Novel triazole derivatives, process for their preparation and pharmaceutical compositions containing them

Abstract

The invention relates to a compound of formula 1

Description

[0001] The present invention relates to novel triazole derivatives, to a process for their preparation and to medicines containing them.

[0002] More particularly, the present invention concerns novel non-peptide compounds displaying affinity for cholecystokinin (CCK) receptors.

[0003] CCK is a peptide which, in response to an ingestion of food, is secreted peripherally and participates in regulating many digestive processes (Crawley J. N. et al., Peptides, 1994, 15 (4), 731-735).

[0004] CCK has since been identified in the brain, and might be the most abundant neuropeptide acting as a neuromodulator of cerebral functions by stimulation of CCK-B type receptors (Crawley J. N. et al., Peptides, 1994, 15 (4), 731-735). In the central nervous system, CCK interacts with dopamine-mediated neuronal transmission (Crawley J. N. et al., ISIS Atlas of Sci., Pharmac. 1988, 84-90). It also plays a role in mechanisms involving acetylcholine, gaba (4-aminobutyric acid), serotonin, opioides, somatostatin, and substance P and in ion channels.

[0005] Its administration brings about physiological changes: palpebral ptosis, hypothermia, hyperglycaemia, catalepsy; and behaviour changes, hypolocomotion, decrease in exploratory ability, analgesia, a change in the learning faculty and a change in sexual behaviour and satiety.

[0006] CCK exerts its biological activity via at least two types of receptors: CCK-A receptors located mainly peripherally, and CCK-B receptors essentially present in the cerebral cortex. The CCK-A receptors of peripheral type are also present in certain zones of the central nervous system, including the postrema area, the tractus solitarius nucleus and the interpedoncular nucleus (Moran T. H. et al., Brain Research, 1986, 362, 175-179; Hill D. R. et al., J. Neurosci. 1990, 10, 1070-1081; with, however, specific differences (Hill D. R. et al., J. Neurosci. 1990, 10, 1070-1081); Mailleux P. et al., Neurosci. Lett., 1990, 117, 243-247; Barrett R. W. et al., Mol. Pharmacol., 1989, 36, 285-290; Mercer J. G. et al., Neurosci Lett., 1992, 137, 229-231; Moran T. H. et al., Trends in Pharmacol. Sci., 1991, 12, 232-236).

[0007] At the periphery, via the CCK-A receptors (Moran T. H. et al., Brain Research, 1986, 362, 175-179), CCK delays gastric emptying, modifies intestinal motility, stimulates gallblader contraction, increases bile secretion and controls pancreatic secretion (McHugh P. R. et al., Fed. Proc., 1986, 45, 1384-1390; Pendleton R. G. et al., J. Pharmacol. Exp. Ther., 1987, 241, 110-116).

[0008] CCK may act in certain cases on the arterial pressure and have an influence on immune systems.

[0009] The role of CCK in the satiety signal is supported by the fact that the plasmatic concentrations of CCK, which are dependent on the composition of the meals (high concentrations of proteins or lipids) are, after meals, higher than those observed before meals (Izzo R. S. et al., Regul. Pept., 1984, 9, 21-34; Pfeiffer A. et al., Eur. J. Clin. Invest., 1993, 23, 57-62; Lieverse R. J. Gut, 1994, 35, 531). In bulimia sufferers, there is a decrease in the secretion of CCK induced by a meal, (Geraciotti T. D. Jr. et al., N. Engl. J. Med., 1988, 319, 683-688; Devlin M. J. et al., Am. J. Clin. Nutr., 1997, 65, 114-120) and a lowering of the CCK concentrations in the cerebrospinal fluid (Lydiard R. B. et al., Am. J. Psychiatry, 1993, 150, 1099-1101). In the T lymphocytes, which is a cell compartment that may reflect central neuronal secretions, the basal CCK concentrations are significantly lower in patients suffering from bulimia nervosa (Brambilla F. et al., Psychiatry Research, 1995, 37, 51-56).

[0010] Treatments (for example with L-phenylalanine, or trypsin inhibitors) which increase the secretion of endogenous CCK give rise to a reduction in feeding in several species, including man (Hill A. J. et al., Physiol. Behav. 1990, 48, 241-246: Ballinger A B administration of exogenous CCK reduces feeding in many species, including man (Crawley J. N. et al. Peptides 1994, 15, 731-755).

[0011] The inhibition of feeding by CCK is mediated by the CCK-A receptor. Devazepide, an antagonist which is selective for the CCK-A receptors, inhibits the anorexigenic effect of CCK, whereas the selective agonists of these receptors inhibit feeding (Asin K. E. et al., Pharmacol. Biochem. Behav. 1992, 42, 699-704; Elliott R. L. et al., J. Med. Chem. 1994, 37, 309-313; Elliott R. L. et al., J. Med. Chem. 1994, 37, 1562-1568). Furthermore, OLEFT rats, which do not express the CCK-A receptor, are insensitive to the anorexigenic effect of CCK (Miyasaka K. et al., 1994, 180, 143-146).

[0012] Based on these lines of evidence of the key role of CCK in the peripheral satiety signal, the use of CCK agonists and antagonists as medicines in the treatment of certain eating behaviour disorders, obesity and diabetes is indisputable. A CCK-receptor agonist can also be used therapeutically in the treatment of emotional and sexual behaviour disorders and memory disorders (Itoh S. et al., Drug. Develop. Res., 1990, 21, 257-276), schizophrenia, psychosis (Crawley J. N. et al., Isis Atlas of Sci., Pharmac., 1988, 84-90 and Crawley J. N. Trends in Pharmacol. Sci., 1991, 12, 232-265), Parkinson's disease (Bednar I. et al., Biogenic amine, 1996, 12 (4), 275-284), tardive dyskinesia (Nishikawa T. et al., Prog. Neuropsychopharmacol. Biol. Psych., 1988, 12, 803-812; Kampen J. V. et al., Eur. J. Pharmacol., 1996, 298, 7-15) and various disorders of the gastrointestinal sphere (Drugs of the Future, 1992, 17 (3), 197-206).

[0013] CCK-A receptor agonists of CCK are described in the literature. For example, certain products having such properties are described in EP 383,690 and WO 90/06937, WO 95/28419, WO 96/11701 or WO 96/11940.

[0014] Most of the CCK-A agonists described to date are of peptide nature. Thus, FPL 14294 derived from CCK-7 is a powerful, unselective CCK-A agonist towards CCK-B receptors. It has powerful inhibitory activity on feeding in rats and in dogs after intranasal administration (Simmons R. D. et al., Pharmacol. Biochem. Behav., 1994, 47 (3), 701-708; Kaiser E. F. et al., Faseb, 1991, 5, A864). Similarly, it has been shown that A-71623, a tetrapeptide agonist which is selective for CCK-A receptors, is effective in models of anorexia over a period of 11 days and leads to a significant reduction in weight gain when compared with the control in rodents and cynomologous monkeys (Asin K. E. et al., Pharmacol. Biochem. Behav., 1992, 42, 699-704). Similarly, structural analogues of A 71623, which have good efficacy and selectivity for CCK-A receptors, have powerful anorexigenic activity in rats (Elliott R. L. et al., J. Med. Chem., 1994, 37, 309-313; Elliott R. L. et al., J. Med. Chem., 1994, 37, 1562-1568). GW 7854 (Hirst G. C. et al., J. Med. Chem., 1996, 38, 5236-5245), a-1,5-benzodiazepine, is an in vitro CCK-A receptor agonist. This molecule is also active orally on the contraction of the gallblader in mice and on feeding in rats.

[0015] It has now been found, surprisingly, that a series of triazole derivatives has partial or total agonist activity towards CCK-A receptors.

[0016] The compounds according to the invention underwent systematic studies in order to characterize:

[0017] their ability to displace [125I]-CCK from its binding sites present on rat pancreatic membranes (CCK-A receptor) or 3T3 cells which express the human CCK-A recombinant receptor;

[0018] their affinity towards the CCK-B receptor, present on guinea pig cortex membranes, some of the compounds being selective or unselective CCK-A receptor ligands;

[0019] their CCK-A receptor agonist property by means of their capacity to: induce in vitro a mobilization of intracellular calcium in 3T3 cells which express human CCK-A receptor.

[0020] The triazole derivatives according to the present invention are CCK-A agonists since they are capable of stimulating partially, or totally like CCK, the mobilization of intracellular calcium in a cell D line which expresses human CCK-A recombinant receptor. They are, surprisingly, much more powerful than the thiazole derivatives described in patent applications EP 518,731 and EP 611,766, than the thiadiazole derivatives described in patent application EP 620,221, or than the benzodiazepin derivatives described in patent EP 667,344.

[0021] The reason for this is that these thiazole, thiadiazole and benzodiazepine derivatives are incapable of inducing this mobilization of intracellular calcium mediated by the CCK-A receptor.

[0022] The triazole derivatives according to the invention are also much more powerful than these thiazole, thiadiazole or benzodiazepine derivatives by virtue of their capacity to block in vivo, via the intraperitoneal route, gastric emptying in mice.

[0023] Thus, the CCK-A agonist properties were studied in vivo, by assessing their capacity to block gastric emptying in mice or to bring about, again in vivo, emptying of the gallblader in mice.

[0024] Certain derivatives also have CCK-B receptor antagonist activity.

[0025] Thus, the present invention relates to compounds of formula: 2

[0026] in which:

[0027] R1 represents a (C2-C6)alkyl; a group —(CH2)n-G with n ranging from 0 to 5 and G representing a non-aromatic C3-C13 mono- or polycyclic hydrocarbon group optionally substituted with one or more (C1-C3)alkyl; a phenyl(C1-C3)alkyl in which the phenyl group is optionally substituted one or more times with a halogen, with a (C1-C3)alkyl or with a (C1-C3) alkoxy; a group —(CH2)nNR2R3 in which n represents an integer from 1 to 6 and R2 and R3, which may be identical or different, represent a (C1-C3)alkyl or constitute, with the nitrogen atom to which they are attached, a morpholino, piperidino, pyrrolidinyl or piperazinyl group;

[0028] X1, X2, X3 or X4 each independently represents a hydrogen or halogen atom, a (C1-C6)alkyl, a (C1-C3)alkoxy or a trifluoromethyl; it being understood that only one from among X1, X2, X3 and X4 possibly represents a hydrogen atom;

[0029] R4 represents hydrogen, a group —(CH2) COOR5 in which n is as defined above and R5 represents a hydrogen atom, a (C1-C6)alkyl or a (C6-C10)aryl-(C1-C6)alkyl; a (C1-C6)alkyl; a group —(CH2)nOR5 or a group —(CH2)nNR2R3 in which n, R2, R3 and R5 are as defined above; a group —(CH2)n-tetrazolyl in which n is as defined above,

[0030]  or R4 represents one of these groups in the form of an alkali-metal or alkaline-earth metal salt;

[0031] Y1, Y2 and Y3 independently represent a hydrogen, a halogen, a (C1-C3)alkyl, a (C1-C3)alkoxy, a nitro, cyano, (C1-C6)acylamino, carbamoyl, trifluoromethyl, a group COOR6 in which R6 represents hydrogen, or (C1-C3)alkyl;

[0032]  or one of the salts or solvates thereof.

[0033] According to the present invention, “(C1-C6)alkyl” or “(C2-C6)alkyl” is understood to mean a straight or branched alkyl having 1 to 6 carbon atoms or 2 to 6 carbon atoms respectively.

[0034] The alkoxy radical denotes an alkyloxy radical in which alkyl is as defined above.

[0035] The acyl radical denotes an alkyl carbonyl radical in which alkyl is as defined above. (C1-C6)acylamino is a (C1-C6)alkylcarbonylamino.

[0036] The non-aromatic C3-C13 hydrocarbon groups 3 comprise saturated or unsaturated, fused or bridged, mono- or polycyclic radicals, which may be terpenic. These radicals are optionally mono- or polysubstituted with a (C1-C3)alkyl. The monocyclic radicals include cycloalkyls, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclododecyl. The polycyclic radicals include, for example, norbornane, adamantane, hexahydroindane, norbornene, dihydrophenalene, bicyclo[2.2.1]heptane, bicyclo[3.3.1]nonane and tricyclo[5.2.1.02.6]decane.

[0037] According to the present invention, the term halogen is understood to mean an atom chosen from fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine.

[0038] Examples of aryl groups are phenyl and naphthyl.

[0039] The alkali-metal or alkaline-earth metal cations are preferably chosen from those of sodium, potassium and calcium.

[0040] When a compound according to the invention has one or more asymmetric carbons, the optical isomers of this compound form an integral part of the invention.

[0041] When a compound according to the invention has stereoisomerism, for example of axial-equatorial type, the invention comprises all the stereoisomers of this compound. The salts of the compounds of formula (I) according to the present invention comprise those with inorganic or organic acids which allow a suitable separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphorsulphonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, hydrobromide, sulphate, hydrogensulphate, dihydrogenphosphate, maleate, fumarate, 2-naphthalenesulphonate or para-roluenesulphonate.

[0042] The salts of the compounds of formula (I) also comprise salts with organic or inorganic bases, for example alkali-metal or alkaline-earth metal salts, such as sodium, potassium or calcium salts, sodium and potassium salts being preferred, or with an amine, such as trometamol, or alternatively arginine or lysine salts or salts of any physiologically acceptable amine.

[0043] The functional groups optionally present in the molecule of the compounds of formula (I) and in the reaction intermediates can be protected, either in permanent form or in temporary form, with protecting groups which ensure an unequivocal synthesis of the expected compounds.

[0044] The expression temporary protecting group for the amines, alcohols or carboxylic acids is understood to mean protecting groups such as those described in “Protective Groups in Organic Synthesis, Greene T. W. and Wuts P. G. M., published John Wiley and Sons, 1991, and in Protecting Groups, Kocienski P. J., 1994, Georg Thieme Verlag.

[0045] The compounds (I) can contain precursor groups for other functions which are generated subsequently in one or more other steps.

[0046] The compounds of formula (I) in which R, represents a cyclohexyl-(C1-C3)alkyl are preferred compounds.

[0047] Also preferred are the compounds of formula (I) in which the phenyl in position 5 of the triazole is trisubstituted, preferably with a methoxy in positions 2 and 6 and with a methyl in position 4.

[0048] Even more preferred are the compounds of formula (I) in which the phenyl in position 5 of the triazole is trisubstituted, preferably with a methoxy in positions 2 and 5 and with a methyl or a chlorine in position 4. 3

[0049] in which R1, R4, X1, X2, X3 and X4 are as defined for (I); a salt or solvate thereof, are preferred.

[0050] Among these compounds, those in which 4

[0051] represents 2,6-dimethoxy-4-methylphenyl are preferred.

[0052] The compounds of formula: 5

[0053] in which R1 and R4 are as defined for (I); a salt or solvate thereof, are more particularly preferred.

[0054] The compounds of formula: 6

[0055] in which R1, R4, Y1, Y2 and Y3 are as defined for (1), and X2 represents methyl or a chlorine atom, a salt or solvate thereof, are most particularly preferred.

[0056] The subject of the present invention is also a process for the preparation of the compounds of formula (I), comprising the reaction of an aminotriazole, of formula: 7

[0057] in which R1, X1, X2, X3 and X4 are as defined for (I) either with an indolecarboxylic acid derivative of formula: 8

[0058] in which R4, Y1, Y2 and Y3 are as defined above for (1), or with an indolecarboxylic acid derivative of formula: 9

[0059] in which Y1, Y2 and Y3 are as defined above for (I) and R′4 is a precursor group of R4, in which case the compound of formula: 10

[0060] in which R1, X1, X2, X3, X4, Y1, Y2 and Y3 are as defined for (I) and R′4 is a precursor group of R4, R4 being as defined for (I);

[0061] is formed as an intermediate in order to obtain the compounds of formula (I) or a salt or solvate thereof.

[0062] The intermediate compounds (I′) lead to the compounds of formula (I) by conversion of the group R′4 into R4, which is carried out in a manner which is known per se according to conventional processes of organic chemistry.

[0063] The aminotriazoles of formula 7 constitute novel key intermediates which are useful for the preparation of the compounds (I) and form a subject of the invention.

[0064] The starting materials are commercially available or are prepared according to the methods below.

[0065] Scheme 1 below illustrates a route for synthesizing the compounds of formula 7.

[0066] Scheme 2 below illustrates the preparation of the compounds of formula (I) from the aminotriazoles of formula 7. 1112

[0067] When R4=—(CH2)nCOOH, the compounds (I) are obtained from the corresponding T esters, which are themselves obtained from Scheme 2.

[0068] When R4=—(CH2)n-tetrazolyl, the compounds (I) are obtained from the corresponding nitrites of formula: 13

[0069] in which R′4=—(CH2)n—C≡N

[0070] by reacting azidotrimethylsilane in the presence of dibutyltin oxide according to the process described in J. Org. Chem. 1993, 58, 4139-4141.

[0071] The compounds of formula (I′) are obtained according to Scheme 2, from compounds 7 and 8′ of formula: 14

[0072] in which R′4=—(CH2)n—C≡N.

[0073] The substituted benzoic acids are commercially available or are prepared by adaptation of the processes described in the literature, for example:

[0074] 1) by regioselective, lithiation of substituted benzenes, followed by carboxylation of the lithiated derivative with CO2, according to Scheme 3: 15

[0075] with Z1=Br or H depending on the nature and/or position of the substituents X1, X2, X3 and X4, according to N. S. Narasimhan et al., Indian J. Chem., 1973, 11, 1192; R. C. Cambie et al., Austr. J. Chem., 1991, 44, 1465; T. de Paulis et al., J. Med. Chem., 1986, 29, 61; or alternatively

[0076] 2) by regioselective formylation of substituted benzenes, followed by oxidation of the substituted benzaldehyde with KMnO4, according to Scheme 4: 16

[0077] according to the method described by S. B. Matin et al., J. Med. Chem., 1974, 17, 877; or alternatively

[0078] 3) by haloform oxidation, according to R. Levine et acylation of substituted benzenes (C.A. Bartram et al., J. Chem. Soc., 1963, 4691) or by Fries rearrangement of substituted acyloxybenzenes according to S. E. Cremer et al., J. Org. Chem., 1961, 26, 3653, according to Schemes 5 and 6 below: 17

[0079] The acids substituted in position 2 with a methoxy can be prepared from a substituted phenol derivative by reaction of acetic anhydride in pyridine, followed by a Fries reaction in the presence of aluminium chloride in order to give the hydroxyacetophenone, on which is reacted methyl iodide in alkaline medium in order finally to obtain, by a haloform reaction, the expected acid 1′ according to Scheme 6 below: 18

[0080] The benzamidoguanidine 2 is obtained by acylation of aminoguanidine hydrogen carbonate with the benzoyl chloride obtained from benzoic acid 1 by standard processes (SOCl2, oxalyl chloride in an inert solvent), according to an adaptation of the process described by E. Hoggarth, J. Chem. Soc., 1950, 612. It Pan also be obtained according to the alternative route described in this same publication according to Scheme 7 below: 19

[0081] The thermal cyclization of the benzamidoguanidine 2 in a solvent with a high boiling point, such as diphenyl ether, leads to the aryl-5-amino-3-triazole 3 according to an adaptation of the process described by E. Hoggarth, J. Chem. Soc., 1950, 612.

[0082] The protection of the primary amino function of the triazole 3 in the form of diphenylimine leads to the N-protected triazole 4, according to an adaptation of a process described by M. J. O'Donnell et al., J. Org. Chem., 1982, 47, 2663.

[0083] The compound 4 can also be obtained according to an alternative route which consists in treating the triazole 3, which has been converted beforehand into the hydrochloride 3′, with diphenylimine, according to Scheme 8 below: 20

[0084] The N-alkylation of the diphenyliminotriazole 4 with an alkyl halide R1X, under phase transfer conditions (strong base in concentrated aqueous solution, in the presence of an immiscible organic co-solvent and a quaternary ammonium catalyst) leads predominately to the triazole 5, accompanied by a very small amount of the triazole 6. The strong bases used can be aqueous NaOH or KOH solutions at concentrations of 6M to 12M. The cosolvent can be toluene or benzene and the quaternary ammonium can be selected from any quaternary ammonium salt, and more particularly TBAB (tetrabutylammonium bromide).

[0085] a) The N-alkylation of the diphenyliminotriazole 4 can be carried out in a non-aqueous medium (dimethylformamide or tetrahydrofuran for example) in the presence of a strong base such as K2CO3 or 23 NaH.

[0086] b) An alternative route can also be selected, such as the one described by E. Akerblom, Acta Chem. Scand., 1965, 19, 1142, in which an alkylating agent is used in an alcohol such as ethanol in the presence of a solid strong base such as KOH or NaOH.

[0087] The triazole 5 is very easily separated from its isomer 6 by chromatography on a column of silica or flash chromatography, depending on the nature of the group R1. Cleavage of the product 5, obtained after separation from its minor isomer, is carried out in an aqueous acid medium such as 1N HCl, according to an adaptation of the process described by J. Yaozhong et al., Tetrahedron, 1988, 44, 5343 or M. J. O'Donnell et al., d. Org. Chem., 1982, 47, 2663. It allows the amino-3-triazoles N-alkylated in position 1, of formula 7, to be obtained.

[0088] The indolcarboxylic compounds of formula 8 were prepared according to processes described in Patent No. EP 611,766 according to Scheme 9 below: 21

[0089] The carboxylic indoles 8 in which R′4=—(CH2)n—C≡N

[0090] were prepared according to an analogous process presented in Scheme 9a below: 22

[0091] The indoles 11 are commercially available or are prepared by adaptation of the processes described in the literature, for example according to L. Henn et D al., J. Chem. Soc. Perkin Trans. I, 1984, 2189 according to Scheme 10 below: 23

[0092] or alternatively, for example, according to the Fischer synthesis (V. Prelog et al., Helv. Chim. Acta., 1948, 31, 1178) according to Scheme 11 below: 24

[0093] or according to the Japp-Klingemann synthesis (H. Ishii et al., J. Chem. Soc. Perkin. Trans. 1, 1989, 2407) according to Scheme 12 below: 25

[0094] The compounds of formula (I) above also comprise those in which one or more hydrogen, carbon or halogen, in particular chlorine or fluorine atoms have been replaced by their radioactive isotope, for example tritium or carbon-14. Such labelled compounds are useful in research, metabolism or pharmacokinetics studies, in biochemical tests as receptor ligands.

[0095] The compounds of formula (I) underwent studies of in vitro binding to the CCK-A and CCK-B receptors, using the method described in Europ. J. Pharmacol. 1993, 232, 13-19.

[0096] The agonist activity of the compounds towards the CCK-A receptors was evaluated in vitro in 3T3 cells expressing the human CCK-A receptor, by measuring the mobilization of the intracellular calcium ([Ca++]i), according to a technique derived from that of Lignon M F et al., Eur. J. Pharmacol., 1993, 245, 241-245. The calcium concentration [Ca++]i is evaluated with Fura-2 by the method of the double excitation wavelength. The ratio of the fluorescence emitted at two wavelengths gives the concentration of [Ca++]i after calibration (Grynkiewiez G. et al., J. Biol. Chem., 1985, 260, 3440-3450).

[0097] The compounds of the invention stimulate the [Ca++]i partially, or totally such as CCK, and thus behave as CCK-A receptor agonists.

[0098] A study of the agonist effect of the compounds on gastric emptying was carried out as follows. Female Swiss albino CD1 mice (20-25 g) are placed on a solid fast for 18 hours. On the day of the experiment, the products (as a suspension in 1% carboxymethyl cellulose solution or in 0.6% methylcellulose solution) or the corresponding vehicle are administered intraperitoneally, 30 minutes before administering a charcoal meal (0.3 ml per mouse of a suspension in water of 10% charcoal powder, 5% gum arabic and 1% carboxymethyl cellulose) or orally one hour earlier. The mice are sacrificed five minutes later by cervical dislocation, and gastric emptying is defined as the presence of charcoal in the intestine beyond the pyloric sphincter (Europ. J. Pharmacol., 1993, 232, 13-19). The compounds of formula (I) partially or completely block gastric emptying, like CCK itself, and thus behave as CCK-receptor agonists. Some of them have ED50 (the effective dose which induces 50% of the effect of CCK) values of less than 0.1 mg/kg intraperitoneally.

[0099] A study of the agonist effect of the compounds on gallblader contraction was carried out as follows.

[0100] Female Swiss albino CD1 mice (20-25 g) are placed on a solid fast for 24 hours. On the day of the experiment, the products (as a suspension in 1% carboxymethyl cellulose solution or in 0.6% methyl cellulose solution) or the corresponding vehicle are administered orally. The mice are sacrificed by cervical dislocation one hour after administering the products, and the gallbladers are removed and weighed. The results are expressed in mg/kg of body weight (Europ. J. Pharmacol., 1993, 232, 13-19).

[0101] The compounds of formula (I) partially or totally contract the gallblader, like CCK itself, and thus behave as CCK-receptor agonists. Some of them have ED50 (the effective dose which induces 50% of the weight decrease of the vesicles observed with CCK) of less than 0.1 mg/kg orally.

[0102] Consequently, the compounds of formula (I) are D used as type-A CCK-receptor agonists, for the preparation of medicines intended to combat diseases whose treatment requires stimulation by total or partial agonism of the CCK-A receptors of cholecystokinin. More particularly, the compounds of formula (I) are used for the manufacture of medicines intended for the treatment of certain disorders of the gastrointestinal sphere (prevention of gallstone, irritable bowel syndrome), eating disorders and obesity, and associated pathologies such as diabetes and hypertension. The compounds (I) induce a state of satiety and are thus used to treat eating behaviour disorders, to regulate the appetite and to reduce food intake, to treat bulimia and obesity and to bring about weight loss. The compounds (I) are also useful in emotional and sexual behaviour disorders and memory disorders, in psychosis, and in particular schizophrenia, Parkinson's disease and tardive dyskinesia. They can also serve in the treatment of appetite disorders, i.e. to regulate the desire for eating, in particular the consumption of sugars, carbohydrates, alcohol or drugs and more generally of appetizing ingredients.

[0103] The compounds of formula (I) have little toxicity; their toxicity is compatible with their use as medicines for the treatment of the above diseases and disorders.

[0104] No signs of toxicity are observed with these compounds at the pharmacologically active doses, and their toxicity is thus compatible with their medical use as medicines.

[0105] The subject of the present invention is thus also pharmaceutical compositions containing an effective dose of a compound according to the invention or of a pharmaceutically acceptable salt thereof, and suitable excipients. The said excipients are chosen according to the pharmaceutical composition and the desired mode of administration.

[0106] In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular administration, the active principles of formula (I) above, or the optional salts thereof, can he administered in unit forms of administration, mixed with standard pharmaceutical supports, to animals and to humans for the prophylaxis or treatment of the above diseases and disorders. The appropriate unit forms of administration comprise oral forms such as tablets, gelatin capsules, powders, granules and oral suspensions and solutions, sublingual, buccal, intratracheal and intranasal forms of administration, subcutaneous, intramuscular or intravenous forms of administration and rectal forms of administration. The compounds according to the invention can be used in creams, ointments, lotions or eye drops for topical administration.

[0107] In order to obtain the desired prophylactic or therapeutic effect, the dose of active principle can range between 0.01 and 50 mg per kg of body weight and per day.

[0108] Each unit dose can contain from 0.5 to 1000 mg, preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical support. This unit dose can be administered 1 to 5 times per day so as to administer a daily dose of from 0.5 to 5000 mg, preferably from 1 to 2500 mg.

[0109] When a solid composition in tablet form is prepared, the main active ingredient is mixed with a pharmaceutical vehicle, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other suitable materials, or alternatively they can be treated such that they have a sustained or delayed activity and so that they release a predetermined amount of active principle continually.

[0110] A preparation in gelatin capsule form is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard gelatin capsules.

[0111] A preparation in syrup or elixir form or for administration in the form of drops can contain the active ingredient together with a sweetener, preferably a calorie-free sweetener, methylparaben and propylparaben as antiseptic, as well as a flavouring agent and a suitable dye. The water-dispersible powders or granules can contain the active ingredient mixed with dispersing agents or wetting agents, or suspension agents such as polyvinylpyrrolidone, as well as with sweeteners or flavour enhancers.

[0112] For rectal administration, use is made of suppositories which are prepared with binders that melt at the rectal temperature, for example cocoa butter or polyethylene glycols. Aqueous suspensions, isotonic saline solutions or sterile, injectable solutions which contain pharmacologically compatible dispersing agents and/or wetting agents, for example propylene glycol or butylene glycol, are used for parenteral administration.

[0113] The active principle can also be formulated in the form of microcapsules, optionally with one or more supports or additives, or alternatively with matrices such as a polymer or a cyclodextrin (patch, sustained-release forms).

[0114] The compositions according to the invention can be used in the treatment or prevention of various complaints in which CCK is of therapeutic value.

[0115] The compositions of the present invention can contain, along with the products of formula (I) above or the pharmaceutically acceptable salts thereof, other active principles which can be used in the treatment of the diseases or disorders indicated above.

[0116] Advantageously, the compositions of the present invention contain a product of formula (I.1), (I.2) or (I.3) above, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Preparation of the Synthetic Intermediates

[0117] A. Preparation of the Acids 1 (Variants)

[0118] 2,5-Dimethoxy-4-methylbenzoic Acid (Compound A.1)

[0119] a) 2,5-Dimethoxy-4-methylbenzaldehyde

[0120] After stirring a mixture of 8.5 ml of N-methylformanilide (0.068 mol) and 6.3 ml of phosphorus oxytrichloride (0.068 mol) at room temperature for 40 minutes, 17.8 g of 2,5-dimethoxytoluene (0.117 mol) are introduced. The reaction mixture is heated for 6 hours at 50° C. and then, after returning to a temperature of 20° C., it is hydrolysed with 100 ml of aqueous 10% sodium acetate solution, extracted twice with diethyl ether and concentrated. The residue is taken up in aqueous sodium hydrogen sulphite solution and extracted twice with diethyl ether. The aqueous phase is basified (pH=12) in order to give white crystals; m.p.=83° C.; yield=67%.

[0121] b) 2,5-Dimethoxy-4-methylbenzoic Acid

[0122] 23.86 g (0.132 mol) of 2,5-dimethoxy-4-methylbenzaldehyde dissolved in 500 ml of water are heated to 75° C. and 29.3 g (0.185 mol) of potassium permanganate dissolved in 500 ml of water are introduced. The reaction mixture is left for 2 hours at 75° C., the pH is adjusted to 10 with 10% sodium hydroxide solution and the insoluble material is filtered off while hot and rinsed three times with 80 ml of hot water. The filtrate is cooled and the precipitate formed is filtered off and dried under vacuum at 40° C. to give white crystals; m.p.=120° C.; yield=71%.

[0123] 2,5-Dimethoxy-4-chlorobenzoic Acid (Compound A.2)

[0124] a) 2,5-Dimethoxy-4-chlorophenyl Methyl Ketone

[0125] 162.5 g of aluminium trichloride (1.2 mol) are added, at room temperature, to 2 litres of carbon tetrachloride, followed, at 0° C., by dropwise addition of 82 ml of acetyl chloride (1.2 mol) and then 200 g of 1,4-dimethoxy-2-chlorobenzene (1.2 mol). The reaction mixture is left for 3 and a half hours at 0° C. and is then hydrolysed with 700 ml of water. The organic phase is washed with 2 M sodium hydroxide solution, dried over anhydrous sodium sulphate and concentrated. The semi-crystalline residue is taken up in petroleum ether, filtered and dried to give white crystals; m.p.=96° C.; yield=70%.

[0126] b) 2,5-Dimethoxy-4-chlorobenzoic Acid

[0127] 278 g of potassium hydroxide (4.96 mol) are added to 800 ml of water, followed, at 5° C., by dropwise addition of 84 ml of bromine (1.6 mol). The reaction mixture is left for one hour at room temperature. The aqueous sodium hypobromite solution obtained is added to 107 g of 2,5-dimethoxy-4-chlorophenyl methyl ketone (0.494 mol) dissolved in 1.5 litres of 1,-4-dioxane. After one hour at 20° C., the reaction mixture is heated for one hour at reflux. When the reaction is complete, 100 ml of aqueous sodium hydrogen sulphite solution are introduced and the solvent is then evaporated off. The residue is acidified with 6 N hydrochloric acid solution and is then extracted twice with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate and concentrated. The residue is solidified in diisopropyl ether, to give white crystals; m.p.=160° C.; yield=91%.

[0128] 2,6-Dimethoxy-4-methylphenylbenzoic Acid (Compound A.3)

[0129] 231.6 g (1.5 mol) of 3,5-dimethoxytoluene are dissolved in 1 litre of diethylether, followed by dropwise addition, under nitrogen and at room temperature, of 1 litre of a 1.6 N solution of butyllithium (1.6 mol) in hexane. The reaction mixture is left for 18 hours at room temperature and then, after cooling to −30° C., 1 litre of diethyl ether is added and carbon dioxide is bubbled through for one hour, while maintaining the temperature at −30° C. The reaction mixture is taken up in 6 litres of 2 M sodium hydroxide solution, the aqueous phase is separated out after settling has taken place and is acidified with 6 N hydrochloric acid solution. The precipitate formed is filtered off, rinsed with water and dried under vacuum at 40° C. in order to obtain white crystals; m.p.=187° C.; yield=88%.

[0130] B. Preparation of Substituted Indoles and Variants Thereof

[0131] Preparation of Ethyl 5-methyl-1H-2-indole Carboxylate (Compound B.1)

[0132] 1st Method: (Japp-Klingemann Method):

[0133] 7.2 g (0.104 mol) of sodium nitrite dissolved in 40 ml of water are added, at −5° C., to a mixture of 10.7 g (0.1 mol) of 4-methylaniline, 74 ml of 12 N hydrochloric acid and 140 ml of water. The reaction mixture is stirred for 15 minutes at −5° C. and is neutralized by addition of 8.1 g of sodium acetate. 12.33 g (0.085 mol) of ethyl α-methyl-acetoacetate and 80 ml of ethanol are introduced into a three-necked flask, followed, at 0° C., by 4.8 g (0.085 mol) of potassium hydroxide dissolved in 20 ml of water and 100 g of ice. The diazonium solution prepared above is added dropwise, at 0° C., to this reaction mixture and the resulting mixture is left for 18 hours at 0° C. The aqueous phase is extracted 4 times with 50 ml of ethyl acetate and the organic phases are combined and dried over anhydrous sodium sulphate. The residue is taken up in 100 ml of toluene and 16.3 g (0.085 mol) of para-toluene sulphonic acid monohydrate. The mixture is then heated slowly to 110° C. and maintained at this temperature for 5 hours. After cooling and then addition of saturated sodium carbonate solution, the insoluble material is removed by filtration and the organic phase is separated out after settling has taken place, dried over anhydrous sodium sulphate and concentrated. The residue is chromatographed on a column of silica gel, eluent: 30/70 (v/v) dichloromethane/cyclohexane, to give beige-coloured crystals; m.p.=94° C.; yield=25%.

[0134] Preparation of Ethyl 4-methyl-1H-2-indolecarboxylate (Compound B2)

[0135] 2nd Method:

[0136] Step 1: Preparation of the Azide

[0137] 9.3 g (0.405 mol) of sodium are added portionwise to 200 ml of ethanol. 16.2 g (0.135 mol) of ortho-tolualdehyde dissolved in 52.2 g (0.405 mol) of ethyl azidoacetate are introduced dropwise, at −20° C., into this solution of ethoxide in ethanol. After 2 hours at −10° C., the reaction mixture is poured onto 400 ml of water and the precipitate formed is filtered off. It is dried for 18 hours at 40° C. under vacuum in order to obtain white crystals; m.p.=55° C.; yield=78%.

[0138] Step 2: Cyclization of the Azide

[0139] 19.5 g (0.0844 mol) of the azide prepared according to Step 1 are added portionwise to 100 ml of xylene heated to 140° C. Once the addition is complete, the reaction mixture is left for 1 hour at 140° C. The xylene is concentrated and the residue is taken up in isopropyl ether, filtered and dried for 18 hours under vacuum at 40° C., in order to obtain white crystals; m.p.=141° C.; yield=62%.

[0140] Preparation of 5-ethyl-1H-2-indolecarboxylic Acid (According to the Fischer Method)—(Compound B.3)

[0141] 3rd Method:

[0142] Step 1: 4-Ethylphenylhydrazine Hydrochloride.

[0143] 150 ml of water and 160 ml of 12N hydrochloric acid are added to 24.2 g (0.2 mol) of 4-ethylaniline. The mixture is cooled to 0° C. and 14 g (0.2 mol) of sodium nitrite dissolved in 140 ml of water are then introduced dropwise. After 1 hour at 0° C., 112 g (0.496 mol) of stannous chloride dihydrate dissolved in 90 ml of 12 N hydrochloric acid are added to the reaction mixture, at −10° C. After 1 hour 30 at −10° C., the reaction mixture is filtered in order to obtain a brown solid, m.p.=198° C.; yield=95%.

[0144] Step 2: Ethyl 2-[2-(4-ethylphenyl)-hydrazono]propanoate

[0145] 23 ml (0.2 mol) of ethyl pyruvate are added to 34.5 g (0.2 mol) of 4-ethylphenylhydrazine hydrochloride prepared above in suspension in 500 ml of ethanol, and the reaction mixture is heated for 3 hours 30 at reflux. The mixture is then cooled to a temperature of 20° C. and the ethanol is evaporated off. The solid residue is washed with pentane and dried at 40° C. under vacuum in order to obtain a colourless liquid; yield=94%.

[0146] Step 3: Ethyl 5-ethyl-1H-2-indolecarboxylate

[0147] 19 g (0.1 mol) of para-toluene sulphonic acid monohydrate are added portionwise, over 7 hours at reflux, to 44 g (0.188 mol) of hydrazone prepared above, suspended in 300 ml of toluene. The mixture is cooled to a temperature of 20° C. and an insoluble material is separated out by filtration and rinsed with toluene. The filtrate is flashed with saturated aqueous potassium carbonate solution; the phases are separated after settling has taken place and the organic phase is dried over anhydrous sodium sulphate and concentrated. The residue is purified by chromatography on a column of silica gel with the eluent: 5/5 (v/v) dichloromethane/cyclohexane, in order to obtain beige-coloured crystals; m.p.=94° C.; yield=51%.

[0148] step 4: 5-Ethyl-1H-2-indolecarboxylic Acid

[0149] 15.8 g (0.073 mol) of ethyl 5-ethyl-2-indolecarboxylate prepared according to Step 3 are added to 150 ml of 1,4-dioxane, followed by 45 ml of 2 M sodium hydroxide solution (0.09 mol). The reaction mixture is left for 48 hours at room temperature. After evaporation of the 1,4-dioxane, the residue is taken up in 6 N hydrochloric acid solution and the precipitate formed is filtered off and dried under vacuum at 60° C. in order to give the 5-ethyl-1H-2-indolecarboxylic acid in the form of white crystals; m.p.=184° C.; yield=92%.

[0150] Preparation of the N-Alkyl 1H-2-Indolecarboxylic Acids

[0151] 5-Ethyl-1-(methoxycarbonylmethyl)-1H-2-indolecarboxylic Acid—(Compound B.4)

[0152] Step 1: Benzyl 5-ethyl-1H-2-indolecarboxylate

[0153] 12.7 g (0.067 mol) of 5-ethyl-1H-2-indolecarboxylic acid and 10 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mol) are successively added to 70 ml of dimethylformamide. The reaction mixture is left for 40 minutes at 0° C., after which 10.6 ml of benzyl bromide (0.089 mol) are introduced dropwise. After reaction for 18 hours at room temperature, the reaction mixture is poured onto 300 ml of water and the precipitate formed is filtered off, rinsed with water and then dried for 18 hours at 50° C. under vacuum in order to give yellow crystals: m.p.=99° C.; yield=90%.

[0154] Step 2: Benzyl 5-ethyl-1-(methoxycarbonylmethyl)-1H-2-indolecarboxylate

[0155] 75 ml of dimethylformamide are added to 1.5 g (0.031 mol) of sodium hydride as a 50° suspension in oil, followed by portionwise addition of 7.9 g (0.0283 mol) of benzyl 5-ethyl-1H-2-indolecarboxylate prepared according to Step 1. After 40 minutes at 0° C., 3.5 ml (0.0315 mol) of methyl bromoacetate are introduced dropwise and the reaction mixture is left for 2 hours at 20° C. 300 ml of ethyl acetate are added, the mixture is washed with 2×300 ml of water, the phases are then separated after settling has taken place and the organic phase is dried over anhydrous sodium sulphate and concentrated. 9.5 g of colourless oil are obtained; yield=95%.

[0156] Step 3: 5-Ethyl-1-(methoxycarbonylmethyl)-1H-2-indolecarboxylic Acid

[0157] 2.5 g of 10% Pd/C are added to 9.5 g (0.0269 mol) of benzyl 5-ethyl-1-(methoxycarbonylmethyl)-1H-2-indolecarboxylate prepared according to Step 2, dissolved in 150 ml of ethanol, followed by addition of 40 ml of cyclohexene (0.395 mol). The reaction mixture is heated for 2 hours at 70° C. and is then cooled to a temperature of 20° C. The reaction mixture is filtered through talc and the filtrate is evaporated to dryness. The residue is dried for 18 hours at 40° C. under vacuum, in order to give beige-coloured crystals; m.p.=181° C.; yield=90%.

[0158] Compounds B5 to B70 described in Table I below are synthesized by working according to the above Preparations, starting with appropriate synthetic intermediates.

TABLE I
26
COMPOUND No.	Y1	Y2	Y3	R4	m.p.: ° C.
B5	5-C2H5	H	H	—(CH2)2CO2CH3	128
B6	5-C2H5	H	H	—(CH2)3CO2C2H5	94
B7	5-C2H5	H	H	—(CH2)4CO2C2H5	oil
B8	4-CH3	5-CH3	H	—(CH2CO2CH3	208
B9	4-CH3	5-CH3	H	—(CH2)2CO2CH3	170
B10	4-CH3	5-CH3	H	—(CH2)3CO2C2H5	183
B11	5-C2H5	H	H	—(CH2)3CO2C2H5	oil
B12	5-Cl	H	H	—CH2CO2CH3	207
B13	5-Cl	H	H	—(CH2)2CO2CH3	175
B14	5-Cl	H	H	—(CH2)3CO2C2H5	152
B15	5-Cl	H	H	—(CH2)4CO2C2H5	99
B16	5-Cl	H	H	—(CH2)3CO2C2H5	93
B17	5-CH3	H	H	—CH2CO2CH3	211
B18	5-CH3	H	H	—(CH2)2CO2CH3	174
B19	5-CH3	H	H	—(CH2)4CO2C2H5	188
B21	5-CH3	H	H	—(CH2)3CO2C2H5	91
B22	4-OCH3	5-CH3	6-OCH3	—CH2CO2CH3	220
B23	4-OCH3	5-CH3	6-OCH3	—CH2CH2CO2CH3	200
B24	4-OCH3	5-CH3	6-OCH3	—(CH2)3CO2C2H5	134
B25	5-OCH3	H	H	—CH2CO2CH3	195
B26	5-OCH3	H	H	—(CH2)2CO2CH3	157
B27	5-OCH3	H	H	—(CH2)3CO2C2H5	119
B28	5-OCH3	H	H	—(CH2)4CO2C2H5	87
B29	5-OCH3	H	H	—(CH2)3CO2C2H5	70
B30	5-CH3	H	H	—CH3	230
B31	5-CH3	H	H	—CH2CH3	206
B32	5-CH3	H	H	—CH2CH2OCH3	158
B33	5-OCH3	H	H	—CH2CH2OCH3	170
B34	4-CH3	H	H	—CH2CO2CH3	206
B35	4-CH3	H	H	—(CH2)2CO2CH3	118
B36	5-OC2H5	H	H	—CH2CO2CH3	188
B37	5-OC2H5	H	H	—(CH2)2CO2CH3	158
B38	5-OC2H5	H	H	—(CH2)3CO2C2H5	131
B39	4-OCH3	6-OCH3	H	—CH2COOCH3	195
B40	4-OCH3	6-OCH3	H	—(CH2)2COOCH3	191
B41	4-OCH3	6-OCH3	H	—(CH2)3COOC2H5	154
B42	4-OCH3	5-CH3	6-OCH3	—(CH2)3CO2C2H5	132
B43	5-Cl	H	H	—CH3	248
B44	5-CH3	H	7-CH3	—CH2CO2CH3	208
B45	5-CH3	H	7-CH3	—(CH2)2CO2CH3	—
B46	5-CH3	H	7-CH3	—(CH2)3CO2C2H5	183
B47	5-Cl	H	H	—(CH2)2OCH3	182
B48	4-CH3	5-CH3	6-OCH3	—CH2CO2CH3	185
B49	4-CH3	5-CH3	6-OCH3	—CH2CH2CO2CH3	197
B50	4-CH3	5-CH3	6-OCH3	—(CH2)3COOC2H5	143
B51	4-CH3	H	7-CH3	—CH2COOCH3	118
B52	4-CH3	H	7-CH3	—(CH2)3COOC2H5	108
B53	5-OCH3	H	7-CH3	—CH2COOCH3	215
B54	4-CH3	6-CH3	H	—CH2COOCH3	112
B55	4-CH3	6-CH3	H	—(CH2)2COOC2H5	152
B58	6-C2H6	H	H	—CH2COOCH3	158
B57	6-C2H6	H	H	—(CH2)3COOC2H5	142
B58	5-OCH3	H	7-CH3	—(CH2)3COOC2H5	oil
B59	6-C2H5	H	H	—(CH2)2COOCH3	166
B60	5-Cl	H	7-CH3	—CH2COOCH3	209
B61	5-OCH3	H	7-OCH3	—CH2COOHCH3	186
B62	5-OCH3	H	7-OCH3	—(CH2)3COOC2H5	138
B63	5-OCH3	6-OCH3	H	—CH2COOCH3	202
B64	5-F	H	7-CH3	—CH2COOCH3	242
B65	5-F	H	7-CH3	—(CH2)3COOC2H5	142
B66	5-Cl	H	7-CH3	—(CH2)3COOC2H5	181
B67	5-OCH3	6-OCH3	H	—(CH2)2COOCH3	166
B68	5-OCH3	6-OCH3	H	—(CH2)3COOC2H5	oil
B69	5-CH3	7-Cl	H	—CH2COOCH3	210
B70	4-CH3	6-OCH3	7-CH3	—CH2COOCH3	211

[0159] 4,5-Dimethyl-1-(3-cyanopropyl)-1H-2-indolecarboxylic acid (Compound B71)

[0160] Step 1: Ethyl 4,5-dimethyl-1-(3-cyanopropyl)-1H-2-indolecarboxylate

[0161] 75 ml of dimethylformamide are added to 1.92 g (0.040 mol) of sodium hydride as a 50% suspension in oil, followed by portionwise addition of 7.9 g (0.0363 mol) of ethyl 4,5-dimethyl-1H-2-indole-carboxylate. After stirring for 40 minutes at 0° C., 4.0 ml (0.040 mol) of 4-bromobutyronitrile are introduced dropwise and the reaction mixture is maintained for 2 hours at 20° C. 300 ml of ethyl acetate are added, the mixture is washed with twice 300 ml of water, the phases are separated after settling has taken place and the organic phase is then dried over anhydrous sodium sulphate and concentrated. 9.8 g of colourless oil are obtained; Yield=95%.

[0162] Step 2: 4,5-Dimethyl-1-(3-cyanopropyl)-1H-2-indole-carboxylic Acid

[0163] 9.8 g (0.0345 mol) of ethyl 4,5-dimethyl-1-(3-cyanopropyl)-1H-2-indolecarboxylate are added to 150 ml of 1,4-dioxane, followed by addition of 25 ml of 2 M sodium hydroxide solution (0.05 mol). The reaction mixture is maintained for 48 hours at room temperature. After evaporation of the 1,4-dioxane, the residue is taken up in 6 M hydrochloric acid solution and the precipitate formed is filtered off and dried under reduced pressure at 60° C. in order to give the 4,5-dimethyl-1-(3-cyanopropyl)-1H-2-indole-carboxylic acid in the form of white crystals; m.p.=175° C., yield=92%.

[0164] Compounds B72 to B75 presented in Table Ia below are prepared in the same way.

TABLE Ia
27
COMPOUND					m.p.:
No.	Y1	Y2	Y3	R′4	° C.
B72	5-C3H5	H	H	—(CH2)3—C≡N	137
B73	5-C2H5	H	H	—CH2—C≡N	229
B74	5-OCH3	H	H	—CH2—C≡N	190
B75	5-CH3	6-CH3	7-OCH3	—(CH2)3—C≡N	181

[0165] C. Preparation of the Benzamidoguanidine Derivatives Preparation of 2,6-dimethoxy-4-methylbenzamidoguanidine (Compound C.1)

[0166] 1 ml of dimethylformamide is added to 353 g (1.8 mol) of 2,6-dimethoxy-4-methylbenzoic acid suspended in 1.5 litres of toluene, followed by dropwise addition of 190 ml of oxalyl chloride (2.16 mol). The reaction mixture is left for two hours at room temperature and is then evaporated to dryness. The crystalline residue is added portion-wise to a suspension of 293.8 g of aminoguanidine hydrogen carbonate (2.16 mol) in 2.5 litres of pyridine at ±5° C. and is left for 18 hours at 20° C. The reaction mixture is evaporated to dryness and the residue is then taken up in 1 litre of 2 M sodium hydroxide solution. The precipitate is filtered off and is rinsed with a minimum amount of water and then dried under vacuum at 60° C. in order to obtain a crystalline residue; m.p.=222° C.; yield=81%.

[0167] D. Preparation of the 3-Aminotriazole Derivatives

[0168] 3-Amino-5-(2,6-dimethoxy-4-methylphenyl)-1,2,4-triazole (Compound D.1)

[0169] 2 litres of diphenyl ether are added to 230 g (0.91 mol) of 2,6-dimethoxy-4-methylbenzamidoguanidine, after which the reaction mixture is heated for 5 minutes at 220° C. The mixture is cooled to 80° C. and the precipitate is then filtered off, rinsed with diisopropyl ether and dried under vacuum at 60° C. in order to obtain crystals; m.p.=286° C.; yield=93%.

[0170] Compound D2 to D11 described in Table II below are synthesized in the same way, by working according to this Preparation and using the appropriate starting materials.

TABLE II
28
COMPOUND					m.p.:
No.	X1	X2	X3	X4	° C.
D2	2-OCH3	4-OCH3	6-OCH3	H	297
D3	2-OCH3	4-OCH3	5-OCH3	H	240
D4	2-OCH3	4-CH3	5-OCH3	H	248
D5	2-OCH3	4-Cl	5-OCH3	H	282
D6	2-OCH3	4-CH3	6-CH3	H	286
D7	2-OCH3	4-OCH3	5-CH3	H	248
D8	2-OCH3	4-CH3	5-CH3	H	286
D9	2-OCH3	3-Cl	6-OCH3	H	215
D10	2-OCH3	3-CH3	6-OCH3	H	236
D11	2-OCH3	4-CH3	5-CH3	6-OCH3	237

[0171] E. Preparation of the Diphenylimino Derivatives

[0172] Preparation of N-[3-(2,6-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-5-yl]-N-diphenylmethyleneamine (Compound E.1)

[0173] 105 g (0.45 mol) of 3-amino-5-(2,6-dimethoxy-4-methylphenyl)-1,2,4-triazole suspended in 200 ml of xylene and 150 g (0.9 mol) of benzophenoneimine are heated at 140° C. for 48 hours under a stream of argon. The reaction mixture is cooled to a temperature of 80° C. and is then poured into 4 litres of isopropyl ether and the precipitate formed is filtered off, rinsed with diisopropyl ether and dried for 18 hours at 50° C.; m.p.=126° C.; yield 90%.

TABLE III
29
COMPOUND No.	X1	X2	X3	X4	m.p.:° C.
E2	2-OCH3	4-OCH3	6-OCH3	H	143
E3	2-OCH3	4-OCH3	5-OCH3	H	235
E4	2-OCH3	4-CH3	5-OCH3	H	228
E5	2-OCH3	4-Cl	5-OCH3	H	236
E6	2-OCH3	4-CH3	5-CH3	H	171
E7	2-OCH3	4-CH3	5-CH3	H	240
E8	2-OCH3	3-Cl	6-OCH3	H	152
E9	2-OCH3	3-CH3	6-OCH3	H	169
E10	2-OCH3	4-CH3	5-CH3	6-OCH3	110

[0174] F. Preparation of the 1-Substituted 3-Amino Triazoles

[0175] Preparation of 1-(2-cyclohexylethyl)-5-(2,6-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-amine (Compound F.1)

[0176] a) N-Alkylation of the Triazole

[0177] 300 ml of aqueous 6 N sodium hydroxide solution, 24 g (0.06 mol) of N-[3-(2,6-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-5-yl]-N-diphenylmethyleneamine and 2.7 g of tetrabutylammonium bromide are added successively to 400 ml of toluene. 17 g (0.09 mol) of 2-bromoethyl cyclohexane are added dropwise to the reaction mixture, heated to 70° C. The reaction is continued for two hours at 80° C. The organic phase is separated out after settling has taken place and is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is chromatographed on a column of silica gel with the eluent: 90/10 (v/v) toluene/ethyl acetate. 21.4 g of colourless oil are obtained; yield=70%.

[0178] b) Hydrolysis of the Diphenylimine Function

[0179] 100 ml of 1N hydrochloric acid solution are added to 10.3 g (0.02 mol) of N-[1-(2-cyclohexylethyl)-5-(2,6-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]-N-diphenylmethyleneamine dissolved in 200 ml of methanol. The reaction mixture is left for 18 hours at room temperature and is then evaporated to dryness. The oily residue is solidified in diethyl ether and the precipitate obtained is filtered off and dried under vacuum at 40° C.; m.p.=136° C. (hydrochloride); yield=90%.

TABLE IV
30
					m.p.: ° C.
COMPOUND No.	X1	X2	X4	R1	(hydrochloride)
F2	2-OCH3	4-CH3	6-OCH3	31	135
F3	2-OCH3	4-CH3	6-OCH3	—CH2—C6H5	215
F4	2-OCH3	4-CH3	6-OCH3	—(CH2)4—CH3	143
F5	2-OCH3	4-CH3	6-OCH3	32	238
F6	2-OCH3	4-CH3	6-OCH3	—CH2CH2—CH6H5	200
F7	2-OCH3	4-CH3	6-OCH3	—(CH2)4—CH—(CH2)2	172
F8	2-OCH3	4-CH3	6-OCH3	33	187
F9	2-OCH3	4-CH3	6-OCH3	34	180
F10	2-OCH3	4-CH3	6-OCH3	—(CH2)2—N(CH2)2	148
F11	2-OCH3	4-CH3	6-OCH3	35	190
F12	2-OCH3	4-CH3	6-OCH3	—(CH2)3—CH3	212
F13	2-OCH3	4-CH3	6-OCH3	36	198
F14	2-OCH3	4-CH3	6-OCH3	37	219
F15	2-OCH3	4-CH3	6-OCH3	—CH2—CH—(C6H5)2	132
F16	2-OCH3	4-CH3	6-OCH3	38	197
F17	2-OCH3	4-CH3	6-OCH3	39	217
F18	2-OCH3	4-CH3	6-OCH3	40	208
F19	2-OCH3	4-CH3	6-OCH3	41	136
F20	2-OCH3	4-CH3	6-OCH3	42	204
F21	2-OCH3	4-CH3	6-OCH3	43	202
F22	2-OCH3	4-CH3	6-OCH3	44	196
F23	2-OCH3	4-CH3	5-OCH3	45	148
F24	2-OCH3	4-CH3	5-OCH3	46	192
F25	2-OCH3	4-CH3	5-OCH3	47	188
F26	2-OCH3	4-CH3	5-OCH3	48	168
F27	2-OCH3	4-CH3	6-OCH3	49	189
F28	2-OCH3	4-CH3	6-OCH3	50	180
F29	2-OCH3	4-CH3	6-OCH3	51	168
F30	2-OCH3	4-CH3	6-OCH3	52	188
F31	2-OCH3	4-CH3	5-OCH3	53	200
F32	2-OCH3	4-CH3	5-OCH3	54	206
F33	2-OCH3	4-CH3	6-OCH3	—CH2CH2CN	244
F34	2-OCH3	4-CH3	5-OCH3	55	218
F35	2-OCH3	4-Cl	5-OCH3	56	127
F36	2-OCH3	4-Cl	6-OCH3	57	159
F37	2-OCH3	3-CH3	6-OCH3	58	168

[0180] 1-(2-Cyclohexylethyl)-5-(2,6-dimethoxy-4,5-di-methylphenyl)-1H-1,2,4-triazol-3-amine (Compound F38) is prepared in a similar manner, starting with Compound E10; m.p.=180° C.

[0181] G. Preparation of the Amidotriazole Derivatives with Non-N-Substituted Indoles

[0182] Synthesis of N-[1-(2-chlorobenzyl)-5-(2,6-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]-5-chloro-1H-2-indolecarboxamide (Compound G.1).

[0183] 0.2 ml of thionyl chloride (0.0028 mol) is added, at 0° C., to a solution of 1 ml of pyridine (0.013 mol) in 30 ml of methylene chloride. After 15 minutes at 0° C., 500 mg (0.0025 mol) of 5-chloroindolecarboxylic acid are introduced and the reaction mixture is left for 30 minutes at 0° C. 0.91 g (0.0028 mol) of 1-[(2-chlorophenyl)methyl]-5-(2,6-dimethoxy-4-methylphenyl)-1H-1,2,4-triazole-3-amine hydrochloride is added to the acyl chloride formed and the mixture is left for 18 hours at 20° C.

[0184] The reaction mixture is washed with 1 M sodium hydroxide solution. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is chromatographed on silica gel with the eluent: 95/5 (v/v) dichloromethane/methanol, to give 0.980 g of crystals: m.p.=262° C.; yield=73%.

TABLE V
59
COMPOUND No.	60	R1	61	m.p.:° C.
G2	62	63	64	271
G3	65	66	67	301
G4	68	69	70	251
G5	71	72	73	248
G8	74	75	76	283
G7	77	78	79	253
G8	80	81	82	229
G9	83	84	85	262
G10	86	87	88	270
G11	89	90	91	245
G12	92	93	94	139
G13	95	96	97	210 (HCl)
G14	98	99	100	210 (HCl)
G15	101	102	103	252
G18	104	105	106	181

[0185] H. Preparation of the Aminotriazole Derivatives with N-Substituted Indoles

EXAMPLE 1

[0186] Methyl 2-[2-({[1-(2-cyclohexylethyl)-5-(2,6-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino}carbonyl)-5-ethyl-1H-indol-1-yl]acetate

[0187] 1 ml of pyridine (0.013 mol) and 0.21 ml of thionyl chloride (0.00029 mol) are added successively to 15 ml of dichloromethane. After 15 minutes at 0° C., 0-0.627 g of 5-ethyl-1-methoxycarbonylmethyl-1H-2-indolecarboxylic acid (0.0024 mol) is introduced, followed by 0.9 g of 1-(2-cyclohexylethyl)-5-(2,6-dimethoxy-4-methylphenyl)-1H-1,2,4-triazole-3-amine hydrochloride. The reaction mixture is left for 18 hours at room temperature, after which an acidic washing and then a basic washing are carried out. The organic phase is dried over anhydrous sodium sulphate and concentrated. The oily residue is chromatographed on silica gel with the eluent: 98.5/1.5 (v/v) dichloromethane/methanol, to give a white powder; m.p.=191° C.; yield=87%.

EXAMPLE 2

[0188] 2-[2-({[1-(2-Cyclohexylethyl)-5-(2,6-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino}carbonyl)-5-ethyl-1H-indol-1-yl]acetic Acid

[0189] 1.8 ml (0.0018 mol) of 1 N sodium hydroxide solution are added to 530 mg (0.0009 mol) of methyl 2-[2-({[1-(2-cyclohexylethyl)-5-(2,6-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl]amino}carbonyl)-5-ethyl-1H-indol-1-yl] prepared according to Example 1, dissolved in 50 ml of methanol. After 18 hours at room temperature, the reaction mixture is evaporated to dryness. The residue is taken up in ethyl acetate and 0.5 N hydrochloric acid solution. The organic phase is separated out after settling has taken place, dried over anhydrous sodium sulphate and concentrated. The residue is purified by chromatography on a column of silica gel with the eluent: 92/8 (v/v) dichloromethane/methanol, to give white crystals; m.p.=198° C.; yield=91%.

[0190] Examples 3 to 511 described in Tables VI and VII below are prepared in the same way, by working according to Examples 1 and 2 above, starting with appropriate intermediates.

TABLE VI
107
EXAMPLE No.	108	R1	R4	m.p.: ° C. (salt)
3	109	110	—CH2CO2CH3	185
4	111	112	—CH2CO2H	226
5	113	114	—CH2CO2CH3	118
6	115	116	—CH2CO2H	230
7	117	118	—CH2CH2CO2CH3	101
8	119	—(CH2)4CH3	—CH2CO2CH3	192
9	120	121	—CH2CH2CO2H	210
10	122	—(CH2)4CH3	—CH2CO2H	205
11	123	124	—CH2CO2CH3	189
12	125	126	—CH2CO2H	218
13	127	128	—CH2CO2CH3	138
14	129	130	—CH2CO2CH3	115
15	131	132	—CH2CO2CH3	167
16	133	134	—CH2CO2CH3	180
17	135	136	—CH2CO2CH3	203
18	137	138	—CH2CO2CH3	158
19	139	140	—CH2CO2H	217 (HCl)
20	141	142	—CH2CO2H	168
21	143	144	—CH2CO2H	271
22	145	146	—CH2CO2H	181
23	147	—(CH2)3CH3	—CH2CO2CH3	220
24	148	149	—CH2CO2H	220 (HCl)
25	150	151	—CH2CO2CH3	165
26	152	153	—CH2CO2H	198
27	154	155	—CH2CO2CH3	132
28	156	—(CH2)3CH3	—CH2CO2H	220
29	157	158	—CH2CO2CH3	144
30	159	160	—CH2CO2H	169
31	161	162	—CH2CO2H	203 (HCl)
32	163	164	—CH2CO2H	180
33	165	166	—CH2CO2CH3	172
34	167	168	—CH2CO2H	216
35	169	170	—CH2CO2CH3	128
36	171	172	—CH2CO2CH3	158
37	173	—(CH2)2CH(CH3)2	—CH2CO2H	272
38	174	—CH2CH(CH3)2	—CH2CO2CH3	206
39	175	—CH2CH(CH3)2	—CH2CO2H	189
40	176	177	—CH2CO2H	175
41	178	179	—CH2CO2H	158
42	180	181	—CH2CO2CH3	180
43	182	183	—CH2CO2CH3	161
44	184	185	—CH2CO2CH3	210
45	186	187	—CH2CO2CH3	191
46	188	189	—CH2CO2H	182
47	190	191	—CH2CO2H	195
48	192	193	—CH2CO2CH3	201
49	194	195	—CH2CO2CH3	194
50	196	197	—CH2CO2H	204
51	198	199	—CH2CO2CH3	129
52	200	201	—CH2CO2H	213
53	202	203	—CH2CO2H	182
54	204	205	—CH2CO2H	151
55	206	207	—CH2COOCH3	192
56	208	209	—CH2CO2CH3	173
57	210	211	—CH2CO2H	229
58	212	213	—CH2CO2H	195
59	214	215	—CH2CO2CH3	133
60	216	217	—CH2CO2H	175
61	218	219	—CH2CH2CO2CH3	178
62	220	221	—CH2CH2CO2H	235
63	222	223	—(CH2)3CO2C2H5	144
64	224	225	—(CH2)3CO2H	141
65	226	227	—(CH2)4CO2C2H5	95
66	228	229	—(CH2)4CO2C2H5	101
67	230	231	—(CH2)4CO2H	266
68	232	233	—(CH2)4CO2H	157
69	234	235	—(CH2)3CO2C2H5	114
70	236	237	—(CH2)3CO2C2H5	76
71	238	239	—(CH2)3CO2C2H5	85
72	240	241	—(CH2)3CO2H	243
73	242	243	—(CH2)3CO2H	138
74	244	245	—(CH2)3CO2H	150
75	246	247	—CH2CO2CH3	201
76	248	249	—CH2CO2CH3	162
77	250	251	—CH2COOH	200
78	252	253	—CH2COOH	168 (HCl)
79	254	255	—CH2COOH	211
80	256	257	—CH2COOH	243 (HCl)
81	258	259	—CH2COOH	188 (2HCl)
82	260	261	—CH2COOCH3	200
83	262	263	—CH2COOCH3	170
84	264	265	—CH2COOCH3	137
85	266	267	—CH2COOH	168
86	268	269	—CH2COOCH3	156

[0191]

TABLE VII
	(I)
270
EXAMPLE No.	271	R1	272	m.p.: ° C. (salt)
87	273	274	275	145
88	276	277	278	147
89	279	280	281	156
90	282	283	284	221
91	285	286	287	243
92	288	289	290	207
93	291	292	293	196
94	294	295	296	310 (Na salt)
95	297	298	299	221
96	300	301	302	214
97	303	304	305	202
98	306	307	308	194
99	309	310	311	285
100	312	313	314	194 (Na salt)
101	315	316	317	132
102	318	319	320	277 (Na salt)
103	321	322	323	195
104	324	325	326	264
105	327	328	329	266 (Na salt)
106	330	331	332	161
107	333	334	335	196
108	336	337	338	174
109	339	340	341	190
110	342	343	344	83
111	345	346	347	242
112	348	349	350	223
113	351	352	353	205
114	354	355	356	191
115	357	358	359	154
116	360	361	362	233
117	363	364	365	82
118	366	367	368	257
119	369	370	371	181
120	372	373	374	275
121	375	376	377	132
122	378	379	380	135
123	381	382	383	263
124	384	385	386	250
125	387	388	389	154
126	390	391	392	184
127	393	394	395	207
128	396	397	398	179
129	399	400	401	175
130	402	403	404	188 (Na salt)
131	405	406	407	235
132	408	409	410	177
133	411	412	413	141
134	414	415	416	108
135	417	418	419	144
136	420	421	422	196
137	423	424	425	249 (Na salt)
138	426	427	428	176 (Na salt)
139	429	430	431	198
140	432	433	434	212
141	435	436	437	140
142	438	439	440	159
143	441	442	443	121
144	444	445	446	158
145	447	448	449	220
146	450	451	452	266 (Na salt)
147	453	454	455	206 (Na salt)
148	456	457	458	210 (Na salt)
149	459	460	461	213
150	462	463	464	247
151	465	466	467	183
152	468	469	470	230 (Na salt)
153	471	472	473	252 (Na salt)
154	474	475	476	132
155	477	478	479	138
156	480	481	482	188
157	483	484	485	196
158	486	487	488	82
159	489	490	491	215
160	492	493	494	177
161	495	496	497	233
162	498	499	500	131
163	501	502	503	241
164	504	505	506	120
165	507	508	509	145
166	510	511	512	144 (Na salt)
167	513	514	515	114
168	516	517	518	148
169	519	520	521	202
170	522	523	524	231 (HCl)
171	525	526	527	237 (2HCl)
172	528	529	530	208
173	531	532	533	231 (2HCl)
174	534	535	536	268 (Na salt)
175	537	538	539	195
176	540	541	542	164
177	543	544	545	215
178	546	547	548	232
179	549	550	551	200 (Na salt)
180	552	553	554	199
181	555	556	557	233 (HCl)
182	558	559	560	101
183	561	562	563	246 (HCl)
184	564	565	566	217
185	567	568	569	108
186	570	571	572	219
187	573	574	575	87
188	576	577	578	263
189	579	580	581	184 (Na salt)
190	582	583	584	140
191	585	586	587	187
192	588	589	590	208 (HCl)
193	591	592	593	200 (HCl)
194	594	595	596	197 (2HCl)
195	597	598	599	186 (2HCl)
196	600	601	602	148
197	603	604	605	136
198	606	607	608	170
199	609	610	611	130
200	612	613	614	282 (Na salt)
201	615	616	617	101
202	618	619	620	273 (Na salt)
203	621	622	623	231
204	624	625	626	225 (Na salt)
205	627	628	629	112
206	630	631	632	108
207	633	634	635	122
208	636	637	638	155
209	639	640	641	162 (Na salt)
210	642	643	644	225 (Na salt)
211	645	646	647	130
212	648	649	650	141
213	651	652	653	177
214	654	655	656	126
215	657	658	659	213
216	660	661	662	241
217	663	664	665	257
218	666	667	668	221 (2HCl)
219	669	670	671	152
220	672	673	674	87
221	675	676	677	182 (2HCl)
222	678	679	680	168
223	681	682	683	205
224	684	685	686	256 (HCl)
225	687	688	689	198
226	690	691	692	95
227	693	694	695	196 (Na salt)
228	696	697	698	200 (Na salt)
229	699	700	701	145
230	702	703	704	258
231	705	706	707	157
232	708	709	710	265
233	711	712	713	157
234	714	715	716	211 (HCl)
235	717	718	719	209 (HCl)
236	720	721	722	222 (2HCl)
237	723	724	725	240 (HCl)
238	726	727	728	217
239	729	730	731	129
240	732	733	734	138
241	735	736	737	215 (2HCl)
242	738	739	740	83
243	741	742	743	205 (2HCl)
244	744	745	746	125
245	747	748	749	94
246	750	751	752	234
247	753	754	755	170
248	756	757	758	143
249	759	760	761	107
250	762	763	764	206 (2HCl)
251	765	766	767	240 (Na salt)
252	768	769	770	184
253	771	772	773	238 (Na salt)
254	774	775	776	122
255	777	778	779	121
256	780	781	782	251 (Na salt)
257	783	784	785	200
258	786	787	788	151 (2HCl)
259	789	790	791	241
260	792	793	794	157
261	795	796	797	170
262	798	799	800	191
263	801	802	803	193
264	804	805	806	198
265	807	808	809	163
266	810	811	812	205
267	813	814	815	114
268	816	817	818	223 (HCl)
269	819	820	821	159
270	822	823	824	295 (Na salt)
271	825	826	827	227
272	828	829	830	102
273	831	832	833	162
274	834	835	836	240 (Na salt)
275	837	838	839	250 (Na salt)
276	840	841	842	161
277	843	844	845	177
278	846	847	848	297 (Na salt)
279	849	850	851	127
280	852	853	854	303
281	855	856	857	111
282	858	859	860	191
283	861	862	863	289
284	864	865	866	273
285	867	868	869	131 (HCl)
286	870	871	872	156
287	873	874	875	160
288	876	877	878	181
289	879	880	881	157
290	882	883	884	140 (Na salt)
291	885	886	887	174 (Na salt)
292	888	889	890	170 (Na salt)
293	891	892	893	247 (Na salt)
294	894	895	896	220 (Na salt)
295	897	898	899	151
296	900	901	902	216 (Na salt)
297	903	904	905	104
298	906	907	908	111
299	909	910	911	159 (Na salt)
300	912	913	914	218
301	915	916	917	142
302	918	919	920	254
303	921	922	923	240
304	924	925	926	204 (K salt)
305	927	928	929	262 (Na salt)
306	930	931	932	169
307	933	934	935	103
308	936	937	938	242
309	939	940	941	104
310	942	943	944	235 (HCl)
311	945	946	947	196
312	948	949	950	259 (Na salt)
313	951	952	953	130
314	954	955	956	92
315	957	958	959	170
316	960	961	962	187 (K salt)
317	963	964	965	260 (Na salt)
318	966	967	968	132
319	969	970	971	112
320	972	973	974	258
321	975	976	977	188
322	978	979	980	293
323	981	982	983	258 2HCl
324	984	985	986	149
325	987	988	989	118
326	990	991	992	97
327	993	994	995	138
328	996	997	998	179
329	999	1000	1001	189
330	1002	1003	1004	200
331	1005	1006	1007	151
332	1008	1009	1010	119
333	1011	1012	1013	102
334	1014	1015	1016	143
335	1017	1018	1019	135
336	1020	1021	1022	151
337	1023	1024	1025	138
338	1026	1027	1028	195 (HCl)
339	1029	1030	1031	185
340	1032	1033	1034	116
341	1035	1036	1037	98
342	1038	1039	1040	149
343	1041	1042	1043	146
344	1044	1045	1046	273 (HCl)
345	1047	1048	1049	202
346	1050	1051	1052	167
347	1053	1054	1055	279 (Na salt)
348	1056	1057	1058	80
349	1059	1060	1061	134
350	1062	1063	1064	130
351	1065	1066	1067	122
352	1068	1069	1070	99
353	1071	1072	1073	218
354	1074	1075	1076	96
355	1077	1078	1079	168
356	1080	1081	1082	248
357	1083	1084	1085	196
358	1086	1087	1088	174 (Na salt)
359	1089	1090	1091	198
360	1092	1093	1094	186
361	1095	1096	1097	233
362	1098	1099	1100	216 (Na salt)
363	1101	1102	1103	191 (K salt)
364	1104	1105	1106	240
365	1107	1108	1109	198
366	1110	1111	1112	247 (HCl)
367	1113	1114	1115	185 (HCl)
368	1116	1117	1118	165 (Na salt)
369	1119	1120	1121	175 (K salt)
370	1122	1123	1124	226
371	1125	1126	1127	204
372	1128	1129	1130	74
373	1131	1132	1133	147
374	1134	1135	1136	194
375	1137	1138	1139	199
376	1140	1141	1142	214 (HCl and Na salt)
377	1143	1144	1145	147 (HCl and Na salt)
378	1146	1147	1148	156 (Na salt)
379	1149	1150	1151	219 (Na salt)
380	1152	1153	1154	131
381	1155	1156	1157	148
382	1158	1159	1160	85
383	1161	1162	1163	141
384	1164	1165	1166	161
385	1167	1168	1169	151
386	1170	1171	1172	268 (Na salt)
387	1173	1174	1175	155
388	1176	1177	1178	195 (Na salt)
389	1179	1180	1181	214
390	1182	1183	1184	293 (HCl)
391	1185	1186	1187	271
392	1188	1189	1190	177
393	1191	1192	1193	264 (Na salt)
394	1194	1195	1196	281 (Na salt)
395	1197	1198	1199	257 (K salt)
396	1200	1201	1202	107
397	1203	1204	1205	124
398	1206	1207	1208	166
399	1209	1210	1211	220 (Na salt)
400	1212	1213	1214	246
401	1215	1216	1217	202
402	1218	1219	1220	266 (Na salt)
403	1221	1222	1223	128
404	1224	1225	1226	144
405	1227	1228	1229	224 (Na salt)
406	1230	1231	1232	158
407	1233	1234	1235	117
408	1236	1237	1238	134
409	1239	1240	1241	185 (HCl)
410	1242	1243	1244	144 (HCl)
411	1245	1246	1247	178 (Na salt)
412	1248	1249	1250	207
413	1251	1252	1253	191 (Na salt)
414	1254	1255	1256	228 (2HCl)
415	1257	1258	1259	203 (2HCl)
416	1260	1261	1262	290 (Na salt)
417	1263	1264	1265	257 (K salt)
418	1266	1267	1268	228
419	1269	1270	1271	217
420	1272	1273	1274	168
421	1275	1276	1277	113
422	1278	1279	1280	201 (HCl)
423	1281	1282	1283	146 (HCl)
424	1284	1285	1286	198 (HCl)
425	1287	1288	1289	167
426	1290	1291	1292	244 (Na salt)
427	1293	1294	1295	245 (K salt)
428	1296	1297	1298	151
429	1299	1300	1301	157
430	1302	1303	1304	205
431	1305	1306	1307	248 (Na salt)
432	1308	1309	1310	240 (Na salt)
433	1311	1312	1313	144 (Na salt)
434	1314	1315	1316	220 (Na salt)
435	1317	1318	1319	108
436	1320	1321	1322	77
437	1323	1324	1325	270 (HCl)
438	1326	1327	1328	278 (HCl)
439	1329	1330	1331	179 (Na salt)
440	1332	1333	1334	167 (HCl)
441	1335	1336	1337	164
442	1338	1339	1340	150 (Na salt)
443	1341	1342	1343	113
444	1344	1345	1346	185
445	1347	1348	1349	209
446	1350	1351	1352	295 (Na salt)
447	1353	1354	1355	221 (Na salt)
448	1356	1357	1358	190
449	1359	1360	1361	246
450	1362	1363	1364	196
451	1365	1366	1367	139
452	1368	1369	1370	109
453	1371	1372	1373	217 (Na salt)
454	1374	1375	1376	245
455	1377	1378	1379	238 (Na salt)
456	1380	1381	1382	173
457	1383	1384	1385	169
458	1386	1387	1388	164 (HCl)
459	1389	1390	1391	116
460	1392	1393	1394	243
461	1395	1396	1397	159
462	1398	1399	1400	227
463	1401	1402	1403	150
464	1404	1405	1406	208 (HCl)
465	1407	1408	1409	254
466	1410	1411	1412	108
467	1413	1414	1415	91
468	1416	1417	1418	139
469	1419	1420	1421	265 (Na salt)
470	1422	1423	1424	188
471	1425	1426	1427	190 (HCl)
472	1428	1429	1430	243 (HCl)
473	1431	1432	1433	98
474	1434	1435	1436	86
475	1437	1438	1439	275
476	1440	1441	1442	175
477	1443	1444	1445	205
478	1446	1447	1448	132
479	1449	1450	1451	83
480	1452	1453	1454	97
481	1455	1456	1457	82
482	1458	1459	1460	274 (Na salt)
483	1461	1462	1463	271
484	1464	1465	1466	237 (HCl)
485	1467	1468	1469	144 (HCl)
486	1470	1471	1472	228 (HCl and Na salt)
487	1473	1474	1475	168 (Na salt)
488	1476	1477	1478	138
489	1479	1480	1481	124
490	1482	1483	1484	138
491	1485	1486	1487	224
492	1488	1489	1490	197
493	1491	1492	1493	210 (Na salt)
494	1494	1495	1496	274 (Li salt)
495	1497	1498	1499	99
496	1500	1501	1502	248
497	1503	1504	1505	>300 (Na salt)
498	1506	1507	1508	148 (K salt)
499	1509	1510	1511	226 (Na salt)
500	1512	1513	1514	139 (K salt)
501	1515	1516	1517	190 (Na salt)
502	1518	1519	1520	237 (K salt)
503	1521	1522	1523	230 (K salt)
504	1524	1525	1526	208
505	1527	1528	1529	202 (K salt)
506	1530	1531	1532	109
507	1533	1534	1535	181 (K salt)
508	1536	1537	1538	117
509	1539	1540	1541	225 (K salt)
510	1542	1543	1544	178
511	1545	1546	1547	254 (K salt)

EXAMPLE 512

2-{N-[5-(4-chloro-2,5-dimethoxyphenyl)-1-(2-cyclohexylethyl)-1H-1,2,4-triazol-3-yl]carbamoyle}-4,5-dimethyl-1-[3-(2H-1,2,3,4-tetrazol-5-yl)-propyl]-1H-indole

[0192] Step 1: 4-[2-({[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-chlorophenyl)-1H-1,2,4-triazol-3-yl]amino}carbamoyl)-4,5-dimethyl-1H-1-indolyl]butyronitrile

[0193] 1 ml of pyridine (0.013 mol) and 0.21 ml (0.0029 mol) of thionyl chloride are successively added to 15 ml of dichloromethane. After 15 minutes at 0° C., 0.615 g of 4,5-dimethyl-1-(3-cyanopropyl)-1H-2-indolecarboxylic acid (0.0024 mol) and then 0.9 g of 1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-chlorophenyl)-1H-1,2,4-triazole-3-amine hydrochloride are introduced. The reaction mixture is maintained for 18 hours at room temperature, after which an acidic washing and a basic washing are carried out. The organic phase is dried over anhydrous sodium sulphate and concentrated under reduced pressure. The oily residue is chromatographed on a column of silica gel, eluting with a 99.5/1.5 (v/v) mixture to give a white powder; m.p.=178° C.; yield=87%.

[0194] Step 2: 2-{N-[5-(4-chloro-2,5-dimethoxyphenyl)-1-(2 cyclohexylethyl)-1H-1,2,4-triazol-3-yl]carbamoyle}-4,5-dimethyl-1-[3-(2H-1,2,3,4-tetrazol-5-yl)propyl]-1H-indole

[0195] 0.5 ml of azidotrimethylsilane and 0.030 g of dibutyltin oxide are added to 0.720 g (0.0012 mol) of 4-[2-({[1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4-chlorophenyl)-1H-1,2,4-triazol-3-yl]amino}carbonyl)-4,5-dimethyl-1H-1-indolyl]butyronitrile dissolved in 15 ml of tetrahydrofuran and the mixture is refluxed for 18 hours. The reaction mixture is allowed to cool to room temperature, the tetrahydrofuran is removed under reduced pressure and the residue is chromatographed on a column of silica gel, eluting with a 95/5 (v/v) dichloromethane/methanol mixture. A white solid is obtained; m.p.=233° C., yield=78%.

[0196] This procedure described for Example 512 is also used for Examples 303, 304, 316, 317, 356, 357, 361, 362, 363, 368, 369, 392, 394, 395, 430, 431 and 432.

[0197] The potassium and sodium salts of these compounds are obtained in acetonitrile by addition of one equivalent of base at room temperature, followed by evaporation of the solvent under reduced pressure and then drying.

Claims

1. Compound of formula:

2. Compound of formula (I) according to claim 1, in which R1, R4, X1, X2, X3 and X4 are as defined in claim 1 and Y1, Y2 and Y3 represent hydrogen; a salt or solvate thereof.

3. Compound of formula (I) according to claim 1, in which R1 and R4 are as defined in claim 1, Y1, Y2 and Y3 represent hydrogen; and

4. Compound of formula (I) according to claim 1, in which R1, R4, Y1, Y2 and Y3 are as defined in claim 1, and

5. Compound of formula (I) according to claim 1, in which R1, R4, Y1, Y2 and Y3 are as defined in claim 1, and

6. Compound of formula:

7. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 5, comprising the step consisting in reacting an aminotriazole of formula:

8. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 5, comprising the reaction of an aminotriazole of formula:

9. Pharmaceutical composition containing, as active principle, a compound of formula (I) according to claim 1, or one of the pharmaceutically acceptable salts thereof.

10. Pharmaceutical composition containing, as active principle, a compound according to claim 2, or one of the pharmaceutically acceptable salts thereof.

11. Pharmaceutical composition containing, as active principle, a compound according to claim 3, or one of the pharmaceutically acceptable salts thereof.

12. Pharmaceutical composition containing, as active principle, a compound according to claim 4, or one of the pharmaceutically acceptable salts thereof.

13. Pharmaceutical composition containing, as active principle, a compound according to claim 5, or one of the pharmaceutically acceptable salts thereof.

14. Use of a compound according to any one of claims 1 to 5 for the preparation of medicines intended to treat eating behaviour disorders and obesity and to reduce the intake of food.

15. Use of a compound according to any one of claims 1 to 5, for the preparation of medicines intended to treat tardive dyskinesia.

16. Use of a compound according to any one of claims 1 to 5 for the preparation of medicines intended to treat disorders of the gastrointestinal sphere.