HUP0500461A2 - Pyperazine derivatives of alkyl-oxindoles - Google Patents

Abstract

Piperazine derivatives of alkyl oxindoles (I) or their acid addition salts are new. Piperazine derivatives of alkyl oxindoles of formula (I) or their acid addition salts are new. R 1 and R 2H, halo, 1-7C alkyl, 1-7C alkoxy or trifluoromethyl; R 3H; R 4 and R 5linear or branched 1-7C alkyl or alkoxy, or H, halo, or trifluoromethyl; m : 1 - 4. An independent claim is included for the preparation of (I). [Image] ACTIVITY : CNS-Gen.; Antidepressant; Tranquilizer; Neuroleptic; Antimanic; Nootropic; Cerebroprotective; Vasotropic; Neuroprotective; Cardiovascular-Gen.; Hypotensive; Gastrointestinal-Gen. MECHANISM OF ACTION : 5-Hydroxytryptamine (5-HT 7) receptor binder; alpha 1 receptor binder; Sinaptosomal serotonin uptake inhibitor. The efficacy of 3-{4-[4-(3-chlorophenyl)-piperazin-1-yl]-butyl}-1,3-dihydro-2H-indol-2-one (a1) was tested for binding to 5-HT 7 receptor. For determination of 5-HT 7 receptor binding, human cloned receptors were used and 3 ETA -lizergic acid diethyl amide (LSD) (1 nM) and 3 ETA -prazosine (0.3 nM) were used as ligands. The measurements of non-specific binding were performed using clozapine (25 mu M) and prazosine (1 mu M). It was observed that (a1) showed a K i value of less than 100 M/l.

Description

The invention relates to novel substituted indol-2-one derivatives of general formula (I) and their salts, their preparation, pharmaceutical compositions containing these derivatives and the use of compounds of general formula (I) as pharmaceuticals, in which

R and R independently represent a hydrogen atom, a halogen atom, an alkyl group having 1-7 carbon atoms, an alkoxy group having an alkyl chain having 1-7 carbon atoms, or a trifluoromethyl group;

R represents a hydrogen atom;

R and R are independently hydrogen, halogen, trifluoromethyl, or a straight or branched alkyl or alkoxy group having 1 to 7 carbon atoms;

m has the value 1, 2, 3 or 4.

U.S. Patent No. 4,452,808 describes 4-aminoalkyl-indol-2-one derivatives that selectively act on the D2 receptor and are useful in the treatment of hypertension. Among the compounds protected by the patent, 4-[2-(di-N-propylamino)ethyl]-2(3H)-indolone is used in clinical practice for the treatment of Parkinson's disease.

European Patent No. 281,309 relates to indol-2-one derivatives containing an aryl-piperazinyl-alkyl substituent at position 5, which are useful for the treatment of psychotic disorders. Among the compounds covered by the patent, 5-[2-[4-(1,2benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, which exerts its effect through interaction with the D ₂ and 5-HT 1a and 5-HT ₂ receptors, is used in clinical practice as an antipsychotic.

European patent No. 376,607 describes indol-2-one derivatives substituted with an alkyl-piperazinyl-aryl group at position 3, which exert their effect on the 5-HTi _A receptor and can be used to treat central nervous system diseases.

International patent application WO 98/008816 relates to psychotropic indol-2-one derivatives containing a substituted alkylpiperazinyl, substituted alkylpiperidinyl or alkylcyclohexyl group in the 3-position. The application does not contain any teaching as to the activity profile of the described derivatives and mentions only the treatment of depression and anxiety as a therapeutic area.

In the 20th century, the acceleration of technical and social development means a constant need for adaptation for humans, which in unfavorable cases can lead to the development of adaptation disorders. These adaptation disorders are a very important risk factor for the development of mental or psychosomatic diseases, such as anxiety syndrome, stress disorder, depression, schizophrenia, diseases of the sensory organs, gastrointestinal diseases, cardiovascular diseases, and diseases of the excretory system.

Current therapy for these conditions primarily uses drugs that act via the benzodiazepine system (e.g. diazepam) or central 5-HT _1A receptors (e.g. buspirone, ziprasidone). In the case of psychosomatic conditions, anti-anxiety therapy is supplemented with antihypertensive (acting on α1 or α2 receptors) or anti-ulcer (acting as H1 receptor antagonists) drugs.

However, benzodiazepine-type anxiolytics have a number of unpleasant side effects. They are strongly sedative, impair concentration and memory, and have a muscle tone-reducing effect. The currently available anxiolytic agents (buspirone, selective serotonin reuptake inhibitors, SSRIs) only begin to exert their effect after 10-14 days of administration, and they also have anxiolytic effects in the initial period of administration. These side effects that impair quality of life significantly limit their scope of application.

In addition to the stress of adapting to the environment, another major problem of modern societies is the rapid aging of the population. Thanks to the achievements of modern medicine, life expectancy has increased, and the number of diseases that occur as a result of the aging process or develop in old age, especially mental illnesses, has increased dramatically. Finding a solution to the treatment of Alzheimer's disease, vascular dementia, and senile dementia has become a social problem.

As a result of the above processes, the demand for new effective drugs that can treat these diseases more effectively than currently available drugs has increased significantly.

The aim of our invention is to develop pharmaceutical active ingredients that have a more favorable effect profile than those currently used, do not exhibit the disadvantages and side effects listed above, and at the same time can be used to prevent or cure diseases of the central nervous system and the cardiovascular system.

The subject of our invention is new substituted indol-2-one derivatives of general formula (I), a process for their preparation, pharmaceutical compositions containing compounds of general formula (I), a process for the preparation of these pharmaceutical compositions, and the use of compounds of general formula (I) for the treatment of central nervous system diseases.

The basis of our invention is the surprising discovery that, unlike compounds of similar structure known in the prior art, the 3-alkyl-indol-2-one derivatives of general formula (I) bind significantly to both 5-ΗΤγ and ω receptors and significantly inhibit the synaptosomal reuptake of serotonin. It is therefore expected that their therapeutic applicability extends to the treatment of both central nervous system and cardiovascular diseases.

The invention relates to novel substituted indol-2-one derivatives of general formula (I) and their salts, their preparation, pharmaceutical compositions containing these derivatives and the use of compounds of general formula (I) as pharmaceuticals, in which < 2 ·

R and R independently represent a hydrogen atom, a halogen atom, an alkyl group having 1-7 carbon atoms, an alkoxy group having an alkyl chain having 1-7 carbon atoms, or a trifluoromethyl group;

R represents a hydrogen atom;

R and R are independently hydrogen, halogen, trifluoromethyl, or a straight or branched alkyl or alkoxy group having 1 to 7 carbon atoms;

m has the value 1, 2, 3 or 4.

In the present patent application, the term alkyl group means a straight or branched alkyl group having 1 to 7 carbon atoms, preferably 14 carbon atoms, for example methyl, ethyl, 1-propyl, 2-propyl, n-butyl, iso-butyl or tert-butyl.

The term halogen atom means a fluorine, chlorine, bromine or iodine atom, preferably a chlorine or bromine atom.

The term leaving group means an alkylsulfonyloxy or arylsulfonyloxy group, for example a methylsulfonyloxy or p-toluenesulfonyloxy group; or a halogen atom, preferably a bromine atom or a chlorine atom.

Pharmaceutically acceptable acid addition salts are non-toxic, pharmaceutically acceptable acid addition salts of compounds of general formula (I) with inorganic or organic acids. Examples of inorganic acids suitable for the formation of such salts are hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or sulfuric acid. Examples of organic acids which can be used are formic acid, acetic acid, propionic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, malonic acid, oxalic acid, mandelic acid, glycolic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or methanesulfonic acid. Also considered as pharmaceutically acceptable salts are carbonates and hydrogen carbonates.

A preferred group of compounds of formula (I) are those compounds in which R is hydrogen, halogen, or alkyl having 1-7 carbon atoms; R ² and R ³ are hydrogen; R ⁴ is hydrogen or halogen; R ⁵ is halogen; m is 4; and pharmaceutically acceptable acid addition salts thereof.

A further preferred group of compounds of general formula (I) are those derivatives in which R ¹ represents a hydrogen atom or a halogen atom; R ² , R ³ and R 4 represent a hydrogen atom; R ⁵ represents a halogen atom; m is 4; and their pharmaceutically acceptable acid addition salts.

Particularly preferred representatives of the compounds of general formula (I) are 3-{4-[4-(4-chlorophenyl)piperazin-1-yl]butyl}-6-fluoro-1,3-dihydro-277-indol-2-one, 3-{4-[4-(4-fluorophenyl)piperazin-1-yl]butyl}-1,3-dihydro-277-indol-2-one, 3-{4-[4-(4-chlorophenyl)piperazin-1-yl]butyl}-1,3-dihydro-277-indol-2-one, 3-{4-[4-(3-chlorophenyl)piperazin-1-yl]butyl}-1,3-dihydro-277-indol-2-one, 3-{4-[4-(3-chlorophenyl)piperazin-1-yl]butyl}-5-methyl-1,3-dihydro277-indol-2-one, 3-{4-[4-(4-Chloro-phenyl)-piperazin-1-yl]-butyl}-5-methyl-1,3-dihydro-277indol-2-one and 3-{4-[4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-butyl}-1,3-dihydro-277indol-2-one and their pharmaceutically acceptable acid addition salts.

A further subject of our invention is a process for the preparation of compounds of general formula (I).

According to variant (a), a compound of general formula (II), in which L represents a hydroxy group, is reacted with an alkyl or arylsulfonyl chloride in the presence of an organic base, and then the resulting compound, in which L represents an alkyl or arylsulfonyloxy group, m is 1, 2, 3 or 4, is reacted with a piperazine derivative of general formula (ITT) in the presence of an acid scavenger.

According to variant (b), a compound of general formula (V), where R ¹ , R ² , R ³ and R ⁴ are as defined above, is reacted with a compound of general formula (VI), in which m is 1, 2, 3 or 4, L is a leaving group, preferably a chlorine atom or a bromine atom, in the presence of a strong base.

The compound of formula (I), where R'-R ⁵ and m are as defined above, can be prepared by reacting a compound of formula (II), where R'-R ³ and m are as defined above, and L is a leaving group, with a compound of formula (III), where R ⁴ and R ⁵ are as defined above, in an analogous manner to the methods known from the literature [Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1992, 4th edition, Preface (ed.: D. Klamann); RC Larock: Comprehensive Organic Transformations, 2nd edition, John Wiley & Sons, New York, 1999, 789; DA Walsh, YH. Chen, JB Green, JC Nolan, JM Yanni J. Med. Chem. 1990, 33, 1823-1827],

During the preparation of the compound of general formula (II), the formation of the substituents can be carried out in any order, analogously to the methods known from the literature. The compounds of general formula (II) are conveniently prepared by reacting the compound of general formula (IV) where L and m are as defined above, L' is a leaving group or a group convertible thereto, with the compound of general formula (V) constructed in analogy to the methods known from the literature, where R'-R ³ are as defined above [Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1977, 4th edition, volume V/2b; AR Katntzky, Ch. W. Rees: Comprehensive Heterocyclic Chemistry, 1st edition, Pergamon, Oxford, 1984, volume 4 (eds.: CW Bird, GWH Cheeseman), 98-150 and 339-366; GM Karp Org. Prep. Proc. Int. 1993, 25, 481-513; B. Volk, T. Mezei, Gy. Simig Synthesis 2002, 595-597; AS Kende, JC Hodges Synth. Commun. 1982, 12, 1-10, B. Volk, Gy. Until Eur. J. Org. Chem. 2003, 18, 3991-3996].

The compound of formula (I) wherein R'-R ⁵ and m are as defined above can also be prepared by reacting the compound of formula (V) wherein R'-R ³ are as defined above with the compound of formula (VI) wherein R ⁴ -R ⁵ and m are as defined above and L is a leaving group, in an analogous manner to the methods known from the literature [RJ Sundberg: The chemistry of indoles, Academic Press, New York, 1970, Chapter VII; AR Katntzky, Ch. W. Rees: Comprehensive Heterocyclic Chemistry, 1st ed., Pergamon, Oxford, 1984, Volume 4 (eds.: CW Bird, GWH Cheeseman), 98-150 and 339-366; GM Karp Org. Prep. Proc. Int. 1993, 25, 481-513; AS Kende, JC Hodges Synth.

Commun. 1982, 12, 1-10; W.W. Wilkerson, A.A. Kergaye, S.W. Tam J. Med. Chem. 1993,36,2899-2907],

The compound of formula (I) in which R'-R ⁵ and m have the above meanings can also be prepared by introducing the substituents R'-R ⁵ in a different order in the last step. In this case, a compound of formula (I) is used as the starting material, in which, except for the substituent to be introduced - which may be R ¹ , R ² , R ³ , R ⁴ or R ⁵ - all other meanings are as described above. The introduction and transformation of the substituents is carried out in an analogous manner to the methods known from the literature [Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1977, 4th edition, IV/la-d; V/2b volume], The introduction of substituents may also require the application and removal of protecting groups, which are discussed in more detail in TW Greene, Protective groups in organic synthesis, John Wiley & Sons, 1981.

^The molecules of general formula (ΠΙ), (IV), (V) and (VI) are known from the literature or can be prepared by analogy with the routes known from the literature.

After the compounds of general formula (I) have been prepared, they can be liberated from their salts or converted into a pharmaceutically acceptable acid addition salt by methods known in the art.

A further subject of our invention are pharmaceutical compositions comprising the compounds of general formula (I) and their pharmaceutically acceptable acid addition salts, as well as one or more carriers or excipients known per se.

The pharmaceutical composition according to the invention generally contains 0.1-95% by weight, preferably 1-50% by weight, most preferably 5-30% by weight of active ingredient.

The pharmaceutical compositions of the invention can be administered orally (e.g. in the form of powders, tablets, coated tablets, capsules, microcapsules, dragees, solutions, suspensions or emulsions), parenterally (e.g. in the form of intravenous, intramuscular, subcutaneous or intraperitoneal injection preparations or infusion preparations), rectally (e.g. in the form of suppositories), transdermally (e.g. in the form of patches), as implants or topically (e.g. in the form of creams, ointments or patches). The pharmaceutical compositions of the invention in solid, soft or liquid dosage forms can be prepared using methods known per se in the art.

Orally administrable solid pharmaceutical compositions containing the compounds of general formula (I) or their pharmaceutically acceptable acid addition salts as pharmaceutical active ingredients may contain fillers or carriers (e.g. lactose, glucose, starch, calcium phosphate, microcrystalline cellulose), binders (e.g. gelatin, sorbitol, polyvinylpyrrolidone), disintegrants (e.g. croscarmellose, Na-carboxymethylcellulose, crospovidone), tabletting aids (e.g. magnesium stearate, talc, polyethylene glycol, silicic acid, silicon dioxide) and surfactants (e.g. sodium lauryl sulfate).

Orally administrable liquid pharmaceutical compositions containing the compounds of formula (I) or their pharmaceutically acceptable acid addition salts as pharmaceutical active ingredients may be, for example, solutions, suspensions or emulsions, and may contain suspending agents (e.g. gelatin, carboxymethylcellulose), emulsifying agents (e.g. sorbitan monooleate), solvents (e.g. water, oils, glycerin, propylene glycol, ethanol), pH adjusting agents (e.g. acetate, phosphate, citrate buffers) and stabilizing agents (e.g. methyl 4-hydroxybenzoate).

Parenterally applicable liquid pharmaceutical preparations containing the compounds of general formula (I) or their pharmaceutically acceptable acid addition salts as active pharmaceutical ingredients are sterile isotonic solutions which, in addition to solvents, may contain pH-regulating substances and preservatives.

Soft pharmaceutical preparations, such as suppositories, containing the compounds of general formula (I) or their pharmaceutically acceptable acid addition salts as active pharmaceutical ingredients contain the active ingredient uniformly distributed in the suppository base (e.g. polyethylene glycol or cocoa butter).

The invention also relates to the use of compounds of general formula (I) or their pharmaceutically acceptable acid addition salts for the production of a pharmaceutical composition suitable for the prevention or treatment of central nervous system or psychosomatic disorders, including anxiety disorders, in particular generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social phobia, agoraphobia, phobias related to specific situations, post-traumatic stress disorder, post-traumatic memory disorder, cognitive disorder, central nervous system-derived sexual dysfunction, depression, schizophrenia, gastrointestinal diseases, cardiovascular diseases, in particular hypertension.

Pharmaceutical preparations containing the compounds of the general formula (I) or their pharmaceutically acceptable acid addition salts as active ingredients according to the invention can be prepared by using methods known per se in pharmaceutical technology. The active ingredient is mixed with solid or liquid pharmaceutical carriers and excipients and is brought into galenic form. Carriers and excipients that can be used in pharmaceutical production and the methods that can be used are described in the literature (Remington’s Pharmaceutical Sciences, Edition 18, Mack Publishing Co., Easton, USA, 1990).

The pharmaceutical compositions of the invention, which contain the compound of general formula (I) or its pharmaceutically acceptable acid addition salts as active ingredient, contain the active ingredient in a dosage unit formulation.

A typical daily dose of the compounds of structural formula (I) or their acid addition salts with pharmaceutically acceptable acids for adult patients is 0.1 to 1000 mg per kilogram of body weight. The daily dose is administered in one or more divided doses. The actual dose is influenced by several factors and is a medical decision.

A further subject of our invention is the use of compounds of general formula (I) or their pharmaceutically acceptable acid addition salts for the prevention or treatment of central nervous system and psychosomatic disorders, including anxiety disorders, in particular generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social phobia, agoraphobia, phobias related to specific situations, stress disorder, post-traumatic stress disorder, post-traumatic memory disorder, cognitive disorder, central nervous system sexual dysfunction, depression, schizophrenia, mental decline caused by brain cell death, Alzheimer's disease, stroke, dementias, as well as gastrointestinal diseases, cardiovascular diseases, primarily hypertension.

The basis of our invention is the surprising discovery that, unlike compounds of similar structure known in the prior art, the 3-alkyl-indol-2-one derivatives of general formula (I) bind significantly to both 5-HT ₇ and ? receptors and inhibit the synaptosomal reuptake of serotonin. Such a unique activity profile among indolone derivatives has not been reported in any of the compounds known in the prior art.

To determine the 5-HT ₇ receptor binding, cloned human receptors were used, and to determine the α 1 receptor binding, rat frontal cortex preparations isolated from the brain regions of male Wistar rats weighing 120-200 g were used. The effect of the compounds of the invention on serotonin uptake was examined on cortex preparations isolated from rat brain. The protein content of the membrane preparations was determined by the method of Lowry (1951).

In the 5-HT ₇ and αι receptor binding assay, the ligands were ³ H-lysergic acid diethylamide (LSD) (1.0 nM) and ³ H-prazosin (0.3 nM), the non-specific binding ligands were clozapine (25 μΜ) and prazosin (1 μΜ). The αι receptor binding assay was performed according to the method of Reader and Greengrass ( Reader, TA, Briere, R., Grondin, L.: J. Neural Transm. 68, p. 79 (1987); Greengrass, P., Brenner, R.: Eur. J. Pharmacol. 55, p. 323 (1979) ). In the serotonin uptake assay, the ligand was tritiated serotonin, and the non-specific binding ligand was fluoxetine (100 μΜ). The Ki values were determined in the assays. In the test, we considered those compounds effective for which the K value was less than 100 M/l. Our results are given in Tables 1-3.

Table 1

5-HTγ receptor binding assay

Example number Kj M/l 5. <100 6. <100 7. <100 8. <100 9. <100 10. <100 11. <100 12. <100 14. <100 15. <100 16. <100 17. <100 18. <100

Λ ·/:·;·

Table 2. «ι receptor binding assay

Example number Out M/l 5. <100 6. <100 7. <100 8. <100 9. <100 11. <50 12. <100 17. <50 18. <50

Table 3

Serotonin uptake inhibition assay

Example number Out M/l 8. <100 17. <100 18. <100

1 :·* :·;· I?

As shown in Tables 1-3, the compounds of the invention bind significantly to 5-HTγ and α1 receptors and significantly inhibit the synaptosomal reuptake of serotonin.

Based on the pharmacological test results, it can be stated that the compounds of our invention have a valuable activity profile, which allows their use for the prevention and treatment of mental and cardiovascular diseases. Such diseases include depression, anxiety, obsessive-compulsive disorder, panic disorder, social phobia, schizophrenia, mood disorders, mania, mental decline, brain catastrophe, cell death in specific areas of the central nervous system, mental decline caused by brain cell death, Alzheimer's disease, dementia, post-traumatic disease, stress disease, and diseases of the cardiovascular system, especially hypertension.

The process according to the invention is illustrated by the following examples, without limiting the scope of the invention:

Preparation of mesyl esters (“Process A”)

The 3-(4-hydroxybutyl)-oxindoles are prepared as known from the literature [B. Volk, T. Mezei, Gy. Símig Synthesis 2002, 595; B. Volk, Gy. Símig Eur. J Org. Chem. 2003, 18, 3991-3996] mmol of 3-(4-hydroxybutyl)-oxindole is dissolved in 150 ml of THF, 15.2 ml (110 mmol) of triethylamine is added, then the solution is cooled to -78 °C with an acetone-dry ice bath. At this temperature, 8.5 ml (110 mmol) of mesyl chloride is added dropwise while stirring, and after the dropwise addition, the solution is allowed to warm to room temperature. After stirring for one hour at room temperature, the triethylamine hydrochloride is filtered off, the filtrate is evaporated, the residue is taken up in ethyl acetate and shaken with 10% hydrochloric acid solution until the pH of the aqueous phase is acidic. The organic phase is dried over sodium sulfate, evaporated, the residual oil is crystallized by trituration with diisopropyl ether, then stirred in 100 ml of diisopropyl ether, filtered, washed with hexane

J. ,:. ··«· and dried. The product is purified by recrystallization. The recrystallization solvents are indicated next to the melting point for each material.

Example 1

3-(4-Mesyloxybutyl)-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to method "A" starting from 3-(4-hydroxybutyl)-1,3-dihydro-27f-indol-2-one.

M.p.: 84-85 °C (heptane-ethyl acetate).

IR (KBr): 3180, 1705 (C=O) cm ^-1 .

1H-NMR (CDC1 ₃ , TMS, 400 MHz): 9.33 (1H, s), 7.22 (1H, d, J = 7.1 Hz), 7.21 (1H, t, J = 7.0 Hz), 7.03 (1H, t, J = 7.5 Hz), 6.93 (1H, d, J = 7.6 Hz), 4.19 (2H, t, J = 6.5 Hz), 3.49 (1H, t, J = 6.0 Hz), 2.97 (3H, s), 2.05-1.98 (2H, m), 1.82-1.72 (2H, m) 1.58-1.40 (2H, m) ppm.

¹³ C-NMR (CDCl3, TMS, 101 MHz): 180.5, 141.6, 129.1, 127.9, 123.9, 122.3, 109.9, 69.5, 45.7, 37.2, 29.6, 28.9, 21.6 ppm.

Example 2

5-Fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to method "A" starting from 5-fluoro-3-(4-hydroxybutyl)-1,3-dihydro-2H-indol-2-one.

M.p.: 106-108 °C (hexane-ethyl acetate).

IR(KBr): 3169, 1702 (C=O), 1356, 1175 (SO ₂ ) cm ¹ .

1H-NMR (CDC1 ₃ , TMS, 500 MHz): 1.43-1.55 (2H, m), 1.73-1.83 (2H, m), 1.97-2.05 (2H, m), 2.99 (3H, s), 3.50 (1H, t, J = 5.9 Hz), 4.21 (2H, dq, J = 1.4, 6.3 Hz), 6.86 (1H, dd, J = 4.3, 8.4 Hz), 6.93 (1H, dt, J = 2.3, 9.0 Hz), 6.97 (1H, dd, J = 2.0, 7.3 Hz), 9.22 (1H, s) ppm.

¹³ C-NMR (CDC1 ₃ , TMS, 125.6 MHz): 180.2, 158.9 (d, J - 240.6 Hz), 137.5 (d, J = 1.7 Hz), 130.8 (d, J = 8.5 Hz), 114.3 (d, J = 27.5 Hz), 111.9 (d, J = 24.8 Hz), 110.4 (d, J= 8.1 Hz), 69.4, 46.2, 37.3, 29.5, 28.9, 21.5 ppm.

Example 3

6-Fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-22H-indol-2-one

The title compound was prepared according to method "A" starting from 6-fluoro-3-(4-hydroxybutyl)-1,3-dihydro-2H-indol-2-one.

M.p.: 106-108 °C (hexane-ethyl acetate).

IR(KBr): 3161, 1705 (C=O), 1335, 1313, 1167 (SO ₂ ) cm' ¹ .

’H-NMR (CDCI3, TMS, 500 MHz): 1.46-1.51 (2H, m), 1.78 (2H, kv, J = 6.7 Hz), 2.00 (2H, q, J = 8.1 Hz), 2.99 (3H, s), 3.46 (1H, t, J = 5.9 Hz), 4.21 (2H, dt, J = 1.5, 6.5 Hz), 6.68 (1H, dd, J = 2.3, 8.8 Hz), 6.72 (1H, dt, J = 2.3, 8.9 Hz), 7.15 (1H, dd, J = 5.4, 8.1 Hz), 9.15 (1H, sz) ppm.

¹³ C-NMR (CDCI3, TMS, 125.6 MHz): 21.6, 28.9, 29.7, 37.3, 45.3, 69.5, 98.6 (d, J = 27.4 Hz), 108.7 (d, J = 22.5 Hz), 124.5 (d, J = 3.0 Hz), 124.9 (d, J = 9.5 Hz), 142.8 (d, J = 11.8 Hz), 162.6 (d, 7=244.6 Hz), 180.7 ppm.

Example 4

5-Methyl-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to method "A" starting from 3-(4-hydroxybutyl)-5-methyl-1,3-dihydro-2H-indol-2-one.

M.p.: 89-90 °C (hexane-ethyl acetate).

IR (KBr): 3175, 1710 (C=O), 1351, 1176 (SO ₂ ) cm ¹ .

’H-NMR (CDCl3, TMS, 400 MHz): 9.13 (1H, s), 7.03 (1H, s), 7.01 (1H, dd, J = 7.9, 0.8 Hz), 6.81 (1H, d, J = 7.9 Hz), 4.20 (2H, t, J = 6.5 Hz), 3.45 (1H, t, J = 5.9 Hz), 2.98 (3H, s), 2.33 (3H, s), 1.99 (2H, q, J=7.4 Hz), 1.79-1.75 (2H, m), 1.51-1.42 (2H, m)ppm.

¹³ C-NMR (CDCl3, TMS, 101 MHz): 180.4, 139.1, 131.7, 129.2, 128.2, 124.7, 109.5, 69.6, 45.8, 37.2, 29.6, 28.9, 21.5, 21.0 ppm.

Coupling reaction of mesyl esters with bases (method B)

In the coupling reaction, the corresponding mesyl ester and the secondary amine are coupled with each other. The melt of the amine (12 mmol) is heated to 120 °C with slow stirring, at this temperature the mesyl compound (12 mmol) and sodium carbonate (1.36 g; 12 mmol) are added. After a reaction time of 1 hour, the melt is allowed to cool, ethyl acetate and water are added, and the phases are separated. The organic phase is evaporated, the residual oil is chromatographed on a short column with ethyl acetate as eluent, and the target compounds are prepared as the main product of the column.

Processing method 1: If the product crystallizes after columnarization by trituration with diethyl ether, it is filtered and the filtered material is recrystallized from a mixture of hexane and ethyl acetate to obtain the white crystalline target compounds.

2nd processing method: If the basic product does not crystallize upon addition of diethyl ether, dissolve it in 200 ml of ether, filter off the small amount of suspended precipitate, and add a calculated amount (1 mol equivalent) of hydrochloric acid ether diluted with 50 ml of diethyl ether dropwise to the clear solution at room temperature over half an hour, while stirring vigorously. The precipitated white salt is filtered, washed with ether and hexane, and dried in a vacuum drying gun at room temperature for 3 hours.

3. processing method: If the basic product does not crystallize upon addition of diethyl ether and does not give a readily filterable salt with hydrochloric acid, it is dissolved in 100 ml of ethyl acetate while hot and a solution of 1 mole equiv of oxalic acid dihydrate in 30 ml of hot ethyl acetate is added dropwise while stirring over 10 minutes. During cooling, the white oxalate salt precipitates, the salt is filtered off after cooling to room temperature, washed with ethyl acetate and hexane, and dried.

Example 5

3-{4-[(3-Chloro-phenyl)-piperazin-1-yl]-butyl}-6-fluoro-1,3-dihydro-2H-indol-2-one monooxalate

The title compound was prepared according to procedure "B", using work-up method 3, starting from 6-fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(3-chlorophenyl)piperazine.

M.p.: 217-219 °C.

IR(KBr): 3256, 1712 (C=O), 1626, 1139 cm ¹ .

*H-NMR (DMSO-íZ ₆ , TMS, 400 MHz): 1.29-1.26 (2H, m), 1.65-1.58 (2H, m), 1.89-1.80 (2H, m), 2.88 (2H, t, J = 7.9 Hz), 3.08 (4H, w), 3.38 (4H, w), 3.44 (1H, t, J = 5.4 Hz), 6.65 (1H, dd, J = 2.4, 9.1 Hz), 6.75 (1H, dt, J = 2.4, 9.1 Hz), 6.89 (1H, dd, J = 1.3, 7.8 Hz), 6.94 (1H, dd, J = 1.8, 8.4 Hz), 7.01 (lH,t, J = 2.1 Hz), 7.24 (1H, t, J = 8.2 Hz), 7.297.22 (1H, m), 10.5 (1H, s) ppm.

¹³ C-NMR (DMSO-J _6i TMS, 101 MHz): 22.7, 24.0, 29.6, 44.6, 45.7, 51.0, 55.8, 97.6 (d, J = 27.1 Hz), 107.4 (d, J = 21.7 Hz), 114.2, 115.2, 119.1, 125.4 (d, J = 15.3 Hz), 125.5 (d, J = 7.4 Hz), 130.7, 134.1, 144.5 (d, J = 12.2 Hz), 151.4, 162.1 (d, J = 240.7 Hz), 164.4, 179.4 ppm.

Elemental analysis:

C24H27ClFN3O5 (491.95)

Calcd: C 58.60, H 5.53, Cl 7.21, N 8.54 %

Found: C 58.48, H 5.52, Cl 7.11, N 8.50%.

Example 6

3-{4-[4-(3-Chloro-phenyl)-piperazin-1-yl]-butyl}-5-fluoro-1,3-dihydro-27Z-indol-2-one monohydrochloride

The title compound was prepared according to Method "B", using Workup Method 2, starting from 5-fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(3-chlorophenyl)piperazine.

M.p.: 180-184 °C.

IR(KBr): 3421, 3145, 1712 (C=O), 1189, 778 cm' ¹ .

'H-NMR (DMSO-íZ _ö , TMS, 400 MHz): 1.33-1.24 (2H, m), 1.93-1.70 (4H, m), 3.16-3.03 (4H, m), 3.18 (2H, m), 3.38 (1H, m), 3.49 (2H, d, J = 12.4 Hz), 3.86 (2H, d, J = 12.9 Hz), 6.81 (1H, dd, J = 4.5, 8.4 Hz), 6.87 (1H, dd, J = 7.9, 1.4 Hz), 6.96 (1H, dt, J = 2.1, 8.4 Hz), 7.00 (1H, m), 7.05 (1H, t, J = 2.0 Hz), 7.21 (1H, dd, J = 2.0, 8.5 Hz), 7.25 (1H, t, J = 8.2 Hz), 10.4 (1H, s, 10.9 (1H, sz) ppm.

¹³ C-NMR (DMSO-í/ ₆ , TMS, 101 MHz): 22.5, 23.1, 29.3, 45.0, 45.5 (d, J = 1.5 Hz), 50.4 , 55.2, 109.9 (d, J = 8.0 Hz), 111.2 (d, J = 24.4 Hz), 114.0 (d, J = 23.3 Hz), 114.3, 115.4, 119.4, 130.8, 131.6 (d, 7 = 8.4 Hz), 134.1, 139.1 (d,7 = 1.5 Hz), 151.0, 158.1 (d,7 = 236.1 Hz), 178.8 ppm.

L.

Elemental analysis:

C2 ₂ H ₂₆ C1 ₂ FN ₃ O (438.38)

Calculated: H 5.98, Cl 16.17, N 9.59 %.

Measured: H 6.26, Cl 15.50, N 9.17 %.

Example 7

3-{4-[4-(4-Chloro-phenyl)-piperazin-1-yl]-butyl}-5-fluoro-1,3-dihydro-27-indol-2-one monohydrochloride

The title compound was prepared according to procedure “B” using work-up method 2 starting from 5-fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-27-indol-2-one and 1-(4-chlorophenyl)piperazine.

M.p.: 193-196 °C.

IR(KBr): 3145, 1712 (C=O), 821 cm' ¹ .

1H-NMR (DMSO-íZ ₆ , TMS, 400 MHz): 1.32-1.22 (2H, m), 1.95-1.71 (4H, m), 3.20-3.06 (6H, m), 3.53-3.49 (3H, m), 3.80-3.76 (2H, m), 6.82 (1H, dd, J = 4.5, 8.5 Hz), 7.04-6.98 (1H, m), 7.01 (2H, d, J = 9.1 Hz), 7.21 (1H, dd, J = 2.1, 8.6 Hz), 7.28 (2H, d, J = 9.1 Hz), 10.5 (1H, s), 11.1 (1H, sz) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 22.5, 23.1, 29.3, 42.6, 45.3, 45.4, 45.6 (d, J = 1.9 Hz), 50.5, 55.1, 110.0 (d, J = 8.4 Hz), 112.1 (d, J = 24.4 Hz), 114.0 (d, J = 23.3 Hz), 117.6, 117.7, 123.7, 129.0, 131.6 (d, J = 8.4 Hz), 139.2 (d, J = 1.9 Hz), 148.7, 149.1, 158.1 (d, J = 235.8 Hz), 178.8 ppm.

Elemental analysis:

_{C22H26C12FN3O} ( _438.38 ).

Calcd: C 60.28, H 5.98, Cl 16.17, N 9.59%.

Found: C 59.35, H 5.93, Cl 16.44, N 9.46%.

Example 8

3-{4-[4-(4-Chloro-phenyl)-piperazin-1-yl]-butyl}-6-fluoro-1,3-dihydro-2H-indol-2-one monohydrochloride

The title compound was prepared according to Method B, using Workup Method 2, starting from 6-fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)piperazine.

M.p.: 149-151 °C.

IR (KBr): 3148, 2586, 2459, 1716 (C=O) cm ¹ .

1H-NMR (DMSO-1Z ₆ , TMS, 400 MHz): 1.31-1.07 (2H, m), 1.91-1.66 (4H, m), 3.21-2.99 (6H, m), 3.51 (1H, t, J = 5.9 Hz), 3.65-3.60 (2H, m), 3.81-3.78 (2H, m), 6.69-6.64 (1H, m), 6.80-6.72 (1H, m), 7.03-6.99 (2H, m), 7.32-7.26 (3H, m), 10.6-10.5 (1H, s), 11.2 (1H, sz) ppm.

¹³ C-NMR (CD ₃ OD, TMS, 101 MHz): 182.2, 164.4 (d, J = 243.0 Hz), 150.0, 144.7 (d, J = 12.2 Hz), 130.3, 128.6, 127.3, 126.5 (d, J = 9.5 Hz), 119.5, 109.4 (d, J = 22.5 Hz), 99.2 (d, J = 27.5 Hz), 57.8, 53.1, 48.0, 46.7, 30.7, 25.0, 21.6 ppm.

Elemental analysis:

C22H26Cl2FN3O (438.38)

Calculated: CH 5.98, Cl 16.17, N 9.59%.

Measured: CH 5.94, Cl 15.51, N 9.16 %.

Example 9

3-{4-[4-(3-Chloro-phenyl)-piperazin-1-yl]-butyl}-5-methyl-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method B, using Workup Method 1, starting from 5-methyl-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(3-chlorophenyl)piperazine.

Op.: 122-124 °C (hexane-EtOAc).

IR (KBr): 3174 (NH), 1690 (C=O) cm ^-1 .

1H-NMR (CDC1 ₃ , TMS, 400 MHz): 1.58-1.38 (4H, m), 2.00-1.95 (2H, m), 2.33 (3H, s), 2.36 (2H, t, J = 7.6 Hz), 2.54 (4H, t, J = 5.1 Hz), 3.17 (4H, t, J = 5.1 Hz), 3.44 (1H, t, J = 6.0 Hz), 6.76 (1H, ddd, J = 0.7, 2.5, 8.2 Hz), 6.78 (1H, d, J = 8.1 Hz), 6.79 (1H, ddd, J = 0.8, 1.9, 7.8 Hz), 6.85 (1H, t, J = 2.1 Hz), 7.01 (1H, d, J = 7.9 Hz), 7.04 (1H, d, J = 0.5 Hz), 7.14 (1H, t, J = 8.2 Hz), 8.78 (1H, s) ppm.

¹³ C-NMR (CDCI3, TMS, 101 MHz): 180.5, 152.3, 139.1, 134.9, 131.7, 129.9, 129.7, 128.1, 124.9, 119.1, 115.6, 113.7, 109.3, 58.2, 52.9, 48.5, 46.0, 30.4, 26.7, 23.7, 21.1 ppm.

Elemental analysis:

_{C23H28C1N3O ( 397.95} )

Calcd: C 69.42, H 7.09, Cl 8.91, N 10.56%.

Found: C 69.29, H 7.12, Cl 8.69, N 10.51%.

Example 10

3-{4-[4-(4-Chloro-phenyl)-piperazin-1-yl]-butyl}-5-methyl-1,3-dihydro-2/7-indol-2-one

The title compound was prepared according to Method B, using Workup Method 1, starting from 5-methyl-3-(4-mesyloxybutyl)-1,3-dihydro-22f-indol-2-one and 1-(4-chlorophenyl)piperazine.

M.p.: 159-161 °C (EtOAc).

IR (KBr): 3186, 1702 (C=O) cm ^-1 .

1H-NMR (CDC1 ₃ , TMS, 400 MHz): 1.58-1.37 (4H, m), 2.02-1.95 (2H, m), 2.32 (3H, s), 2.55 (4H, t, J = 5.0 Hz), 3.13 (4H, t, J = 5.0 Hz), 3.44 (1H, t, J = 5.9 Hz), 6.78 (1H, d, J = 7.8 Hz), 6.81 (2H, d, J = 9.1 Hz), 6.99 (1H, d, J = 7.9 Hz), 7.04 (1H, s), 7.18 (2H, d, J = 9.1Hz), 8.88 (1H, s)ppm.

¹³ C-NMR (CDCI3, TMS, 101 MHz): 180.5, 149.9, 139.1, 131.6, 129.7, 128.8, 128.1, 124.8, 124.4, 117.1, 109.3, 58.2, 53.0, 49.0, 46.0, 30.3, 26.7, 23.7, 21.1 ppm.

Elemental analysis:

_{C23H28C1N3O ( 397.95} ).

Calcd: C 69.42, H 7.09, Cl 8.91, N 10.56%.

Found: C 68.76, H 7.10, Cl 8.80, N 10.54%.

Example 11

3-{4-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-butyl}-1,3-dihydro-2 H -indol-2-one

The title compound was prepared according to Method B, using Workup Method 1, starting from 3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(4-fluorophenyl)piperazine.

Op.: 113-115 °C (hexane-EtOAc).

IR (KBr): 3192, 1720 (C=O) cm ^-1 .

1H-NMR (CDCl3, TMS, 400 MHz): 1.57-1.36 (4H, m), 2.04-1.95 (2H, m), 2.36 (2H, t, J = 7.5 Hz), 2.56 (4H, t, J = 5.0 Hz), 3.09 (4H, t, J = 5.0 Hz), 3.37 (1H, t, J = 5.9 Hz), 6.85 (2H, dd, J = 4.6, 9.2 Hz), 6.89 (1H, d, J = 7.7 Hz), 6.94 (2H, t, J = 8.8 Hz), 7.01 (1H, dt, J — 0.9, 7.5 Hz), 7.19 (1H, d, J = 7.7 Hz), 7.21 (1H, t, J = 6.7 Hz), 9.33 (1H, s) ppm.

^I3 C-NMR (CDCl3, TMS, 101 MHz): 23.7, 26.7, 30.3, 46.0, 50.0, 53.1, 58.2, 109.7, 115.4 (d, J = 22.1 Hz), 117.6 (d, J = 7.6 Hz), 122.1, 124.0, 127.8, 130.0, 141.7, 147.9, 157.0 (d, J = 238.4 Hz), 180.7 ppm.

Elemental analysis:

C22H26FN3O (367.47)

Calculated: C 71.91, H 7.13, F 5.17, N 11.43%.

Measured: C 71.12, H 7.32, N 11.28 %.

Example 12

3-{4-[4-(3,4-Dichlorophenyl)-piperazin-1-yl]-butyl}-1,3-dihydro-2H-indol-2-one

The title compound was prepared according to Method B, using Workup Method 1, starting from 3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(3,4-dichlorophenyl)piperazine.

Op.: 112-114 °C (hexane-EtOAc).

IR(KBr): 3175, 1718 (C=O) cm' ¹ .

H-NMR (CDC1 ₃ , TMS, 400 MHz): 1.47-1.36 (2H, m), 1.60-1.56 (2H, m), 2.04-1.96 (2H, m), 2.44 (2H, t, J = 7.1 Hz), 2.63 (4H, m), 3.20 (4H, m), 3.47 (2H, t, J = 5.9 Hz), 6.71 (1H, dd, J = 2.8, 9.0 Hz), 6.91 (1H, d, J = 9.2 Hz), 6.92 (1H, d, J = 2.9 Hz), 7.02 (1H, t, J = 7.5 Hz), 7.26-7.18 (3H, m), 9.02 (1H, s) ppm.

3

C-NMR (CDCl3, TMS, 101 MHz): 180.4, 150.3, 141.6, 132.7, 130.4, 129.5, 127.9, 124.0, 122.2, 120.6, 117.3, 115.3, 109.7, 57.9, 48.2, 45.9, 45.9, 30.1, 26.2, 23.5 ppm.

Elemental analysis:

_{C22H25C12N3O ( 418.37 )}

Calcd: C 63.16, H 6.02, Cl 16.95, N 10.04%.

Found: C 63.04, H 6.02, Cl 16.78, N 10.01%.

Example 13

3-{4-[4-(4-Chloro-2-methylphenyl)-piperazin-1-yl]-butyl}-1,3-dihydro-277-indol-2-one monohydrochloride

The title compound was prepared according to Method B, using Workup Method 2, starting from 3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(4-chloro-2-methylphenyl)piperazine.

M.p.: 224-225 °C.

IR (KBr): 3229, 2456, 1708 (C=O) cm ^-1 .

H-NMR (DMSO-í/ ₆ , TMS, 400 MHz): 1.32-1.20 (2H, m), 1.91-1.70 (4H, m), 2.21 (3H, s), 3.08 (8H, sz), 3.43 (3H, t, J = 5.8 Hz), 6.81 (1H, d, J = 7.7 Hz), 6.93 (1H, dt, J = 0.6, 7.5 Hz), 7.00 (1H, d, J = 8.6 Hz), 7.14 (1H, t, J = 7.7 Hz), 7.18 (1H, dd, J = 2.5, 8.5 Hz), 7.23 (1H, d, J = 2.4 Hz), 7.24 (1H, d, J = 7.6 Hz), 10.38 (1H, s), 10.97 (1H, sz) ppm.

¹³ C-NMR (DMSO-rig, TMS, 101 MHz): 17.4, 22.7, 23.2, 29.6, 45.0, 48.2, 51.4, 55.3, 109.4, 120.9, 121.4, 124.2, 126.5, 127.7, 127.8, 129.7, 130.6, 134.7, 142.9, 148.9, 178.9 ppm.

Elemental analysis:

C23H29Cl2N3O (434.41).

Calcd: C 63.59, H 6.73, Cl 16.32, N 9.67%.

Found: C 63.71, H 6.74, Cl 16.01, N 9.54%.

Example 14

3-{4-[4-(3-Chloro-4-fluorophenyl)piperazin-1-yl]butyl}-1,3-dihydro-227-indol-2-one monohydrochloride

The title compound was prepared according to Method B, using Workup Method 2, starting from 3-(4-mesyloxybutyl)-1,3-dihydro-2-tindol-2-one and 1-(3-chloro-4-fluorophenyl)piperazine.

M.p.: 180-183 °C.

IR (KBr): 3432, 1709 (C=O), 735 cm' ¹ .

1H-NMR (DMSO-7 ₆ , TMS, 400 MHz): 1.36-1.23 (2H, m), 1.94-1.72 (4H, m), 3.15-3.04 (4H, m), 3.19 (2H, t, J = 12.0 Hz), 3.51-3.44 (3H, m), 3.78 (2H, d, J= 12.2 hz), 6.85 (1H, d, J= 7.7 Hz), 7.02-6.93 (2H, m), 7.22-7.15 (2H, m), 7.32-7.26 (2H, m), 10.43 81H, s), 11.2 (1H, s) ppm.

¹³ C-NMR (DMSO-7 ₆ , TMS, 101 MHz): 22.7, 23.1, 29.6, 45.0, 45.6, 50.4, 55.2, 109.4, 116.3 (d, J=6.5 hz), 117.1 (d, 7= 21.4 Hz), 117.6, 119.9 (d, J = 18.3 Hz), 121.4, 124.2, 127.8, 129.7, 142.9, 147.2, 151.5 (d, 7 = 239.2 Hz), 178.9 ppm.

Elemental analysis:

C22H26Cl2FN3O (438.38)

Calcd: C 60.28, H 5.98, Cl 16.17, N 9.59%.

Found: C 59.60, H 6.06, Cl 15.85, N 9.32%.

• ί» 4 β · * ^: Γ ::

Example 15

3-{4-[4-(4-Chloro-3-trifluoromethylphenyl)piperazin-1-yl]butyl}-1,3-dihydro-227-indol-2-one monohydrochloride

The title compound was prepared according to Method "B", using Workup Method 2, starting from 3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(4-chloro-3-trifluoromethylphenyl)piperazine.

M.p.: 123-125 °C.

IR (KBr): 3150, 1709 (C=O), 2554, 2462, 1129 cm' ¹ .

H-NMR (DMSO-dö, TMS, 400 MHz): 1.34-1.26 (2H, m), 1.94-1.74 (4H, m), 3.09-3.06 (4H, m), 3.30 (2H, t, J= 12.3 Hz), 3.64-3.47 (3H, m), 3.94 (2H, d, J= 12.6 Hz), 6.86 (1H, d, J= 7.6 Hz), 6.96 (1H, t, 7 = 7.4 Hz), 7.18 (1H, t, J = 7.6 Hz), 7.28 (1H, d, J= 7.6 Hz), 7.35 (1H, d, J= 2.2 Hz), 7.36-7.27 (1H, m), 7.54 (1H, d, J= 8.8 Hz), 10.44 (1H, s), 11.30 (1H, sz) ppm.

¹³ C-NMR (DMSO-dö, TMS, 101 MHz): 22.7, 23.1, 29.6, 44.8, 45.0, 50.2, 55.1, 109.4, 114.4 (q, 7=5.0 Hz), 120.0 (q), 120.5, 121.4, 123.1 (q, 7 = 273.1 Hz), 124.2, 127.2 (q, 7 = 30.1 Hz), 127.8, 129.7, 132.3, 142.9, 148.6, 178.9 ppm.

Elemental analysis:

C23H26Cl2F3N3O (488.38)

Calcd: C 56.57, H 5.37, Cl 14.52, F 11.67, N 8.60%.

Found: C 55.88, H 5.45, Cl 14.44, N 8.59%.

Example 16

5-Fluoro-3-{4-[4-(4-fluorophenyl)-piperazin-1-yl]-butyl}-1,3-dihydro-2 H -indol-2-one

The title compound was prepared according to Method B, using Workup Method 1, starting from 5-fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-2-indol-2-one and 1-(4-fluorophenyl)piperazine.

Op.: 135-137 °C (hexane-EtOAc).

IR (KBr): 3169, 1703 (C=O) cm ¹ .

1H-NMR (DMSO- ₇ , TMS, 400 MHz): 1.35-1.16 (2H, m), 1.46-1.35 (2H, m), 1.96-1.77 (2H, m), 2.26 (2H, t, J= 6.9 Hz), 2.44 (4H, t, J= 4.8 Hz), 3.02 (4H, t, J= 4.8 Hz), 3.48 (1H, t, J= 5.6 Hz), 6.79 (1H, dd, J= 4.5, 8.4 Hz), 6.92 (2H, dd, J= 4.8, 9.3 Hz), 7.03 (2H, t, J= 8.9 Hz), 7.06-6.96 (1H, m), 10.36 (1H, s) ppm.

¹³ C-NMR (DMSO-7 ₆ , TMS, 101 MHz): 23.1, 26.3, 29.5, 45.8, 49.1, 52.8, 57.6, 109.8 (d, J = 8.4 Hz), 112.0 (d, 7=24.4 Hz), 113.8 (d, 7=22.9 Hz), 115.4 (d, 7= 22.1 Hz), 131.8 (d, 7 = 8.4 Hz), 139.1, 148.1, 156.1 (d, 7= 235.4 Hz), 158.0 (d, J= 235.7 Hz), 179.0 ppm.

Elemental analysis:

C22H25F2N3O (385.46)

Calculated: H 6.54, N 10.90 %.

Measured: H 6.67, N 10.40 %.

Example 17

3-{4-[4-(4-Chloro-phenyl)-piperazin-1-yl]-butyl}-1,3-dihydro-2/Z-indol-2-one

The title compound was prepared according to Method B, using Workup Method 1, starting from 3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)piperazine.

Op.: 136-137 °C (hexane-EtOAc).

IR (KBr): 3203, 1718 (C=O), 754 cm' ¹ .

1H-NMR (CDC1 ₃ , TMS, 400 MHz): 1.58-1.36 (4H, m), 2.05-1.96 (2H, m), 2.36 (2H, t, J = 7.5 Hz), 2.55 (4H, t, J = 5.0 Hz), 3.13 (4H, t, J = 5.0 Hz), 3.48 (1H, t, J = 6.0 Hz), 6.81 (2H, d, J = 9.2 Hz), 6.88 (1H, d, J = 7.7 Hz), 7.02 (1H, dt, J = 0.9, 7.6 Hz), 7.18 (2H, d, J = 9.1 Hz), 7.24-7.15 (2H, m), 8.60 (1H, s) ppm.

¹³ C-NMR (CDC13, TMS, 101 MHz): 180.3, 149.9, 141.5, 129.7, 128.8, 127.8, 124.4, 124.1, 122.2, 117.1, 109.6, 58.2, 53.0, 49.1, 45.9, 30.4, 26.8, 23.7 ppm.

Elemental analysis:

_{C22H26C1N3O ( 383.93} )

Calcd: C 68.83, H 6.83, Cl 9.23, N 10.94%.

Found: C 68.49, H 6.89, Cl 9.08, N 10.81%.

Example 18

3-{4-[4-(3-Chloro-phenyl)-piperazin-1-yl]-butyl}-1,3-dihydro-2 N -indol-2-one

The title compound was prepared according to procedure “B” using work-up method 1 starting from 3-(4-mesyloxybutyl)-1,3-dihydro-27-indol-2-one and (3-chlorophenyl)piperazine.

Op.: 112-114 °C (hexane-EtOAc).

IR (KBr): 3200, 1715 (C=O), 750 cm' ¹ .

1H-NMR (CDCl ₃ , TMS, 400 MHz): 1.57-1.38 (4H, m), 2.03-1.97 (2H, m), 2.35 (2H, t, J = 7.5 Hz), 2.54 (4H, t, J = 5.0 Hz), 3.16 (4H, t, J = 5.0 Hz), 3.48 (1H, t, J = 5.9 Hz), 6.75 (1H, ddd, J = 0.6, 2.4, 8.4 Hz), 6.78 (1H, ddd, J = 0.7, 1.9, 7.8 Hz), 6.85 (1H, t, J = 2.1 Hz), 6.90 (1H, d, J = 7.7 Hz), 7.02 (1H, dt, J = 0.9, 7.5 Hz), 7.14 (1H, t, J = 8.1 Hz), 7.21 (1H, dt, J = 0.7, 7.7 Hz), 7.22 (1H, d, J = 7.3 Hz), 9.05 (1H, s) ppm.

¹³ C-NMR (CDCI3, TMS, 101 MHz): 180.6, 152.3, 141.7, 134.9, 129.9, 129.6, 127.8, 124.1, 122.2, 119.1, 115.6, 113.7, 109.7, 58.2, 52.9, 48.5, 46.0, 30.3, 26.7, 23.7 ppm.

Elemental analysis:

_{C22H26C1N3O ( 383.93} )

Calcd: C 68.83, H 6.83, Cl 9.23, N 10.94%.

Found: C 68.31, H 6.90, Cl 9.08, N 10.77%.

Example 19

3-{4-[4-(3-Chloro-4-fluorophenyl)piperazin-1-yl]butyl}-6-fluoro-1,3-dihydro-277-indol-2-one monohydrochloride

The title compound was prepared according to Method B, using Workup Method 2, starting from 6-fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-4-fluorophenyl)piperazine.

M.p.: 218-224 °C.

IR (KBr): 2577, 1717 (C=O) cm' ¹ .

1H-NMR (DMSO-7 ₆ , TMS, 500 MHz): 1.35-1.24 (2H, m), 1.94-1.74 (4H, m), 3.07 (2H, t, J= 7.7 Hz), 3.21 (2H, s), 3.49-3.40 (3H, m), 3.80-3.77 (2H, m), 6.69 (1H, dd, J= 2.4, 9.3 Hz), 6.76 (1H, dt, 7= 2.4, 9.1 Hz), 7.00 (1H, dt, J= 3.4, 9.2 Hz), 7.19 (1H, dd, J= 2.9, 6.4 Hz), 7.31-7.27 (2H, m), 10.64 (1H, s), 11.29 (1H, s) ppm.

¹³ C-NMR (DMSO-7 ₆ , TMS, 125.6 MHz): 22.6, 23.1, 29.6, 44.6, 45.6, 50.4, 55.2, 97.6 (d, 7=26.9 Hz), 107.3 (d, 7= 22.2 Hz), 116.3 (d,7=6.4 Hz), 117.1 (d, J=21.4 Hz), 117.6, 119.9 (d, 7= 17.9 Hz), 125.4, 125.4 (d, 7= 2.6 Hz), 144.5 (d, 7= 12.4 Hz), 147.2 (d, 7 = 2.1 Hz), 151.5 (d, 7= 238.8 Hz), 162.1 (d, 7= 241.0 Hz), 179.3 ppm.

Elemental analysis

C22H25Cl2F2N3O (456.37)

Calcd: C 57.90, H 5.52, Cl 15.54, N 9.21%.

Found: C 57.25, H 5.51, Cl 15.22, N 9.01%.

Example 20

5-Fluoro-3-[4-(4-phenyl-piperazin-1-yl)-butyl]-1,3-dihydro-27H-indol-2-one

The title compound was prepared according to Method B, using Workup Method 1, starting from 5-fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-phenylpiperazine.

Melting point: 140-144 °C.

IR (KBr): 3188 (NH), 1705 (C=O) cm ^-1 .

1H-NMR (CDC1 ₃ , TMS, 500 MHz): 1.45-1.34 (2H, m), 1.57-1.52 (2H, m), 1.99-1.95 (2H, m), 2.36 (2H, t, J= 7.7 Hz), 2.57 (4H, t, 7= 5.0 Hz), 3.17 (4H, t, 7 = 5.0 Hz), 3.47 (1H, t, 7 = 6.0 Hz), 6.80 (1H, dd, 7= 4.3, 8.4 Hz), 6.84 (1H, t, 7= 7.3 Hz), 6.92-6.87 (3H, m), 6.97 (1H, dd, 7= 1.8, 8.1 Hz), 7.24 (2H, dd, J= Ί.3, 8.8 Hz), 9.52 (1H, s) ppm.

¹³ C-NMR (CDCI3, TMS, 125.6 MHz): 23.6, 26.6, 30.2, 46.5 (d, 7 = 1.7 Hz), 49.0, 53.1, 58.1, 110.1 (d, 7=8.1 Hz), 112.0 (d, 7= 24.8 Hz), 114.1 (d, 7= 23.5 Hz), 115.9, 119.6, 129.0, 131.2 (d,7=8.1 Hz), 137.6 (d,7=2.1 Hz), 151.2, 158.9, 180.7 ppm.

Elemental analysis

_{C22H26FN3O ( 367.47} )

Calculated: C 71.91, H 7.13, N 11.43%.

Measured: C 72.17, H 7.04, N 11.45 %.

Example 21

3-{4-[4-(3-Chloro-4-fluorophenyl)piperazin-1-yl]butyl}-5-fluoro-1,3-dihydro-277-indol-2-one monohydrochloride

The title compound was prepared according to Method B, using Workup Method 2, starting from 5-fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-4-fluorophenyl)piperazine.

M.p.: 234-237 °C.

IR(KBr): 3143.2579, 1712 (00), 1189, 734 cm' ¹ .

'H-NMR (DMSO-7 ₆ , TMS, 500 MHz): 1.33-1.23 (2H, m), 1.95-1.67 (4H, m), 3.78-3.04 (10H, m), 3.51 (1H, t, 7 = 5.8 Hz), 6.83 (1H, dd, J= 4.4, 8.4 Hz), 7.03-6.97 (2H, m), 7.227.17 (2H, m), 7.29 (1H, t, J= 9.1 Hz), 10.45 (1H, s), 11.1 (1H, sz) ppm.

¹³ C-NMR (DMSO-7 ₆ , TMS, 125.6 Hz): 22.6, 23.2, 29.3, 45.6, 45.7, 50.5, 55.2, 109.9 (d, J = 8.1 Hz), 112.1 (d, J = 24.8 Hz), 114.0 (d, J = 8.1 Hz) 23.5 Hz), 116.3 (d,7=6.8 Hz), 117.1 (d, 7 = 21.8 Hz), 117.6, 119.9 (d, 7= 17.9 Hz), 131.6 (d, 7= 8.6 Hz), 139.1 (d, 7 = 1.7 Hz), 147.3, 151.5 (d, 7= 239.3 Hz), 158.1 (d, 7= 235.9 Hz), 178.8 ppm.

Elemental analysis

C ₂₂ H ₂₅ C1 ₂ F ₂ N ₃ O (456.37)

Calcd: C 57.90, H 5.52, Cl 15.54, N 9.21%.

Found: C 57.88, H 5.63, Cl 14.94, N 9.04%.

Example 22

3-{4-[4-(3,5-Dichlorophenyl)-piperazin-1-yl]-butyl}-1,3-dihydro-277-indol-2-one monohydrochloride

The title compound was prepared according to Method B, using Workup Method 2, starting from 3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(3,5-dichlorophenyl)piperazine.

M.p.: 201-205 °C.

IR (KBr): 3416, 3178, 2583, 1706 (OO), 753 cm' ¹ .

1H-NMR (DMSO-<7 ₆ , TMS, 500 MHz): 1.33-1.24 (2H, m), 1.73 (2H, m), 1.94-1.78 (2H, m), 3.04 (4H, w), 3.25 (2H, w), 3.46 (3H, t, J= 6.0 Hz), 3.92 (2H, sz), 6.83 (1H, d, J = 7.7 Hz), 6.95 (1H, d, J= 1.5 Hz), 6.95 (1H, dt, J= 1.0, 7.5 Hz), 7.04 (1H, d, 1.4 Hz), 7.18 (1H, tt, J= 1.0, 7.6 Hz), 7.27 (1H, d, J = 7.3 Hz), 10.40 (1H, s), 11.02 (1H, sz) ppm.

^,3 C-NMR (DMSO-<7 ₆ , TMS, 125.6 MHz): 22.7, 23.1, 29.6, 44.6, 45.0, 50.2, 55.2, 109.4, 113.8, 118.3, 121.4, 124.2, 127.8, 129.7, 134.9, 142.9, 151.5, 178.9 ppm.

Elemental analysis

C22H26Cl3N3O (454.83)

Calcd: C 58.10, H 5.76, Cl 23.38, N 9.24%.

Found: C 59.10, H 5.90, Cl 22.44, N 9.22%.

Example 23

3-{4-[4-(3,4-Dichlorophenyl)-piperazin-1-yl]-butyl}-5-fluoro-1,3-dihydro-2/7-indol-2-one

The title compound was prepared according to Method B, using Workup Method 1, starting from 5-fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(3,4-dichlorophenyl)piperazine.

M.p.: 118-120 °C.

IR (KBr): 3200, 1709 (C=O), 835 cm ¹ .

1H-NMR (DMSO-ti ₆ , TMS, 500 MHz): 1.29-1.21 (2H, m), 1.42 (2H, kv, J= 7.2 Hz), 1.931.80 (2H, m), 2.25 (2H, t, J = 6.1 Hz), 2.42 (4H, t, J= 4.9 Hz), 3.13 (4H, t, J= 4.9 Hz), 3.48 (1H, t, 5.7 Hz), 6.79 (1H, dd, J= 4.5, 8.4 Hz), 6.91 (1H, dd, J= 2.9, 9.0 Hz), 6.99 (1H, dt, J= 2.3, 8.9 Hz), 7.10 (1H, d, 2.8 Hz), 7.16 (1H, dd, J= 2.2, 8.4 Hz), 7.37 (1H, d, J= 9.0 Hz), 10.35 (1H, d, J= 9.0 Hz) ppm.

1T

C-NMR (DMSO-eZö, TMS, 125.6 MHz): 23.1, 26.3, 29.5, 45.8, 47.7, 52.5, 57.6, 109.8 (d, 8.3 Hz), 112.0 (d, J = 24.4 Hz), 113.8 (d, J = 23.0 Hz), 115.3, 116.2, 119.6, 130.6, 131.6, 131.8 (d, J= 8.3 Hz), 139.1 (d, J = 1.5 Hz), 150.9, 158.0 (d, J= 235.8 Hz), 178.9 ppm.

Elemental analysis

C22H24Cl2FN3O (436.36)

Calcd: C 60.56, H 5.54, Cl 16.25, N 9.63%.

Found: C 60.71, H 5.64, Cl 16.14, N 9.72%.

Example 24

3-[4-(4-Phenyl-piperazin-1-yl)-butyl]-1,3-dihydro-2 H -indol-2-one

The title compound was prepared according to Method B, using Workup Method 1, starting from 3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-phenylpiperazine.

M.p.: 110-113 °C.

IR (KBr): 3191, 1705 (C=O) cm ^-1 .

*H-NMR (DMSO-í7 ₆ , TMS, 500 MHz): 1.31-1.24 (2H, m), 1.43 (2H, kv, J= 7.2 Hz), 1.821.79 (1H, m), 1.91-1.81 (1H, m), 2.25 (2H, t, J= 7.3 Hz), 2.43 (4H, t, J= 5.0 Hz), 3.07 (4H, t, J= 4.9 Hz), 3.42 (1H, t, 4.9 Hz), 6.76 (1H, t, J= 7.2 Hz), 6.82 (1H, d, J= 7.7 Hz), 6.90 (1H, dd, J = 1.0, 7.8 Hz), 6.94 (1H, dt, 1.0, 7.6 Hz), 7.21-7.14 (3H, m), 7.24 (1H, d, J= 7.3 Hz), 10.35 (1H, s) ppm.

¹³ C-NMR (DMSO- _d6 , TMS, 125.6 MHz): 23.3, 26.4, 29.9, 45.3, 48.3, 52.9, 57.8, 109.3, 115.4, 118.8, 121.3, 124.1, 127.7, 129.0, 129.9, 142.9, 151.2, 179.1 ppm.

Elemental analysis

C22H27N3O (349.48)

Calculated: C 75.61, H 7.79, N 12.02%.

Measured: C 74.53, H 7.81, N 11.81%.

Example 25

6-Fluoro-3-{4-[4-(4-fluorophenyl)-piperazin-1-yl]-butyl}-1,3-dihydro-2H-indol-2-one monohydrochloride

The title compound was prepared according to Method B, using Workup Method 2, starting from 6-fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(4-fluorophenyl)piperazine.

M.p.: 184-189 °C.

IR (KBr): 3125, 1717 (C=O), 1512 cm' ¹ .

1H-NMR (DMSO-J ₆ , TMS, 500 MHz): 1.32-1.24 (2H, m), 1.92-1.73 (4H, m), 3.17-3.06 (6H, m), 3.52-3.45 (3H, m), 3.70-3.68 (2H, m), 7.31-6.66 (7H, m), 10.62 (1H, s), 11.2 (1H, sz) ppm.

¹³ C-NMR (DMSO-í/ö, TMS, 125.6 MHz): 22.6, 23.1, 29.6, 44.6, 46.2, 50.6, 55.1, 97.6 (d, J = 26.9 Hz), 107.3 (d, J = 22.0 Hz), 115.6 (d, J = 22.0 Hz), 118.0, 125.3, 125.4, 144.5, 146.6, 155.8, 157.7, 161.1, 163.0, 179.3 ppm.

Elemental analysis

C ₂₂ H ₂₆ C1F ₂ N ₃ O (421.92)

Calcd: C 62.63, H 6.21, Cl 8.40, N 9.96%.

Found: C 62.37, H 6.31, Cl 8.41, N 9.78%.

Claims (17)

Patent claims: 1. Substituted 3-alkylindol-2-one derivatives of general formula (I) in which R and R are independently hydrogen, halogen, C1-7 alkyl, C1-7 alkoxy or trifluoromethyl; R represents a hydrogen atom; R ⁴ and R ⁵ are independently hydrogen, halogen, trifluoromethyl, or a straight or branched alkyl or alkoxy group having 1 to 7 carbon atoms; m is 1, 2, 3 or 4; and pharmaceutically acceptable acid addition salts of the compounds of formula (I). 2. 3-alkylindol-2-one derivatives of the general formula (I) in which R ¹ represents a hydrogen atom, a halogen atom, an alkyl group having 1-7 carbon atoms; R ² and R ³ represent hydrogen; R ⁴ represents a hydrogen atom or a halogen atom; R ⁵ represents a halogen atom; m has the value 4; and their pharmaceutically acceptable acid addition salts. 3. 3-alkylindol-2-one derivatives of general formula (I) in which R ¹ represents a hydrogen atom or a halogen atom; R ² , R ³ and R ⁴ represent a hydrogen atom; R ⁵ represents a halogen atom; m has the value 4; and their pharmaceutically acceptable acid addition salts. 4. 3-{4-[4-(4-Chlorophenyl)piperazin-1-yl]butyl}-6-fluoro-1,3-dihydro-2-indol-2-one according to claim 1 and its pharmaceutically acceptable acid addition salts. 5. 3-{4-[4-(4-fluorophenyl)piperazin-1-yl]butyl}-1,3-dihydro-2-indol-2-one according to claim 1 and its pharmaceutically acceptable acid addition salts. 6. 3-{4-[4-(4-Chlorophenyl)piperazin-1-yl]butyl}-1,3-dihydro-2H-indol-2-one according to claim 1 and its pharmaceutically acceptable acid addition salts. 7. 3-{4-[4-(3-Chlorophenyl)piperazin-1-yl]butyl}-1,3-dihydro-2-indol-2-one according to claim 1 and its pharmaceutically acceptable acid addition salts. 8. 3-{4-[4-(3-Chloro-phenyl)-piperazin-1-yl]-butyl}-5-methyl-1,3-dihydro-2H-indol-2-one according to claim 1, and its pharmaceutically acceptable acid addition salts. 9. 3-{4-[4-(4-Chloro-phenyl)-piperazin-1-yl]-butyl}-5-methyl-1,3-dihydro-2H-indol-2-one according to claim 1, and its pharmaceutically acceptable acid addition salts. 10. 3-{4-[4-(4-Chloro-3-trifluoromethylphenyl)piperazin-1-yl]butyl}1,3-dihydro-2H-indol-2-one according to claim 1, and its pharmaceutically acceptable acid addition salts. 11. Pharmaceutical compositions comprising, as active ingredient, at least one compound of general formula (I) according to any one of claims 1-10 in a pharmaceutically effective amount, formulated in a solid, soft or liquid pharmaceutical form. 12. A pharmaceutical composition according to claim 11 for the prevention or treatment of central nervous system disorders, in particular depression, anxiety, obsessive-compulsive disorder, panic disorder, social phobia, schizophrenia, mood disorder, mania, mental decline, brain catastrophe, cell death in specific areas of the central nervous system, mental decline caused by brain cell death, Alzheimer's disease, dementia, post-traumatic disease, stress disease, diseases of the cardiovascular system, in particular high blood pressure. 13. A process for the preparation of compounds of general formula (I) according to claim 1, wherein R and R are independently hydrogen, halogen, C1-7 alkyl, C1-7 alkoxy or trifluoromethyl; R ³ represents a hydrogen atom; R ⁴ and R ⁵ are independently hydrogen, halogen, trifluoromethyl, or a straight or branched alkyl or alkoxy group having 1 to 7 carbon atoms; m is 1, 2, 3 or 4; characterized in that (a) a compound of general formula (II), where L represents a hydroxy group, is reacted with an arylsulfonyl chloride or a straight or branched alkylsulfonyl chloride having 1-7 carbon atoms, preferably methylsulfonyl chloride, in the presence of an organic base, and then the resulting compound of general formula (II), where L represents an aryl or alkylsulfonyloxy group, is reacted with a pyridine derivative of general formula (III) in the presence of an acid scavenger, or (b) a compound of general formula (V) is reacted with a compound of general formula (VI) in the presence of a strong base. 15. 3-Alkyl-indol-2-one derivatives of general formula (I) according to any one of claims 1-10, for use as a medicament. 16. A method for the preparation of a pharmaceutical composition suitable for the prevention or treatment of central nervous system disorders, in particular depression, anxiety, obsessive-compulsive disorder, panic disorder, social phobia, schizophrenia, mood disorder, mania, mental decline, brain catastrophe, cell death in specific areas of the central nervous system, mental decline caused by brain cell death, Alzheimer's disease, dementia, post-traumatic disease, stress disease, diseases of the cardiovascular system, in particular high blood pressure, characterized in that the compound of general formula (I) according to any one of claims 1-10 or their pharmaceutically acceptable acid addition salt is mixed with a suitable amount of a pharmaceutically acceptable carrier and, if desired, other pharmaceutically acceptable excipients and brought into galenic form. 17. Use of the compounds according to claims 1-10 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a pharmaceutical composition suitable for the prevention or treatment of central nervous system disorders, in particular mental decline, brain catastrophe, cell death in specific areas of the central nervous system, mental decline caused by brain cell death, Alzheimer's disease, dementia, post-traumatic disease, stress disease, diseases of the cardiovascular system, in particular high blood pressure. 18. A method for the prevention or treatment of diseases of the central nervous system, in particular depression, anxiety, obsessive-compulsive disorder, panic disorder, social phobia, schizophrenia, mood disorder, mania, mental decline, brain catastrophe, cell death in specific areas of the central nervous system, mental decline caused by brain cell death, Alzheimer's disease, dementia, post-traumatic disease, stress disease, and diseases of the cardiovascular system, in particular high blood pressure, characterized in that a preparation containing at least one compound of general formula (I) according to claim 1 or a salt thereof formed with a pharmaceutically suitable acid addition organic or inorganic acid in a therapeutically effective amount, in a solid, soft or liquid pharmaceutical form, is administered to the person in need of treatment. iwGr.'.v· György Mihályi, Deputy CEO Dr. Gábor Blaskó, Research Director