FR2699533A1 - N-2-piperazinyl 4-amino:benzamide derivs. having antiemetic and antipsychotic activity - Google Patents

Abstract

Cis and trans isomers of N-((1,4-dialkyl-6-aryl piperazin-2-yl) methyl) benzamides of formula (I), and their acid addn. salts are new. In (I), R1 = opt. substd. phenyl, 4-7C aromatic heterocyclic having 1-4 heteroatoms or a gp. (i); X1-X5 = H, Cl, Br, F, CF3, methyl, nitro, methoxy or ethoxy; R2 = H or 1-12C alkyl pref. Me, Et or Pr; R3 and/or R'3 = H or alkyl carbonyl or NR3R'3 = H; R4 and R5 = H or 1-12C alkyl pref. Me, Et or Pr; and R6 may be H, Cl, Br, F, CF3, methyl, nitro, amino, methoxy, ethoxy, -SO2CH3, -SO2NH2, -SO2C2H5.12 Cpds. are specifically claimed including cis and trans 4-amino-5-chloro-N-((6-(4-chlorophenyl)- 4-ethyl-1-methyl piperazin-2-yl)methyl)- 2-methoxybenzamide and the corresp. cis and trans 2-ethoxy benzamides.

Description

N- ((1,4-di-alkyl-6-arylpiperazin-2-yl) methyl j benzamide derivatives (cis or trans isomers)
Pharmacological properties and applications
The present invention relates to new derivatives of N- (1, 4-dialkyl-6-arylpiperazin-2-yl) methyl J benzamides in the form of cis or trans isomers as well as their salts, their methods of preparation and their pharmacological activity.

 The very important developments, observed in recent years, in the field of serotoninergic receptors, have led us to focus on the molecules interacting with this type of receptor. Their number increased from 2 in 1979 (5-HT1 and 5-HT2), to 8 or 9 in 1990 (5-HTlA, 5-HT1B, 5-HTlC, 5-HTlD, 5-HTlE, 5-HT2, 5 -HT3 and 5-HT4). Orthomethoxybenzamides (metoclopramide) have historically been the first class of antiemetics. Their property of increasing gastric motility will not be attributed to a blockage of serotonergic receptors until twenty years later. From the metoclopramide which represents the leader of this class of many molecules, more or less derived from the skeleton Benzamide bases have been synthesized. Some benzamides are selective 5-HT3 receptor antagonists (Zacopride) and others are potent dopamine D2 receptor antagonists (Tropapride).

 The 5-HT3 brain receptors seem to help control behavior. Several arguments are in favor of such an effect. 5-HT3 receptor agonists increase mesolimbic activity and dopaminergic function. Antagonists such as ondensetron, zacopride and ICS 205-930 oppose these effects.

1.Derivatives of N - ((1,4-dialkyl-6-arylpiperazin-2-yl) methyl) benzamides, in the form of cis or trans isomers, and their addition salts with mineral or organic acids. These derivatives correspond to general formulas I or II.

I Cis isomer II Trans isomer - in which R1 is an aryl group
The term "aryl" denotes non-heterocyclic aromatic groups of the phenyl type, substituted or not, as well as heterocyclic aromatic groups having 4 to 7 carbon atoms in the aromatic ring, and 1 to 4 heteroatoms which may be oxygen, nitrogen, sulfur, of the furan, pyridine, oxazole type.

- dans lesquelles X1 et/ou X2 et/ou X3 et/ou X4 et/ou X5 peuvent être égaux par exemple à H, Cl, Br, F, CF3, CH3, NO2, OCH3, OC2H5; - dans lesquelles R2 peut être un atome d'hydrogène et un groupe alkyle de préférence méthyle, éthyle ou propyle - dans lesquelles R3 et/ou R'3 peuvent être un atome d'hydrogène ou un groupement carbonyle-alkyle
Le terme "alkyle" désigne des groupes hydrocarbonés aliphatiques contenant 1 à 12 atomes de carbone, à chaîne droite ou ramifiée. On préfère les groupes alkyles inférieurs, c'est-à-dire les groupes alkyles contenant 1 à 3 atomes de carbone.- in which R1 can have the structure

- in which X1 and / or X2 and / or X3 and / or X4 and / or X5 can be equal for example to H, Cl, Br, F, CF3, CH3, NO2, OCH3, OC2H5; - in which R2 can be a hydrogen atom and an alkyl group, preferably methyl, ethyl or propyl - in which R3 and / or R'3 can be a hydrogen atom or a carbonyl-alkyl group
The term "alkyl" refers to aliphatic hydrocarbon groups containing 1 to 12 carbon atoms, straight or branched chain. Preferred are lower alkyl groups, i.e., alkyl groups containing 1 to 3 carbon atoms.

- in which - NR3R'3 can be hydrogen - in which R4 can be a hydrogen atom and an alkyl group preferably methyl, ethyl or propyl - in which R5 can be a hydrogen atom and an alkyl group preferably methyl, ethyl or propyl - in which X6 can be equal for example to H, Cl, Br, F, CF3, CH3, NO2, NH2,
OCH3, OC2H5, S02NH2, S02CH3, S02C2H5;
The addition salts with mineral or organic acids can for example be the salts formed with hydrochloric acid, maleic acid.

The process for obtaining the derivatives of formula I or II consists in carrying out a condensation of orthoalkoxybenzoic acid with different substitutions and of (1,4-dialkyl-6-arylpiperazin-2-ylmethyl) amines, either in the form of cis isomers either as trans isomers, the 6-aryl group being in the equatorial position.

These new compounds can be salified after addition with mineral or organic acids used in therapy such as hydrochloric acid, maleic acid for example.

A synthetic example for the compounds MMS11 (trans isomer) and MMS 13 (cis isomer) can be transposed for all the derivatives.

4-chloro-ss-nitrostryrene
In a 1 liter flask, introduce 20 g of 4-chlorobenzoic aldehyde, 5 g of dry ammonium acetate. 2 ml of acetic anhydride, 60 ml of glacial acetic acid and 25 ml of nitromethane. Heat the mixture at 90 "C for 4 hours. Then add 10 ml of water. Let cool. The compound crystallizes in the medium. The nitrostyrene is isolated by filtration; wash with a little ethanol and dry. The product obtained is sufficiently pure for the rest of the synthesis Yield: 73%, PF: 118-1200C.

1- (4-chlorophenyl) -2-nitroethyl (methyl) amine, HCl
Dissolve 0.037 moles of nitrostyrene in 80 ml of THF. Add 0.21 mole of methylamine. Shake the whole for 30 min. Acidify with concentrated hydrochloric acid to pH1. Filter the precipitate obtained. Wash with ether and air dry. YId: 55%, PF: 2350C 2- (4-chlorophenyl) -N-methylethylene-1,2-diamine
In a Erlenmeyer flask suspend 10 g of 1- (4-chlorophenyl) -2 -nitroethyl (methyl) amine, HCl in 200 ml (of a mixture of 100 ml of ethanol 950 and 100 ml of hydrochloric acid at 17 Cool the Erlenmeyer flask in ice, add 20 g of zinc in small portions, shake for 15 min, filter the excess zinc.

 Concentrate the filtrate under vacuum. Then add 150 ml of water and basify with excess ammonia. Extract twice with 100 ml of dichloromethane. Wash the organic phases with water and dry them with magnesium sulfate.

Evaporate to dryness under vacuum. An oily residue is obtained. Yid: 95%.

N- [2-tert-butoxycarboxamido-1- (4-chlorophenyl) ethyl] -N-methylcarba
tert-butyl mat
In a 250 ml flask dissolve the preceding compound in 150 ml of
dichloromethane. Then add 2.2 eq. di-tert-butyl dicarbonate.

Leave to stir for 30 min. at room temperature. Evaporate under vacuum
the solvent and recover the remaining white precipitate in ether. Filter,
dry the white crystals. Yid: 90%.

N1 (4ch1orophenyl) 2 (teubutoxyNethy1carboxamido) iN-methyi
tert-bu ty le carbamate.

In a 100 ml flask put 0.45 g of sodium hydride and wash it with 3 ml of
toluene. Add 12 ml of dimethylformamide, then add 2.0 g of the compound
above, 2g dissolved in 20 ml of DMF. Shake 30 min., Then add 0.62 ml of
ethyl bromide in solution in 12 ml of DMF. Leave to stir for 30
min. at room temperature, then heat between 60-700C for 2 hours.

-Add 100 ml of water and extract with 100 ml of ethyl acetate. Wash phases
organic with water and dry over magnesium sulfate. Evaporate under vacuum
the filtrate; an oily residue is obtained. YId: 60%
1- (4-chlorophenyl) -N'-ethyl-N-methylethylene-1,2-diamine
Dissolve 3.0 g of the above compound in 15 ml of trifluoroacetic acid. Shake
vigorously for 30 min. Then evaporate the acid in vacuo. Recover the
oily product in 50 ml of chloroform and basify with ammonia
concentrated by adding it dropwise cold. Extract with chloroform. Wash
the organic phases with water and dry them over magnesium sulfate.

 Evaporate under vacuum. The residue obtained is oily. YId: 97%.

6- (4-chlorophenyl) -4-ethyl-1-methylpiperazine-2-carbonitrile
Dissolve 1.7 mmol of the above compound in 6 ml of benzene. Add 1.1 eq.

of 2,3-dibromopropionitrile when cold between 0-50C. Then add 1.5 eq. of
diisopropylethylamine. Let the reaction medium return to temperature
ambient and shake for 10 hours. Filter the diisopropylethylamine hydrochloride and
concentrate the organic phase. Take up the evaporation residue with 20 ml of water
and extract twice with 20 ml of dichloromethane. Chromatograph the extract
organic on silica column the two isomers are separated by
chromatography on a silica column. (mobile phase: hexane-ether- 20:80)
Trans isomer Rf: 0.7; Oily product, Yield: 38%
Cis isomer: Rf: 0.4; Oily product, Yield: 23% t6- (4-chlorophenyl) -4-ethyl-1-methylpiperazin-2-ylmethyl} amine (trans isomer and cis isomer)
To 500 mg of the preceding product add 5 equivalents of lithium aluminum hydride in 30 ml of THF. Add a solution of 1.5 mmol of the above product in 20 ml of THF drop by drop. Leave in contact for 1 hour. at room temperature. Then add to OOC, drop by drop, 2 ml of water and 2 ml of 1N sodium hydroxide. Remove the precipitate by filtration; the filtrate is extracted twice with 30 ml of dichloromethane. Dry the organic phase over sodium sulfate and evaporate the filtrate. Oily products, Yield: 95% methyl 4-aminosalicylate
Suspend 30.0 g (0.2 mole) of p-amino-salicylic acid in 200 ml of absolute methanol. Add 40 ml of concentrated sulfuric acid when cold. Heat 12 hours at reflux. Cool and basify with a 10% aqueous sodium carbonate solution. Filter and wash the crystals obtained with water. To dry. Yid: 95%, PF 1200C.

Methyl 4-acetamido salicylate
Add to OOC, 47 ml of acetic anhydride to 33.2 g of the preceding ester. Stir for 3 hours at room temperature then add 100 ml of water, filter and wash the crystals obtained with water. To dry. Yield: 90%, PF: 1520C methyl 4-acetamido-2-ethoxybenzoate
Dissolve 10.4 g of the preceding hydroxyester in 30 ml of dimethylformamide.

Add 21.2 g of potassium carbonate and 15.2 ml of dimethyl sulfate. Heat at 50 "C for 6 hours. Pour the reaction mixture into water. Filter the precipitate and recrystallize it from a toluene-hexane mixture (50:50). Yield: 97%,
PF: 1520C.

Methyl 4-acetamido-5-chloro-2-ethoxybenzoate
Dissolve 26.5 g of the above ester in 75 ml of dimethylformamide. Add 15.52 g of N-chlorosuccinimide. Heat at 700C for 2 hours. The mixture is poured into water. Filter the precipitate and wash it with water. Recrystallize from methanol. YId: 97%, FP: 1430C 4-acetamido-5-chloro-2-ethoxybenzoic acid
Dissolve 4.4 g of sodium hydroxide in 75 ml of water and 40 ml of methanol. Add 27.2 g of previous ester. Heat at 60 "C for 1 hour. Cool the solution and evaporate the methanol. Resume with water and acidify with hydrochloric acid. The precipitate formed is filtered. Wash the precipitate with water and recrystallize it from ethanol Yield: 73%, PF: 1700C.

4-amino-5-chloro-2-ethoxybenzoic acid
Dissolve 2.2 g of soda in 10 ml of water and 5 ml of ethanol. Add the previous acid and heat at reflux for 5 hours. Cool the solution and neutralize with hydrochloric acid. Filter the precipitate, wash with water and recrystallize from methanol. YId: 98%, PF: 1680C.

Preparation of benzamides
Dissolve 1 mmol of substituted benzoic acid in 15 ml of acetone. Add 1.2 eq. Drop by drop. of triethylamine, then at -150C, 1.05 eq. ethyl chloroformate (1.05 mmol in 5 ml acetone). Shake 30 min. at -150C. Add 1.05 eq drop by drop. piperazine amine in solution in 5 ml of acetone. Let the reaction medium return to room temperature and stir for 2 hours. Filter the triethylamine hydrochloride and concentrate the organic phase. Take up the evaporation residue with 20 ml of water and extract twice with 20 ml of dichloromethane. Acidify the combined organic phases with 3N hydrochloric acid, then basify the aqueous phase with an aqueous 10% potassium bicarbonate solution. Extract with dichloromethane. Dry the organic phase with magnesium sulfate and concentrate in vacuo.

4 amino-5-chloro-N-ff6- (4-chlorophenyl) -4-ethyl-1-methylpiperazin -2-yl) methyl) -2-ethoxybenzamide (trans isomer) MMS11
Crystallization takes place in ethyl acetate / ether (1: 2), recrystallization takes place in ethyl acetate. Yid: 49% FP: 1550C. The 4-chlorophenyl substituent is in an equatorial position.

1H-NMR (CDCl3) = 1.05 (t, 3H, CH3-CH2-N); 1.49 (t, 3H, CH3-CH2-0); 2.05-2.43 (m, 7H,
CH3-CH2-N, CH3-N, HSax, H3ax); 2.65-2.93 (m, 2H, H5eq, H3eq); 3.04-3.13 (m, 1H, H2); 3.61-3.72 (m, 2H, CH2-NCO); 3.81-3.91 (m, 1H, H6ax); 4.12 (q, 2H, CH3-CH2-O); 6.28 (s, 1H, Ha); 7.26-7.38 (m, 4H, arom); 8.03 (s, 1 Hech, HNCO); 8.12 (s, 1H, H6).

4-amino-S-chloro-N-ff6- (4-chlorophenyl) -4-ethyl-1-methylpiperazin- 2-yl} methyl} -2-ethoxybenzamide (cis isomer) MMS13
Crystallization takes place in ethyl acetate. Yid: 58%, PF ": 196" C.

The 4-chlorophenyl substituent is in an equatorial position.

 1H-NMR (CDCl3) = 1.05 (t, 3H, CH3-CH2-N); 1.48 (t, 3H, CH3-CH2-O); 1.99 (t, 1H, HSax); 2.10-2.22 (m, 4H, CH3-N, H3ax); 2.36 (q, 2H, CR '. -CH 2-N); 2.51-2.58 (m, 1H, H2); 2.82-2.98 (m, 2H, HSeq, H6ax); 3.33 (dt, 1H, H3eq); 3.50-3.63 (m, 1H, CH2-NCO); 3.82 (dd, 1H, CH2-NCO); 4.17-4.22 (m, 2H, CH3-CH2-O); 4.36 (s, 2H, NH2); 6.34 (s, 1H, Ha); 7.26-7.41 (m, 4H, arom); 8.04-8.13 (m, 2H, H6, HNCO).

Among the other compounds prepared, the structures of particular interest are 4-amino-5-chloro-N- {{6- (4-chlorophenyl) -4-ethyl- 1-methylpiperazin-2-yl J methyl J -2-methoxybenzamide (isomer trans) MMS 10 4-amino-5-chloro-N- {{6- (4-chlorophenyl) -4-ethyl- 1-methylpiperazin-2-yl J methyl) -2-methoxybenzamide (cis isomer) MMS 12 4- amino-5-chloro-2-methoxy-N- {{6- (4-methoxyphenyl) -4-ethyl- 1-methylpiperazin-2-yl} methyl) benzamide (trans isomer) MMS14 4-amino-5- chloro-2-ethoxy-N- {{6- (4-methoxyphenyl) -4-ethyl- 1-methylpiperazin 2-yl) methyljbenzamide (trans isomer) MMS 15 4-amino-5-chloro-2-methoxy-N- {{6 - (4-methoxyphenyl) -4-ethyl - 1 -methyl- piperazin-2-yl J methyl J benzamide (cis isomer) MMS16 5- (aminosulfonyl) -N- {{6- (4-chlorophenyl) - 4-ethyl- 1-methylpiperazin-2-yl J methyl) -2-methoxybenzamide (trans isomer) MMS17 4-amino-5-chloro-N- {{6- (4-fluorophenyl) -4-ethyl-1 -methylpiperazine -2-yl J methyl) -2 -methoxybenzamide (trans isomer) MMS18 4-amino-5-chloro-N- {{6- (4-fluorophenyl) -4-ethyl- 1 -methylpiperazin-2-yl J methyl) -2-methoxybenzamide (cis isomer) MMS19 4-amino-5-chloro-2-ethoxy-N- ff 6- (4-fluorophenyl) -4-ethyl- 1-methylpiperazin-2 yl} methyl) benzamide (cis isomer) MMS20 4-amino-5-chloro- 2-ethoxy-N- I f 6- (4-fluorophenyl) -4-ethyl- 1-methylpiperazin-2- yl) methyl) benzamide (trans isomer) MMS21
The compounds synthesized were subjected to a pharmacological study.

The purpose of this study is to search, using the technique of specific bonds, for the interaction of the synthesized benzamides (MMS series) with the 5-HT3 serotoninergic receptors.

The preparations used are membranes of the entorhinal cortex (5-HT3 receptors) and of the striatum of rats (D2 receptors) (Wistar rats weighing approximately 300 g, 53940 Le
Genest St Isle) prepared respectively according to ISHII K. KANO T., ANDO J. YOSHIDA H., Eur. J. Pharmacol. 1986, 123, 271-278; TERAI M., HIDAKA K., NAKAMURA Y, Eur. J.

Pharmacol., 1989, 173, 177-182; TEITLER M., WEISBERT E., Biotech Update (Dupont
NEN), 1991, 6, 1-11.

The membrane fractions are filtered (GF / B Whatman filters) and washed 3 times using a Cell Harvester filtration system (Brandel). Filters are placed in vials containing scintillating liquid (Form 989; Dupont NEN) and counted using a liquid scintillation counter (LS 6000 Beckman).

The experimental conditions are
Protocol and expression of results
For the semi-quantitative study, the molecules are tested at two concentrations: 10-7M and 10-SM (n = 3). The quantitative study was carried out using 10 concentrations (n = 2)
For each receptor, serotonergic 5-HT3 or dopaminergic D2, the respective reference molecule is MDL 72222 and butaclamol; each reference molecule is tested at 8 concentrations (n = 2).

Control measurements are carried out in the absence of a molecule.

The specific binding is calculated by the difference between the total binding and the specific binding determined in the presence of an excess of non-radioactive ligand.

The IC50 values (inhibitory concentration 50% specific binding) are calculated from the Hill equation:
E / Emax = [Dln / [D] n + Kn
E = specific bond
D = concentration of the molecule
K = dissociation constant
n = Hill coefficient
The parameters are determined by "curve-fitting" using the SIGMA PLOTIEL software
The results are expressed in percentage of specific binding and in percentage of inhibition of this binding compared to the control without molecule. Values are presented as means + esm (standard error to the mean) of n independent measurements.

Results
The percentages of inhibition obtained with the MMS compounds on the D2 receptor are much lower than those obtained with butaclamol.

Inhibition percentages obtained with the different molecules studied on the 5-HT3 receptor. The values of IC50 and the coefficient of
Hill (nH) obtained with the reference molecule: MDL 72222.

5-HT3 Receptor Molecules
MDL 72222 IC50 nH
51.9 nM 1.05
10-7M 10-5 M MMS10 75 114 MMSîl 67 112 MMS12 35 112 MMS13 43 108 MMS14 63 108
MMS15 53 107 MMS16 21 106 MMS18 55 109 MMS19 9 99
MMS20 56 111
For the quantitative study in view of the results obtained during the semi-quantitative analysis, four molecules were selected: these are the compounds MMS10, MMS11, MMS13 and MMS 21.

IC50 and Hill coefficient values determined for MMS 10, MMS 11,
MMS 13 and MMS 21 as well as for MDL 72222.

5-HT3 receivers
IC50 nH molecules
MMS 10 74nM 1.01 MMSll 57nM 0.85
MMS13 175nM 0.94
MMS21 189nM 1.14
MDL 72222 36nM 0.90
The recommended drugs include as active ingredient at least one MMS compound; they can be used in therapy when the pathology can be treated with compounds interacting with central and peripheral 5-HT3 receptors of the antiemetic type and of the antipsychotic type.

Claims (6)

1. New derivatives of N- {(1,4-dialkyl-6-arylpiperazin-2-yl) methyl Jbenzamides, in the form of cis or trans isomers, as well as their addition salts with mineral or organic acids, characterized in that they correspond to general formulas I or II.

The term "aryl" denotes non-heterocyclic aromatic groups of the phenyl type, substituted or not, as well as heterocyclic aromatic groups having 4 to 7 carbon atoms in the aromatic ring, and 1 to 4 heteroatoms which may be oxygen, nitrogen, sulfur, of the furan, pyridine, oxazole type.  I Cis isomer II Trans isomer - in which R1 is an aryl group  - in which X1 and / or X2 and / or X3 and / or X4 and / or X5 can be equal for example to H, C1, Br, F, CF3, CH3, NO2, OCH3, OC2H5.

- in which R1 can have the structure - in which R2 can be a hydrogen atom and an alkyl group, preferably methyl, ethyl or propyl. - in which R3 and / or R'3 can be a hydrogen atom or a carbonyl-alkyl group. The term "alkyl" refers to aliphatic hydrocarbon groups containing 1 to 12 carbon atoms, straight or branched chain. Preferred are lower alkyl groups, i.e., alkyl groups containing 1 to 3 carbon atoms. - in which - NR3 R'3 can be hydrogen. - in which R4 may be a hydrogen atom and an alkyl group, preferably methyl, ethyl or propyl. - in which R5 may be a hydrogen atom and an alkyl group, preferably methyl, ethyl or propyl. OCH3, OC2H5, S02NH2, SO2CH3, SO2C2H5. - in which X6 can be equal for example to H, C1, Br, F, CF3, CH3, NO2, NH2, The addition salts with mineral or organic acids can for example be the salts formed with hydrochloric acid, maleic acid. 2. Method for obtaining the derivatives of formula I or II according to claim 1, characterized in that it consists in carrying out a condensation of orthoalkoxybenzoic acid with different substitutions and (1,4-dialkyl-6arylpiperazin-2 -yl methyl) amines. 3. Method for obtaining the derivatives according to any one of claims 1 to 2 characterized in that it consists in using (1,4-dialkyl-6-arylpiperazin-2-yl methyl) amines either in the form of the cis isomer is in the form of a trans isomer, the 6-aryl group being in the equatorial position. 4. Method for obtaining the derivatives according to any one of claims 1 to 3 characterized in that they can be salified after addition with mineral or organic acids, such as hydrochloric acid, maleic acid for example. 5. Compounds according to any one of claims 1 to 5, characterized in that they can have a particularly advantageous structure, namely 4-amino-5-chloro-N- {6- (4-chlorophenyl) -4-ethyl- 1 -methylpiperazin-2-yl J methyl J -2-methoxybenzamide (trans isomer) MMS10 4-amino-5-chloro-N- {{6- (4-chlorophenyl) -4-ethyl- 1 -methylpiperazin-2-yl J methyl -2-methoxybenzamide (cis isomer) MMS12 4-amino-5-chloro-N- {{6- (4-chlorophenyl) -4-ethyl- 1-methylpiperazin-2-yl J methylj -2-ethoxybenzamide (isomer trans) MMS11 4-amino-5-chloro-N- {{6- (4-chlorophenyl) -4-ethyl- 1-methylpiperazin-2-yl J methyl J-2-ethoxybenzamide (cis isomer) MMS13 4-amino-5 -chloro-2-methoxy-N- {{6- (4-methoxyphenyl) -4-ethyl- 1 -methylpiperazin-2-yl J methyl Jbenzamide (trans isomer) MMS14 4-amino-5-chloro-2- ethoxy-N- {{6- (4-methoxyphenyl) -4-ethyl-1-methylpiperazin- 2-yl} methyl} benzamide (trans isomer) MMS 15 4- amino-5-chloro-2-methox yN- {{6- (4-methoxyphenyl) -4-ethyl-1-methylpiperazin-2-yl} methyl} benzamide (cis isomer) MMS16 5- (aminosulfonyl) -N- {{6- (4-chlorophenyl) - 4-ethyl-1-methylpipe-razin-2-yI J methyl) -2-methoxybenzamide (trans isomer) MMS17 4-amino-5-chloro-N - {{6- (4-fluorophenyl) -4-ethyl- 1 -methylpiperazin-2-yl J methyl) -2-methoxybenzamide (trans isomer) MMS 18 4-amino-5-chloro-N- {{6- (4-fluorophenyl) -4-ethyl-1 -methylpiperazin-2-yl J methyl) -2-methoxybenzamide (cis isomer) MMS19 4-amino-5-chloro-2-ethoxy-N- {{6- (4-fluorophenyl) -4-ethyl- 1-methylpiperazin-2-yl} methyl} benzamide (cis isomer) MMS20 4-amino-5-chloro-2-ethoxy-N- ({6- (4-fluorophenyl) -4-ethyl-1-methylpiperazin-2- ylJmethylJbenzamide (trans isomer) MMS21 6. Medicines characterized in that they comprise as active ingredient at least one compound according to any one of the formulas I or II according to claims 1 and 5, usable in therapy when the pathology can be treated with compounds interacting with central and peripheral 5-HT3 receptors of the antiemetic and antipsychotic type.