DE10248925A1 - New compounds with dopaminergic and / or serotonergic activity - Google Patents

Abstract

The present invention relates to the novel compounds of 4- [2- (4-arylpiperazin-1-yl) ethoxy] benzo-1,2-diamine I, their derivatives in the form of benzoimidazole-2-thiones, benzoimidazoles, benzoimidazole-2 -one and benzotriazoles and the use of their pharmacologically acceptable salts as dopaminergic and serotonergic agents and the processes for their preparation.

Description

The present invention relates to novel compounds and their use as dopaminergic and serotoninergic agents and the processes for their preparation.

In human medicine are dopaminergic and serotoninergic pharmaceuticals are widely used today. dopaminergic and serotoninergic pharmaceuticals came in the form of in the early 1950s Chlorpromazine, a dopamine antagonist, launched on the market for the first time. To date, various antagonists and agonists have found wide Diffusion in human medicine for the treatment of numerous diseases such as Parkinson's, schizophrenia and various neurohumoral Disorders.

In the scientific literature there are various review articles on this topic: Glennon, R.A. and Westkaemper, R.B. Trends in Receptor Research, Pharmaco Chemistry Library Vol. 18, p. 185 - 207, El sevier, 1989; Horn, A.S, Comprehensive Med. Chem., Ed. Hansch, C., Vol. 3, p. 231 - 290, Pergamon Press, 1990; Saxena, P.R., Clarke, D.E., Ford, A.P.D.W., Mylecharane, E.J., Tyers, M.B., Barnes, J.C., Yocca, F.D. Pharmacological Sciences: Perspectives for Research and Therapy in the Late 1990s, p. 231, ed. Bikhauser Verlag; Howard, H.R. Exp. Opin. Ther. patent (1997) 7 (4) p. 353-369; Kerrigan, F. Exp. Opin. Ther. Patents (1998) 8 (4) p. 439-460; Lie'geois, J-F., Eyrolles, L., Bruhwyler, J., Delarge, J. Curr. Med. Chem. 5, p. 77-100, 1998; Nakazato, A., Okuyama, S. Exp. Opin. Ther. Patents (2000) 10 (1) p. 75-98.

In addition to their positive properties at least have the substances currently used sometimes numerous disadvantages in the form of undesirable side effects. by virtue of these side effects grew the need for development new pharmaceuticals that minimize these side effects are reduced.

The aim of the invention was therefore the provision of new substances with a dopaminergic and / or serotoninergic activity.

This task is done by the new Compounds according to independent claims 1 and 2 and the process for their preparation according to claims 3 to 14 solved. The use of the new substances is defined in claims 15 and 16. The wording of all claims will hereby incorporated by reference into the content of this description.

In this invention new compounds, some of which are both dopaminergic and serotoninergic activity have, and described their synthesis.

These novel compounds have valuable pharmacological properties in the form of selective effects on the dopaminergic and serotonergic system by stimulating, predominantly D ₂ , dopamine receptors and 5HT _1A serotonin receptors.

The present invention encompasses the new Connections 1 to V. The new connections are through the following structural formulas:

4-[2-(4-Arylpiperazin-1-yl)-ethoxy]-benzo-l,2-diamin I,
5-[2-(4-Arylpiperazin-1-yl)-ethoxy]-1H-benzoimidazol II;
5-[2-(4-Arylpiperazin-1-yl)-ethoxy]-1,3-dihydrobenzoimidazol-2-thion III;
5-[2-(4-Arylpiperazin-1-yl)-ethoxy]-1,3-dihydrobenzoimidazol-2-on IV und
6-[2-(4-Arylpiperazin-1-yl)-ethoxy]-1H-benzotriazol V, wobei Aryl ein Element der Gruppe Phenyl, 2-Methoxyphenyl, 3-Methoxyphenyl, 4-Methoxyphenyl, 2-Chlorophenyl, 3-Chlorophenyl, 4-Chlorophenyl und 3-Trifluoromethylphenyl ist. 1

4- [2- (4-arylpiperazin-1-yl) ethoxy] benzo-1,2-diamine I,
5- [2- (4-arylpiperazin-1-yl) ethoxy] -1H-benzoimidazole II;
5- [2- (4-arylpiperazin-1-yl) ethoxy] -1,3-dihydrobenzoimidazol-2-thione III;
5- [2- (4-arylpiperazin-1-yl) ethoxy] -1,3-dihydrobenzoimidazol-2-one IV and
6- [2- (4-Arylpiperazin-1-yl) ethoxy] -1H-benzotriazole V, where aryl is an element from the group phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl , 4-chlorophenyl and 3-trifluoromethylphenyl.

The basic synthetic route of compound I is in 2 depicted from top to bottom and can be described as follows for the following reactions starting from nitrophenol XII: alkylation 1> reduction 1>nitration>hydrolysis> alkylation 2> reduction 2.

Starting from the commercially available Nitrophenol XII is obtained by a first alkylation XI, from which subsequently results from a first reduction X. By subsequent nitriding X forms IX, which is converted to VII by hydrolysis becomes. VII is reacted with VIII to VI as alkylation reagent, from which the target molecule I emerges through a second reduction.

This target molecule is identified by four different ones Modifications to the new compounds II, III, IV and V implemented.

Figure 2

In the first alkylation step, the compound 1- (2-chloroethoxy) -4-nitrobenzene XI starting from nitrophenol XII by an alkylation reaction with 1,2-dichloroethane in an organic solvent from the group methyl ethyl ketone, acetonitrile, DMF, toluene and / or xylene in the presence an inorganic base from the group Li, Na, K, CaCO _{3 obtained} at elevated temperature.

In the subsequent reduction step Compound 1- (2-chloroethoxy) -4-nitrobenzene XI with zinc dust in a mixture of acetic acid and acetic anhydride converted to N- [4- (2-chloroethoxy) phenyl) acetamide X.

In the following nitration N- [4- (2-Chloroethoxy) phenyl) acetamide X by direct nitration with boiling 20% nitric acid converted to N- [4- (2-chloroethoxy) -2-nitrophenyl] acetamide IX.

Then N- [4- (2-chloroethoxy) -2-nitrophenyl] acetamide IX is converted to 4- (2-chloroethoxy) -2- by hydrolysis in a boiling 4N inorganic acid, preferably HCl, HBr or H ₂ SO ₄ . nitrophenylamine VII hydrolyzed.

In the subsequent alkylation step the compounds of the general formula 4- {2- [4-arylpiperazin-1-yl] ethoxy} -2-nitrophenylamine VI starting from the commercially available piperazines VIII (where Aryl an element from the group phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 3-trifluoromethylphenyl) with 4- (2-chloroethoxy) -2-nitrophenylamine VII in an alkylation reaction in the presence of an inorganic Base, preferably sodium carbonate and / or potassium iodide, at elevated temperature receive.

In the final reduction step the compounds of the general formula 4- [2- (4-arylpiperazin-1-yl) ethoxy] benzo-1,2-diamine I by reducing the compounds of the general formula 4- {2- [4-arylpiperazin-1-yl] ethoxy} -2-nitrophenylamine VI using Raney nickel in a mixture of one or more alcohols, preferably methanol, ethanol, n-propanol and / or i-propanol, and a chlorinated hydrocarbon, especially dichloroethane, prepared in the presence of hydrazine hydrate.

By heating the connections of the general formula I with

• a) formic acid for the Production of benzoimidazoles (II) or
• b) carbon disulfide, XOH (X = Li, Na, K, R ₄ N; R = alkyl) and an alcohol from the group consisting of methanol, ethanol, n-propanol and / or i-propanol for the preparation of benzoimidazole-2-thiones (III-1 to 8) or
• c) 1,1'-carbonyldiimidazole in an aprotic organic solvent, preferably acetonitrile, for the Production of benzoimidazol-2-ones (IV-1 to 8) or
• d) a nitrite MNO ₂ (M = Li, Na, K) in a weak acid, preferably acetic acid or propionic acid, for the preparation of benzotriazoles (V-1 to 3), the compounds of general formula II, III, IV and V manufactured ( 3 ).

Figure 3

IR, ¹ H NMR and mass spectroscopic investigations confirm the structures of the newly produced compounds.

All new compounds were tested for their in vitro binding affinity for the D ₁ and D ₂ dopamine and 5HT _1A serotonin receptors. Table 1 shows the results of the measurements of the affinities and selectivities of the new ligands for binding to the D, and D ₂ dopaminergic and 5HT _1A serotoninergic receptors.

Table 1

The stated measured values correspond to the mean values of three independent experiments, the triplicate with eight competing ligand concentrations in the range from 10 ^-4 to 10 ^-10 M and 0.2 nM on [ ³ H] SCH 23390 and [ ³ H] spiperone and 0.6 nM on [ ³ H] -8-OH-DPAT were carried out. The affinity of the ligands is shown in the form of the inhibition constants (Ki) in nM.

[ ³ H] SCH 23390 (D ₁ -selective), [ ³ H] spiperone (D ₂ -selective) and B-OH- [ ³ H] DPAT (5NT _1A -selective) were used as radioligands (Kosti, S. et al. Pharm. Forsch., Drug Res. 44, 697-702, 1994; Hojer, D., Engel, G., Kalkman, HO, Eur. J. Pharmacol. 118, 13-23, 1985).

Freshness, from the hippocampus and Cauda, synaptosomal membranes isolated from cattle were used Obtaining dopamine and serotonin receptors.

The following is the method according to the invention as well as the connections through detailed description of special embodiments as well as explained by examples. In these embodiments, individual Features of the invention alone or in combination with other features be realized. The particular embodiments described are for explanation only and for better understanding of the invention and are not to be understood in any way restrictive.

Experimental and examples

1. Synthesis of 4- [2- (4-arylpiperazin-1-yl) ethoxy] benzo-1,2-diamine I ( 2 )

a) Method for alkylation of 4-nitrophenol XII

To a solution of 4-nitrophenol XII (0.5 mol) in 350 ml of methyl ethyl ketone became 60 g with stirring (0.5 mol) anhydrous potassium carbonate and 150 ml 1,2-dichloroethane added. The reaction mixture was refluxed with stirring for 36 h. After this At the end of the reaction, the reaction mixture was brought to room temperature chilled and poured into 1 liter of water. The reaction products were 3x with extracted 300 ml of methylene chloride. After removing the solvent the crude product was recrystallized from 90% ethanol.

b) Reduction method of 1- (2-chloroethoxy) -4-nitrobenzene XI

0.25 mol of 1- (2-chloroethoxy) -4-nitrobenzene XI was dissolved in a mixture of 300 ml of acetic acid and 250 ml of acetic anhydride. The mixture was stirred and 195 g of zinc dust was added in three portions. The reaction mixture was heated to 80 ° C. in an oil bath with stirring. After the end of the reaction, after about 6 hours, the reaction mixture was filtered through a sintered glass filter, and the filtrate was then evaporated in vacuo. The crude product was recrystallized from ethanol.

c) Nitriding method of N- [4- (2-chloroethoxy) phenyl] acetamide X

Fine powdered N- [4- (2-chloroethoxy) phenyl] acetamide X (0.2 mol) was added portionwise to 300 ml of boiling 20% nitric acid stir added. After 1 h the reaction mixture was cooled and over 500 g crushed Poured ice. The precipitate was filtered and with cold water washed. The crude product was recrystallized from 90% ethanol.

d) Method of hydrolysis of N- [4- (2-chloroethoxy) -2-nitrophenyl] acetamide IX

0.1 mol of N- [4- (2-chloroethoxy) -2-nitrophenyl] acetamide IX were in 120 ml of 4N hydrochloric acid resuspended and for Refluxed for 4 h. The reaction solution was cooled to room temperature and over Night at 4 ° C cooled. The crystals were separated by filtration and from 90% Recrystallized ethanol.

e) General method for the alkylation of piperazines VIII.

To a solution of 20 mmol of 4- (2-chloroethoxy) -2-nitrophenylamine VII, 22 mmol of a piperazine VIII, 25 ml of dimethylformamide (DMF) was a mixture of 3.18 g of sodium carbonate and 1 g of potassium iodide with stirring added and 24 h at 80 ° C heated. After cooling the precipitate was discarded and the filtrate evaporated in vacuo. The residue was about Silica gel, chromatographically cleaned and from hot isopropanol recrystallized.

The connections of the general Formula VI:

4- [2- (4-phenylpiperazin-1-yl) ethoxy] -2-nitrophenylamine VI-1;
4- {2- [4- (2-methoxyphenyl) piperazin-1-yl] ethoxy} -2-nitrophenylamine VI-2;
4- {2- [4- (3-methoxyphenyl) piperazin-1-yl] ethoxy} -2-nitrophenylamine VI-3;
4- {2- [4- (4-methoxyphenyl) piperazin-1-yl] ethoxy} -2-nitrophenylamine VI-4;
4- {2- [4- (2-chlorophenyl) piperazin-1-yl] ethoxy} -2-nitrophenylamine VI-5;
4- {2- [4- (3-chlorophenyl) piperazin-1-yl] ethoxy} -2-nitrophenylamine VI-6;
4- {2- [4- (4-chlorophenyl) piperazin-1-yl] ethoxy} -2-nitrophenylamine VI-7;
4- {2- [4- (3-Trifluoromethylphenyl) piperazin-1-yl] ethoxy} -2-nitrophenylamine VI-8 were synthesized in the same manner using equimolar amounts of the corresponding starting compound VIII, where Ar is an element of Phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 3-trifluoromethylphenyl.

f) General method to reduce the compounds VI

0.4 - 0.5 g Raney nickel was in small quantities with stirring to a solution from 6.5 mmol of the nitro compound VI in 12 ml of ethanol, 12 ml of 1,2-dichloroethane and 2 ml (20 mmol) hydrazine hydrate added at 30 ° C. After the full addition Raney nickel, the mixture was in a water bath for 60 min. on 50 ° C heated and then via Celite filtered. The filtrate was evaporated in vacuo and the crude product for the further syntheses used.

Compounds of the general formula I:
4- [2- (4-phenylpiperazin-1-yl) ethoxy] benzo-1,2-diamine I-1;
4- {2- [4- (2-methoxyphenyl) piperazin-1-yl) ethoxy} benzo-1,2-diamine I-2;
4- {2- [4- (3-methoxyphenyl) piperazin-1-yl) ethoxy} benzo-1,2-diamine I-3;
4- {2- [4- (4-methoxyphenyl) piperazin-1-yl) ethoxy} benzo-1,2-diamine I-4;
4- {2- [4- (2-chlorophenyl) piperazin-1-yl) ethoxy} benzo-1,2-diamine I-5;
4- {2- [4- (3-chlorophenyl) piperazin-1-yl) ethoxy} benzo-1,2-diamine I-6;
4- {2- [4- (4-chlorophenyl) piperazin-1-yl) ethoxy} benzo-1,2-diamine I-7; 4- {2- [4- (3-Trifluoromethylphenyl) -piperazin-1-yl) -ethoxy} -benzo-1,2-diamine I-8 were prepared in the same way using equimolar amounts of the corresponding starting compounds VI-1 bis 8 synthesized.

2. Synthesis of compounds II, III, IV and V ( 3 )

a) General method for the synthesis of 1H-benzoimidazoles II

2 mmol of the diamine I was heated together with 5.6 mmol of 96% formic acid to 100 ° C. for 2 h. After cooling to room temperature, 5 ml of 10% sodium hydrogen carbonate solution were added, the product was extracted with methylene chloride and concentrated in vacuo. The resulting 1H ben Zoimidazole was purified by chromatography and recrystallized from hot ethanol.

The compounds of the general formula II:
5- [2- (4-phenylpiperazin-1-yl) ethoxy] -1H-benzoimidazole II-1;
5- {2- [4- (2-methoxyphenyl) piperazin-1-yl] ethoxy} -1H-benzoimidazole II-2;
5- {2- [4- (3-methoxyphenyl) piperazin-1-yl] ethoxy} -1H-benzoimidazole II-3;
5- {2- [4- (4-methoxyphenyl) piperazin-1-yl] ethoxy} -1H-benzoimidazole II-4;
5- {2- [4- (3-Trifluoromethylphenyl) piperazin-1-yl] ethoxy} -1H-benzoimidazole II-5 were synthesized in the same way using equimolar amounts of the corresponding starting compound I-1 to 5.

b) General method of synthesis the benzoimidazole-2-thione III 0.28 ml carbon disulfide (5.8 mmol) and 0.28 g KOH in 0.6 ml water were added to 2 mmol of diamine I, previously dissolved in 5 ml ethanol added. After three hours Activated carbon was added to reflux and the entire suspension was added via Celite filtered. The solvent was removed in vacuo, the residue resuspended in 10% sodium hydrogen carbonate solution, with methylene chloride extracted and concentrated in vacuo. The resulting benzoimidazole-2-thione was purified by chromatography and recrystallized from hot ethanol.

The compounds of the general formula III:
5- [2- (4-phenylpiperazin-1-yl) ethoxy] -1,3-dihydro-benzoimidazol-2-thione III-1;
5- {2- [4- (2-methoxyphenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-thione III-2;
5- {2- [4- (3-methoxyphenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-thione III-3;
5- {2- [4- (4-methoxyphenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-thione III-4;
5- {2- [4- (2-chlorophenyl) piperazin-l-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-thione III-5;
5- {2- [4- (3-chlorophenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-thione III-6;
5- {2- [4- (4-chlorophenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-thione III-7;
5- {2- [4- (3-Trifluoromethylphenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-thione III-8 were prepared in the same manner using equimolar amounts of the corresponding starting compound I- 1 to 8 synthesized.

c) General Method for the Synthesis of Benzoimidazol-2-ones IV 1.4 g of 1,1'-carbonyldiimidazole (8.6 mmol) were added in portions to a stirred solution of 12 ml of dry acetonitrile and 0.72 g of the diamine 1 ( 2 mmol) added at room temperature. After the addition was complete, the reaction mixture was stirred for a further 30 min. stirred and then stored at 4 ° C overnight. The solvent was removed in vacuo and the residue was recrystallized from a chloroform / ethanol mixture. The compounds of the general formula IV:
5- [2- (4-phenylpiperazin-1-yl) ethoxy] -1,3-dihydrobenzoimidazol-2-one IV-1;
5- {2- [4- (2-methoxyphenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-one IV-2;
5- {2- [4- (3-methoxyphenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-one IV-3;
5- {2- [4- (4-methoxyphenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-one IV-4;
5- {2- [4- (2-chlorophenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-one IV-5;
5- {2- [4- (3-chlorophenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-one IV-6;
5- {2- [4- (4-Chlorophenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-one IV-7;
5- {2- [4- (3-Trifluoromethylphenyl) piperazin-1-yl] ethoxy} -1,3-dihydrobenzoimidazol-2-one IV-8 were prepared in the same manner using equimolar amounts of the corresponding starting compound I- 1 to 8 synthesized.

d) The general method for the synthesis of 1H-benzotriazoles V

To a chilled solution of 0.24 g sodium nitride (3.47 mmol) in 0.36 ml of water, a mixture of 0.8 g of the Pour Diamins I (3.1 mmol) in 0.7 ml acetic acid and 1.4 ml water. After the full The reaction mixture was added for a further 10 to 15 min. on Heated to 70 ° C and subsequently cooled to room temperature. The solution was neutralized with 10% sodium carbonate solution, with methylene chloride extracted and then concentrated in vacuo. The resulting benzotriazoles were purified by chromatography and recrystallized from hot ethanol.

The compounds of the general formula V:
6- [2- (4-phenylpiperazin-1-yl) ethoxy] -1H-benzotriazole V-1;
6- {2- [4- (2-methoxyphenyl) piperazin-1-yl] ethoxy} -1H-benzotriazole V-2;
6- {2- [4- (3-Trifluoromethylphenyl) piperazin-1-yl] ethoxy} -1H-benzotriazole V-3 were synthesized in the same manner using equimolar amounts of the corresponding starting compound I-1 to 3.

3. Preparation of the membranes, radioligands Binding assays and data analysis

The synaptosomal membranes for the radioligand binding assay were described in (Soskic at al. J. Pharm. Pharmacol. 43, 27-31, 1990) described from the nuclei of fresh cauda and the hippocampus obtained from cattle [ ³ H] SCH23390 (specific activity 80 Ci per mM), [ ³ H] spiperone (specific activity 70.5 Ci per mM) and 8-OH- [ ³ H] DPAT (specific activity 223 Ci per mM) were used to label the D ₁ , D ₂ and 5-HT _1A receptors (Amersham Biosciences GmbH, Braunschweig, Germany).

a) [ ³ H] spiperone receptor binding assay

The [ ³ H] spiperone binding was examined at membrane protein concentrations of 0.7 mg per ml in a solution containing 1 mM EDTA, 4 mM magnesium chloride, 1.5 mM calcium chloride, 5 mM potassium chloride, 120 mM sodium chloride and 25 mM Contains Tris-HCl. The experiment was carried out at 37 ° C at a pH of 7.4 for 20 min. performed in a total volume of 1 ml. The binding of the radioligand to 5-HT ₂ receptors was prevented by 50 nM ketanserin. The Ki values were determined by competing binding to 0.2 mM radioligands and 8-10 different concentrations of each new compound from II-V in the range of 10 ^-4 -10 ^-10 mol. Nonspecific binding was measured in the presence of 1 mM (+) - butaclamol. The reaction was stopped by rapid filtration through a Whatman GF / C filter, which was then washed three times with 5 ml of ice-cold incubation buffer. Each measurement was determined in triplicate. The radioactivity retained was measured by placing the dry filter in 10 ml of a toluene-based scintillation solution and counting in a scintillation counter (1219 Rackbeta Wallac) with an efficiency of 51-55% for tritium.

b) [ ³ H] SCH23390 receptor binding assay

The binding of [ ³ H] SCH23390 was examined using the same rapid filtration assay as described under a), but in the absence of ketanserin.

c) 8-OH- [ ³ H] DPAT receptor binding assay

The 8-OH- [ ³ H] DPAT bond was examined in a solution of the following composition:

1 mM EDTA, 4 mM magnesium chloride, 1.5 mM calcium chloride, 5 mM potassium chloride, 120 mM sodium chloride, 25 mM Tris-HCl as well as 10 μM nialamide and 0.1% ascorbic acid and a membrane protein concentration of 0.7 mg per ml, 0, 6 nM radioligands and various concentrations of the new molecules II to V to be tested in the range from 10 ^-10 -10 ^-4 M. The assay was carried out in a final volume of 0.5 ml at a pH of 7.4. The reaction vessels were kept for 20 min. incubated at 37 ° C and the reaction was stopped by vacuum filtration through a Whatman GF / B filter. The filters were washed three times with 5 ml of ice-cold 25 mM Tris-HCl buffer (pH 7.4), and the radioactivity bound to the filter was measured by liquid citation spectrometry. Specific binding to the 5-HT _1A receptor was defined as the difference between binding in the absence and in the presence of 10 µM 5-hydroxytryptamine.

Claims (16)

Compounds of the general structural formula

as well as the pharmacologically acceptable salts, where Ar is an element from the group: phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 3-trifluoromethylphenyl. Compounds of the general structural formula,

where Ar is an element from the group phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 3-trifluoromethylphenyl. A method of making a connection of the general formula II according to claim 1, characterized in that a Compound of general formula I according to claim 1 reacted with formic acid becomes. A process for the preparation of a compound of general formula III according to claim 1, characterized in that a compound of general formula I according to claim 1 with carbon disulfide, XOH (X = Li, Na, K, R ₄ N; R = alkyl) and one Alcohol of the group methanol, ethanol, n-propanol and / or i-propanol is reacted. A method of making a connection of the general formula IV according to claim 1, characterized in that a Compound of general formula I according to claim 1 with 1,1'-carbonyldiimidazole is reacted in an aprotic organic solvent. A process for the preparation of a compound of the general formula V according to claim 1, characterized in that a compound of the general formula I according to claim 1 is reacted with MNO ₂ (M = Li, Na, K) and a weak acid, preferably acetic acid or propionic acid becomes. A method of making a connection of the general formula I according to claim 1, characterized in that it by reduction of a compound of general formula VI according to claim 2 is manufactured. A method according to claim 7, characterized in that the Reduction with Raney nickel takes place. A process for the preparation of a compound of the general formula VI, characterized in that it is obtained by alkylating amines of the general formula VIII,

where Ar is an element from the group phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 3-trifluoromethylphenyl, with 4- (2-chloroethoxy) -2-nitrophenylamine VII

will be produced. A process for the preparation of a compound VII according to claim 9, characterized in that it is obtained by hydrolysis of acetanilide IX

will be produced. A process for the preparation of a compound IX according to claim 10, characterized in that it is obtained by nitrating acetanilide X

will be produced. A process for the preparation of a compound of formula X according to claim 11, characterized in that it by reduction and subsequent acetylation of the nitro compound XI

is made with zinc dust in a mixture of acetic acid and acetic anhydride. A process for the preparation of a compound XI according to claim 12, characterized in that it prepared by alkylation of 4-nitrophenol XII with 1,2-dichloroethane becomes. A method according to any one of claims 7 to 13 for the preparation of a compound of general formula I. according to claim 1, characterized in that by Alkylation of 4-nitrophenol XII with 1,2-dichloroethane a nitro compound XI, by reduction and subsequent acetylation of compound XI with Zinc dust in a mixture of acetic acid and acetic anhydride is an acetanilide X, an acetanilide IX by nitrating compound X, by hydrolysis Compound IX is 4- (2-chloroethoxy) -2-nitrophenylamine VII, by alkylation of amines of the general formula VIII (where Ar is an element from the group phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and 3-trifluoromethylphenyl) is a compound with compound VII of the general formula VI and finally by reducing the compound VI with Raney nickel compound I is prepared. The use of the compounds according to claim 1 for the treatment and / or prevention of suffering, in particular Nerve disorders, the compounds mediating a change in dopamine and / or serotonin Effect neurotransmission. Pharmaceutical composition or medicament, characterized in that they at least one compound according to claim 1 and optionally conventional auxiliaries contains.