HRP980258A2 - New triazole derivatives, process for the preparation thereof and pharmaceutical preparations containing them - Google Patents

Description

The described invention relates to new triazole derivatives, to the process for their preparation and to medications containing them.

More precisely, the described invention has for its object new compounds, which are not similar to peptides, as cholecystokinin (CCK) receptors.

CCK is a peptide that is secreted at the peripheral level in response to the introduction of food into the stomach, and takes part in the regulation of numerous digestive processes. (J.N., et al.: "Peptides", 15 (4), 731-735, (1994)).

CCK was identified through brain tracing, and may be the neuropeptide most active as a neuromodulator of cerebral functions through stimulation of CCK-B type receptors (Crawley J. N, et al.: "Peptides", 15 (4), 731-735 , (1994)). In the central nervous system, CCK interacts with the transmission neuronal medium via dopamine (Crawley J.N.W., et al.: "ISIS Atlas of Sci., Pharmac", 84-90, (1988)). CCK intervenes equally in mechanisms involving acetylcholine, 4-aminobutyric acid (gaba), serotonin, opiates, somatostatin, and substance P at the ionic level.

Its application causes physiological modifications, for example palpebral ptosis, hypotemia, hyperglycemia, catalepsy, and behavioral modifications, for example hypolocomotoricity, reduction of exploration, analgesia, modification of learning ability, modification of the carrier of sexuality and satiety.

CCK shows its biological activity through the intermediary of two types of receptors: CCK-A receptors, which are localized mainly in the periphery, and CCK-B receptors, which are present mainly in the cerebral cortex. CCK-A receptors of the peripheral type are also present in certain areas of the central nervous system including the area of the nucleus, the center of the solitary tract and the interpeduncular center (Moran T. H., et al.: "Brain Research", 362, 175-179, (1986); Hill D. R., et al.: "J. Neurosci", 10, 1070-1081, (1990), with corresponding differences depending on the type of recipient (Hill D.R., et al.: "J. Neurosci", 10, 1070 -1081, (1990)); Mailleux P., et al.: "Neurosci Lett.", 117, 243-247, (1990); Baret R. W., et al.: "Mol. Pharmacol.", 36, 285-290, (1989); Mercer J. G., et al.: "Neurosci Lett.", 137, 229-231, (1992); Moran T. H., et al.: "Trends in Pharmocol. Sci.", 12 , 232-236, (1991)).

In the periphery, through the intermediary of the CCK-A receptor (Moran T.H., et al.: "Brain Research", 362, 175-179, (1986)), CCK retards gastric emptying, modulates intestinal motility, stimulates vesicular contraction, increases bile secretion , controls pancreatic secretion (McHugh P. R., et al.: "Fed. Proc.", 45, 1384-1390, (1986); Pendleton R. G., et al.: "J. Pharmocol. Exp. Ther.", 241, 110-116, (1987)).

In certain cases, CCK can affect arterial pressure and affect the immune system.

The role of CCK in the satiety signal was confirmed through its action by the fact that the plasmatic concentrations of CCK, which depend on the composition of the meal (high concentrations of proteins or lipids), were higher after the meal than those observed before the meal (Izzo R. S., et al.: "Regul Pept.", 9, 21-34, 1984); Pfeiffer A, et al.: "Eur. J. Clin. Invest.", 23, 57-62, (1993); Lieverse R. J.: "Gut", 35, 501, (1994)). In bulimia, there is a decrease in CCK secretion that is induced with a meal (Geraciotti T. D. Jr., et al.: "N. Engl. J. Med.", 319, 683-688, (1988); Devlin M. J., et al. : "Am. J. Clin. Nutr.", 65, 114-120, (1997)) and decreasing CCK concentrations in the cerebrospinal fluid (Lydiard R. B, et al.: "Am. J. Psychiatry", 150, 1099-1101, (1993)). In T lymphocytes, one cell part can reject central neuronal secretions, and therefore the basal concentrations for CCK are significantly lower in patients suffering from Bulimia nervosa (Brambilla F., et al.: "Psychiatry Research", 37, 51-56, (1995)).

Treatments (for example with L-phenylalanine or trypsin inhibitors) that increase the secretion of endogenous CCK cause a decrease in food intake in several domestic species (domestic animals) (Hill A. J., et al.: "Physiol. Behav.", 48, 241-246 , (1990); Ballinger A.B., et al.: "Metobolism" 43, 735-738, (1994)). Likewise, administration of exogenous CCK reduces feed intake in a number of domestic species (Crawley J.N., et al.: "Peptides" 15, 731-755, (1994)).

Inhibition of feed intake by CCK is induced via the CCK-A receptor. Indeed, devazepide, a selective CCK-A receptor antagonist, inhibits the anorexigenic effect for CCK when selective agonists of these receptors inhibit feed intake (Asin K. E., et al.: "Pharmacol. Biochem. Behav.", 42, 699-704, (1992 .); Elliott R.L., et al.: "J. Med. Chem.", 37, 309-313, (1994); Elliott R. L., et al.: "J. Med. Chem.", 37, 1562- 1568, (1994)). Even more, OFLET rats, which do not express the CCK-A receptor, were insensitive to the anorexigenic effect of CCK (Miyasaka K., et al., 180, 143-146, (1994)).

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

CCK-A receptor agonists for CCK have been described in the literature. For example, certain products possessing such properties are described in EP 383690, WO 90/06937, WO 95/28419, WO 96/11701, and WO 96/11940.

Most of the CCK-A agonists described to date are peptide in nature. Thus, FPL 14294 describes a CCK-7 derivative that is a potent agonist for CCK-A non-selective vis-a-vis the CCK-B receptor. This derivative possesses potent inhibitory activity of food intake in rats and dogs after intranasal administration (Simmons R.D., et al.: "Pharmacol. Biochem. Behav.", 47 (3), 701-708, (1994); Kaiser E. F., et al.: "Faseb", 5, A864, (1991)). Likewise, it has been shown that A-71623, a tetrapeptide selective agonist for CCK-A receptors, is effective in an anorexic model over a period of 11 days and causes a significant reduction in the weight of food intake compared to control animals in rodents and cynomolgus monkeys (Asin K.E., and dr.: "Pharmacol. Biochem. Behav.", 42, 699-704, (1992)). Similarly, structural analogs of A 71623, which possess good efficacy and selectivity for CCK-A receptors, had potent anorexigenic activity in rats (Elliott R.L., et al.: "J. Med. Chem.", 37, 309-313 , (1994); Elliott R.L., et al.: "J. Med. Chem.", 37, 1562-1568, (1994)). According to GW 7854 (Hirst G. C., et al.: "J. Med. Chem.", 39, 5236-5245, (1996)), benzodiazepine-1,5 is an in vitro agonist of the CCK-A receptor. This molecule administered orally is equally active on gallbladder contractions in mice and food intake in rats.

Now, remarkably, a series of triazole derivatives have been found to possess partial or complete agonistic activity at CCK-A receptors.

The compounds according to the described invention are the object of systematic studies aimed at characterizing:

- their ability to replace [125I]-CCK of their binding sites which is present on pancreatic membranes in rats (CCK-A receptor) or 3T3 cells expressing human recombinant CCK-A receptor;

- of their affinity vis-a-vis the CCK-B receptor that is present on the membranes of the guinea pig cortex, certain compounds are selective ligands or not of the CCK-A receptor;

- their agonist properties for CCK-A receptors through their capacity to induce in vitro mobilization of intracellular calcium in 3T3 cells expressing the human CCK-A receptor.

The triazole derivatives, according to the described invention, are CCK-A agonists since they are able to partially or completely stimulate, as CCK does, the mobilization of intracellular calcium in a cell line expressing the human recombinant CCK-A receptor. These derivatives are remarkably much more potent than the derivatives, for example thiazoles described in patent applications EP 518731, EP 611766, thiadiazoles described in patent EP 620221, and benzodiazepines described in patent EP 667344.

Indeed, these thiazole, thiazole and benzodiazepine derivatives are unsuitable for the induction of this CCK-A receptor-mediated mobilization of intracellular calcium.

The thiazole derivatives of the present invention are also much more potent than these thiazole, thiadiazole or benzothiazepine derivatives in their in vivo blocking capacity when administered intraperitoneally to mice suffering from gastritis.

Therefore, the agonistic properties of CCK-A were studied in vivo, in order to examine their capacity to block the onset of gastritis in mice or induce, always in vivo, the onset of gallbladder swelling in mice.

Certain derivatives also have CCK-B receptor antagonistic activity.

Therefore, the described invention relates to compounds of the formula:

[image]

where

R1 represents a (C2-C6) alkyl radical, the group -(CH2)n-G, where n ranges from 0 to 5, and G represents a non-aromatic mono- or polycyclic hydrocarbon group containing C3-C13 carbon atoms, which is optionally substituted with one or multiple (C1-C3) alkyl radicals; phenyl (C1-C3) alkyl group, where the phenyl group is optionally substituted with one or more halogens, with (C1-C3) alkyl or (C1-C3) alkoxy radical; the group -(CH2)nNR2R3, where n represents an integer between 1 and 6, and R2 and R3 identical or different each represent a (C1-C3) alkyl radical, or form with a nitrogen atom to which morpholino, piperidino, pyrrolidinyl or piperazinyl are attached group;

X 1 , X 2 , X 3 , or X 4 each independently represents a hydrogen atom, a halogen atom, a (C 1 -C 6 ) alkyl radical, (C 1 -C 6 ) alkoxy, or trifluoromethyl, where only one of X 1 , X 2 , X 3 , or X 4 can be expected to represent possibly a hydrogen atom;

R 4 represents hydrogen, the group -(CH 2 )nCOOR 5 , where n is as defined above, and R 5 represents a hydrogen atom, a radical (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl-(C 1 -C 6 )alkyl; radical (C1-C6) alkyl; the group (CH2)nOR5, or the group (CH2)nNR2R3, where n, R2, R3 and R5 are as defined above, the group (CH2)n-tetrazolyl, where n is as defined above, or

R 4 represents one of these groups in the form of an alkali metal salt or an alkaline earth metal salt;

Y1, Y2 and Y3 each independently represent a hydrogen atom, a halogen atom, a radical (C1-C3) alkyl, (C1-C3) alkoxy, nitro, cyano, (C1-C6) alkylamino, carbamoyl, trifluoromethyl, a COOR6 group, where R6 represents a hydrogen atom or a (C1-C3) alkyl radical;

or to one of its salts or solvates.

According to the described invention, the radical "(C1-C6) alkyl" or "(C2-C6) alkyl" means a normal or branched alkyl radical comprising from 1 to 6, or respectively from 2 to 6 carbon atoms.

"Alkoxy" radical means an alkyloxy radical wherein the alkyl radical is as defined above.

The radical "acyl" means an alkylcarbonyl radical wherein the alkyl radical is as defined above.

"(C1-C6) acylamino" is an alkyl carbonyl amino radical comprising C1-C6 carbon atoms.

Hydrocarbon non-aromatic groups containing C3-C13 include mono- or poly-cyclic radicals, condensed or bridged, saturated or unsaturated, which are possibly turpentine. These radicals are optionally mono- or poly-substituted with the (C1-C3) alkyl radical. Monocyclic radicals include cycloalkyls, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl. Polycyclic radicals include, for example, normornane, adamantane, hexahydroindane, norbornene, dihydrophenalene, bicyclo[2,2,1]heptane, bicyclo[3,3,1]nonane; tricyclo[5,2,1,02,6]decane.

According to the described invention, "halogen" means an atom selected from the group consisting of fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

Examples of aryl groups are phenyl and naphthyl.

Cations of alkali and alkaline earth metals are preferably chosen from sodium, potassium or calcium.

As the compounds according to the invention possess one or more asymmetric carbons, all optical isomers of these compounds form an integral part of the described invention.

Since the compounds according to the invention have stereoisomerism, for example of the axial-equatorial type, the invention covers all stereoisomers of these compounds.

Salts of compounds of formula (I) according to the described invention include salts with mineral and salts with organic acids that allow separation or suitable crystallization of compounds of formula (I). Such acids are picric acid, oxalic acid or an optically active acid, for example tartaric acid, dibenzoyltartaric acid, mandelic acid or camphosulfonic acid, and those which form physiologically acceptable salts, such as hydrochloride, hydrobromide, sulphate, bisulphate, biphosphate, amleate , fumarate, 2-naphthalenesulfonate, and paratoluenesulfonate.

Salts of the compounds of formula (I) also include salts with organic or inorganic bases, for example salts with alkali metals or salts with alkaline earth metals, such as sodium, potassium, calcium, sodium and potassium salts, or salts with an amine such as which is trometamol, as well as salts with arginine, lysine or other physiologically acceptable amine.

Functional groups that are possibly present in the molecule of the compound of formula (I) and in the reaction intermediates can be protected, say in a permanent form or in a temporary form, with protective groups that can ensure the synthesis of the desired compound.

Temporary protecting groups for amines, alcohols or carboxylic acids are understood to be protecting groups such as those described by Greene T.W. and Wuts P.G.M:. in "Protective Groups in Organic Synthesis", published by John Wiley & Sons, (1991), and in Kocienski P. J: "Protecting Groups", published by Georg Thieme Verlag, (1994).

Compounds of formula (I) may contain precursor groups of other functionalities, which are formed later in one or more different stages.

Compounds of formula (I) in which R1 represents cyclohexyl (C1-C3) alkyl are preferred compounds.

Also preferred are compounds of formula (I) in which the phenyl in the 5-position of the triazole is tri-substituted, preferably with methoxy in the 2- and 6-position, and with methyl in the 4-position.

Even more preferred are compounds of formula (I) in which the phenyl in the 5-position of the thiazole is tri-substituted with methoxy in the 2- and 5-position, and with methyl or chlorine in the 4-position.

Compounds of formula (I.1) are particularly preferred:

[image]

wherein R 1 , R 4 , X 1 , X 2 , X 3 and X 4 are as defined for formula (I), salts thereof or solvates thereof.

Among these compounds, those in which

[image]

represents 2,6-dimethoxy-4-methylphenyl.

Compounds of formula (I.2) are even more preferable:

[image]

where R 1 and R 4 are as defined for compounds of formula (I), salts thereof or solvates thereof.

The most preferred are the compounds of formula (I.3):

[image]

where R 1 , R 4 , X 1 , Y 1 , Y 2 and Y 3 are as defined for formula (I) and X 2 represents methyl or a chlorine atom; their salts or their solvates.

The described invention also has for its object a process for obtaining compounds of formula (I), which includes the reaction of aminotriazole of formula 7:

[image]

wherein R 1 , X 1 , X 2 , X 3 and X 4 are as defined for formula (I);

* say with an indole derivative of a carboxylic acid of formula 8: ;[image] ;wherein R 4 , Y 1 , Y 2 and Y 3 are as defined hereinabove for formula (I); ;* let's say with the indole derivative of the carboxylic acid of formula 8':

[image]

wherein Y1, Y2 and Y3 are as defined hereinabove for formula (I) and R'4 is a precursor group for R4 in which case an intermediate compound of formula (I') is formed:

[image]

where R 1 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 and Y 3 are as defined for formula (I) and R' 4 is a precursor group for R 4 , wherein R 4 is as defined for formula ( AND);

in order to obtain compounds of formula (I), their salts or their solvates.

Intermediate compounds (I') lead to compounds of formula (I) through the transformation of the group R'4 into R4, which is carried out in a known manner according to the usual procedures in organic chemistry.

Aminotriazoles of formula 7 form key intermediates, which are new, and which are applicable for obtaining compounds of formula (I), and therefore also represent the object of the described invention.

The starting products are available commercially or can be obtained by the procedures described hereinbelow.

Scheme 1 which follows illustrates the synthetic route for compounds of formula 7.

Scheme 2 which follows illustrates the preparation of compounds of formula (I) starting from aminotriazoles of formula 7.

Scheme 1: Preparation of substituted 3-aminotriazoles of formula 7

[image]

Scheme 2: Preparation of 3-aminotriazole of formula (I)

[image]

When R4 is the group -(CH2)nCOOH, the compounds of formula (I) are obtained starting from the corresponding esters according to scheme 2.

When R4 is the group -(CH2)n-tetrazolyl, the compounds of formula (I) are obtained starting from the corresponding nitriles of the formula:

[image]

in which R'4 is -(CH2)n-C=N,

under the action of azidotrimethylsilane in the presence of dibutyltin oxide, according to the procedure described in "J. Org. Chem.", 58, 4139-4141, (1993).

Compounds of formula (I') are obtained according to scheme 2, starting from compound of formula 7 and compound of formula 8':

[image]

wherein R'4 is -(CH2)n-C=N.

Substituted benzoic acids are commercially available or obtained by adaptation of procedures described in the literature, for example:

1) by regioselective lithiation of substituted benzenes, which is further followed by carboxylation of the lithiated derivative with CO2, according to scheme 3 which follows:

Scheme 3

[image]

with Z1=Br or H following the nature and/or position of the substituents X1, X2, X3, X4 according to: N. S. Narasimhan, et al.: "Indian J. Chem.", 11, 1192, (1973); R. C. Cambie, et al.: "Austr. J. Chem.", 44, 1465, (1994); T. de Paulis, et al.: "J. Med. Chem.", 29, 61, (1986); or also

2) by means of the regioselective formulation of substituted benzenes, which follows the oxidation of substituted benzaldehyde by KMnO4, according to scheme 4 given here below:

Scheme 4

[image]

according to the procedure described by S. B. Matin, et al.: "J. Med. Chem.", 17, 877, (1974); or also

3) by haloform oxidation according to R. Levine, et al.: "J. Am. Chem. Soc.", 72, 1642, (1959) of aromatic methyl ketones obtained by Friedal-Crafts acylation of substituted benzenes (C. A. Bartram , et al.: "J. Chem. Soc.", 4691, (1963)), or also by the Fries displacement of substituted acyloxybenzenes according to S. E. Cremer, et al.: "J. Org. Chem.", 26, 3653, (1961), according to schemes 5 and 6 given below:

Scheme 5

[image]

Acids substituted in the 2-position with methoxy can be obtained starting from the phenol-substituted derivative by the reaction of acetic anhydride in pyridine, which is followed by a Fries reaction in the presence of aluminum chloride to give acetophenone, which is then reacted with methyl iodide in an alkaline medium to give the final by the haloform reaction of the expected acid of formula 1' according to scheme 6, which is given here below:

Scheme 6

[image]

Benzamidoguanidine of formula 2 is obtained by acylation of aminoguanidine bicarbonate using benzoic acid chloride, which was obtained starting from benzoic acid of formula 1 according to classical procedures (SOCl2, oxalyl chloride in an inert solvent) according to the adaptation of the procedure described by E. Hoggarth: "J. Chem. Soc., 612, (1950).

It can also be obtained according to the variant described in this same publication according to scheme 7 which follows:

Scheme 7

[image]

Thermal cyclization of benzamidoguanidine of formula 2 in a high-boiling solvent such as diphenyl ether gives the aryl-5-amine-3-triazole of formula 3 according to an adaptation of the procedure described by E. Hoggarth: "J. Chem. Soc.", 612, (1950).

Protection of the primary amine function of the triazole of formula 3 in the diphenylamine form gives the N-protected triazole, according to an adaptation of the procedure described by M. J. O'Donnell, et al.: "J. Org. Chem.", 47, 2663, (1982).

The compound of formula 4 can also be obtained according to one variant which consists in treating the triazole of formula 3, which has previously been transformed into the hydrochloride of formula 3', with diphenylamine according to scheme 8 given here below:

Scheme 8

[image]

N-Alkylation of a diphenyliminotriazole of formula 4 with an alkyl halide R1X under phase transfer conditions (strong base in concentrated aqueous solution, in the presence of a water-immiscible organic cosolvent and quaternary ammonium as a catalyst) affords very abundant triazoles of formula 5, together with very little triazole of formula 6. Aqueous solutions of NaOH or KOH concentration from 6M to 12M can be used as strong bases. The co-solvent can be toluene, benzene and quaternary ammonium, where all quaternary ammonium salts are preferred, especially TBAB (tetrabutylammonium bromide).

a) The N-alkylation of the diphenyliminotriazole of formula 4 can be carried out in a non-aqueous medium (for example dimethylformamide, tetrahydrofuran) in the presence of a strong base, such as K 2 CO 3 or NaH.

b) Another variant can also be used, such as the one described by: "Acta Chem. Scand.", 19, 1142, (1965), in which an alkylating agent is used in an alcohol such as ethanol, in in the presence of a solid strong base such as KOH or NaOH.

The triazole of formula 5 is very easily separated from its isomer of formula 6 by chromatography on a silica column or by pulse chromatography, depending on the nature of the R1 group.

The dissolution of the product of example 5, which was obtained after the separation of its minor isomer, is carried out in an acidic aqueous medium such as 1N HCl, following the adaptation of the procedure described by J. Yaozhong, et al.: "Tetrahedron", 44, 5343, ( 1988), or M.J. O'Donnell, et al.: "J. Org. Chem.", 47, 2663, (1982). This makes it possible to obtain amino-3-triazole N-alkylated in the position of formula 7.

Carboxylic indoles of formula 8 are obtained according to the procedures described in patent no. EP 611766, according to scheme 9 given here below:

Scheme 9

[image]

Carboxylic indoles of formula 8' in which R'4 is -(CH2)n-C=N are obtained according to a procedure analogous to the procedure shown in scheme 9 bis, which is given here below:

Scheme 9 bis

[image]

Indoles of formula 11 are commercially available or are obtained by adaptation of procedures described in the literature, for example by L. Henn, et al.: "J. Chem. Soc. Perkin Trans. I", 2189, (1984), according to scheme 10 which is given here below:

Scheme 10

[image]

or even for example, according to Fisher's synthesis (V. Prelog, et al.: "Helv. Chim. Acta.", 31, 1178, (1948)) according to scheme 11 given here below.

Scheme 11

[image]

or still according to the Japp-Klingemann synthesis (H. Ishii, et al.: "J. Chem. Soc. Perkin. Trans. 1", 2407, (1989)), according to Scheme 12 given here below:

Scheme 12

[image]

Compounds of formula (I) also include all those compounds in which one or more hydrogen atoms, halogen atoms, mainly chlorine or fluorine, have been replaced by their radioactive isotopes, for example tritium or carbon-14. Such labeled compounds are used in metabolic or pharmacokinetic research, and in biochemical assays as receptor ligands.

Compounds of formula (I) are the subject of in vitro binding to CCK-A and CCK-B receptors using the procedure described in "Europ. J. Pharmacol.", 232, 13-19, (1993).

Agonistic activity of the compounds vis-a-vis the CCK-A receptor was determined in vitro in 3T3 cells expressing the human CCK-A receptor, by measuring the mobilization of intracellular calcium ([Ca++]i), according to the technique developed by Lignon MF, et al. : "J. Pharmacol.", 245, 241-245, (1993). The concentration of [Ca++]i was determined with Fura-2 according to the procedure of double long-term pulse excitation. The value of the fluorescence emission of two long-term pulses gives the concentration of [Ca++]i after calibration (Grynkiewiez G., et al.: "J. Biol. Chem.", 260, 344-3450, (1985)).

The compounds according to the invention stimulate [Ca++]i partially or completely like CCK, i.e. they act as CCK-A receptor agonists.

The study of the agonistic effect of the compounds on gastric damage was performed as follows. Female Swiss albino CD1 mice (20-25 g) were kept without food for 18 hours. On the day of the experiment, the products (suspension in 1% carboxy methyl cellulose solution or 0.6% methyl cellulose solution) or the appropriate vehicle, are applied intraperitoneally for 30 minutes before the administration of the carbon meal (0.3 ml per mouse suspension in water, and 10% carbon powder, 5% gum arabic and 1% carboxy methyl cellulose) or are administered orally 1 hour before the mentioned meal. Mice were killed 5 minutes later by neck screwing, and gastric damage was defined as the presence of carbon in the gut beyond the pyloric sphincter ("Europ. J. Pharmacol.", 232, 13-19, (1993)). Compounds of formula (I) block gastric damage partially or completely like CCK, i.e. they act as CCK receptor agonists. Some of these compounds have a DE50 (dose efficiency causing 50% CCK effect) of less than 0.1 mg/kg when administered intraperitoneally.

The study of the agonistic effect of the compounds on the contraction of the gallbladder was performed as follows. Female Swiss albino CD1 mice (20-25 g) were kept without food for 24 hours. On the day of the experiment, the products (suspension in a 1% solution of carboxy methyl cellulose or a 0.6% solution of methyl cellulose) or a suitable carrier are administered orally. The mice were killed 1 hour after the application of the product, and the gall bladders were removed and measured. Results are expressed as mg/kg body weight ("Europ. J. Pharmacol.", 232, 13-19, (1993)).

Compounds of formula (I) contract the gallbladder partially or completely like CCK, i.e. they act as CCK receptor agonists. Some of these compounds have a DE50 (dose efficacy causing 50% reduction in bladder mass observed with CCK) of less than 0.1 mg/kg when administered orally.

Therefore, the compounds of formula (I) were used as CCK type A receptor agonists to obtain medicines intended for the treatment of diseases whose treatment requires stimulation through full or partial agonism of the CCK A cholecystokinin receptor. More precisely, the compounds of formula (I) were used for the production of medicines intended for the treatment of certain disorders of the gastrointestinal sphere (prevention of gallstones, irritable bowel syndrome), resistance to food, obesity, and related pathologies such as diabetes and hypertension. The compounds of formula (I) induce a state of satiety, and are therefore applicable for treating disorders of food intake, regulating appetite and reducing food intake, for treating bulimia and obesity, and for inducing body weight loss. The compounds of formula (I) are also applicable in problems including emotional, sexual and amnesia problems, in psychoses and mainly schizophrenia, in Parkinson's disease and tardive dyskinesia. These compounds can also be used in the treatment of desire disorders, which means to regulate the desire for consumption, especially for the consumption of sweets, carbohydrates, alcohol or drugs, and sweet ingredients in general.

The compounds of formula (I) are very slightly toxic, and their toxicity is compatible with their use as medicines for the treatment of the disorders and diseases listed above.

No sign of poisoning has been observed with these compounds at doses that are pharmacologically active, ie their toxicity is therefore compatible with their medical use as drugs.

The described invention also has for its object pharmaceutical preparations containing an effective dose of the compounds according to the invention or its pharmaceutically acceptable salts and usual excipients. The mentioned excipients are chosen according to the pharmaceutical form and method of desired application.

In the pharmaceutical preparations of the described invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular administration, the active principles of formula (I) as above or their eventual salts can be used in single administration forms, in a mixture with conventional pharmaceutical carriers in humans and other animals for the prophylaxis or treatment of the disorders and diseases listed above. Suitable forms for single administration include oral forms such as tablets, gels, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal, subcutaneous, intramuscular or intravenous forms and forms for rectal application. For topical application, preparations according to the invention can be used in the form of creams, pomades, lotions or salves.

Finally, in order to achieve the desired prophylactic or therapeutic effect, the dose of the active principle can vary between 0.01 and 50 mg per kilogram of body weight per day.

Each individual dose may contain from 0.5 to 1000 mg, preferably from 1 to 500 mg of active ingredients in combination with a pharmaceutical carrier. This single dose can be administered 1 to 5 times during the day in such a way that the daily dose is from 0.5 to 5000 mg, preferably from 1 to 2500 mg.

In order to obtain a solid preparation in the form of tablets, the component active principle is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or their analogues. Tablets can be wrapped with sucrose, cellulose derivative or other suitable substances, or they can be treated in such a way that they acquire extended or delayed activity, and that they can continuously release a predetermined amount of active principle.

When preparing preparations in gels, the active ingredient is mixed with a diluent, and the resulting mixture is poured into soft or hard gels.

A preparation in the form of a syrup or elixir, or a preparation for use in the form of drops, may contain an active ingredient together with a sweetener, preferably with a non-caloric one, methylparaben or propylparaben as an antiseptic, as well as an agent that gives taste or an appropriate color. Powders or granules which are dispersible in water may contain the active ingredient in admixture with dispersing agents or wetting agents, or with suspension forming agents, such as polyvinyl pyrrolidone, as well as with sweeteners or flavor correctors.

For rectal administration, suppositories are prepared that are obtained with a binding material that melts at rectal temperature, for example with cocoa butter or with polyethylene glycols. For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile solutions and injectable solutions containing dispersing agents and/or wetting agents that are pharmacologically compatible, for example propylene glycol or butylene glycol, are used.

The active principle can also be formulated in the form of microcapsules, possibly with more carriers or additives as well as with matrices such as polymer or cyclodextrin (adhesive additive, extended release forms).

The preparations according to the invention can be used in the treatment or prevention of various conditions where CCK is therapeutically useful.

The preparations of the described invention can contain, in addition to the products of formula (I) or their pharmaceutically acceptable salts, other active principles that can be used in the treatment of the aforementioned disorders or diseases.

Suitably, the preparations of the described invention contain a product of the formula (I.1), (I.2) or (I.3) described above, or their salts, solvates or hydrates which are pharmaceutically acceptable.

OBTAINING INTERMEDIATES OF SYNTHESIS

A. OBTAINING ACIDS 1 (Variants)

2,5-dimethoxy-4-methylbenzoic acid (Compound A.1)

a) 2,5-dimethoxy-4-methylbenzaldehyde

After mixing 8.5 ml of N-methylformanilide (0.068 mol) and 6.3 ml of phosphorus oxide trichloride (0.068 mol) at room temperature for 40 minutes, 17.8 g of 2,5-dimethoxytoluene (0.117 mol) was introduced into this mixture. The reaction mixture is heated for 6 hours at 50 °C, after which it is allowed to reach a temperature of 20 °C, after which it is hydrolyzed using 100 ml of 10% aqueous sodium acetate solution, extracted twice in diethyl ether and concentrated. The residue is taken up with aqueous sodium bisulfite and extracted twice with diethyl ether. The aqueous phase was made alkaline (pH = 12) to obtain white crystals; T.t. = 83 °C; yield = 67%.

b) 2,5-dimethoxy-4-methylbenzoic acid

23.86 g (0.132 mol) of 2,5-dimethoxy-4-methylbenzaldehyde as a solution in 500 ml of water are heated to 75 °C, and then 29.3 g (0.185 mol) of potassium permanganate are introduced as a solution in 500 ml of water. . The reaction mixture is left for 2 hours at 75 °C, and then the undissolved part is removed when warm. After that, the pH of the mixture is adjusted to 10 using a 10% aqueous sodium hydroxide solution and washed three times with 80 ml of warm water each. The filtrate is cooled, and the formed precipitate is filtered and dried under vacuum at 40 °C to obtain white crystals; T.t. = 120 °C; yield = 71%.

2,5-dimethoxy-4-chlorobenzoic acid (Compound A.2)

a) (2,5-dimethoxy-4-chlorophenyl)methylketone

162.5 g of aluminum trichloride (1.2 mol) is added to 2 liters of carbon tetrachloride at room temperature, after which 82 ml of acetyl chloride (1.2 mol) is added drop by drop at a temperature of 0 °C, and then 200 g of 1,4-dimethoxy-2-chlorobenzene (1.2 mol). The reaction mixture is left for 3.5 hours at 0 °C and then hydrolyzed with 700 ml of water. The organic phase is washed with 2M sodium hydroxide solution, dried over anhydrous sodium sulfate and concentrated. The semi-crystalline residue is taken up in petroleum ether, filtered and dried to obtain white crystals; T.t. = 96 °C; yield = 70%.

b) 2,5-dimethoxy-4-chlorobenzoic acid

Add 278 g of potassium hydroxide (4.96 mol) to 800 ml of water, then add 84 ml of bromine (1.6 mol) drop by drop at 5 °C. The reaction mixture is left for 1 hour at room temperature. The resulting aqueous solution of sodium hypobromite was added to 107 g of (2,5-dimethoxy-4-chlorophenyl)methylketone (0.494 mol) as a solution in 1.5 liters of 1,4-dioxane. After 1 hour at 20 °C, the reaction mixture is heated for 1 hour at reflux. at the end of the reaction, 100 ml of sodium bisulfite aqueous solution is introduced, then the solvent is evaporated. The residue is acidified with 6N hydrochloric acid solution, after which it is extracted twice in ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is concentrated in diisopropyl ether to give white crystals; T.t. = 160 °C; yield = 91%.

2,6-dimethoxy-4-methylphenylbenzoic acid (Compound A.3)

231.6 g (1.5 mol) of 3,5-dimethoxytoluene are dissolved in 1 liter of diethyl ether, and then 1 liter of a 1.6 N solution in hexane of butyllithium (1.6 mol) is added dropwise under nitrogen at room temperature. The reaction mixture is left for 18 hours at room temperature, after which it is cooled to -30 °C, 1 liter of diethyl ether is added and carbon dioxide is bubbled for 1 hour while maintaining the temperature at -30 °C. The reaction mixture is taken with 6 liters of 2M aqueous sodium hydroxide solution, the aqueous phase is decanted and acidified with a 6N hydrochloric acid solution. The formed precipitate is filtered, washed in water and dried under vacuum at 40 °C to obtain white crystals; T.t. = 187 °C; yield = 88%.

B. PREPARATION OF SUBSTITUTED INDOLES AND THEIR VARIANTS

Preparation of ethyl 5-methyl-1-H-2-indole carboxylate (Compound B.1)

First procedure (Japp-Klingemann procedure):

At -5 °C, 7.2 g (0.104 mol) of sodium nitrite in the form of a solution in 40 ml of water is added 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 was stirred for 15 minutes at -5 °C and then neutralized by adding 8.1 g of sodium acetate. 12.33 g (0.085 mol) of ethyl �-methylacetoacetate, 80 ml of ethanol are introduced into the tricol, and then 4.8 g (0.085 mol) of potassium hydroxide in the form of a solution in 20 ml of water and 100 g of ice are added at 0 °C. . The diazonium solution obtained previously was added drop by drop to this reaction mixture at 0 °C and left for 18 hours at 0 °C. The aqueous phase is extracted 4 times with 50 ml of ethyl acetate each, the organic phases are separated and dried over anhydrous sodium sulfate. The residue is taken with 100 ml of toluene and 16.3 g (0.085 mol) of toluene sulfonic acid para monohydrate. It is then gently heated to 110 °C and further maintained at this temperature for 5 hours. After cooling, saturated sodium carbonate solution is added, the undissolved portion is discarded by filtration, and the organic phase is decanted, dried over anhydrous sodium sulfate, and concentrated. The residue is chromatographed on a silica gel column eluting with a mixture of dichloromethane/cyclohexane 30/70 (v/v) to obtain beige crystals; T.t. = 94 °C; yield = 25%.

Preparation of ethyl 4-methyl-1H-2-indolecarboxylate (Compound B.2)

Second procedure:

1st stage: Obtaining azide

9.3 g (0.405 mol) of sodium is added in portions to 20 ml of ethanol. 16.2 g (0.135 mol) of ortho-tolualdehyde as a solution in 52.2 g (0.405 mol) of ethyl azidoacetate is introduced into this solution of ethylate in ethanol, drop by drop, at -20 °C. After 2 hours at -10 °C, the reaction mixture is poured into 400 ml of water, after which the formed precipitate is filtered. It is dried for 18 hours at 40 °C under vacuum to obtain white crystals; T.t. = 55 °C; yield = 78%.

2nd step: azide cyclization

19.5 g (0.0844 mol) of the azide obtained according to step 1 is added in portions to 100 ml of xylene heated to 140 °C. After the addition is complete, the reaction mixture is left for 1 hour at 140 °C. The xylene was removed by concentration, and the residue was taken up in isopropyl ether, filtered, and dried for 18 h under vacuum at 40 °C to give white crystals; T.t. = 141 °C; yield = 62%.

Preparation of 5-ethyl-1H-2-indolecarboxylic acid (according to Fischer's method) (Compound B.3)

Third procedure:

1st step: 4-ethylphenylhydrazine hydrochloride

150 ml of water and 160 ml of 12 N hydrochloric acid are added to 24.2 g (0.2 mol) of 4-ethylaniline. The mixture is cooled to 0 °C, after which 14 g (0.2 mol) of sodium nitrite is introduced drop by drop in the form of a solution in 140 ml of water. After 1 hour at 0 °C, 112 g (0.496 mol) of stano chloride dihydrate in the form of a solution in 90 ml of 12 N hydrochloric acid was added to the reaction mixture at -10 °C. After 1.5 hours at -10 °C, the reaction mixture is filtered to obtain a brown solid; T.t. = 198 °C; yield = 95%.

2nd step: ethyl 2-[2-(4-ethylphenyl)hydrazono]propanoate

Into 34.5 g (0.2 mol) of 4-ethylphenylhydrazine hydrochloride previously obtained as a suspension in 500 ml of ethanol, 23 ml of 90.2 mol) ethyl pyruvate is added, and the reaction mixture is heated for 3.5 hours at reflux. It is then cooled to a temperature of 20 °C and the ethanol is evaporated. The solid residue was washed with pentane and dried at 40 °C under vacuum to give a colorless liquid; yield = 94%.

3rd step: ethyl 5-ethyl-1H-2-indolecarboxylate

In 44 g (0.188 mol) of hydrazone, which was previously obtained in the form of a suspension in 300 ml of toluene, 19 g (0.1 mol) of toluene sulfonic acid vapor monohydrate was added over 7 hours in portions at reflux. It is cooled to a temperature of 20 °C, and the undissolved part is removed by filtration and washed in toluene. The filtrate is washed with a saturated aqueous solution of potassium carbonate; it is decanted, dried over anhydrous sodium sulfate and concentrated. The residue is purified by chromatography on a silica gel column eluting with a mixture of dichloromethane/cyclohexane 5/5 (v/v) to obtain beige crystals; T.t. = 94 °C; yield = 51%.

4th step: 5-ethyl-1H-2-indolecarboxylic acid

To 150 ml of 1,4-dioxane, add 15.8 g (0.073 mol) of ethyl 5-ethyl-2-indolecarboxylate obtained according to step 3, and then add 45 ml of 2M sodium hydroxide solution (0.09 mol) . The reaction mixture is left for 48 hours at room temperature. After evaporation of 1,4-dioxane, the residue is taken in a 6N solution of hydrochloric acid, and the formed precipitate is filtered and dried under vacuum at 60 °C, in order to obtain 5-ethyl-1H-2-indole carboxylic acid in the form of white crystals; T.t. = 184 °C; yield = 92%.

PREPARATION OF N-ALKYLATED 1H-2-INDOLCARBOXYLIC ACIDS

5-ethyl-1-(methoxycarbonylmethyl)-1H-2-indolecarboxylic acid (Compound B.4)

1st step: besyl 5-ethyl-1H-2-indolecarboxylate

In 70 ml of dimethylformamide, 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 added. The reaction mixture was left for 40 minutes at 0 °C, after which 10.6 ml of benzyl bromide (0.089 mol) was added dropwise. After 18 hours of reaction at room temperature, the reaction mixture is poured into 300 ml of water, and the precipitate formed is filtered, washed in water, and then dried for 18 hours at 50 °C under vacuum to obtain yellow crystals; T.t. = 99 °C; yield = 90%.

2nd step: Benzyl 5-ethyl-1-(methoxy carbonyl methyl)-1H-2-indole carboxylate

In 1.5 g (0.031 mol) of sodium hydride in the form of a 50% suspension in oil, 75 ml of dimethylformamide is added, and then in portions 7.9 g (0.0283 mol) of benzyl 5-ethyl-1H-2-indolecarboxylate which was obtained according to step 1. After 40 minutes at 0 °C, 3.5 ml (0.0315 mol) of methyl bromoacetate were introduced drop by drop, and the reaction mixture was left for 2 hours at 20 °C. Add 300 ml of ethyl acetate and wash with 2 x 300 ml of water, after which it is decanted, and the organic phase is dried over anhydrous sodium sulfate and concentrated. Thus, 9.5 g of colorless oil is obtained; yield = 95%.

3rd step: 5-ethyl-1-(methoxy carbonyl methyl)-1H-2-indole carboxylic acid

In 9.5 g (0.0296 mol) of benzyl 5-ethyl-1-(methoxy carbonyl methyl)-1H-2-indole-carboxylate obtained according to step 2, in the form of a solution in 150 ml of ethanol, 2.5 g of 10% Pd/C, and then 40 ml of cyclohexane (0.395 mol). The reaction mixture is heated for 2 hours at 70 °C and then cooled to a temperature of 20 °C. The reaction mixture is filtered on talc, and the filtrate is evaporated to dryness. The residue is dried for 18 hours at 40 °C under vacuum to obtain beige crystals; T.t. = 181 °C; yield = 90%.

Proceeding as in the preparations described above, and starting from the appropriate synthetic intermediates, compounds B5 to B70 are synthesized which are described in Table 1, herein below.

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4,5-dimethyl-1-(3-cyanopropyl)-1H-2-indole carboxylic acid (Compound B.71)

1st stage: Ethyl 4,5-dimethyl-1-(3-cyanopropyl)-1H-2-indole carboxylate

75 ml of dimethyl formamide was added to 1.92 g (0.040 mol) of sodium hydride in the form of a 50% suspension in oil, and then 7.9 g (0.0363 mol) of ethyl 4,5-dimethyl-1H-2- indolecarboxylate. After 40 minutes of stirring at 0 °C, 4.0 ml (0.040 mol) of 4-bromo butyronitrile is introduced drop by drop, and the reaction mixture is maintained for 2 hours at 20 °C. Add 300 ml of ethyl acetate, wash twice with 300 ml of water each, and then decant, and the organic phase is dried over anhydrous sodium sulfate and concentrated. 9.8 g of colorless oil is obtained; yield = 95%.

2nd step: 4,5-dimethyl-1-(3-cyanopropyl)-1H-2-indolecarboxylic acid

9.8 g (0.0345 mol) of ethyl 4,5-dimethyl-1-(3-cyano-propyl)-1H-2-indolecarboxylate is added to 150 ml of 1,4-dioxane, followed by 25 ml of a 2M sodium solution hydroxide (0.05 mol). The reaction mixture is kept for 48 hours at room temperature. After evaporation of 1,4-dioxane, the residue is taken up with 6M hydrochloric acid solution, and the formed precipitate is filtered and dried under reduced pressure at 60 °C to obtain 4,5-dimethyl-1(3-cyanopropyl)-1H-2- indolecarboxylic acids in the form of white crystals; T.t. = 175 °C, yield = 92 %.

Compounds B.72 to B75 listed in Table I bis, here below, are obtained in the same way.

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C. OBTAINING BENZAMIDOGUANIDINE DERIVATIVES

Preparation of 2,6-dimethoxy-4-methylbenzamidoguanidine (Compound C.1)

To 353 g (1.8 moles) of 2,6-dimethoxy-4-methylbenzoic acid in the form of a suspension in 1.5 liters of toluene, 1 ml of dimethylformamide is added, and then, dropwise, 190 ml of oxalyl chloride (2.16 mole). The reaction mixture is left for 2 hours at room temperature, after which it is evaporated to dryness. The crystalline residue is added in portions to a suspension of 293.8 g of aminogunanidine bicarbonate (2.16 mol) in 2.5 liters of pyridine at + 5 °C, and left for 18 hours at 20 °C. The reaction mixture is evaporated to dryness, and the residue is then taken up with 1 liter of 2M sodium hydroxide solution. The precipitate is filtered and washed with a minimum amount of water, after which it is dried under vacuum at 60 °C to obtain a crystalline residue; T.t. = 222 °C; yield = 81%.

D. OBTAINING 3-AMINOTRIAZOLE DERIVATIVES

3-amino-5-(2,6-dimethoxy-4-methylphenyl)-1,2,4-triazole (Compound D.1)

To 230 g (0.91 mol) of 2,6-dimethoxy-4-methylbenzamidoguanidine, 2 liters of diphenyl ether are added, after which the reaction mixture is heated for 5 minutes at 220 °C. It is cooled to a temperature of 80 °C, and then the precipitate is filtered and washed with diisopropyl ether, and dried under vacuum at 60 °C to obtain crystals; T.t. = 286 °C; yield = 93%.

Working according to these results, and using the appropriate starting products, compounds D2 to D11 described in Table II below are synthesized in the same manner.

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E. OBTAINING DIPHENYLAMINO DERIVATIVES

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

105 g (0.45 mol) of 3-amino-5-(2,6-dimethoxy-4-methylphenyl)-1,2,4-triazole in the form of a suspension in 200 ml of xylene and 150 g ( 0.9 mol) of benzophenoneimine during 48 hours under an argon flow. It is cooled to a temperature of 80 °C, and then the reaction mixture is poured into 4 liters of isopropyl ether, after which the formed precipitate is filtered, washed in diisopropyl ether and dried for 18 hours at 50 °C; T.t. = 126 °C; yield = 90%.

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F. PREPARATION OF 3-AMINO SUBSTITUTED 1-TRIAZOLES

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

a) N-alkylation of triazoles

300 ml of 6N aqueous 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. 17 g (0.09 mol) of 2-bromoethylcyclohexane was added dropwise to the reaction mixture heated to 70 °C. The reaction mixture is maintained for 2 hours at 80 °C. The organic phase is decanted, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is chromatographed on a silica gel column eluting with a mixture of toluene/ethyl acetate 90/10 (v/v). Thus, 21.4 g of colorless oil is obtained; yield = 70%.

b) Hydrolysis of the diphenylamine function

In 10.3 g (0.02 mol) N-[1-(2-cyclohexylethyl)-5-(2,6-dimethoxy-4-methylphenyl)-1H-1,2,4-triazol-3-yl] -N-diphenylmethyl enamine in the form of a solution in 200 ml of methanol is added to 100 ml of 1N hydrochloric acid solution. The reaction mixture is left at room temperature for 18 hours, after which it is evaporated to dryness. The oily residue is condensed in diethyl ether, and the precipitate obtained is filtered and dried under vacuum at 40 °C; T.t. = 136 °C (hydrochloride); yield = 90%.

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Starting from compound E10, compound 1-(2-cyclohexylethyl)-5-(2,6-dimethoxy-4,5-dimethylphenyl)-1H-1,2,4-triazol-3-amine (Compound F38); T.t. = 180 °C.

G. OBTAINING AMIDOTRIAZOLE DERIVATIVES WITH UNSUBSTITUTED INDOLES

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)

To a solution of 1 ml of pyridine (0.013 mol) in 30 ml of methylene chloride, 0.2 ml of thionyl chloride (0.0028 mol) is added at 0 °C. After 15 minutes at 0 °C, 500 mg (0.0025 mol) of 5-chloroindole carboxylic acid was introduced and the reaction mixture was 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-triazol- 3-amine hydrochloride and left for 18 hours at 20 °C. The reaction mixture is washed with 1M sodium hydroxide solution. The organic phase is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel eluting with a mixture of dichloromethane/methanol 95/5 (v/v) to obtain 0.980 g of crystals; T.t. = 262 °C; yield = 73%.

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H. PREPARATION OF AMINOTRIAZOLE DERIVATIVES WITH N-SUBSTITUTED INDOLES

Example 1

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

1 ml of pyridine (0.013 mol) and 0.21 mol of thionyl chloride (0.00029 mol) were successively added to 15 ml of dichloromethane. After 15 minutes at 0 °C, 0.627 g of 5-ethyl-1-methoxycarbonylmethyl-1H-2-indolecarboxylic acid are introduced, followed by 0.9 g of 1-(2-cyclohexylethyl)-5-(2,6-dimethoxy- 4-methylphenyl)-1H-1,2,4-triazol-3-amine. The reaction mixture is left for 18 hours at room temperature, after which acid washing and finally base washing are performed. The organic phase is dried over anhydrous sodium sulfate and concentrated. The oily residue is chromatographed on silica gel eluting with a mixture of dichloromethane/methanol 98.5/1.5 (v/v) to obtain a white powder; T.t. = 191 °C; yield =

87%.

Example 2

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

In 530 mg (0.0009 mol) 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 obtained according to example 1 in the form of a solution in 50 ml of methanol, 1.8 ml (0.0018 mol) of 1N solution is added sodium hydroxide. After 18 hours at room temperature, the reaction mixture is evaporated to dryness. The residue is taken up with ethyl acetate and 0.5 N hydrochloric acid solution, after which it is decanted, and the organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by chromatography on a silica gel column eluting with a mixture of dichloromethane/methanol 92/8 (v/v) to obtain white crystals; T.t. = 198 °C; yield = 91%. Starting from the appropriate intermediates, and working according to Examples 1 and 2, Examples 3 to 511 are obtained in the same manner and are listed in Tables VI and VII below.

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Example 3

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

1st step: 4-[2-({[1-(2-cyclohexyl-ethyl)-5-(2,5-dimethoxy-4-chlorophenyl)-1H-1,2,4-triazol-3-yl] carbonyl}-4,5-dimethyl-1H-indolyl]butyronitrile

1 ml of pyridine (0.013 mol) and 0.21 mol (0.0029 mol) of thionyl chloride are successively added to 15 ml of dichloromethane. After 15 minutes at 0 °C, 4,5-dimethyl-1-(3-cyanopropyl)-1H-2-indolecarboxylic acid (0.0024 mol) is introduced, followed by 0.9 g of 1-(2-cyclohexylethyl) hydrochloride. )-5-(2,5-dimethoxy-4-chlorophenyl)-1H-1,2,4-triazol-3-amine. The reaction mixture is maintained for 18 hours at room temperature, after which an acid wash is performed, followed by a base wash. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue is chromatographed on a silica gel column eluting with a mixture of dichloromethane/methanol 98.5/1.5 (v/v) which gives a white powder; T.t. = 178 °C; yield = 87%.

2nd step: 2{N-[5-(4-chloro-2,5-dimethoxyphenyl)-1-(2-cyclohexyl-ethyl)-5-1H-1,2,4-triazol-3-yl]carbamoyl }-4,5-dimethyl-1-[3-(2H-1,2,3,4-tetrazol-5-yl]propyl}-1H-indole

In 0.720 g (0.0012 mol) of 4-[2-({[1-(2-cyclohexyl-ethyl)-5-(2,5-dimethoxy-4-chlorophenyl)-1H-1,2,4-triazole -3-yl]carbonyl}-4,5-dimethyl-1H-indolyl]butyronitrile in the form of a solution in 15 ml of tetrahydrofuran, 0.5 ml of azidotrimethylsilane, 0.030 butyltin oxide are added and heated at reflux for 18 hours. allowed to reach room temperature, tetrahydrofuran is eliminated under reduced pressure, and the residue is chromatographed on a silica gel column eluting with dichloromethane/methanol 95/5 (v/v) to give a white solid; mp = 233 °C; yield = 78 %.

This method 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.

The potassium and sodium salts of these compounds are obtained in acetonitrile by adding an equivalent base at room temperature, which is further followed by evaporation of the solvent under reduced pressure, and further drying.

Claims (16)

1. Compound formula: [image] characterized by: R1 represents a (C2-C6) alkyl radical, the group -(CH2)n-G, where n ranges from 0 to 5, and G represents a non-aromatic mono- or polycyclic hydrocarbon group containing C3-C13 carbon atoms that is optionally substituted with one or more (C1-C3) alkyl radicals; phenyl (C1-C3) alkyl group, where the phenyl group is optionally substituted with one or more halogens, with (C1-C3) alkyl or (with C1-C3) alkoxy radical; the group -(CH2)nNR2R3, where n represents an integer between 1 and 6, and R2 and R3 identical or different each represent a (C1-C3) alkyl radical, or form with a nitrogen atom to which morpholino, piperidino, pyrrolidinyl or piperazinyl are attached group; X1, X2, X3 or X4 each independently represents a hydrogen atom, a halogen atom, a radical (C1-C6) alkyl, (C1-C6) alkoxy, or trifluoromethyl, where only one of X1, X2, X3 or X4 can be expected to represent possibly a hydrogen atom; R 4 represents hydrogen, the group -(CH 2 )nCOOR 5 , where n is as defined above, and R 5 represents a hydrogen atom, a radical (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl-(C 1 -C 6 )alkyl; radical (C1-C6) alkyl; the group (CH2)nOR5 or the group (CH2)nNR2R3, where n, R2, R3 and R5 are as defined above; the group (CH2)n-tetrazolyl, where n is as defined above, or R 4 represents one of these groups in the form of an alkali metal salt or an alkaline earth metal salt; Y1, Y2 and Y3 each independently represent a hydrogen atom, a halogen atom, a radical (C1-C3) alkyl, (C1-C3) alkoxy, nitro, cyano, (C1-C6) alkylamino, carbamoyl, trifluoromethyl, a COOR6 group, where R6 represents a hydrogen atom or a (C1-C3) alkyl radical; or one of its salts or solvates. 2. The compound of formula (I) according to claim 1, characterized in that R1 and R4, X1, X2, X3 and X4 are as defined in claim 1, and Y1, Y2 and Y3 represent hydrogen, or one of its salts or solvates . 3. The compound of formula (I) according to claim 1, characterized in that R1 and R4 are as defined in claim 1, and Y1, Y2 and Y3 represent hydrogen, and [image] represents 2,6-dimethoxy-4-methylphenyl; or one of its salts or solvates. 4. Compound of formula (I) according to claim 1, characterized in that R1 and R4, Y1, Y2 and Y3 are as defined in claim 1, and [image] represents 2,6-dimethoxy-4-methylphenyl; or one of its salts or solvates. 5. Compound of formula (I) according to claim 1, characterized in that R1 and R4, Y1, Y2 and Y3 are as defined in claim 1, and [image] presents [image] ; X 2 represents a methyl or chlorine atom; or one of its salts or solvates. 6. Compound formula [image] wherein R1 and R4, X1, X2, X3 and X4 are as defined in claim 1. 7. The process for obtaining the compound of formula (I), according to one of claims 1 to 5, characterized in that it comprises the reaction of aminotriazole of formula 7: [image] wherein R1, X1, X2, X3 and X4 are as defined for formula (I) in claim 1, with an indole derivative of a carboxylic acid of formula 8: [image] wherein R 4 , Y 1 , Y 2 and Y 3 are as defined hereinbefore for formula (I) in claim 1, to obtain a compound of formula (I), or one of its salts or solvates. 8. Process for obtaining the compound of formula (I), according to one of claims 1 to 5, characterized in that it comprises the reaction of aminotriazole of formula 7: [image] wherein R1, X1, X2, X3 and X4 are as defined for formula (I) in claim 1, * say with the indole derivative of the carboxylic acid of formula 8: [image] wherein R 4 , Y 1 , Y 2 and Y 3 are as defined hereinafter for formula (I) in claim 1, * say with the indole derivative of the carboxylic acid of formula 8': [image] wherein Y1, Y2 and Y3 are as defined hereinabove for formula (I) and R'4 is a precursor group for R4 in which case an intermediate compound of formula (I') is formed: [image] wherein R 1 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 and Y 3 are as defined for formula (I), and R' 4 is a precursor group for R 4 , wherein R 4 is as defined for formula (I ). 9. Pharmaceutical preparation, characterized in that it contains as active principle the compound of formula (I) according to claim 1 or one of its salts which is pharmaceutically acceptable. 10. Pharmaceutical preparation, characterized in that it contains as an active principle the compound of formula (I) according to claim 2 or one of its salts which is pharmaceutically acceptable. 11. Pharmaceutical preparation, characterized in that it contains as an active principle the compound of formula (I) according to claim 3 or one of its salts which is pharmaceutically acceptable. 12. Pharmaceutical preparation, characterized in that it contains as an active principle the compound of formula (I) according to claim 4 or one of its salts which is pharmaceutically acceptable. 13. Pharmaceutical preparation, characterized in that it contains as an active principle the compound of formula (I) according to claim 5 or one of its salts which is pharmaceutically acceptable. 14. A compound according to one of claims 1 to 5, characterized in that it is used to obtain medicines intended for the treatment of food intake disorders, obesity and for reducing food intake. 15. A compound according to any one of claims 1 to 5, characterized in that it is used to obtain medicines intended for the treatment of tardive dyskinesia. 16. A compound according to one of claims 1 to 5, characterized in that it is used to obtain medicines intended for the treatment of disorders of the gastrointestinal sphere.