preparation 5.

Melting point is 248-251 ℃; LCMS: (M + H)⁺＝m/z467uma；¹HNMR：(ppm，DMSO-d6)：2.16(s，3H)，2.24-2.42(m，4H)，2.43-2.57(m，**)，2.98-3.12(m，2H)，6.92(d，J＝1.8Hz，1H)，7.18(d，J＝1.8Hz，1H)，7.26(m，2H)，7.50(m，2H)，8.70(s，1H)，10.78(s，1H).

Example 4：

By working as described in example 1, but using the product of preparation 28 instead of the product of preparation 5 and N-ethylpiperazine instead of N-methylpiperazine, the title compound was obtained.

The melting point is 260-262 ℃; LCMS: (M + H)⁺＝m/z506uma；

¹HNMR：(ppm，DMSO-d6)：0.98(t，J＝7.3Hz，3H)，2.23-2.42(m，6H)，2.42-2.61(m，**)，2.87-3.17(m，2H)，7.14(m，2H)，7.47(m，2H)，7.59(bs，1H)，7.91(bs，1H)，8.91(s，1H)，11.12(bs，1H).

Example 5：

0.14g of the compound of example 1 in 9ml of DMF is charged in a round-bottomed flask equipped with a magnetic stirrer and under nitrogen flow. 0.01g of 60% NaH was added at 0 ℃. Then PhCOCl was added dropwise and allowed to react at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. Organic phase in Na₂SO₄Dried, filtered and evaporated under vacuum. 120 mg of oil are obtained and the product is purified by flash chromatography on a column eluting with ethyl acetate 95/methanol 5 to isolate 20mg of a white solid.

The melting point is 92-94 ℃;¹HNMR：(ppm，DMSO-d6)：2.16(s，3H)，2，24-2.40(m，4H)，2.40-2.50(m，**)，2.94-3.16(m，2H)，7.30(m，2H)，7.45(m，2H)，7.54(m，2H)，7.58-7.66(m，3H)，7.74(s，1H)，8.00(s，1H)，9.14(s，1H)；LCMS：(M+H)⁺＝m/z571uma.

example 6：

0.16g of the product obtained in example 4, 0.47g of potassium hydroxide and 7ml of tert-BuOH were charged into a round-bottomed flask equipped with a magnetic stirrer. The reaction was allowed to proceed at 50 ℃ for 5 hours. Filtered through celite and washed with THF. The filtrate was evaporated under vacuum and the residue was dissolved in ethyl acetate and washed with water. Organic phase in Na₂SO₄Dried, filtered and evaporated under vacuum. 100mg of an oil are obtained which is purified by flash chromatography, elution being carried out with ethyl acetate 8/methanol 2. 10mg of a white solid are isolated.

¹HNMR：(ppm，DMSO-d6)：0.99(t，J＝7.2Hz，3H)，2.25-2.42(m，6H)，2.42-2.62(m，**)，2.92-3.16(m，2H)，7.12(m，2H)，7.47(m，2H)，7.55(bs，1H)，7.64(bs，1H)，7.84(bs，1H)，8.24(bs，1H)，8.75(s，1H)，10.95(bs，1H)；LCMS：(M+H)⁺＝m/z571uma.

Example 7：

By working as described in example 1, but using the product of preparation 9 instead of the product of preparation 5, the title compound was obtained.

Melting point is 217-219 ℃;¹HNMR：(ppm，DMSO-d6)：2.26-2.35(m，6H)，2.44-2.64(m，**)，2.89-3.15(m，5H)，7.19(s，1H)，7.25-7.33(m，33H)，7.46(m，2H)，8.71(bs，1H).LCMS：(M+H)⁺＝m/z461uma.

example 8：

By working as described in example 2, but using the product of preparation 10 instead of the product of preparation 2, the title compound was obtained.

The melting point is 155-;¹HNMR：(ppm，DMSO-d6)：1.03(t，J＝7.2Hz，3H)，2.06(m，2H)，2.31-2.65(m，**)，2.80-3.05(m，4H)，5.46(bs，1H)，6.91(d，J＝1.7Hz，1H)，7.20(d，J＝1.7Hz，1H)，7.49(m，2H)，7.79(m，2H)，9.3(s，1H)，10.8(s，1H).

LCMS：(M+H)⁺＝m/z459uma

table 2 below illustrates the chemical structures and physical properties of some examples according to the present invention. In this table:

in the column "stereoisomers", racemic "represents a racemic mixture, (+) or (-) represents one or the other of the stereoisomers,

in the column "salts", "represents the compound in free base form, whereas" HCl "represents the compound in hydrochloride form and the ratio in parentheses is (acid: base),

-Ph and Bn represent phenyl and benzyl, respectively.

Example 53：

¹HNMR：(ppm，DMSO-d6)：0.86-1.15(m；3H)；2.52-2.78(m；**)；3.02-3.19(m；*)；6.93(d；J＝1.5Hz；1H)；7.06(dd；Ja＝8Hz；Jb＝2Hz；1H)；7.21(d；J＝1.5Hz；1H)；7.56(d；J＝2Hz；1H)；7.67(d；J＝8Hz；1H)；8.96(bs；1H)；10.88(s；1H).

Example 61：

¹HNMR：(ppm，DMSO-d6)：1.08-1.37(m；3H)；2.55-3.50(m；**；*)；6.94(d；J＝2Hz；1H)；6.98(dd；Ja＝8Hz；Jb＝2Hz；1H)；7.21(d；J＝2Hz；1H)；7.33(dd；Ja＝10Hz；Jb＝2Hz；1H)；7.63(m；1H)；8.99(s；1H)；9.83(bs；1H)；10.88(s；1H).

Example 65：

¹HNMR：(ppm，DMSO-d6)：1.14-1.28(m；3H)；2.55-2.80(m；2H)；2.80-3.74(m；*)；6.96(d；J＝2Hz；1H)；7.24(d；J＝2Hz；1H)；7.36(dd；Ja＝8Hz；Jb＝2Hz；1H)；7.75(d；J＝8Hz；1H)；7.84(d；J＝2Hz；1H)；9.27(s；1H)；9.90(bs；1H)；10.96(s；1H).

Example 72：

¹HNMR：(ppm，DMSO-d6)：0.96-1.14(m；6H)；1.14-1.46(m；4H)；1.49-1.63(m；1H)；1.63-1.83(m；2H)；2.16(dd；Ja＝13Hz；Jb＝7Hz；1H)；2.23(dd；Ja＝13Hz；Jb＝7Hz；1H)；2.55(s；3H)；2.81-3.12(m；2H)；3.65(m→q；J＝7Hz；2H)；7.08-7.19(m；2H)；7.22(d；J＝1.8Hz；1H)；7.30(d；J＝1.8Hz；1H)；7.57(d；J＝2Hz；1H)；7.86(d；J＝9Hz；1H)；9.16(s；1H).

Example 75：

¹HNMR：(ppm，DMSO-d6)：0.98(t；J＝7Hz；3H)；2.29(m→q；J＝7Hz；2H)；2.33-2.41(m；4H)；2.44(s；3H)；2.52-2.63(m；**)；3.01(d；J＝15Hz；1H)；3.07(d；J＝15Hz；1H)；6.61(s；1H)；6.91(d；J＝2Hz；1H)；7.11(dd；Ja＝8Hz；Jb＝2Hz；1H)；7.18(d；J＝2Hz；1H)；7.37(d；J＝2Hz；1H)；7.52(d；J＝8Hz；1H)；8.60(s；1H)；10.69(bs；1H).

Example 79：

¹HNMR：(ppm，DMSO-d6)：0.98(t；J＝7Hz；3H)；2.30(m→q；J＝7Hz；2H)；2.33-2.58(m；**)；3.02(d；J＝15Hz；1H)；3.08(d；J＝15Hz；1H)；6.92(d；J＝1.6Hz；1H)；7.20(d；J＝1.6Hz；1H)；7.33-7.41(m；2H)；7.41-7.47(m；2H)；8.78(bs；1H)；10.79(bs；1H).

Example 91：

¹HNMR：(ppm，DMSO-d6)：0.99(t；J＝7Hz；3H)；1.07(t；J＝7Hz；3H)；1.12-1.29(m；2H)；1.47-1.57(m；1H)；1.57-1.72(m；2H)；1.81-1.98(m；2H)；2.12(dd；Ja＝13Hz；Jb＝7Hz；1H)；2.22(dd；Ja＝13Hz；Jb＝7Hz；1H)；2.26-2.40(m；2H)；2.55(s；3H)；2.76-2.91(m；2H)；3.64(m→q；J＝7Hz；2H)；7.07-7.18(m；2H)；7.22(bs；1H)；7.29(bs；1H)；7.57(bs；1H)；7.83(d；J＝9Hz；1H)；9.13(bs；1H).

The compounds according to the invention were tested in vivo.

In vivo assay

Male CrlCDBR rats (Charles river, Italy) weighing 150-Degree (55 ± 10%) of the chamber and a 12 hour light-dark cycle for at least 7 days before using them. Food and water were available ad libitum. Food was removed 18 hours prior to sacrifice. Rats were sacrificed by cervical dislocation and the stomach was surgically removed, opened along minimal curvature and placed in Krebs solution, composition (mM): 118.4 NaCl; 4.7 KCl; 2.5CaCl₂；3.7NaH₂PO₄；1.2MgSO₄；25NaHCO₃(ii) a 5.6 glucose). Care and sacrifice were performed according to the Sanofi-Aventis International ethical guidelines (code e. Thiquelnationalee Sanofi-Aventis) and the International guidelines governing care and treatment of experimental animals (E.E. CDirective86/609, DJL358, 1, 12 December 1987). A narrow strip of approximately 1cm (5mm wide) of the fundus was cut along the longitudinal axis and suspended in 20ml Krebs solution filled at 37 deg.C and treated with 95% O₂-5％CO₂The tank is aerated with the gas mixture. The narrow strip was maintained at 1g static load (chargederepos) and after washing 10 μ M choline (acetylcholine precursor) and 10 μ M indomethacin (prostaglandin synthetase inhibitor) were added to the medium to reduce spontaneous phasic contraction (deportere et al, eur.j. pharmacol.515, 1-3, 160-. The isotonic contraction is initiated by stimulation with an electric field. Two platinum wire electrodes were placed on the surface and bottom of the organ bath and electric field stimulation was performed with a PowerLab stimulator (ADInstructionsPtyLtd, CastleHill, Australia) connected to a multiplex pulse thruster (Fukuda et al, Scand. J. gastroenterol.12, 1209-. Superstimulation was applied to produce maximal contraction (20Hz, pulse width: 2 ms; 5 volts; 150mA applied intermittently every 2 minutes (batchtrains)). Then, the current is reduced to obtain sub-maximal (submaximal) stimulation (50% of the maximal contractile response is reduced). The contraction is recorded by a computer (PowerLab, table 5) with a data recording and analysis system connected via a preamplifier (octalbidiamp) to an isotensory (UgoBasile, varee, Italy). After stabilization, the concentration of growth hormone releasing hormone (0.1 nM-1. mu.M) is plotted-trans-in the presence and absence of incubation (contact time: 30 min) of the antagonist moleculeThe curves should be accumulated. As a reference (100%), a very large electric field stimulus was applied to each strip to rank the response of each test substance. Produce 50% of the maximum Effect (EC)₅₀) The agonist concentration of (a) was adjusted using a four-parameter logistic model (mody leiogestique) according to Ratkovsky and Reedy (Biometrics, 42, 575-. The pKb value of the antagonist is calculated according to the Cheng-Prusoff equation (Kenakin et al, competitive Antagonism, Pharmacological analysis of drug-receptor interaction, 3 rd edition, 331-373, Philadelphia, NewYork; Raven: Lippincott, 1997).

Compounds of formula (I) exhibit antagonist activity against receptors for growth hormone releasing hormone, CI thereof₅₀Value of 10^-6-10^-11M。

For example, compounds 1 and 2 each have 5 × 10^-8M and 1 × 10^-9CI of M₅₀The value is obtained.

Thus, it can be seen that the compounds according to the present invention have antagonist activity to receptors for growth hormone releasing hormone.

The compounds according to the invention are therefore useful for the preparation of medicaments, in particular medicaments for or for the treatment of any condition in which receptors for growth hormone releasing hormone are involved.

Thus, according to another of its aspects, the present invention has for its object a medicament comprising a compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid.

Thus, the compounds according to the invention can be used in humans and animals for the treatment or prevention of different diseases related to growth hormone releasing hormone. Thus, the compounds according to the invention can be used as anorectic agents (agents) for the regulation of appetite, food intake and frequency thereof, as well as for the regulation of body weight in the long term, in particular the weight gain after a diet or treatment regimen. The compounds according to the invention are therefore particularly useful for the prophylaxis or treatment of obesity, appetite disorders, diabetes, overweight and/or the effects thereof.

According to another aspect of the invention, the invention relates to a pharmaceutical composition comprising a compound according to the invention as active ingredient. These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.

The excipients are selected from the usual excipients known to those skilled in the art according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above or its salt may be administered in unit administration form in admixture with conventional pharmaceutical excipients to animals and humans for the prevention or treatment of the above-mentioned disorders or diseases.

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

For example, a unit administration form (tablet form) of a compound according to the invention may comprise the following components:

compound according to the invention 50.0mg

Mannitol 223.75mg

Croscarmellose sodium 6.0mg

Corn starch 15.0mg

Hydroxypropyl methylcellulose 2.25mg

Magnesium stearate 3.0mg

By the oral route, the dose of active ingredient administered per day may be from 0.1 to 100mg/kg (taken in one or more portions). By parenteral route, it can be 0.01-10 mg/kg/day.

There may be specific cases where higher or lower doses are appropriate; such dosages do not depart from the scope of the present invention. According to common practice, i.e. the dosage appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of said patient.

Possible combinations

The invention also relates to the combination of one or more compounds of general formula (I) according to the invention with one or more active ingredients.

As active ingredient or ingredients suitable for the combination, mention may be made in particular of anti-obesity and anti-diabetic agents, and rimonabant, metformin or sulfonylureas.

According to another of its aspects, the invention also relates to a method for the treatment of the above-mentioned pathologies, which comprises the administration to the patient of an effective dose of a compound according to the invention or of one of its pharmaceutically acceptable salts.

According to another of its aspects, the invention also relates to a compound of formula (I), or one of its pharmaceutically acceptable salts, for use in the treatment of the pathologies indicated above.

Claims

1. A compound corresponding to formula (I):

wherein:

represents a single or double bond, and is,

x represents-N<、-CH<Or

Y represents > N-or > CH-, with the understanding that at least one of X, Y represents N;

ar represents phenyl, thienyl, benzothienyl, pyridyl, benzofuranyl or benzothiazolyl, optionally substituted with one or more identical or different substituents selected from: a halogen atom, a C1-6 alkyl group, a perhalogenated C1-3 alkyl group, a C1-6 alkoxy group, a perhalogenated C1-3 alkoxy group and a phenyl group;

r1 represents a hydrogen atom or a C1-6 alkyl group, -C (═ O) C1-6 alkyl group or-C (═ O) phenyl group;

r2, R3 and R4, which are the same or different, located at any available position of the phenyl ring, independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group; perhalogenated C1-3 alkyl, C1-6 alkoxy, phenyl; it is understood that at least one of R2, R3, R4 is not H;

r5 represents C1-6 alkyl or C2-6 alkenyl; and

n represents 1 or 2;

in the form of the base or of an addition salt with an acid, except for 5-chloro-3- (2-chlorophenyl) -1, 3-dihydro-3- [2- (4-methylpiperazin-1-yl) acetylamino ] indol-2-one.

2. A compound according to claim 1, of formula (I) wherein:

represents a single or double bond;

x represents-N<、-CH<Or

Y represents > N-or > CH-;

it is understood that at least one of X, Y represents N;

ar represents phenyl, thienyl, benzothienyl, pyridyl, benzofuranyl or benzothiazolyl, which is optionally substituted with one or more same or different substituents selected from: halogen atom, C1-6 alkoxy, phenyl, perhalogenated C1-3 alkyl, C1-6 alkyl;

r1 represents a hydrogen atom or a C1-6 alkyl group, -C (═ O) C1-6 alkyl group, -C (═ O) phenyl group;

r2, R3 and R4, identical or different, located in any of the available positions of the phenyl ring, independently represent a hydrogen atom, a halogen atom or a C1-6 alkyl, perhalogenated C1-3 alkyl, phenyl, C1-6 alkoxy group, it being understood that at least one of R2, R3, R4 is not H;

r5 represents C1-6 alkyl;

n represents 1 or 2;

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

3. A compound according to claim 1 or 2, as in general formula (I):

represents a single or double bond;

x represents-N<，-CH<Or

Y represents > N-or > CH-;

it is understood that at least one of X, Y represents N;

ar represents phenyl optionally substituted with one or more substituents selected from: a halogen atom, and C1-6 alkoxy, C1-6 alkyl, phenyl, trifluoromethyl, trifluoromethoxy;

r1 represents a hydrogen atom or-C (═ O) C1-6 alkyl, -C (═ O) phenyl or C1-6 alkyl;

r2, R3 and R4, identical or different, located in any available position of the phenyl ring, independently represent a hydrogen atom, a halogen atom, or a C1-6 alkyl or trifluoromethyl group, with the understanding that at least one of R2, R3, R4 is not H;

r5 represents C1-6 alkyl;

n represents 1 or 2;

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

4. A compound according to claim 1 or 2, of formula (I) wherein:

represents a single or double bond;

x represents-N<，-CH<Or

Y represents > N-or > CH-;

it is understood that at least one of X, Y represents N;

ar represents phenyl optionally substituted with one or more substituents selected from: halogen atoms, and methoxy, methyl, tert-butyl, phenyl, trifluoromethyl and trifluoromethoxy groups;

r1 represents a hydrogen atom or — C (═ O) methyl, -C (═ O) phenyl, methyl;

r2, R3 and R4, identical or different, located in any available position of the phenyl ring, independently represent a hydrogen atom, a halogen atom, or a trifluoromethyl group, with the understanding that at least one of R2, R3, R4 is not H;

r5 represents methyl, ethyl or 2-propyl;

n represents 1 or 2;

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

5. A compound according to claim 1 or 2, of formula (I) wherein:

ar represents thienyl, benzothienyl, pyridyl, benzofuranyl or benzothiazolyl, which is optionally substituted with one or more same or different substituents selected from: halogen atom, C1-6 alkoxy, phenyl, perhalogenated C1-3 alkyl, C1-6 alkyl.

6. A compound selected from the following compounds:

In the form of a base or of an addition salt with an acid.

7. A process for the preparation of a compound of formula (I) according to claim 1, comprising the step consisting in:

-reacting said compound of general formula (V) with a compound of general formula (VI):

wherein R2, R3, R4 and Ar are as defined in formula (I),

wherein Hal' and Hal ", which are the same or different, independently represent a halogen atom;

-then, reacting the compound of general formula (III):

with a compound of the general formula (IV):

wherein R2, R3, R4, R5, Y, Ar and n are as defined in formula (I), and Hal "represents a halogen atom;

-optionally followed by a step consisting in reacting the product of formula (I) obtained, wherein X represents-N < and R1 is H, with a compound of formula (II):

R1-Hal(II)

wherein R1, not H, is as defined in formula (I) and Hal represents a halogen atom.

8. The process according to claim 7, further comprising the step of reacting said compound of formula (V) with a compound of formula (VIII):

wherein R2, R3, R4 and Ar are as defined in formula (I),

whereinX, Y, R5 and n are as defined in any one of claims 1 to 6;

optionally followed by reacting the obtained product of formula (I) wherein R1 is H with a compound of formula (II):

R1-Hal(II)

9. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 6, characterized in that it comprises the step of reacting a compound of general formula (XXVIII):

wherein R2, R3, R4 and Ar are as defined in any one of claims 1 to 6, and ALK represents a C1-6 alkyl group.

10. The method according to claim 9, further comprising the step of:

reacting said compound of formula (XXVIII) with a compound of formula (VI):

-then, reacting the compound of formula (XXIX) obtained:

with a compound of the general formula (IV):

wherein R2, R3, R4, R5, R Y, Ar and n are as defined in the general formula (I), ALK represents a C1-6 alkyl group and Hal "represents a halogen atom.

11. The process according to claim 9, further comprising the step of reacting said compound of formula (XXVIII) with a compound of formula (VII):

whereinX, Y, R5 and n are as defined in any one of claims 1 to 6.

12. The process according to any one of claims 7 to 11, further comprising a final step which consists in isolating the desired compound of general formula (I).

13. A compound of formula (III):

wherein R2, R3, R4 and Ar are as defined in any one of claims 1 to 6, and Hal represents a halogen atom except 5-chloro-3- (2-chloroacetamido) -3- (2-chlorophenyl) -1, 3-indolin-2-one.

14. A compound of formula (III) according to claim 13, wherein:

15. A compound of formula (XXVIII):

wherein R2, R3, R4 and Ar are as defined in any one of claims 1 to 6, ALK represents a C1-6 alkyl group.

16. A compound of formula (XXIX):

wherein R2, R3, R4 and Ar are as defined in any one of claims 1 to 6, ALK represents a C1-6 alkyl group and Hal "represents a halogen atom.

17. Pharmaceutical, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 6 or an addition salt of such a compound with a pharmaceutically acceptable acid.

18. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 6.

19. The use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for the prevention or treatment of obesity, diabetes, appetite disorders and excess body weight.

20. A combination comprising one or more compounds according to any one of claims 1 to 6 and one or more active ingredients.