Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

• the present invention relates to 3-disubstituted indol-2-one derivatives, to their preparation and to their therapeutic application.
• Ghrelin is a 28 amino-acid peptide hormone produced mainly in the stomach by a post-translational process after cleavage of pre-pro-ghrelin (Kojima M., et al., Nature 1999; 402: 656-60). Ghrelin is an endogenous ligand of the growth hormone secretagogue pituitary receptor (GHSR1a).
• GHS-R is encoded by two exons: exon 1 encodes the transmembrane domains (TMs) 1-5 and exon 2 encodes TM6 and 7 of the G-protein-coupled receptor (GPCR).
• exon 1 encodes the transmembrane domains (TMs) 1-5
• exon 2 encodes TM6 and 7 of the G-protein-coupled receptor (GPCR).
• the two transcripts have been identified in the pituitary gland and the brain: one encoding the full-length GPCR (GHS-R1a) and the other encoding a truncated receptor (GHS-R1b) lacking TM6 and 7. Only the subtype GHS-R1a is activated by ghrelin and ghrelin mimetics. GHS-R1b is present in the liver and other peripheral tissues, but its function is unknown (Smith R. G. et al., Trends in Endocrinology and Metabolism, 2005, 16, No. 9).
• the ghrelin receptor may also be coupled to the Gs/protein kinase A pathways in certain tissues (Ueno, N. et al., Endocrinology, 2004, 145, 4176-4184; Kim, M. S. et al., Int. J. Obes. Relat. Metab. Disord., 2004, 28: 1264-1271).
• the ghrelin receptor has the relatively uncommon characteristic of having significant ligand-independent constitutive activity (Barazzoni, R. et al., Am. J. Physiol. Endocrinol. Metab., 2004, 288: E228-E235).
• ghrelin Low levels of expression of ghrelin have been documented in various tissues, such as the intestines, the pancreas, the kidneys, the immune system, the placenta, the testicles, pituitary tissue and the hypothalamus ( Horm. Res. 2003; 59 (3): 109-17).
• ghrelin is involved in hunger at mealtimes, and in the initiation of meals.
• the circulating levels decreases with the intake of food and increase after meals, reaching concentrations that are sufficient to stimulate hunger and the intake of food.
• Ingestion of ghrelin stimulates food intake rapidly and transiently, mainly by increasing the appetitive feeding behaviour and the number of meals.
• Ghrelin stimulates the short-term taking of food more efficiently than any other molecule, with the exception of neuropeptide Y, with which it is approximately equipotent (Wren A. M. et al., J. Clin. Endocrinol. Metab., 2001; 86: 5992-5).
• ghrelin is unique in its capacity to exert this effect, whether it is injected peripherally or centrally.
• ghrelin Beyond its role in the initiation of meals, ghrelin also satisfies the established criteria of an adiposity-related hormone involved in regulating the long-term body mass.
• the levels of ghrelin circulate as a function of the energy reserves and display compensatory changes in response to changes in body mass.
• Ghrelin crosses the blood-brain barrier and stimulates the taking of food by acting on certain standard body mass-regulating centres, such as the hypothalamus, the hindbrain and the mesolimbic compensatory system.
• ghrelin chronic administration of ghrelin increases the body mass via diverse concerted actions on the taking of food, energy expenditure and the utilisation of resources.
• Congenital ablation of ghrelin or of the ghrelin receptor gene causes a resistance to feeding-induced obesity, and pharmacological blocking of ghrelin reduces the intake of food and the body mass.
• Ghrelin also exerts both physiological and pharmacological actions on the endocrine pancreas.
• Acylated bioactive ghrelin is produced in the ⁇ cells, recently described in the pancreatic islets (Prado, C. L., et al., 2004, Proc. Natl. Acad. Sci. USA, 101: 2924-2929), potentially providing a local source of ghrelin that acts on the ⁇ cells of the islets.
• Blockage of this function of endogenous ghrelin by means of an antagonist for its receptors substantially reduced the fasted glucose concentrations, attenuated the glycaemic movement and increased the responses to insulin during glucose tolerance tests, suggesting an inhibitory role of ghrelin in the control of insulin secretion (Dezaki, K., et al. 2004 , Diabetes, 53: 3142-3151).
• Ghrelin receptor antagonists could thus regulate hunger, the taking of meals and their frequency, and also, in the long-term, the weight, especially weight gain following diets or therapeutic regimens. Furthermore, in the context of an antidiabetic treatment, ghrelin antagonists could be useful for maintaining the equilibrium between insulin and glucose for controlling diabetic hyperphagia. Ghrelin antagonists could thus be used as anorexic and/or anti-obesity agents, or alternatively in the treatment of diabetes and its effects.
• Patent application WO 95/18105 describes 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[2-(4-methylpiperazin-1-yl)acetamido]indol-2-one and 5-chloro-3-(2-chloroacetamido)-3-(2-chlorophenyl)-1,3-dihydroindol-2-one compounds as synthetic intermediates for 1,3-dihydroindol-2-one derivatives 3-substituted with a nitrogenous group and having affinity for vasopressin and/or oxytocin.
• One subject of the present invention is compounds corresponding to formula (I):
• Y represents >N— or >CH—, it being understood that at least one from among X and Y represents N;
• Ar represents an aryl or heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkyl, (C1-6)haloalkyl, perhalo(C1-3)alkyl, (C1-6)alkoxy, perhalo(C1-3)alkoxy and aryl groups;
• 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 may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, CN, OH, a (C1-6)alkyl group optionally substituted with a halogen atom or an OH; perhalo
• the compounds of formula (I) comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.
• the compounds of formula (I) may exist in the form of bases or of acid-addition salts. Such addition salts form part of the invention.
• salts may be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purifying or isolating the compounds of formula (I) also form part of the invention.
• one group of compounds is constituted by the compounds for which:
• Ar represents an aryl or heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkyl, perhalo(C1-3)alkyl, (C1-6)alkoxy and aryl groups;
• 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 may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, CN, OH or a (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
• one group of compounds is constituted by the compounds for which:
• X represents —N ⁇ , —CH ⁇ or
• Y represents >N— or >CH—, and/or it being understood that at least one from among X and Y represents N; and/or Ar represents an aryl group optionally substituted with one or more substituents chosen from halogen atoms, preferentially chlorine or bromine, and (C1-6)alkoxy, (C1-6)alkyl, aryl, trifluoromethyl and trifluoromethoxy groups; and/or R1 represents a hydrogen atom or a —C( ⁇ O)(C1-6)alkyl, —C( ⁇ O)aryl or (C1-6)alkyl group; and/or R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, preferentially chlorine or bromine, or a (C1-6)alkyl or trifluoromethyl group, it being understood that at least one from among R2, R3 and R4 is other than H; and/or
• X represents —N ⁇ , —CH ⁇ or
• Y represents >N— or >CH—, and/or it being understood that at least one from among X and Y represents N; and/or Ar represents a phenyl or naphthyl group optionally substituted with one or more substituents chosen from halogen atoms, preferentially chlorine or bromine, and methoxy, methyl, tert-butyl, phenyl, trifluoromethyl and trifluoromethoxy groups; and/or R1 represents a hydrogen atom or a —C( ⁇ O)methyl, —C( ⁇ O)phenyl or methyl group; and/or R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, preferentially chlorine or bromine, or a methyl or trifluoromethyl group, it being understood that at least one from among R2, R3 and R4 is other than H; and/or R5 represents a methyl methyl
• Ar represents a heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkyl, perhalo(C1-3)alkyl, (C1-6)alkoxy and aryl groups.
• protecting group Pg means a group that makes it possible firstly to protect a reactive function such as a hydroxyl or an amine during a synthesis, and, secondly, to regenerate the intact reactive function at the end of the synthesis. Examples of protecting groups and of protection and deprotection methods are given in Protective Groups in Organic Synthesis, Greene et al., 2nd edition (John Wiley & Sons, Inc., New York).
• leaving group means a group that may be readily cleaved from a molecule by breaking a heterolytic bond, with loss of an electron pair. This group may thus be readily replaced with another group during a substitution reaction, for example.
• Such leaving groups are, for example, halogens or an activated hydroxyl group such as a methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. group. Examples of leaving groups and references for their preparation are given in Advances in Organic Chemistry , J. March, 3rd edition, Wiley Interscience, pp. 310-316.
• the compounds of general formula (I) may be prepared according to the process that follows:
• R1 which is other than H
• 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 such as K 2 CO 3 , NaH or t-BuO ⁇ K + , in a solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), dimethoxyethane or dimethyl sulfoxide (DMSO).
• a base such as K 2 CO 3 , NaH or t-BuO ⁇ K +
• a solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), dimethoxyethane or dimethyl sulfoxide (DMSO).
• the compound of general formula (III) may be prepared by reacting a compound of general formula (III):
• Y, R2, R3, R4, R5, Ar and n are as defined in the general formula (I).
• This reaction is generally performed using an organic or mineral base, such as K 2 CO 3 , Na 2 CO 3 , pyridine 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 general formula (III) may be prepared from a compound of general formula (V):
• R2, R3, R4, R5 and Ar are as defined in the general formula (I) and Hal′ and Hal′′, which may be identical or different, independently represent a halogen atom, preferably chlorine.
• This reaction is generally performed using pyridine or 4-dimethylaminopyridine in a solvent such as toluene, benzene or dichloromethane, preferentially at a temperature of between room temperature and the reflux point of the solvent.
• a solvent such as toluene, benzene or dichloromethane
• R2, R3, R4, R5, Ar, X, Y and n are as defined in the general formula (I).
• This reaction is generally performed using a halogenating agent, such as a chlorinating agent, for example phosphorus chlorides, especially PCl 5 , or alternatively PCl 3 or POCl 3 .
• a halogenating agent such as a chlorinating agent, for example phosphorus chlorides, especially PCl 5 , or alternatively PCl 3 or POCl 3 .
• the reaction is generally performed in the presence of pyridine or 4-dimethylaminopyridine, in a solvent such as dichloromethane or DMF.
• R2, R3, R4 and Ar are as defined in the general formula (I) and Hal represents a halogen atom, for example chlorine.
• step c of Scheme 2 the compound of formula (V) is prepared from a compound of formula (VIII) by sparging with ammonia gas according to the method described in patent application FR 2 714 378.
• R2, R3, R4 and Ar are as defined in the general formula (I) and Hal represents a halogen atom, for example chlorine.
• the compounds of general formula (XIV) may also be prepared by application or adaptation of the procedures described in the Journal of Heterocyclic Chemistry, 43(4), 1031-1035; 2006.
• R2, R3, R4 and Ar are as defined in the general formula (I) and Alk represents an alkyl group, for example a methyl, ethyl or butyl group.
• This reaction is generally performed using iron, in acidic medium, for example using acetic acid.
• the compound of general formula (XV) may be obtained by reacting a compound of general formula (XVI):
• Ar is as defined in the general formula (I) and Alk represents an alkyl group, for example a methyl, ethyl or butyl group, according to methods known to those skilled in the art and described in the Journal of Heterocyclic Chemistry, 43(4), 1031-1035; 2006, for example in the presence of a base such as t-BuOK or NaH.
• the compound of formula (VII) may be prepared by hydrolysis of a compound of formula (XX):
• R5 and Y are defined as in the general formula (I), in acidic medium, for example using concentrated hydrochloric acid.
• the compound of general formula (XX) may be prepared by reducing a compound of formula (XIX):
• R5 and Y are defined as in the general formula (I), for example using magnesium.
• This reaction is generally performed in a solvent such as methanol or ethanol.
• the compound of general formula (XIX) may be prepared via a Wittig-Horner reaction starting with the compound of general formula (XVIII):
• R5 and Y are defined as in the general formula (I).
• this reaction is performed using a suitable phosphonate derivative, such as diethyl (cyanomethyl)phosphonate.
• the process is advantageously performed in the presence of a base, such as K 2 CO 3 , in a solvent such as THF or dimethoxyethane.
• the compound of formula (VII) may be prepared from a compound of formula (XXII):
• R5 and Y are defined as in the general formula (I), and Alk represents an alkyl group, for example a methyl, ethyl or butyl group.
• This reaction is generally performed in acidic medium, for example using concentrated hydrochloric acid.
• the compound of general formula (XXII) may be prepared by condensation of a compound of general formula (XXI):
• R5 and Y are defined as in the general formula (I), with a corresponding halo compound, such as Hal′′′CH 2 COOAlk, in which Hal′′′ represents a halogen atom such as chlorine and Alk represents an alkyl group, such as ethyl.
• a corresponding halo compound such as Hal′′′CH 2 COOAlk
• Hal′′′ represents a halogen atom such as chlorine
• Alk represents an alkyl group, such as ethyl.
• This reaction is advantageously performed in a solvent such as toluene, benzene or dioxane.
• the compound of formula (VII) may be prepared by hydrolysis of a compound of formula (XXIV):
• R5 and Y are defined as in the general formula (I), in acidic medium, for example using concentrated hydrochloric acid.
• the compound of general formula (XXIV) may be prepared by reaction starting with the compound of general formula (XVIII):
• this reaction is performed in a solvent such as THF.
• the compounds of general formula (I) in which R1 represents an alkyl group and R2, R3, R4, R5, Ar, X, Y and n are as defined in the general formula (I) may also be prepared according to Scheme 5 below:
• the compound of general formula (XXV) may be prepared by reacting a compound of formula (XIII) with a compound of formula (XIV):
• ALK represents a linear or branched saturated aliphatic group containing from 1 to 6 carbon atoms 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 such as K 2 CO 3 , NaH or t-BuO ⁇ K + in a solvent such as DMF, THF, dimethoxyethane or DMSO.
• a base such as K 2 CO 3 , NaH or t-BuO ⁇ K + in a solvent such as DMF, THF, dimethoxyethane or DMSO.
• the compounds of general formula (XXVIII) may be prepared according to methods analogous to those described previously.
• a compound of formula (V) is reacted with a protecting group PG to give the compound of formula (XXX).
• protecting groups PG for the amine include benzimine and t-butyl carbamate. These protecting groups are introduced according to methods known to those skilled in the art, for example in the presence of a base such as K 2 CO 3 , NaOH or triethylamine, in a solvent such as dioxane, THF or DMSO.
• the compound of general formula (XXXI) may be prepared by reacting a compound of formula (XXX) with a compound of formula (XIV)
• ALK represents a linear or branched saturated aliphatic group containing from 1 to 6 carbon atoms and Hal represents a halogen atom, for example chlorine.
• the compound of general formula (XXVIII) is obtained from a compound of formula (XXXI) by removing the protecting group according to well-known methods, for example in acidic medium with HCl or trifluoroacetic acid.
• the compound of formula (I) is converted into an acid-addition salt thereof.
• the process according to the invention may optionally include the step that consists in isolating the desired product of general formula (I).
• a subject of the invention is also the compounds of formula (III), with the exclusion of 5-chloro-3-(2-chloro-acetamido)-3-(2-chlorophenyl)-1,3-dihydroindol-2-one. These compounds are useful as synthetic intermediates for the compounds of formula (I).
• one group of compounds is constituted by the compounds for which:
• Ar represents a heteroaryl group optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and (C1-6)alkyl, perhalo(C1-3)alkyl, (C1-6)alkoxy and aryl groups.
• a subject of the invention is also the compounds of formulae (XXVIII) and (XXIX). These compounds are useful as synthetic intermediates for the compounds of formula (I).
• the melting points were measured using a Büchi B-540 machine.
• the HPLC was performed using a ThermoElectron Surveyor system equipped with an ion-trap mass spectrometry detector and a diode array detector.
• the products are detected by UV at 220 nm.
• the ⁇ D measurements were carried out on a Perkin Elmer model PE341 polarimeter using a cell with a 1 dm optical path.
• step (ii) 3.65 g of the product obtained in step (ii) are placed in 47 ml of concentrated hydrochloric acid in a round-bottomed flask equipped with a magnetic stirrer. The mixture is refluxed for 20 hours. The resulting mixture is diluted with water and extracted with dichloromethane to remove the impurities. The aqueous phase is brought to pH 5-6 and extracted with dichloromethane. The aqueous phase is evaporated under vacuum and a white solid is isolated. This solid is taken up in ethanol to separate the product from the salts. The filtration liquors are evaporated to isolate 3.6 g of pale yellow solid.
• the organic phase is washed with 1N hydrochloric acid solution.
• the aqueous phases are combined, brought to basic pH with aqueous NH 3 solution and extracted with dichloromethane.
• the organic phase is dried, filtered and concentrated to give 540 mg of a white solid product.
• the organic phase is separated out and dried over Na 2 SO 4 , filtered and evaporated under vacuum. The residue is taken up in ethyl acetate and washed with 1N sodium hydroxide solution. The organic phase is dried over Na 2 SO 4 , filtered and evaporated under vacuum. The solid is taken up in ethyl ether and filtered off. 4.7 g of expected product are obtained.
• step (ii) A and B of Preparation 5 By working as described in step (ii) A and B of Preparation 5, but using the compound from the preceding step and (S)-phenylglycinol instead of (R)-phenylglycinol, the title compounds are obtained.
• This compound is prepared from 3-hydroxy-5-methyl-6-chloro-1,3-dihydro-3-(4-chlorophenyl)indol-2-one (compound obtained according to the process described in point (i) of Preparation 8), and 1.2 g thereof are dissolved in 8 ml of DMF. 167 mg of 60% NaH are added at 0° C., under a stream of nitrogen. 260 ⁇ l of CH 3 I are then added and the mixture is reacted for 30 minutes. The resulting mixture is poured into water and extracted with dichloromethane. The organic phase is dried, filtered and concentrated. The product is purified on a column, eluting with 9/1 hexane/EtOAc.
• the compound is obtained by working as described in Preparation 5, but using in step (i) 3,4-dichlorobromobenzene instead of 4-bromotrifluoromethylbenzene.
• the product obtained in the preceding step (157 mg) is dissolved in methanol (550 ⁇ l) and 2.7 ml of a 3N HCl solution are added. After 5 hours at room temperature, the mixture is neutralized with aqueous ammonia and extracted with ethyl acetate. The extracts are dried and evaporated. A semisolid product (112 mg) is obtained.
• Table 1 that follows illustrates the chemical structures and the physical properties of a few preparations according to the invention. In this table:
• reaction mixture is poured into water and extracted with ethyl acetate.
• organic phase is washed with saturated NaHCO 3 solution, dried over Na 2 SO 4 , filtered and evaporated under vacuum.
• 145 mg of an orange-coloured solid are obtained, which product is purified on a column by flash chromatography, eluting with 1/1 ethyl acetate/methanol to give 85 mg of product, which is taken up in isopropyl ether to give 75 mg of white/pink solid product.
• Table 2 illustrates the chemical structures and the physical properties of a few examples of compounds according to the invention. In this table:
• the compounds according to the invention underwent in vivo studies.
• mice Male Crl CD BR rats (Charles River, Italy) weighing 150-175 g were housed in a chamber at regulated temperature (22 ⁇ 1° C.) and humidity (55 ⁇ 10%) and with a 12-hour lightness-darkness cycle, for at least 7 days before their use. Feed and water were available ad libitum. The feed was removed 18 hours before sacrificing the animals. The rats were sacrificed by cervical dislocation, and the stomach was removed surgically, opened along the shorter curvature and placed in a Krebs solution (of composition (mM): 118.4 NaCl; 4.7 KCl; 2.5 CaCl 2 ; 3.7 NaH 2 PO 4 ; 1.2 MgSO 4 ; 25 NaHCO 3 ; 5.6 glucose).
• mM composition
• the strips were maintained at a resting load of 1 g and, after washing, 10 ⁇ M of choline (acetylcholine precursor) and 10 ⁇ M of indomethacin (prostaglandin synthetase inhibitor) were added to the medium, to reduce the spontaneous phasic contractions (Depoortere et al., Eur. J. Pharmacol. 515, 1-3, 160-168, 2003; Dass et al., Neurosciences 120, 443-453, 2003). Isotonic contractions were initiated by stimulation with an electric field.
• Two platinum wire electrodes were placed at the surface and at the bottom of the organ bath, and the electric-field stimulation was performed with a Power Lab stimulator (AD Instruments Pty Ltd, Castle Hill, Australia) coupled to a multiplex pulse propeller (Ugo Basile, Varese, Italy) (Fukuda et al., Scand. J. Gastroenterol. 12, 1209-1214, 2004).
• the supramaximal stimulation was applied to create maximum contractions (20 Hz, pulse width: 2 milliseconds; 5 volts; batch trains every 2 minutes, 150 mA).
• the current was reduced to obtain a submaximal stimulation (50% reduction of the maximum contractile response).
• the contractions were recorded by computer with a data recording and analysis system (Power Lab, Chart 5) connected to isotonic transducers (Ugo Basile, Varese, Italy) via preamplifiers (Octal Bridge Amp). After stabilization, concentration-response cumulative curves for ghrelin (0.1 nM-1 ⁇ M) were plotted, with and without incubation (contact time: 30 minutes) of the antagonist molecules. Supramaximal electric-field stimulation was used for each strip as reference (100%) to classify the responses per test substance.
• the agonist concentration producing 50% of the maximum effect was calculated using a four-parameter logistic model according to Ratkovsky and Reedy ( Biometrics, 42, 575-582, 1986), with adjustment by non-linear regression using the Levenberg-Marquard algorithm in the Everstat software.
• the pKb values for the antagonists were calculated according to the Cheng-Prusoff equation (Kenakin et al., Competitive Antagonism, Pharmacologic Analysis of Drug - Receptor Interaction, 3rd edition, 331-373, Philadelphia, New York; Raven: Lippincott, 1997).
• the compounds of formula (I) show antagonist activity towards the ghrelin receptor with IC 50 values ranging from 10 ⁇ 6 to 10 ⁇ 11 M.
• compounds 1 and 2 have an IC 50 value of 5 ⁇ 10 ⁇ 8 M and 1 ⁇ 10 ⁇ 9 M, respectively.
• the compounds according to the invention have antagonist activity towards the ghrelin receptor.
• the compounds according to the invention may thus be used for the preparation of medicaments, in particular medicaments for preventing or treating any pathology in which the ghrelin receptor is involved.
• a subject of the invention is medicaments comprising a compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid.
• the compounds according to the invention may be used, for man and animals, in the treatment or prevention of various ghrelin-dependent complaints.
• the compounds according to the invention may be used as anorexic agents, for regulating the appetite, the taking of meals and their frequency, and also, in the long-term, the weight, especially weight gain following diets or therapeutic regimens.
• the compounds according to the invention are thus particularly useful for preventing or treating obesity, appetite disorders, diabetes, excess weight and/or the effects thereof.
• the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
• These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
• excipients are chosen, according to the pharmaceutical form and the desired mode of administration, from the usual excipients known to those skilled in the art.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration may be administered in unit administration form, as a mixture with standard pharmaceutical excipients, to animals and human beings, for the prophylaxis or treatment of the above disorders or diseases.
• the appropriate unit administration forms include oral-route forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular or intranasal administration forms, forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• oral-route forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions
• sublingual, buccal, intratracheal intraocular or intranasal administration forms, forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• the compounds according to the invention may be used in creams, gels, ointments or lotions.
• a unit administration form of a compound according to the invention in tablet form may comprise the following components:
• the dose of active principle administered per day may be from 0.1 to 100 mg/kg in one or more dosage intakes. Via the parenteral route, it may be from 0.01 to 10 mg/kg/day
• the dosage that is appropriate to each patient is determined by the practitioner according to the mode of administration, and the weight and response of the said patient.
• the present invention also relates to combinations of one or more compound(s) according to the invention of general formula (I) with one or more active ingredient(s).
• active ingredient(s) that is (are) suitable for the said combinations, mention may be made especially of anti-obesity and antidiabetic agents, and also rimonabant, metformin or sulfonylureas.
• the present invention also relates to a method for treating the pathologies indicated above, which comprises the administration to a patient of an effective dose of a compound according to the invention, or of a pharmaceutically acceptable salt thereof.
• the present invention also relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for treating the pathologies indicated above.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Diabetes (AREA)
• General Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Engineering & Computer Science (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Emergency Medicine (AREA)
• Endocrinology (AREA)
• Child & Adolescent Psychology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Indole Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Plural Heterocyclic Compounds (AREA)

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