Patent Publication Number: US-2004043995-A1

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

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&#39;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 [ 125 I]-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:  
                 
 
       [0026] in which:  
       [0027] R 1  represents a (C 2 -C 6 )alkyl; a group —(CH 2 ) n -G with n ranging from 0 to 5 and G representing a non-aromatic C 3 -C 13  mono- or polycyclic hydrocarbon group optionally substituted with one or more (C 1 -C 3 )alkyl; a phenyl(C 1 -C 3 )alkyl in which the phenyl group is optionally substituted one or more times with a halogen, with a (C 1 -C 3 )alkyl or with a (C 1 -C 3 ) alkoxy; a group —(CH 2 ) n NR 2 R 3  in which n represents an integer from 1 to 6 and R 2  and R 3 , which may be identical or different, represent a (C 1 -C 3 )alkyl or constitute, with the nitrogen atom to which they are attached, a morpholino, piperidino, pyrrolidinyl or piperazinyl group;  
       [0028] X 1 , X 2 , X 3  or X 4  each independently represents a hydrogen or halogen atom, a (C 1 -C 6 )alkyl, a (C 1 -C 3 )alkoxy or a trifluoromethyl; it being understood that only one from among X 1 , X 2 , X 3  and X 4  possibly represents a hydrogen atom;  
       [0029] R 4  represents hydrogen, a group —(CH 2 ) COOR 5  in which n is as defined above and R 5  represents a hydrogen atom, a (C 1 -C 6 )alkyl or a (C 6 -C 10 )aryl-(C 1 -C 6 )alkyl; a (C 1 -C 6 )alkyl; a group —(CH 2 ) n OR 5  or a group —(CH 2 ) n NR 2 R 3  in which n, R 2 , R 3  and R 5  are as defined above; a group —(CH 2 ) n -tetrazolyl in which n is as defined above,  
       [0030]  or R 4  represents one of these groups in the form of an alkali-metal or alkaline-earth metal salt;  
       [0031] Y 1 , Y 2  and Y 3  independently represent a hydrogen, a halogen, a (C 1 -C 3 )alkyl, a (C 1 -C 3 )alkoxy, a nitro, cyano, (C 1 -C 6 )acylamino, carbamoyl, trifluoromethyl, a group COOR 6  in which R 6  represents hydrogen, or (C 1 -C 3 )alkyl;  
       [0032]  or one of the salts or solvates thereof.  
       [0033] According to the present invention, “(C 1 -C 6 )alkyl” or “(C 2 -C 6 )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. (C 1 -C 6 )acylamino is a (C 1 -C 6 )alkylcarbonylamino.  
       [0036] The non-aromatic C 3 -C 13  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 (C 1 -C 3 )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[5.2.1.0 2.6 ]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-(C 1 -C 3 )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.  
                 
 
       [0049] in which R 1 , R 4 , X 1 , X 2 , X 3  and X 4  are as defined for (I); a salt or solvate thereof, are preferred.  
       [0050] Among these compounds, those in which  
                 
 
       [0051] represents 2,6-dimethoxy-4-methylphenyl are preferred.  
       [0052] The compounds of formula:  
                 
 
       [0053] in which R 1  and R 4  are as defined for (I); a salt or solvate thereof, are more particularly preferred.  
       [0054] The compounds of formula:  
                 
 
       [0055] in which R 1 , R 4 , Y 1 , Y 2  and Y 3  are as defined for (1), and X 2  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:  
                 
 
       [0057] in which R 1 , X 1 , X 2 , X 3  and X 4  are as defined for (I) either with an indolecarboxylic acid derivative of formula:  
                 
 
       [0058] in which R 4 , Y 1 , Y 2  and Y 3  are as defined above for (1), or with an indolecarboxylic acid derivative of formula:  
                 
 
       [0059] in which Y 1 , Y 2  and Y 3  are as defined above for (I) and R′ 4  is a precursor group of R 4 , in which case the compound of formula:  
                 
 
       [0060] in which R 1 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2  and Y 3  are as defined for (I) and R′ 4  is a precursor group of R 4 , R 4  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 R 4 , 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.  
                 
 
                 
 
       [0067] When R 4 =—(CH 2 ) n COOH, the compounds (I) are obtained from the corresponding T esters, which are themselves obtained from Scheme 2.  
       [0068] When R 4 =—(CH 2 ) n -tetrazolyl, the compounds (I) are obtained from the corresponding nitrites of formula:  
                 
 
       [0069] in which R′ 4 =—(CH 2 ) 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:  
                 
 
       [0072] in which R′ 4 =—(CH 2 ) 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 CO 2 , according to Scheme 3:  
                 
 
       [0075] with Z 1 =Br or H depending on the nature and/or position of the substituents X 1 , X 2 , X 3  and X 4 , 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 KMnO 4 , according to Scheme 4:  
                 
 
       [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:  
                 
 
       [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:  
                 
 
       [0080] The benzamidoguanidine 2 is obtained by acylation of aminoguanidine hydrogen carbonate with the benzoyl chloride obtained from benzoic acid 1 by standard processes (SOCl 2 , 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:  
                 
 
       [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&#39;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:  
                 
 
       [0084] The N-alkylation of the diphenyliminotriazole 4 with an alkyl halide R 1 X, 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 K 2 CO 3  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 R 1 . 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&#39;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:  
                 
 
       [0089] The carboxylic indoles 8 in which R′ 4 =—(CH 2 ) n —C≡N  
       [0090] were prepared according to an analogous process presented in Scheme 9a below:  
                 
 
       [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:  
                 
 
       [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:  
                 
 
       [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:  
                 
 
       [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 ED 50  (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 ED 50  (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&#39;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                                                                                                  COMPOUND No.   Y 1     Y 2     Y 3     R 4     m.p.: ° C.               B5    5-C 2 H 5     H   H   —(CH 2 ) 2 CO 2 CH 3     128       B6    5-C 2 H 5     H   H   —(CH 2 ) 3 CO 2 C 2 H 5      94       B7    5-C 2 H 5     H   H   —(CH 2 ) 4 CO 2 C 2 H 5     oil       B8    4-CH 3     5-CH 3     H   —(CH 2 CO 2 CH 3     208       B9    4-CH 3     5-CH 3     H   —(CH 2 ) 2 CO 2 CH 3     170       B10   4-CH 3     5-CH 3     H   —(CH 2 ) 3 CO 2 C 2 H 5     183       B11   5-C 2 H 5     H   H   —(CH 2 ) 3 CO 2 C 2 H 5     oil       B12   5-Cl   H   H   —CH 2 CO 2 CH 3     207       B13   5-Cl   H   H   —(CH 2 ) 2 CO 2 CH 3     175       B14   5-Cl   H   H   —(CH 2 ) 3 CO 2 C 2 H 5     152       B15   5-Cl   H   H   —(CH 2 ) 4 CO 2 C 2 H 5      99       B16   5-Cl   H   H   —(CH 2 ) 3 CO 2 C 2 H 5     93       B17   5-CH 3     H   H   —CH 2 CO 2 CH 3     211       B18   5-CH 3     H   H   —(CH 2 ) 2 CO 2 CH 3     174       B19   5-CH 3     H   H   —(CH 2 ) 4 CO 2 C 2 H 5     188       B21   5-CH 3     H   H   —(CH 2 ) 3 CO 2 C 2 H 5      91       B22   4-OCH 3     5-CH 3     6-OCH 3     —CH 2 CO 2 CH 3     220       B23   4-OCH 3     5-CH 3     6-OCH 3     —CH 2 CH 2 CO 2 CH 3     200       B24   4-OCH 3     5-CH 3     6-OCH 3     —(CH 2 ) 3 CO 2 C 2 H 5     134       B25   5-OCH 3     H   H   —CH 2 CO 2 CH 3     195       B26   5-OCH 3     H   H   —(CH 2 ) 2 CO 2 CH 3     157       B27   5-OCH 3     H   H   —(CH 2 ) 3 CO 2 C 2 H 5     119       B28   5-OCH 3     H   H   —(CH 2 ) 4 CO 2 C 2 H 5      87       B29   5-OCH 3     H   H   —(CH 2 ) 3 CO 2 C 2 H 5      70       B30   5-CH 3     H   H   —CH 3     230       B31   5-CH 3     H   H   —CH 2 CH 3     206       B32   5-CH 3     H   H   —CH 2 CH 2 OCH 3     158       B33   5-OCH 3     H   H   —CH 2 CH 2 OCH 3     170       B34   4-CH 3     H   H   —CH 2 CO 2 CH 3     206       B35   4-CH 3     H   H   —(CH 2 ) 2 CO 2 CH 3     118       B36   5-OC 2 H 5     H   H   —CH 2 CO 2 CH 3     188       B37   5-OC 2 H 5     H   H   —(CH 2 ) 2 CO 2 CH 3     158       B38   5-OC 2 H 5     H   H   —(CH 2 ) 3 CO 2 C 2 H 5     131       B39   4-OCH 3     6-OCH 3     H   —CH 2 COOCH 3     195       B40   4-OCH 3     6-OCH 3     H   —(CH 2 ) 2 COOCH 3     191       B41   4-OCH 3     6-OCH 3     H   —(CH 2 ) 3 COOC 2 H 5     154       B42   4-OCH 3     5-CH 3     6-OCH 3     —(CH 2 ) 3 CO 2 C 2 H 5     132       B43   5-Cl   H   H   —CH 3     248       B44   5-CH 3     H   7-CH 3     —CH 2 CO 2 CH 3     208       B45   5-CH 3     H   7-CH 3     —(CH 2 ) 2 CO 2 CH 3     —       B46   5-CH 3     H   7-CH 3     —(CH 2 ) 3 CO 2 C 2 H 5     183       B47   5-Cl   H   H   —(CH 2 ) 2 OCH 3     182       B48   4-CH 3     5-CH 3     6-OCH 3     —CH 2 CO 2 CH 3     185       B49   4-CH 3     5-CH 3     6-OCH 3     —CH 2 CH 2 CO 2 CH 3     197       B50   4-CH 3     5-CH 3     6-OCH 3     —(CH 2 ) 3 COOC 2 H 5     143       B51   4-CH 3     H   7-CH 3     —CH 2 COOCH 3     118       B52   4-CH 3     H   7-CH 3     —(CH 2 ) 3 COOC 2 H 5     108       B53   5-OCH 3     H   7-CH 3     —CH 2 COOCH 3     215       B54   4-CH 3     6-CH 3     H   —CH 2 COOCH 3     112       B55   4-CH 3     6-CH 3     H   —(CH 2 ) 2 COOC 2 H 5     152       B58   6-C 2 H 6     H   H   —CH 2 COOCH 3     158       B57   6-C 2 H 6     H   H   —(CH 2 ) 3 COOC 2 H 5     142       B58   5-OCH 3     H   7-CH 3     —(CH 2 ) 3 COOC 2 H 5     oil       B59   6-C 2 H 5     H   H   —(CH 2 ) 2 COOCH 3     166       B60   5-Cl   H   7-CH 3     —CH 2 COOCH 3     209       B61   5-OCH 3     H   7-OCH 3     —CH 2 COOHCH 3     186       B62   5-OCH 3     H   7-OCH 3     —(CH 2 ) 3 COOC 2 H 5     138       B63   5-OCH 3     6-OCH 3     H   —CH 2 COOCH 3     202       B64   5-F   H   7-CH 3     —CH 2 COOCH 3     242       B65   5-F   H   7-CH 3     —(CH 2 ) 3 COOC 2 H 5     142       B66   5-Cl   H   7-CH 3     —(CH 2 ) 3 COOC 2 H 5     181       B67   5-OCH 3     6-OCH 3     H   —(CH 2 ) 2 COOCH 3     166       B68   5-OCH 3     6-OCH 3     H   —(CH 2 ) 3 COOC 2 H 5     oil       B69   5-CH 3     7-Cl   H   —CH 2 COOCH 3     210       B70   4-CH 3     6-OCH 3     7-CH 3     —CH 2 COOCH 3     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                                                                                                  COMPOUND                   m.p.:       No.   Y 1     Y 2     Y 3     R′ 4     ° C.               B72   5-C 3 H 5     H   H   —(CH 2 ) 3 —C≡N   137       B73   5-C 2 H 5     H   H   —CH 2 —C≡N   229       B74   5-OCH 3     H   H   —CH 2 —C≡N   190       B75   5-CH 3     6-CH 3     7-OCH 3     —(CH 2 ) 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                                                                                                  COMPOUND                   m.p.:       No.   X 1     X 2     X 3     X 4     ° C.               D2   2-OCH 3     4-OCH 3     6-OCH 3     H   297       D3   2-OCH 3     4-OCH 3     5-OCH 3     H   240       D4   2-OCH 3     4-CH 3     5-OCH 3     H   248       D5   2-OCH 3     4-Cl   5-OCH 3     H   282       D6   2-OCH 3     4-CH 3     6-CH 3     H   286       D7   2-OCH 3     4-OCH 3     5-CH 3     H   248       D8   2-OCH 3     4-CH 3     5-CH 3     H   286       D9   2-OCH 3     3-Cl   6-OCH 3     H   215        D10   2-OCH 3     3-CH 3     6-OCH 3     H   236        D11   2-OCH 3     4-CH 3     5-CH 3     6-OCH 3     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                                                                                                  COMPOUND No.   X 1     X 2     X 3     X 4     m.p.:° C.               E2   2-OCH 3     4-OCH 3     6-OCH 3     H   143       E3   2-OCH 3     4-OCH 3     5-OCH 3     H   235       E4   2-OCH 3     4-CH 3     5-OCH 3     H   228       E5   2-OCH 3     4-Cl   5-OCH 3     H   236       E6   2-OCH 3     4-CH 3     5-CH 3     H   171       E7   2-OCH 3     4-CH 3     5-CH 3     H   240       E8   2-OCH 3     3-Cl   6-OCH 3     H   152       E9   2-OCH 3     3-CH 3     6-OCH 3     H   169        E10   2-OCH 3     4-CH 3     5-CH 3     6-OCH 3     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                                                                                                                      m.p.: ° C.       COMPOUND No.   X 1     X 2     X 4     R 1     (hydrochloride)                                            F2   2-OCH 3     4-CH 3     6-OCH 3                           135                F3   2-OCH 3     4-CH 3     6-OCH 3     —CH 2 —C 6 H 5     215        F4   2-OCH 3     4-CH 3     6-OCH 3     —(CH 2 ) 4 —CH 3     143                F5   2-OCH 3     4-CH 3     6-OCH 3                           238                F6   2-OCH 3     4-CH 3     6-OCH 3     —CH 2 CH 2 —CH 6 H 5     200        F7   2-OCH 3     4-CH 3     6-OCH 3     —(CH 2 ) 4 —CH—(CH 2 ) 2     172                F8   2-OCH 3     4-CH 3     6-OCH 3                           187                F9   2-OCH 3     4-CH 3     6-OCH 3                           180               F10   2-OCH 3     4-CH 3     6-OCH 3     —(CH 2 ) 2 —N(CH 2 ) 2     148               F11   2-OCH 3     4-CH 3     6-OCH 3                           190               F12   2-OCH 3     4-CH 3     6-OCH 3     —(CH 2 ) 3 —CH 3     212               F13   2-OCH 3     4-CH 3     6-OCH 3                           198               F14   2-OCH 3     4-CH 3     6-OCH 3                           219               F15   2-OCH 3     4-CH 3     6-OCH 3     —CH 2 —CH—(C 6 H 5 ) 2     132               F16   2-OCH 3     4-CH 3     6-OCH 3                           197               F17   2-OCH 3     4-CH 3     6-OCH 3                           217               F18   2-OCH 3     4-CH 3     6-OCH 3                           208               F19   2-OCH 3     4-CH 3     6-OCH 3                           136               F20   2-OCH 3     4-CH 3     6-OCH 3                           204               F21   2-OCH 3     4-CH 3     6-OCH 3                           202               F22   2-OCH 3     4-CH 3     6-OCH 3                           196               F23   2-OCH 3     4-CH 3     5-OCH 3                           148               F24   2-OCH 3     4-CH 3     5-OCH 3                           192               F25   2-OCH 3     4-CH 3     5-OCH 3                           188               F26   2-OCH 3     4-CH 3     5-OCH 3                           168               F27   2-OCH 3     4-CH 3     6-OCH 3                           189               F28   2-OCH 3     4-CH 3     6-OCH 3                           180               F29   2-OCH 3     4-CH 3     6-OCH 3                           168               F30   2-OCH 3     4-CH 3     6-OCH 3                           188               F31   2-OCH 3     4-CH 3     5-OCH 3                           200               F32   2-OCH 3     4-CH 3     5-OCH 3                           206               F33   2-OCH 3     4-CH 3     6-OCH 3     —CH 2 CH 2 CN   244               F34   2-OCH 3     4-CH 3     5-OCH 3                           218               F35   2-OCH 3     4-Cl   5-OCH 3                           127               F36   2-OCH 3     4-Cl   6-OCH 3                           159               F37   2-OCH 3     3-CH 3     6-OCH 3                           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                                                                                                                      COMPOUND No.                         R 1                           m.p.:° C.                                       G2                                                                     271               G3                                                                     301               G4                                                                     251               G5                                                                     248               G8                                                                     283               G7                                                                     253               G8                                                                     229               G9                                                                     262                G10                                                                     270                G11                                                                     245                G12                                                                     139                G13                                                                     210 (HCl)                G14                                                                     210 (HCl)                G15                                                                     252                G18                                                                     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                                                                                                                      EXAMPLE No.                         R 1     R 4     m.p.: ° C. (salt)                                        3                                               —CH 2 CO 2 CH 3     185                4                                               —CH 2 CO 2 H   226                5                                               —CH 2 CO 2 CH 3     118                6                                               —CH 2 CO 2 H   230                7                                               —CH 2 CH 2 CO 2 CH 3     101                8                         —(CH 2 ) 4 CH 3     —CH 2 CO 2 CH 3     192                9                                               —CH 2 CH 2 CO 2 H   210               10                         —(CH 2 ) 4 CH 3     —CH 2 CO 2 H   205               11                                               —CH 2 CO 2 CH 3     189               12                                               —CH 2 CO 2 H   218               13                                               —CH 2 CO 2 CH 3     138               14                                               —CH 2 CO 2 CH 3     115               15                                               —CH 2 CO 2 CH 3     167               16                                               —CH 2 CO 2 CH 3     180               17                                               —CH 2 CO 2 CH 3     203               18                                               —CH 2 CO 2 CH 3     158               19                                               —CH 2 CO 2 H   217 (HCl)               20                                               —CH 2 CO 2 H   168               21                                               —CH 2 CO 2 H   271               22                                               —CH 2 CO 2 H   181               23                         —(CH 2 ) 3 CH 3     —CH 2 CO 2 CH 3     220               24                                               —CH 2 CO 2 H   220 (HCl)               25                                               —CH 2 CO 2 CH 3     165               26                                               —CH 2 CO 2 H   198               27                                               —CH 2 CO 2 CH 3     132               28                         —(CH 2 ) 3 CH 3     —CH 2 CO 2 H   220               29                                               —CH 2 CO 2 CH 3     144               30                                               —CH 2 CO 2 H   169               31                                               —CH 2 CO 2 H   203 (HCl)               32                                               —CH 2 CO 2 H   180               33                                               —CH 2 CO 2 CH 3     172               34                                               —CH 2 CO 2 H   216               35                                               —CH 2 CO 2 CH 3     128               36                                               —CH 2 CO 2 CH 3     158               37                         —(CH 2 ) 2 CH(CH 3 ) 2     —CH 2 CO 2 H   272               38                         —CH 2 CH(CH 3 ) 2     —CH 2 CO 2 CH 3     206               39                         —CH 2 CH(CH 3 ) 2     —CH 2 CO 2 H   189               40                                               —CH 2 CO 2 H   175               41                                               —CH 2 CO 2 H   158               42                                               —CH 2 CO 2 CH 3     180               43                                               —CH 2 CO 2 CH 3     161               44                                               —CH 2 CO 2 CH 3     210               45                                               —CH 2 CO 2 CH 3     191               46                                               —CH 2 CO 2 H   182               47                                               —CH 2 CO 2 H   195               48                                               —CH 2 CO 2 CH 3     201               49                                               —CH 2 CO 2 CH 3     194               50                                               —CH 2 CO 2 H   204               51                                               —CH 2 CO 2 CH 3     129               52                                               —CH 2 CO 2 H   213               53                                               —CH 2 CO 2 H   182               54                                               —CH 2 CO 2 H   151               55                                               —CH 2 COOCH 3     192               56                                               —CH 2 CO 2 CH 3     173               57                                               —CH 2 CO 2 H   229               58                                               —CH 2 CO 2 H   195               59                                               —CH 2 CO 2 CH 3     133               60                                               —CH 2 CO 2 H   175               61                                               —CH 2 CH 2 CO 2 CH 3     178               62                                               —CH 2 CH 2 CO 2 H   235               63                                               —(CH 2 ) 3 CO 2 C 2 H 5     144               64                                               —(CH 2 ) 3 CO 2 H   141               65                                               —(CH 2 ) 4 CO 2 C 2 H 5      95               66                                               —(CH 2 ) 4 CO 2 C 2 H 5     101               67                                               —(CH 2 ) 4 CO 2 H   266               68                                               —(CH 2 ) 4 CO 2 H   157               69                                               —(CH 2 ) 3 CO 2 C 2 H 5     114               70                                               —(CH 2 ) 3 CO 2 C 2 H 5      76               71                                               —(CH 2 ) 3 CO 2 C 2 H 5      85               72                                               —(CH 2 ) 3 CO 2 H   243               73                                               —(CH 2 ) 3 CO 2 H   138               74                                               —(CH 2 ) 3 CO 2 H   150               75                                               —CH 2 CO 2 CH 3     201               76                                               —CH 2 CO 2 CH 3     162               77                                               —CH 2 COOH   200               78                                               —CH 2 COOH   168 (HCl)               79                                               —CH 2 COOH   211               80                                               —CH 2 COOH   243 (HCl)               81                                               —CH 2 COOH   188 (2HCl)               82                                               —CH 2 COOCH 3     200               83                                               —CH 2 COOCH 3     170               84                                               —CH 2 COOCH 3     137               85                                               —CH 2 COOH   168               86                                               —CH 2 COOCH 3     156                  
 
     [0191]                   TABLE VII                              (I)                                                                                   EXAMPLE No.                         R 1                           m.p.: ° C. (salt)                                                                 87                                                                     145               88                                                                     147               89                                                                     156               90                                                                     221               91                                                                     243               92                                                                     207               93                                                                     196               94                                                                     310 (Na salt)               95                                                                     221               96                                                                     214               97                                                                     202               98                                                                     194               99                                                                     285               100                                                                     194 (Na salt)               101                                                                     132               102                                                                     277 (Na salt)               103                                                                     195               104                                                                     264               105                                                                     266 (Na salt)               106                                                                     161               107                                                                     196               108                                                                     174               109                                                                     190               110                                                                     83               111                                                                     242               112                                                                     223               113                                                                     205               114                                                                     191               115                                                                     154               116                                                                     233               117                                                                     82               118                                                                     257               119                                                                     181               120                                                                     275               121                                                                     132               122                                                                     135               123                                                                     263               124                                                                     250               125                                                                     154               126                                                                     184               127                                                                     207               128                                                                     179               129                                                                     175               130                                                                     188 (Na salt)               131                                                                     235               132                                                                     177               133                                                                     141               134                                                                     108               135                                                                     144               136                                                                     196               137                                                                     249 (Na salt)               138                                                                     176 (Na salt)               139                                                                     198               140                                                                     212               141                                                                     140               142                                                                     159               143                                                                     121               144                                                                     158               145                                                                     220               146                                                                     266 (Na salt)               147                                                                     206 (Na salt)               148                                                                     210 (Na salt)               149                                                                     213               150                                                                     247               151                                                                     183               152                                                                     230 (Na salt)               153                                                                     252 (Na salt)               154                                                                     132               155                                                                     138               156                                                                     188               157                                                                     196               158                                                                     82               159                                                                     215               160                                                                     177               161                                                                     233               162                                                                     131               163                                                                     241               164                                                                     120               165                                                                     145               166                                                                     144 (Na salt)               167                                                                     114               168                                                                     148               169                                                                     202               170                                                                     231 (HCl)               171                                                                     237 (2HCl)               172                                                                     208               173                                                                     231 (2HCl)               174                                                                     268 (Na salt)               175                                                                     195               176                                                                     164               177                                                                     215               178                                                                     232               179                                                                     200 (Na salt)               180                                                                     199               181                                                                     233 (HCl)               182                                                                     101               183                                                                     246 (HCl)               184                                                                     217               185                                                                     108               186                                                                     219               187                                                                     87               188                                                                     263               189                                                                     184 (Na salt)               190                                                                     140               191                                                                     187               192                                                                     208 (HCl)               193                                                                     200 (HCl)               194                                                                     197 (2HCl)               195                                                                     186 (2HCl)               196                                                                     148               197                                                                     136               198                                                                     170               199                                                                     130               200                                                                     282 (Na salt)               201                                                                     101               202                                                                     273 (Na salt)               203                                                                     231               204                                                                     225 (Na salt)               205                                                                     112               206                                                                     108               207                                                                     122               208                                                                     155               209                                                                     162 (Na salt)               210                                                                     225 (Na salt)               211                                                                     130               212                                                                     141               213                                                                     177               214                                                                     126               215                                                                     213               216                                                                     241               217                                                                     257               218                                                                     221 (2HCl)               219                                                                     152               220                                                                     87               221                                                                     182 (2HCl)               222                                                                     168               223                                                                     205               224                                                                     256 (HCl)               225                                                                     198               226                                                                     95               227                                                                     196 (Na salt)               228                                                                     200 (Na salt)               229                                                                     145               230                                                                     258               231                                                                     157               232                                                                     265               233                                                                     157               234                                                                     211 (HCl)               235                                                                     209 (HCl)               236                                                                     222 (2HCl)               237                                                                     240 (HCl)               238                                                                     217               239                                                                     129               240                                                                     138               241                                                                     215 (2HCl)               242                                                                     83               243                                                                     205 (2HCl)               244                                                                     125               245                                                                     94               246                                                                     234               247                                                                     170               248                                                                     143               249                                                                     107               250                                                                     206 (2HCl)               251                                                                     240 (Na salt)               252                                                                     184               253                                                                     238 (Na salt)               254                                                                     122               255                                                                     121               256                                                                     251 (Na salt)               257                                                                     200               258                                                                     151 (2HCl)               259                                                                     241               260                                                                     157               261                                                                     170               262                                                                     191               263                                                                     193               264                                                                     198               265                                                                     163               266                                                                     205               267                                                                     114               268                                                                     223 (HCl)               269                                                                     159               270                                                                     295 (Na salt)               271                                                                     227               272                                                                     102               273                                                                     162               274                                                                     240 (Na salt)               275                                                                     250 (Na salt)               276                                                                     161               277                                                                     177               278                                                                     297 (Na salt)               279                                                                     127               280                                                                     303               281                                                                     111               282                                                                     191               283                                                                     289               284                                                                     273               285                                                                     131 (HCl)               286                                                                     156               287                                                                     160               288                                                                     181               289                                                                     157               290                                                                     140 (Na salt)               291                                                                     174 (Na salt)               292                                                                     170 (Na salt)               293                                                                     247 (Na salt)               294                                                                     220 (Na salt)               295                                                                     151               296                                                                     216 (Na salt)               297                                                                     104               298                                                                     111               299                                                                     159 (Na salt)               300                                                                     218               301                                                                     142               302                                                                     254               303                                                                     240               304                                                                     204 (K salt)               305                                                                     262 (Na salt)               306                                                                     169               307                                                                     103               308                                                                     242               309                                                                     104               310                                                                     235 (HCl)               311                                                                     196               312                                                                     259 (Na salt)               313                                                                     130               314                                                                     92               315                                                                     170               316                                                                     187 (K salt)               317                                                                     260 (Na salt)               318                                                                     132               319                                                                     112               320                                                                     258               321                                                                     188               322                                                                     293               323                                                                     258 2HCl               324                                                                     149               325                                                                     118               326                                                                     97               327                                                                     138               328                                                                     179               329                                                                     189               330                                                                     200               331                                                                     151               332                                                                     119               333                                                                     102               334                                                                     143               335                                                                     135               336                                                                     151               337                                                                     138               338                                                                     195 (HCl)               339                                                                     185               340                                                                     116               341                                                                     98               342                                                                     149               343                                                                     146               344                                                                     273 (HCl)               345                                                                     202               346                                                                     167               347                                                                     279 (Na salt)               348                                                                     80               349                                                                     134               350                                                                     130               351                                                                     122               352                                                                     99               353                                                                     218               354                                                                     96               355                                                                     168               356                                                                     248               357                                                                     196               358                                                                     174 (Na salt)               359                                                                     198               360                                                                     186               361                                                                     233               362                                                                     216 (Na salt)               363                                                                     191 (K salt)               364                                                                     240               365                                                                     198               366                                                                     247 (HCl)               367                                                                     185 (HCl)               368                                                                     165 (Na salt)               369                                                                     175 (K salt)               370                                                                     226               371                                                                     204               372                                                                     74               373                                                                     147               374                                                                     194               375                                                                     199               376                                                                     214 (HCl and Na salt)               377                                                                     147 (HCl and Na salt)               378                                                                     156 (Na salt)               379                                                                     219 (Na salt)               380                                                                     131               381                                                                     148               382                                                                     85               383                                                                     141               384                                                                     161               385                                                                     151               386                                                                     268 (Na salt)               387                                                                     155               388                                                                     195 (Na salt)               389                                                                     214               390                                                                     293 (HCl)               391                                                                     271               392                                                                     177               393                                                                     264 (Na salt)               394                                                                     281 (Na salt)               395                                                                     257 (K salt)               396                                                                     107               397                                                                     124               398                                                                     166               399                                                                     220 (Na salt)               400                                                                     246               401                                                                     202               402                                                                     266 (Na salt)               403                                                                     128               404                                                                     144               405                                                                     224 (Na salt)               406                                                                     158               407                                                                     117               408                                                                     134               409                                                                     185 (HCl)               410                                                                     144 (HCl)               411                                                                     178 (Na salt)               412                                                                     207               413                                                                     191 (Na salt)               414                                                                     228 (2HCl)               415                                                                     203 (2HCl)               416                                                                     290 (Na salt)               417                                                                     257 (K salt)               418                                                                     228               419                                                                     217               420                                                                     168               421                                                                     113               422                                                                     201 (HCl)               423                                                                     146 (HCl)               424                                                                     198 (HCl)               425                                                                     167               426                                                                     244 (Na salt)               427                                                                     245 (K salt)               428                                                                     151               429                                                                     157               430                                                                     205               431                                                                     248 (Na salt)               432                                                                     240 (Na salt)               433                                                                     144 (Na salt)               434                                                                     220 (Na salt)               435                                                                     108               436                                                                     77               437                                                                     270 (HCl)               438                                                                     278 (HCl)               439                                                                     179 (Na salt)               440                                                                     167 (HCl)               441                                                                     164               442                                                                     150 (Na salt)               443                                                                     113               444                                                                     185               445                                                                     209               446                                                                     295 (Na salt)               447                                                                     221 (Na salt)               448                                                                     190               449                                                                     246               450                                                                     196               451                                                                     139               452                                                                     109               453                                                                     217 (Na salt)               454                                                                     245               455                                                                     238 (Na salt)               456                                                                     173               457                                                                     169               458                                                                     164 (HCl)               459                                                                     116               460                                                                     243               461                                                                     159               462                                                                     227               463                                                                     150               464                                                                     208 (HCl)               465                                                                     254               466                                                                     108               467                                                                     91               468                                                                     139               469                                                                     265 (Na salt)               470                                                                     188               471                                                                     190 (HCl)               472                                                                     243 (HCl)               473                                                                     98               474                                                                     86               475                                                                     275               476                                                                     175               477                                                                     205               478                                                                     132               479                                                                     83               480                                                                     97               481                                                                     82               482                                                                     274 (Na salt)               483                                                                     271               484                                                                     237 (HCl)               485                                                                     144 (HCl)               486                                                                     228 (HCl and Na salt)               487                                                                     168 (Na salt)               488                                                                     138               489                                                                     124               490                                                                     138               491                                                                     224               492                                                                     197               493                                                                     210 (Na salt)               494                                                                     274 (Li salt)               495                                                                     99               496                                                                     248               497                                                                     &gt;300 (Na salt)               498                                                                     148 (K salt)               499                                                                     226 (Na salt)               500                                                                     139 (K salt)               501                                                                     190 (Na salt)               502                                                                     237 (K salt)               503                                                                     230 (K salt)               504                                                                     208               505                                                                     202 (K salt)               506                                                                     109               507                                                                     181 (K salt)               508                                                                     117               509                                                                     225 (K salt)               510                                                                     178               511                                                                     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.