MXPA99002916A - Novel phenoxyethylamine derivatives, method of preparation, application as medicine and pharmaceutical compositions containing same - Google Patents

Abstract

The invention concerns novel phenoxyethylamine derivatives having a high affinity for the 5-HT1A receptor, methods for preparing them, pharmaceutical compositions containing them and their use as medicine and particularly as inhibitors of gastric acid secretion or as antiemetic.

Description

NOVEDOSOS DERIVED FROM PHENOXYETHYLAMINE, ITS PREPARATION PROCEDURE, ITS APPLICATION AS MEDICATIONS AND PHARMACEUTICAL COMPOSITIONS THAT THEY CONTAIN DESCRIPTION OF THE INVENTION The 5-HT? A ligands may be useful for the treatment of anxiety, depression and hypertension (5-HT? A receptors of the brain: Behavioral and Neurochemistry Pharmacology: Editors C.T. Dourish, S. Ahlenius, P.H. Huston; Ellis Hor ood LTD, Chischester (1987)). It has also been shown that 5-HT.alpha.-ligands inhibit the secretion of gastric acid (D.C. Evans, J.S. Gidda, Gastroenterology, 104, A76 (1993)), show anti-emetie effects (F.

O ada, Y. Torii, H. Saito, N. Matsuki, Jpn. J.

Pharmacol. , 64, 109 (1994)) and act on the motility of the gastrointestinal system (Serotonin and Gastrointestinal Function, Editors T.S.

Gaginella, J.J. Galligan; CRC Press, Boca Ratón (nineteen ninety five) ) . The present invention relates to the novel derivatives of phenoxyethylamine which possess refj.29753 a high affinity for the 5-HT1A receptor, the processes for its preparation, the pharmaceutical compositions containing them and its use, as medicaments, mainly as inhibitors of gastric acid secretion or as anti-emetics. The invention also aims at the products of the general formula I wherein Ar represents a phenyl substituted by one or more substituents; R represents a hydrocarbon radical containing from 1 to 10 carbon atoms, chosen from alkyl radicals, linear or branched, or cycloalkyl; as well as the salts of these products.

The invention is more particularly aimed at the products of the general formula I as defined above, characterized in that the substituent or substituents which the phenyl radical representing Ar may possess are chosen from the lower alkoxy radicals, -C (0) NRIR2 -NHC (0) R3, -NHC (0) NR4R5 -NHC (0) OR6, in which Ri, R2, R3, R4 and R5 independently represent a hydrogen atom or a lower alkyl, and R6 represents an alkyl lower. In the definitions indicated above, the term "lower alkyl" preferably represents an alkyl radical having from 1 to 6 carbon atoms, straight or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aec-butyl, ter -butyl, isopentyl, neopentyl and hexyl. Cycloalkyl radicals can be chosen from saturated monocyclic radicals having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radicals. The lower alkoxy radicals may correspond to the lower alkyl radicals indicated above. The methoxy, ethoxy or isopropyloxy radicals are preferred. The products of the formula I can form addition salts with the acids, in particular the pharmacologically acceptable acids. Examples of salts are given later in the experimental part. The subject of the invention is in particular the compounds of the general formula I as described above, characterized in that Ar represents a phenyl radical substituted with a substituent selected from methoxy radicals, -C (O) NHMe, -NHC (O) Me, -NHCONH2, -NHCONHMe and NHC (O) OMe, and because R represents the radical terbutyl, neopentyl, cyclopentyl, cyclohexyl or cycloheptyl. s The substituents of the phenyl radical which can have Ar are preferably located in the 2 or 3 position. More particularly, the invention has as its objective the products described below in the examples, in particular the products that respond to the following formulas: N-tert-butyl-5- [. { 2- (2-methoxy phenoxy) ethyl} amino] -pentane ida; -N-cyclohexyl-5- [. { 2- (2-methoxyphenoxy) ethyl} aminoJ-pentanamide; -N-neopentil-5- [. { 2- (2-methoxyphenoxy) ethyl} aminoJ-pentanamide; -N-cyclopentyl-5- [. { 2- (2-methoxyphenoxy) ethyl} amino] -pentane ida; -N-cycloheptyl-5- [. { 2- (2-methoxyphenoxy) ethyl} aminoJ-pentanamide; -N-cyclohexyl-5- [. { 2- (2-methylaminocarbonyl) phenoxy) -ethyl} aminojpentanamide; -N-neopentil-5- [. { 2- (2-methylaminocarbonyl) phenoxy) -ethyl} aminojpentanamide; -N-neopentil-5- [. { 2- (2-aminocarbonylamino) phenoxy) -ethyl} aminojpentanamide; -N-neopentil-5- [. { 2- (3-aminocarbonylamino) phenoxy) -ethyl} amino] pentanamide; -N-cycloheptyl-5- [. { 2- (3-aminocarbonylamino) phenoxy; ethyl} aminojpentanamide; -N-cyclohexyl-5- [. { 2- (3-methylcarbonylamino) phenoxy) -ethyl} aminojpentanamide; -N-neopentil-5- [. { 2- (3-methylcarbonylamino) phenoxy) -ethyl} aminojpentanamide; -N-neopentil-5- [. { 2- (3-methoxycarbonylamino) phenoxy) -ethyl} aminojpentanamide; -N-neopentil-5- [. { 2- (3-methylaminocarbonyl) phenoxy) -ethyl} aminojbutanamide; as well as the salts of these compounds with the mineral or organic acids. Another object of the invention is a process for the preparation of the products of the general formula I as defined above, characterized in that A) or a product of the formula II is reacted II in which Ar has the meaning indicated above, with a product of formula III III wherein X represents a halogen or a pseudo-halogen, to obtain a product of formula IV IV product of the formula IV which is treated with an amine of the formula RNH2 in which R has the meaning indicated above, to obtain a product of the formula V v product of formula V which is transformed into the product of formula I by cleavage of the benzyl functional group, and the product of formula I which can be converted into acid salts by the action of the corresponding acid. B) or a product of the formula VI is reacted wherein Y represents a halogen or pseudo-halogen radical and R has the meaning indicated above, with the N-benzylethanolamine of the formula to obtain a product of formula VII which becomes the product of formula VIII wherein Z represents a halogen or pseudo-halogen radical, product of formula VIII which is reacted with a compound of the general formula ArOH in which Ar has the meaning indicated above, to obtain a product of formula V such as is defined above, product of formula V which is transformed into the product of formula I by cleavage of the group benzyl functional group, and the product of formula I which can be converted into acid salts by the action of the corresponding acid. In the syntheses as presented above, X, Y and Z independently represent a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy, in other words, a halogen or pseudo-halogen group. The reaction of a compound of the general formula II with a compound of the general formula III to obtain a compound of the general formula IV can be easily carried out by heating in a polar solvent, for example acetonitrile or dimethylformamide, in the presence of an inorganic base such as potassium carbonate or sodium carbonate, and optionally a catalyst such as potassium iodide. The esters of the general formula IV obtained in this way can be converted into amides of the general formula V by reaction with the corresponding amine by heating these two compounds, under reflux of the amine, without solvent, preferably under a nitrogen atmosphere or in a aromatic hydrocarbon in the presence of molecular sieve. According to the substituents present on the phenyl radical represented by Ar, the amides V can also be obtained after the hydrolysis of the ester functional group and the peptide coupling with the amines of the general formula RNH2. The amides of general formula V can also be obtained by the reaction of the sodium diethyldiaminealuminates or of an amide complex of lithium and aluminum, prepared from the amines of the general formula RNH2 according to known methods, such as those describe for example in Synlett, 10 827-8 (1994) or in J. Org. Chem., 57 (22), 5831-4 (1992), on the esters of the general formula vi. The compounds of the general formula VII can be prepared by heating a compound of the general formula VI with the N-benzylethanolamine in a polar solvent such as an alcohol, in the presence of an acid acceptor such as a tertiary amine or an inorganic base, such as sodium carbonate or potassium carbonate. Alternatively, the compounds of the general formula VII can be prepared easily by simply heating a compound of the general formula VI with an excess of N-benzylethylanolamine in the absence of a solvent, preferably under a nitrogen atmosphere and at a temperature comprised between 60 ° C and 90 ° C. The compounds of the general formula VII obtained in this way can be converted, for example, to chlorides of the general formula VIII (Z = C1), by reaction with methanesulfonyl chloride in an inert solvent, such as dichloromethane, and in the presence of of an organic base such as triethylamine or diisopropylethylamine. The compounds of the general formula V can be prepared from compounds of the general formula VIII by reacting the latter with a phenoxide anion produced from the compound of the appropriate formula ArOH, using a base such as sodium hydroxide, hydroxide potassium or sodium hydride. The reaction is carried out in an aprotic solvent and, preferably, in a dipolar aprotic solvent such as, for example, dimethylformamide. The compounds of the general formula I are obtained by deprotecting the compounds of the general formula V according to the general methods known to those skilled in the art, for the debenzylation, for example, as catalytic hydrogenation or reaction with a chloroformate such as vinyl chloroformate or a-chloroethyl chloroformate, followed by hydrolysis or methanolysis. Other debenzylation methods such as those described in Protective Groups in Organic Synthesis (T. Green, PGM Wuts, 2nd Ed. J. Wiley and Sons Inc., pp. 364-6 (1991)) can also be used. the measurement where these are compatible with the substituents on the aromatic nucleus of the compounds of the general formula V. The eventual salification of the products of the formula I is also carried out according to the usual methods indicated below in the experimental part. The compounds of the present invention possess interesting pharmacological properties. It is in this way that it has been discovered that the compounds of the present invention have a high affinity for the 5HTiA receptor. The compounds of the present invention can thus be used in different therapeutic applications. The compounds can inhibit the secretion of gastric acid. These can inhibit vomiting induced, for example, by cis-platinum. Of this Thus, the compounds of the invention can be used as anti-emetics or for the treatment of diseases in which it is necessary, or desirable, to reduce the secretion of gastric acid, for example, gastric or duodenal ulcers, gastritis , gastroesophageal reflux, gastric dyspepsia, Zollinger-Ellison syndrome, and nausea. The compounds of the invention can also have an activity on gastric emptying and intestinal motility. These can also be used to fight against constipation, post-surgical atony, and gastroparesis. These can also be used for the treatment of certain diseases of the nervous system such as anxiety, depression, sleep disorders such as insomnia, dependence on certain drugs or drugs, Alzheimer's disease, vertigo, diseases of feeding such as anorexia. The compounds of the invention can also be used for the treatment of diseases of the cardiovascular system, mainly hypertension.

An illustration of the pharmacological properties of the compounds of the invention will be found later in the experimental part. These properties make the products of the formula I suitable for pharmaceutical use. The present application also has the objective, in the form of medicaments, of the products of the general formula I as defined above, as well as the addition salts such as pharmaceutically acceptable mineral or organic acids., of said products of the formula I, as well as the pharmaceutical compositions containing, as an active principle, at least one of the medicaments as defined above. The invention also relates to pharmaceutical compositions containing a compound of the invention or an additive pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. The pharmaceutical composition can be in the form of a solid, for example, powders, granules, tablets, capsules or suppositories. Suitable solid carriers can be, for example, calcium phosphate, stearate magnesium, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine and wax. Pharmaceutical compositions containing a compound of the invention may also be presented in the liquid form, for example, of solutions, emulsions, suspensions, or syrups. Suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water, added to pharmaceutically acceptable oils or fats. Sterile liquid compositions can be used for intramuscular, intraperitoneal, or sub-utero injections, and sterile compositions can also be administered intravenously. Another object of the invention is the use of the products of the formula I as defined above for the preparation of anti-emetics drugs, drugs intended to reduce gastric secretion, drugs intended to accelerate gastric emptying, drugs intended to modify the transit intestinal, medications intended to treat anxiety, depression, sleep disorders, as well as drugs intended to treat cardiovascular diseases. The invention also aims, as novel industrial products, and mainly as industrial novel products intended for the preparation of products of the formula I, for the products of the formulas IV, V, VII and VIII as described above. . The starting materials of the invention, in particular the products of the formulas II, III and VI, are known products or can be prepared from known products. The following references can be cited: N-benzylethanolamine is a product marketed, for example, by ACROS. The products of formula II can be prepared by the classical methods from the corresponding phenoxyethylamines for example by means of benzamide, followed by a reduction with lithium aluminum hydride or an equivalent method. Alternatively, a reductive amination may be used according to the usual methods.

The phenoxyethylamines can be prepared according to the usual methods, for example, by the reaction of a phenol with chloroacetonitrile in basic medium, followed by the reduction of nitrile by lithium and aluminum hydride according to the method described in Chim. . Ther. 8 (3), 259-270 (1973). The products of formula III are commercial or can be manufactured by methods known to the person skilled in the art. It is in this way that the product of formula III, in which X represents a chlorine atom, is marketed by the firm ACROS. The products of the formula VI can be prepared according to the known methods, starting from the pentanoic acid, substituted in the 5-position by a halogen or a pseudo-halogen, or activated derivatives such as the acid chloride or the activated ester, on which the amines of the general formula RNH2 are reacted. The phenolic derivatives of the general formula ArOH are commercially available or can be manufactured by methods known to the person skilled in the art.

The following examples are presented to illustrate the above procedures, and should not in any way be construed as limiting the scope of the invention.

EXPERIMENTAL PART: Example 1 N-cyclohexyl-5- [. { 2- (2-methoxyphenoxy) ethyl} aminoj-pentanamide (I, Ar = 2-methoxyphenyl, R = cyclohexyl; compound No. 2, Table 1) First stage - [benzyl-. { 2- (2-methoxy phenoxy) ethyl) aminojpentanoate methyl (IV, Ar = 2-methoxyphenyl) Potassium carbonate (28.6 g, 0.21 mol) and potassium iodide (0.2 g, 1.2 mmol) are added to a solution of N-benzyl [2- (2-methoxyphenoxy) hydroxy chloride) Jetylamine (26.4 g, 0.09 mol) in dimethylformamide (100 ml). The reaction mixture is stir for 10 minutes at 20 ° C, then a solution of methyl 5-chloropentanoate (15 g, 14.3 ml, 0.1 mol) in dimethylformamide (30 ml) is added dropwise. The mixture is stirred and heated at 60 ° C for 24 hours, then filtered and the solvent is evaporated under reduced pressure. The residue is taken up in dichloromethane (100 ml), washed with water (3 x 50 ml) and dried over magnesium sulfate. Filtration and evaporation of the solvent lead to obtaining an oil which is purified by flash chromatography on silica gel in a mixture of ethyl acetate / heptane (1/1). 30 g (91%) of the desired compound are obtained.

NMR tE (CDC13) r d: 1.55-1.80 (m, 4H), 2.30 (t, 2H, J = 8 Hz), 2.60 (t, 2H, J = 6 Hz), 2.92 (t, .2H, J = 6 Hz), 3.66 (s, 3H), 3.69 (s, 3H), 4.07 (t, 2H, J = 6 Hz), 6.80-6.95 (, 4H), 7.20-7.40 (m, 5H).

Second stage N-cyclohexyl-5- [benzyl-. { 2- (2-methoxyphenoxy) ethyl) aminojpentanamide (V, Ar = 2-methoxyphenyl; R = cyclohexyl) A solution of diethyldihydroalumin sodium (4.44 ml, 8.9 mmol) at a concentration of 2 moles per liter in toluene is added to a solution of cyclohexylamine (1.76 g, 2.03 ml, 18 mmol) in anhydrous toluene (60 ml). The reaction mixture is heated at 110 ° C for 1 hour, then a solution of 5- [benzyl] is added dropwise. { 2- (2-methoxyphenoxy) ethyl} Methyl aminopentanoate (6 g,, 16 mmol) in toluene (25 ml). The mixture is refluxed for 3 hours, and it is left for 18 hours at 20 ° C, then it is neutralized by a 10% solution of acetic acid. The organic phase is extracted and then washed successively with a saturated solution of sodium hydrogen carbonate and then with water. After drying over magnesium sulfate and evaporation of the solvents under reduced pressure, the product is purified by flash chromatography on silica gel in a mixture of ethyl acetate / heptane (2/1). 3.3 g (47%) of the desired product are obtained, in the form of oil.

NMR XH (CDC13), d: 1.00-1.80 (m, 14H), 2.10 (t, 2H, J = 6.6 Hz), 2.60 (t, 2H, J = 7.6 Hz), 2.90 (t, 2H, J = 6 Hz), 3.67 (s, 2H), 3.85 (s, 3H), 4.08 (t, 2H, J = 6 Hz), 6.80-6.90 (m, 4H), 7.25-7.40 (m, 5H).

Third stage N-cyclohexyl-5- [. { 2- (2-methoxyphenoxy) -ethyl) aminojpentanamide (I, Ar = 2-methoxyphenyl, R = cyclohexyl) A catalyst consisting of palladium on 10% wet carbonate (1.5 g) is added to a solution of N-cyclohexyl-5- [benzyl. { 2- (2-methoxyphenoxy) ethyl} aminojpentanamide (3 g, 6.8 mmol) in glacial acetic acid (30 ml) and the mixture is hydrogenated for 2 hours at 20 ° C. The catalyst is removed by filtration and the solvent is evaporated under reduced pressure. The residue, obtained in the form of an acetic acid salt, is taken up in dichloromethane (50 ml) and the base is liberated by treatment with a solution saturated with sodium hydrogen carbonate. The organic phase is collected, washed with water, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The expected product is obtained in the form of a white powder after crystallization from diethyl ether (0.95 g, 40%). The treatment of a solution of this free base (0.72 g) in hot ethanol with a hot ethanolic solution of fumaric acid (0.24 g) gives 0.8 g of compound No. 2 in the form of white crystals, mp = 141.5-144 ° C.

XH NMR (DMSO), d: 1.05-1.30 (m, 5H), 1.50-1.70 (m, 9H), 2.07 (t, 2H, J = 6.6 Hz), 2.94 (t, 2H, J = 6.9 Hz), 3.23 (t, 2H, J = 5.3 Hz), 3.50 (, 1H), 3.77 (s, 3H), 4.21 (t, 2H, J = 5.3 Hz), 6.50 (s, 2H), 6.89-7.03 (, 4H ), 7.71 (d, 1H, J = 7.8 Hz). 1 C NMR (DMSO) 22 24. 25.31, 25.72, 32.78, 32. 91, 35.07, 46.06, 47.30, 47.53, 55.53, 55.78, 65.52, 112.50, 114.74, 120.83, 121.00, 122.26, 135.02, 147.47, 149.58, 168.04, 170.88.

IR (Nujol), cm "1: 3278 (N-H), 1714 (C = 0), 1635 (C = 0), 1548 (C-N), 1577 (C = C), 741 (aromatic C-H).

Example 2 N-cycloheptyl-5- [. { 2- (3- (aminocarbonylamino) phenoxy) ethyl} aminojpentanamide (I, Ar = 3- (aminocarbonylamino) phenyl, R-cycloheptyl: compound No. 10, Table 1) First stage N-cycloheptyl-5- [benzyl- (2-hydroxyethyl) aminojpentanamide (VII, R = cycloheptyl) N-Cycloheptyl-5-bromopentanamide (4.15 g, 15 mmol) in solution in dimethylformamide (20 ml) is added dropwise to a hot (60 ° C) solution of N-benzylethanolamine (2.27 g, 2.13 ml, 15 mmol) in dimethylformamide (25 ml) in the presence of potassium carbonate (4.15 g, 3 mmol). The reaction mixture is stirred for 2 hours at 60 ° C, and then the solvent is evaporated under reduced pressure. The residue is taken up in dichloromethane (50 ml) and washed with water (3 x 30 ml). The organic phase is collected, dried over magnesium sulfate; the solvent evaporates under reduced pressure. The product obtained is purified by flash chromatography on silica gel in a dichloromethane / methanol mixture (90/10) to give 3.04 g (50%) of the expected compound in the form of oil.

Second stage N-cycloheptyl-5- [benzyl- (2-chloroethyl) aminojpentanamide (VIII, Z, Cl, R = cycloheptyl) Methanesulfonyl chloride (0.78 g, 0.52 ml, 6.6 mmol) is added dropwise with stirring to a cooled solution of N-cycloheptyl-5- [benzyl (2-hydroxyethyl) aminojpentanamide (2.14 g, 6 mmol) in dichloromethane (20 g). ml) in the presence of triethylamine (0.69 g, 0.94 ml, 6.6 mmol). Stirring is maintained 18 hours at 20 ° C. The reaction mixture is washed with ice-cold water (25 ml) and then dried with magnesium sulfate. Filtration and evaporation of the solvent under reduced pressure provide 2.2 g (98%) of the desired compound, in the form of an oil. 2 H NMR (CDC13), d: 1.35-2.00 (, 16H), 2.54 (t, 2H, J = 6 Hz), 2.83 (t, 2H, J = 5 Hz), 2.95 (t, 2H, 5 Hz), 3.53 (t, 2H, J = 6 Hz), 3.67 (s, 2H), 4.20 (, 1H), 4.45 (m, 1H), 7.31 (s, 5H).

Third stage N-cycloheptyl-5- [benzyl-. { 2- (3- (aminocarbonylamino) phenoxy) ethyl} Aminojpentanamide (V, Ar = 3- (aminocarbonylamino) phenyl, R-cycloheptyl) Potassium carbonate (0.92 g, 6.6 mmol) is added to a solution of 3-hydroxyphenylurea (1 g, 6.6 mmol) in dimethylformamide (20 ml) and this mixture is stirred for 10 minutes at 20 ° C. Then a solution of N-cycloheptyl-5- [benzyl- (2-chloroethyl) aminojpentanamide (2.21 g, 6 mmol) in dimethylformamide (20 ml) is added dropwise and kept under stirring for 4 hours at 80 ° C. . The solvent is evaporated under reduced pressure, then the residue is taken up in dichloromethane (50 ml) and washed with water, the organic phase is collected and dried, after evaporation of the solvent, the desired compound is obtained, The oil form is purified by flash chromatography on silica gel in a dichloromethane / methanol mixture (95/5) to give 1.75 g (60%) of the pure compound.

XH NMR (CDCl3), d: 1.30-1.90 (m, 16H), 2.12 (t, 2H, J = 6 Hz), 2.53 (t, 2H, J = 6 Hz), 2.80 (t, 2H, 6 Hz) , 3.63 (s = 2H), 3.95 (m, 1H), 4.07 (t, 2H, J = 6 Hz), 4.93 (S, 1H), 5.55 (m, 1H), 6.68 (m, 2H), 7.19- 7.30 (m, 9H).

Fourth Stage N-cycloheptyl-5- [. { 2- (3- (aminocarbonylamino) phenoxy) ethyl} aminojpentanamide A catalyst consisting of palladium on 10% wet carbon (0.3 g) is added to a solution of N-cycloheptyl-5- [benzyl]. { 2- (3- (aminocarbonylamino) phenoxy) ethyl} aminojpentanamide (0.6 g, 1.2 mmol) in methanol (20 ml) and the mixture is hydrogenated for 24 hours at 20 ° C. Next, the catalyst is filtered and replaced with the same amount. The hydrogenation is continued again for 24 hours. The catalyst is removed by filtration and the solvent is evaporated under reduced pressure. The desired product is obtained after purification by flash chromatography on silica gel in a dichloromethane / methanol / ammonia mixture. (90/10/1) (0.25 g, 51%). The treatment of a Solution of this free base (0.11 g) in hot ethanol with a hot ethanolic solution of fumaric acid (33 mg), gives 0.14 g of compound No. 10 in the form of white crystals. Mp = 81-85 ° C.

XH NMR (DMSO), d: 1.34-1.73 (m, 16H), 2.05 (t, 2H, J = 6.4 Hz), 2.84 (t, 2H, J = 6.5 Hz), 3.18 (t, 2H, J = 4.9 Hz), 3.70 (, 1H), 4.11 (t, 2H, J = 5.0 Hz), 5.97 (s, 2H), 6.48 (s, 2H), 6.87 (d, 1H, J = 8.0 Hz), 7.11 (t , 1H, J = 8.1 Hz), 7.28 (m, 1H), 7.73 (d, 1H, J = 7.7 Hz), 8.84 (s, 1H).

IR (KBr), cm "1: 3350 (N-H), 1700 (C = 0), 1677 (urea), 1638 (C = 0), 1596 (C-C), 1550 (C-N).

The processes described above give a compound of the invention in the form of a free base or an addition salt with an acid. If the compound of the invention is obtained in the form of an addition salt with an acid, the free base can be obtained by alkalizing a solution of the addition salt with a base. Conversely, if the product of the process is a free base, the addition salt with an acid, in particular an addition salt with a pharmaceutically acceptable acid, can be obtained by dissolving the free base in an appropriate organic solvent, and treating the solution with an acid, according to the conventional methods of preparing the addition salts with an acid, from the free bases. Examples of addition salts with an acid are those derived from inorganic acids such as sulfuric, hydrochloric, hydrobromic or phosphoric acids, or organic acids such as tartaric, fumaric, maleic, citric, caprylic, benzoic, methanesulfonic, p -toluenesulfonic, benzene phonic, succinic or acetic. For the compounds of the invention which contain an asymmetric center, the racemic mixtures and the individual optically active isomers are also considered as part of the scope of the invention. Table 1 below shows the main compounds prepared according to the above procedures, and which illustrate the invention without limiting its scope. The compounds Nos. 2 and 10 correspond respectively to the products of Examples 1 and 2 described above. The other products have been prepared using the same procedure.

Table 1 Using the aforementioned method, the following products can also be prepared, which also form part of the invention: Pharmacological study of the products of the invention Affinity of the compounds of the invention for the 5-HT? A receptor The affinity of the compounds for serotonergic 5-HTαA receptors is determined by measuring the inhibition of [3Hj8-hydroxy-2 (di-n-propylamino) tetralin ([3HJ8-OH-DPAT] bound to the cerebral cortex of the rat, according to the method of Peroutka and his collaborators [(J. Neuroehe., 47, 529 (1986)]. The cerebral cortices of Sprague rats Dawley males are homogenized in 50 mM Tris-HCl, pH = 7.4 and centrifuged at 40,000 g for 10 minutes at 4 ° C. Buttons or concentrates are collected in suspension in. the same buffer and incubated for 10 minutes at 37 ° C, and the homogenates are again centrifuged at 40,000 g for 10 minutes at 4 ° C.

Competitive inhibition assays of [3HJ8-OH-DPAT] binding are performed three times with unlabeled competitors, with concentrations between 100 pM and 100 μM. The rat cerebral cortex membranes (10 mg wet weight / ml) are incubated with [3 HJ8-OH-DPAT (1 nM) for 30 minutes at 25 ° C in 50 mM Tris-HCl, pH = 7.4 containing 4 mM of calcium chloride, 10 μM of pargyline and 0.1% of ascorbic acid. The bound [3HJ8-OH-DPAT is separated from the [3HJ8-OH-DPAT free by immediate filtration through Whatman GF / B glass fiber filters, using a Brandel cell recuperator. The filters are washed three times with the same buffer at 0-4 ° C and their radioactivity is studied by means of a liquid scintillation spectrometer. The specific binding is obtained by subtracting determined binding in the presence of 1 μM of 8-OH-DPAT of the total binding. The characteristics of the link are analyzed by iterative analysis of non-linear regression by computer, using the Ligand program [Munson and Rodbard, Anal. Biochem., 107, 220 (1980)].

The results for the representative compounds of the invention are given in Table 2 below.

Table 2 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (15)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. The compounds of general formula I: characterized in that: »Ar represents a phenyl substituted with one or more substituents; R represents a hydrocarbon radical containing from 1 to 10 carbon atoms, chosen from alkyl radicals, linear or branched, or cycloalkyl; as well as the salts of these products.

2. The compounds of the general formula I as defined according to claim 1, characterized in that the substituent or substituents which the phenyl radical representing Ar may include are chosen from the lower alkoxy radicals, -C (0) NR? R2, -NHC (0) R3, -NHC (0) NR4R5, -NHC (0) OR6 in which Ri, R2, R3 R4 and Rs represent, independently, a hydrogen atom or a lower alkyl and R6 represents a lower alkyl.

3. The compounds of the general formula I as defined according to any of claims 1 or 2, characterized in that Ar represents a phenyl radical substituted with a substituent selected from the methoxy radicals, -C (O) NHMe, -NHC (O ) Me, -NHCONH2, -NHCONHMe and NHC (O) OMe, and because R represents the terbutyl, neopentyl, cyclopentyl, cyclohexyl or cycloheptyl radical.

4. The compounds of the general formula I, as defined in accordance with any of Claims 1 to 3, and which respond to the following formulas: -N-tert-butyl-5- [. { 2- (2-methoxyphenoxy) ethyl} aminoJ-pentanamide; -N-cyclohexyl-5- [. { 2- (2-methoxyphenoxy) ethyl} aminoJ-pentane ida; -N-neopentil-5- [. { 2- (2-methoxyphenoxy) ethyl} aminoJ-pentanamide; -N-cyclopentyl-5- [. { 2- (2-methoxyphenoxy) ethyl} aminoJ-pentanamide; -N-cycloheptyl-5- [. { 2- (2-methoxyphenoxy) ethyl} aminoJ-pentanamide; -N-cyclohexyl-5- [. { 2- (2-methylaminocarbonyl) phenoxy) -ethyl} aminojpentanamide; -N-neopentil-5- [. { 2- (2-methylaminocarbonyl) phenoxy) -ethyl} aminojpentanamide; s -N-neopentyl-5- [. { 2- (2-aminocarbonylamino) phenoxy) -ethyl} aminojpentanamide; -N-neopentil-5- [. { 2- (3-aminocarbonylamino) phenoxy) -ethyl} aminojpentanamide; -N-cycloheptyl-5- [. { 2- (3-aminocarbonylamino) phenoxy) -ethyl} aminojpentanamide; -N-cyclohexyl-5- [. { 2- (3-methylcarbonylamino) phenoxy) -ethyl} aminojpentanamide; -N-neopentil-5- [. { 2- (3-methylcarbonylamino) phenoxy) -ethyl} aminojpentanamide; -N-neopentil-5- [. { 2- (3-methoxycarbonylamino) phenoxy) -ethyl} aminojpentanamide; -N-neopentil-5- [. { 2- (3-methylaminocarbonyl) phenoxy) -ethyl} aminojpentanamide, as well as the salts of these compounds with mineral or organic acids.

5. The process for preparing the products of the general formula I as defined according to claim 1, characterized in that: A) or a product of the formula II is reacted II wherein Ar has the indicated meaning in accordance with claim 1, with a product of formula III III in which X represents a halogen or a pseudo-halogen, to obtain a product of formula IV IV product of the formula IV which is treated with an amine of the formula RNH2 in which R has the meaning indicated above, to obtain a product of the formula V v B) or a product of the formula VI is reacted wherein Y represents a halogen or pseudo-halogen radical and R has the meaning indicated above, with the N-benzylethanolamine of the formula / \ / OH to obtain a product of formula VII which becomes the product of formula VIII wherein Z represents a halogen or pseudo-halogen radical, product of formula VIII which is reacted with a compound of the general formula ArOH in which Ar has the indicated meaning according to claim 1, to obtain a product of Formula V as defined above, product of formula V which is transformed into the product of formula I by cleavage of the benzyl functional group, and the product of formula I which can be converted into acid salts by the action of the corresponding acid.

6. As medicaments, the products of the formula I as defined according to claim 1, as well as the addition salts with the pharmaceutically acceptable mineral or organic acids of said products of the formula I.

7. As medicaments, the products of the formula I, as defined according to any of claims 2 to 4, as well as the addition salts with the pharmaceutically acceptable mineral or organic acids of the products of the formula I.

8. The pharmaceutical compositions, characterized in that they contain, as an active principle, at least one of the medicaments as defined according to any of claims 6 or 7.

9. The use of the products of the formula I as defined according to any of claims 1 to 4, for the preparation of antiemetic drugs.

10. The use of the products of the formula I as defined in accordance with any of claims 1 to 4, for the preparation of drugs intended to reduce gastric secretion.

11. The use of the products of the formula I as defined in accordance with any of claims 1 to 4, for the preparation of drugs intended to accelerate gastric emptying. >

12. The use of the products of the formula I as defined in accordance with any of the indications 1 to 4, for the preparation of drugs intended to modify intestinal transit.

13. The use of the products of the formula I as defined in accordance with any of claims 1 to 4, for the preparation of medicaments intended to treat anxiety, depression, sleep disorders.

14. The use of the products of the formula I as defined according to any of claims 1 to 4, for the preparation of medicaments intended to treat cardiovascular diseases, mainly hypertension.

15. As novel industrial products, the compounds of formulas IV, V, VII and VIII as defined in claim 5.