KR20070021252A - Piperazine derivatives of alkyl oxindoles - Google Patents

Abstract

The present invention relates to novel indole-2-one derivatives of formula (I) having an advantageous activity profile for the prevention and treatment of central nervous system and cardiovascular diseases.

Description

Piperazine Derivatives of Alkyl Oxindoles {PIPERAZINE DERIVATIVES OF ALKYL OXINDOLES}

The present invention relates to novel, substituted indole-2-one derivatives and pharmaceutically acceptable acid addition salts thereof, and methods of preparing such compounds. The present invention also encompasses pharmaceutical compositions containing said novel indole-2-one derivatives and the use of said compounds for the treatment of diseases.

More specifically, the present invention relates to novel indole-2-one derivatives of formula (I) and pharmaceutically acceptable acid addition salts thereof:

Where

R ¹ and R ² are independently hydrogen, halogen, alkyl or alkoxy having 1 to 7 carbon atom (s), or trifluoromethyl;

R ³ is hydrogen;

Q is nitrogen, R ⁴ and R ⁵ are independently hydrogen, halogen, trifluoromethyl, straight or branched chain alkyl or alkoxy having 1 to 7 carbon atom (s), and R ⁶ is hydrogen, halogen, 1 Alkyl or alkoxy having from 7 to 7 carbon atom (s), or R ⁴ and R ⁵ together form ethylenedioxy;

Q is a CH group, R ⁴ and R ⁵ together form ethylenedioxy and R ⁶ is halogen or alkoxy having 1 to 7 carbon atom (s), or

Q is a CH group and R ⁴ , R ⁵ and R ⁶ are independently alkyl or alkoxy or halogen having 1 to 7 carbon atom (s);

m is 1, 2, 3 or 4.

US Patent 4,452,808 discloses 4-aminoalkyl indol-2-one derivatives with selective D ₂ receptor activity. These compounds can be used to treat hypertension. One of the compounds set forth in this patent, 4- [2- (di-N-propylamino) ethyl] -2 (3H) -indoleone, is used for the clinical treatment of Parkinson's disease.

EP 281,309 discloses indole-2-one derivatives having an arylpiperazinyl-alkyl substituent at the 5 position, which can be used for the treatment of psychotic diseases. One of the compounds described in this patent is 5- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -ethyl] -6-chloro-1,3- Dihydro-2H-indol-2-one is D ₂ , 5-HT _1A and It is active by interaction with the 5-HT ₂ receptor and is used in clinical treatment as an antipsychotic.

EP 376,607 discloses indole-2-one derivatives substituted at the 3-position by alkylpiperazinyl-aryl groups, which are active against the 5-HT _1A receptor, useful for the treatment of central neurological diseases.

International patent application WO 98/008816 discloses indole-2-one derivatives with alkyl-piperazinyl, substituted alkyl-piperidinyl or alkyl-cyclohexyl groups substituted in the 3-position. These compounds are psychotropic. The patent specification does not mention anything about the activity profile of the compound and mentions only the treatment of depression and anxiety as a field of application.

The acceleration of social science development in the twentieth century continues to put pressure on human adaptation, which can lead to the inadvertent occurrence of compliance disorders. Adaptation disorders are important risk factors for the development of diseases of mental or mental-body origin, such as anxiety syndrome, stress disorders, depression, schizophrenia, diseases of the sensory organs, diseases of the gastrointestinal tract, cardiovascular diseases and diseases of the secretory organs.

For the treatment of this clinical pattern, the widest range of agents used was active against the benzodiazepine system (eg diazepam) or against the central 5-HT _1A receptor (eg buspyrone, ziprasidone). In the case of psychosomatic diseases, treatment for anxiety is often complemented by the administration of a medicament with antihypertensive activity (acting on α ₁ or α ₂ receptor), or gastric ulcer inhibitory activity (H ₁ -receptor antagonist).

However, benzodiazepine type anti-anxiety agents have several unpleasant side effects. These anti-anxiety agents have a strong calming activity resulting in a decline in concentration and memory, and have a muscle relaxation effect. These side effects affect the quality of life of the patient in an unintended way, thus limiting the scope of application of these drugs.

In addition to the stresses of adapting to the environment, another major problem in modern society is the accelerated population aging. As a result of modern medical science, life expectancy has increased, and the disease caused by aging, particularly many mental illnesses, is rapidly increasing. Therapeutic solutions for Alzheimer's disease, vascular dementia, and senile dementia are emerging as social problems.

As listed above, there is an urgent need for new and efficient drugs that are more effective against the disease than those currently used.

Summary of the Invention

It is an object of the present invention to develop a pharmaceutical ingredient with an advantageous profile of activity than is currently used, which avoids the disadvantages and undesirable side effects specified above, and which at the same time can be used for the treatment and prevention of central nervous and cardiovascular diseases.

The present invention is based on the surprising recognition that substituted indol-2-one derivatives of formula (I) bind well with both 5-HT ₇ and α ₁ receptors, in contrast to prior art compounds of similar structure. Therefore, application of these compounds will include treatment of central nervous and cardiovascular diseases.

According to one aspect of the invention, R ¹ and R ² are independently hydrogen, halogen, alkyl or alkoxy having 1 to 7 carbon atom (s), or trifluoromethyl;

R ³ is hydrogen;

Q is nitrogen,

R ⁴ and R ⁵ are independently hydrogen, halogen, trifluoromethyl, straight or branched chain alkyl or alkoxy having 1 to 7 carbon atom (s),

R ⁶ is hydrogen, halogen, alkyl or alkoxy having 1 to 7 carbon atom (s), or

R ⁴ and R ⁵ together form ethylenedioxy;

Q is a CH group, R ⁴ and R ⁵ together form ethylenedioxy and R ⁶ is halogen or alkoxy having 1 to 7 carbon atom (s), or

Q is a CH group and R ⁴ , R ⁵ and R ⁶ are independently alkyl or alkoxy or halogen having 1 to 7 carbon atom (s);

There is provided a novel 3-substituted indol-2-one derivative of formula (I) wherein m is 1, 2, 3 or 4 and a pharmaceutically acceptable acid addition salt thereof.

As used herein, the term "alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 7, preferably 1 to 4 carbon atom (s) (eg, methyl, ethyl, 1 -Propyl, 2-propyl, n-butyl, isobutyl or tert-butyl groups and the like).

The term "halogen" includes fluorine, chlorine, bromine and iodine atoms, preferably chlorine or bromine.

Leaving groups are alkylsulfonyloxy or arylsulfonyloxy groups such as methylsulfonyloxy (mesyloxy) or p-toluenesulfonyloxy groups; Halogen atoms, preferably bromine or chlorine.

The term "pharmaceutically acceptable acid addition salt" denotes a nontoxic salt of a compound of formula (I) formed with a pharmaceutically acceptable organic or inorganic acid. Inorganic acids suitable for salt formation are, for example, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid or nitric acid. As the organic acid, 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, Naphthalic acid or methanesulfonic acid can be used. In addition, carbonates and hydrocarbon salts are also considered pharmaceutically acceptable salts.

Preferred groups of compounds of formula (I) include Q, which is nitrogen; R ¹ and R ² are independently hydrogen, halogen, alkyl having 1 to 7 carbon atom (s) or alkoxy or trifluoromethyl; R ³ represents hydrogen; R ⁴ and R ⁵ are independently hydrogen, halogen, trifluoromethyl or straight or branched chain alkyl or alkoxy having 1 to 7 carbon atom (s), and R ⁶ is hydrogen, halogen, 1 to 7 carbon atoms Alkyl or alkoxy with (s), or R ⁴ and R ⁵ together form ethylenedioxy; belonging to compounds wherein m is 1, 2, 3 or 4 and pharmaceutically acceptable acid addition salts thereof.

Another advantageous group of compounds of formula (I) are those in which R ¹ and R ² are independently hydrogen, halogen, alkyl or alkoxy or trifluoromethyl having 1 to 7 carbon atom (s), and R ³ is hydrogen ego; Q is a CH group and R ⁴ and R ⁵ together form ethylenedioxy, R ⁶ is halogen or alkoxy having 1 to 7 carbon atom (s), or Q is a CH group, R ⁴ , R ⁵ and R ⁶ is independently halogen or alkyl or alkoxy having 1 to 7 carbon atom (s), wherein m is 1, 2, 3 or 4 and pharmaceutically acceptable acid addition salts thereof.

Particularly advantageous representative compounds of formula (I) are the following derivatives: 3- {4- [4- (7-chloro-2,3-dihydrobenzo [1,4] dioxin-5-yl) -piperazine- 1-yl] -butyl} -5-fluoro-1,3-dihydro-2H-indol-2-one, 3- {4- [4- (5-chloro-2-methoxyphenyl) -piperazine -1-yl] -butyl} -1,3-dihydro-2H-indol-2-one, 5-fluoro-3- {4- [4- (3-methoxyphenyl) -piperazine-1- Il] -butyl} -1,3-dihydro-2H-indol-2-one, and pharmaceutically acceptable acid addition salts thereof.

According to a further aspect of the present invention there is provided a process for preparing a compound of formula (I) and a pharmaceutically acceptable acid addition salt thereof,

(a) a compound of formula (II), wherein L is hydroxy, arylsulfonyl chloride or straight or branched chain alkylsulfonyl chloride having 1 to 7 carbon atom (s) in the presence of an organic base , Preferably reacting with methylsulfonyl chloride, and thus obtaining the compound of formula (II), wherein L is aryl- or alkylsulfonyloxy, in the presence of an acid binder Reacted with a azine derivative,

(b) A method is provided comprising reacting a compound of formula (V) with a compound of formula (VI) in the presence of a strong base:

Where

L in formula (VI) is a leaving group, preferably chlorine or bromine,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above,

m is 1, 2, 3 or 4.

Compounds of formula (I) wherein R ¹ -R ⁶ , m and Q are mentioned above, are compounds of formula (II) wherein R ¹ -R ³ and m are as mentioned above and L is Leaving groups, preferably alkylsulfonyloxy, most preferably methylsulfonyloxy, are selected from the compounds of formula III wherein R ⁴ -R ⁶ and Q are as mentioned above and Houben. Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1992, ed. 4, vol. E16d (ed .: D. Klamann); RC Larock: Comprehensive Organic Transformations, ed. 2, John Wiley & Sons, New York, 1999, 789; DA Walsh, YH. Chen, JB Green, JC Nolan, JM Yanni J. Med. Chem. 1990, 33, 1823-1827] can be prepared by the reaction according to a method known from.

During the preparation of the compounds of formula (II), the formation of substituents can be carried out optionally proceeding according to methods known in the literature. The compounds of formula (IV) are formulated as compounds of formula (V) wherein R ¹ -R ⁴ are as mentioned above and Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1977, ed. 4, vol. V / 2b; AR Katritzky, Ch. W. Rees: Comprehensive Hetero-cyclic Chemistry, ed. 1, Pergamon, Oxford, 1984, vol. 4. (ed .: 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. Simig Eur. J. Org. Chem. 2003, 18, 3991-3996 It is easy to prepare the compound of formula (II) by reacting according to the known method from:

L- (CH ₂ ) _m -L '(IV)

Wherein L and m are as mentioned above and L 'is a leaving group or a group which can be converted to a leaving group.

Compounds of formula (I) wherein R ¹ -R ⁶ and m are as mentioned above may be selected from compounds of formula (V) wherein R ¹ -R ³ are as mentioned above; Wherein R ⁴ -R ⁶ , m and Q are as mentioned above, L is a leaving group) and RJ Sundberg: The chemistry of indoles, Academic Press, New York, 1970, chapter VII .; AR Katritzky, Ch. W. Rees: Comprehensive Heterocyclic Chemistry, 1 ^th Edition, Pergamon, Oxford, 1984, vol. 4 (ed .: 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; WW Wilkerson, AA Kergaye, SW Tam J. Med. Chem. 1993, 36, 2899-2907 , which may be prepared by reacting according to methods known in the art.

Compounds of formula (I) in which R ¹ -R ⁶ , m and Q are mentioned above, can be prepared by successive succession in the last step to form substituents R ¹ -R ⁶ . In this case, the compound of formula (I) is used as starting material, except for the one formed which may be any one selected from R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , All substituents are as mentioned above. Introduction and conversion of substituents are described in Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1977, 4 ^th Edition, IV / la-d; vol. V / 2b kotet]. It may be necessary to apply or remove protecting groups during the introduction of substituents. This method is specified in TW Greene, Protective groups in organic synthesis, John Wiley & Sons, 1981.

Compounds of formula (III), (IV), (V) and (VI) are known in the literature or can be prepared by analogous methods.

Compounds of formula (I) can be converted from these salts to free or pharmaceutically acceptable acid addition salts by methods known from the literature.

According to a further aspect of the invention there is provided a pharmaceutical composition comprising as an active ingredient a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof together with one or more conventional carrier (s) or adjuvant (s). do.

Pharmaceutical compositions according to the invention generally contain 0.1 to 95% by weight, preferably 1 to 50% by weight, in particular 5 to 30% by weight of the active ingredient.

Pharmaceutical compositions of the invention may be administered orally (eg, powders, tablets, coated tablets, capsules, microcapsules, pills, solutions, suspensions or emulsions), parenteral administration (eg, intravenous, intramuscular, subcutaneous or Infusions for intraperitoneal use), rectal administration (eg suppositories), transdermal administration (eg bandages) or topical administration (eg ointment or bandages) or in the form of implants. May be suitable. Solid, soft or liquid pharmaceutical compositions according to the invention can be prepared by methods commonly used in the pharmaceutical industry.

Solid pharmaceutical compositions for oral administration containing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof include fillers or carriers (e.g., lactose, glucose, starch, calcium phosphate, microcrystalline cellulose), binders (e.g., , Gelatin, sorbite, polyvinyl pyrrolidone), disintegrants (e.g. croscarmellose, Na-carboxy-methyl cellulose, crospovidone), tableting aids (e.g. magnesium stearate, talc, polyethylene glycol, silicic acid, dioxide) Silicon) and surfactants (eg, sodium lauryl sulfate).

Liquid compositions suitable for oral administration may be solutions, suspensions or emulsions. Such compositions include suspending agents (eg gelatin, carboxymethyl cellulose), emulsifiers (eg sorbitan monooleate), solvents (eg water, oil, glycerol, propylene glycol, ethanol), buffers (eg acetate, phosphate) , Citrate buffer) and preservatives (eg, methyl-4-hydroxybenzoate).

Liquid pharmaceutical compositions suitable for parenteral administration are generally sterile isotonic solutions, optionally containing buffers and preservatives in addition to solvents.

Soft pharmaceutical compositions, such as suppositories, containing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof as the active ingredient, the active ingredient uniformly dispersed in suppository base materials (e.g., polyethylene glycol or coconut butter) It contains.

According to a further aspect of the invention, a central neurological disease or mental body disease, in particular generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social phobia, agoraphobia, phobia associated with a particular situation, post traumatic stress disorder, post traumatic memory disorder Cognitive impairment, sexual dysfunction of central nervous system origin, depression, schizophrenia; The use of 3-substituted indol-2-one derivatives of formula (I) or pharmaceutically acceptable acid addition salts thereof is provided for the manufacture of pharmaceutical compositions suitable for the treatment or prevention of gastrointestinal diseases, and cardiovascular diseases.

Pharmaceutical compositions according to the invention can be prepared by methods known in the pharmaceutical industry. The active ingredient is mixed with a pharmaceutically acceptable solid or liquid carrier and / or adjuvant, which mixture is in the form of a herbal. Such carriers and auxiliaries, along with methods that can be used in the pharmaceutical industry, are disclosed in Remington's Pharmaceutical Sciences, Edition 18, Mack Publishing Co., Easton, USA, 1990.

Pharmaceutical compositions according to the invention generally contain a unit dose. The daily dose of an adult may generally be from 0.1 to 1000 mg of the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof per kg body weight. Such daily doses may be administered in one or more portion (s). In fact, the daily dose depends on several factors and is determined by the physician.

According to a further aspect of the invention, anxiety syndromes, in particular generalized anxiety disorders, panic disorders, obsessive compulsive disorder, social phobia, agoraphobia, phobias associated with certain situations, stress disorders, post-traumatic stress disorders, post-traumatic memory disorders, cognition To treat disorders, sexual dysfunction of origin of the central nervous system, depression, schizophrenia, mental decline due to neurodegeneration, Alzheimer's disease, stroke, dementia, and also gastrointestinal diseases, and central nervous system diseases, including cardiovascular diseases, especially hypertension Or for the prevention of the use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

The present invention is based on the surprising recognition that the 3-alkyl-indol-2-one derivative of formula (I) binds well with both 5-HT ₇ and α ₁ receptors in contrast to prior art compounds of similar structure.

To measure the 5-HT ₇ receptor affinity, human cloned receptors were used. α ₁ receptor binding was measured from isolated frontal cortex preparations of male Wistar rats weighing 120-200 g. The protein content of the membrane preparations was measured by the method of Lowry (1951).

In the 5-HT ₇ and α ₁ receptor binding studies, the ligands were ³ H-lizergic acid diethylamide (LSD) (1.0 nM) and ³ H-prazosin (0.3 nM). Clozapine (25 μM) and prazosin (1 μM) were used to measure nonspecific binding. α ₁ receptor binding studies were conducted by Reader and Greengrass (Greengrass) method (Reader, TA, Briere, R., Grondin, L .: J. Neural Transm. 68, p. 79 (1987); Greengrass, P , Brenner, R .: Eur. J. Pharmacol. 55, p. 323 (1979)).

IC ₅₀ is the concentration at which the difference between total and nonspecific binding is 50%. Compounds with IC ₅₀ values of less than 100 nmol are considered effective in this test. The experimental results are shown in Tables 2 and 3.

Table 1

5-HT ₇ Receptor Binding

TABLE 2

α ₁ receptor binding

As can be seen from Tables 1 and 2 above, the compounds of the present invention bind well to both 5-HT ₇ and α ₁ receptors.

Based on the above experiments, it can be seen that the compounds according to the invention have a valuable therapeutic profile which is particularly suitable for the treatment or prevention of the mental and cardiovascular diseases specified above.

More details of the invention are described in the following examples, but the scope of protection should not be limited to the examples.

Preparation of Mesyl Ester (Method, "A")

Suitable 3- (4-hydroxybutyl) -oxindoles are described in B. Volk, T. Mezei, Gy. Simig Synthesis 2002, 595; B. Volk, Gy. Simig Eur. J. Org. Chem. 2003, 18, 3991-3996].

55 mmol of 3- (4-hydroxybutyl) -oxindole was dissolved in 150 ml of THF, 15.2 ml (110 mmol) of triethyl amine was added and the solution was cooled to -78 ° C in acetone-dry ice bath. . While stirring at the same temperature, 8.5 ml (110 mmol) mesyl chloride were added dropwise and the solution was allowed to warm to room temperature. Stir at room temperature for 1 hour, triethyl amine hydrochloride is filtered off, the filtrate is evaporated, the residue is dissolved in ethyl acetate and washed with 10% by volume of hydrogen chloride solution until the pH of the aqueous phase becomes acidic. Extracted once. The organic phase was dried over sodium sulphate, evaporated and the residual oil crystallized by trituration with diisopropyl ether, stirred in 100 ml of diisopropyl ether, filtered, washed with hexanes and dried. The product was purified by recrystallization from the solvent indicated above after the melting point of this 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-2H-indol-2-one.

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

IR (KBr): 3180, 1705 (C = 0) cm ^-1 _.

¹ H-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 (CDC1 ₃ , 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 .

¹ H-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, doublet of doublets, 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-2H-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 .

¹ H-NMR (CDCl ₃ , 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, br s) ppm.

¹³ C-NMR (CDC1 ₃ , 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, J = 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 .

¹ H-NMR (CDC1 ₃ , 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 (CDC1 ₃ , 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 Ester with Base (Method “B”)

The melt of secondary amine (12 mmol) was warmed to 120 ° C. with gentle stirring and mesyl compound (12 mmol) and sodium carbonate (1.36 g; 12 mmol) were added at the same temperature. The mixture was allowed to react for 1 hour, the melt cooled, ethyl acetate and water were added and the phases separated. The organic phase was evaporated and the residual oil was chromatographed on a short column using ethyl acetate as eluent. As main product, the desired compound was obtained.

Treatment Method 1: If the product purified by column chromatography was obtained as crystals when rubbed with diethyl ether, it was filtered and recrystallized from a mixture of hexane and ethyl acetate. The desired compound was obtained in the form of white crystals.

Treatment method 2: If the basic product was not obtained as crystals upon addition of diethyl ether, it was dissolved in 200 ml of ether, a small amount of suspended precipitate was filtered off, in a pure solution, in ether diluted with 50 ml of diethyl ether. Dissolved calculated amount (1 molar equivalent) of hydrogen chloride was added dropwise with vigorous stirring. The separated white salt was filtered off, washed with ether and hexanes and dried in vacuo pistol for 3 hours at room temperature.

Treatment method 3: If the basic product is not obtained as crystals upon addition of diethyl ether and does not provide a salt that can be filtered well with hydrogen chloride, it is dissolved in 100 ml of hot ethyl acetate and 1 in 30 ml of hot ethyl acetate. A molar equivalent of a solution of oxalic acid dihydrate was added within 10 minutes with stirring. The white oxalate salt was separated by cooling. Filter at room temperature, wash with ethyl acetate and hexanes and dry.

Example 5

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

The title compound was subjected to Treatment Method 1 starting from 3- (4-mesyloxybutyl) -1,3-dihydro-2H-indol-2-one and 1- (pyridin-2-yl) -piperazine Prepared according to Method B.

M.p .: 131-132 ° C. (hexane-ethyl acetate).

IR (KBr): 3189, 1706 (C = O), 1665 cm ^-1 .

¹ H-NMR (CDC1 ₃ , TMS, 400 MHz): 1.59-1.38 (4H, m), 2.05-1.95 (2H, m), 2.35 (2H, t, J = 7.5 Hz), 2.51 (4H, t, J = 5.1 Hz), 3.47 (1H, t, J = 5.9 Hz), 3.52 (4H, t, J = 5.1 Hz), 6.61 (1H, t, J = 6.1 Hz), 6.62 (1H, d, J = 8.7 Hz), 6.89 (1H, d, J = 7.7 Hz), 7.01 (1H, dt, J = 1.0, 7.5 Hz), 7.20 (1H, t, J = 7.8 Hz), 7.22 (1H, d, J = 7.0 Hz), 7.45 (1H, dt, J = 2.0, 7.9 Hz), 8.18 (1H, ddd, J = 0.8, 2.0, 4.9 Hz) ppm.

¹³ C-NMR (CDC1 ₃ , TMS, 101 MHz): 180.6, 159.5, 147.8, 141.7, 137.3, 129.7, 127.8, 124.0, 122.1, 113.2, 109.7, 107.0, 58.3, 52.9, 46.0, 45.1, 30.2, 26.7, 23.7 ppm.

Elemental Analysis for Formula C ₂₁ H ₂₆ N ₄ 0 (350.47):

Calc. For C 71.97, H 7.48, N 15.99%.

Found: C 70.86, H 7.48, N 15.76%.

Example 6

3- {4- [4- (7-chloro-2,3-dihydrobenzo [1,4] dioxin-5-yl) -piperazin-1-yl] -butyl } -1,3-dihydro -2H-indole-2-one monooxalate

The title compound was converted to 3- (4-mesyloxybutyl) -1,3-dihydro-2H-indol-2-one and 1- (7-chloro-2,3-dihydrobenzo- [1,4] di. Prepared according to Method B by applying Treatment Method 3 starting from Auxin-5-yl) -piperazine.

M.p .: 236-238 ° C.

IR (KBr): 3273, 3013, 1710 (C = 0) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 1.38-1.22 (2H, m), 1.70-1.60 (2H, m), 1.95-1.75 (2H, m), 2.95 (2H, t, J = 7.5 Hz), 3.18 (8H, br s), 3.44 (1H, t, J = 6.1 Hz), 4.25 (4H, s), 6.64 (1H, d, J = 2.4 Hz), 6.50 (1H, d, J = 2.4 Hz), 6.84 (1H, d, J = 7.7 Hz), 6.95 (1H, t, J = 7.5 Hz), 7.17 (1 H, t, J = 7.6 Hz), 7.26 (1H, d, J = 7.3 Hz), 8.7 = 2H, br s), 10.4 (1H, s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 179.0, 164.7, 144.6, 142.9, 141.2, 135.1, 129.7, 127.8, 124.4, 124.2, 121.4, 111.4, 110.7, 109.4, 64.2, 64.1, 55.7, 51.2, 47.3, 45.1, 29.6, 23.7, 22.8 ppm.

Elemental Analysis for Formula C ₂₆ H ₃₀ ClN ₃ 0 ₇ (532.00):

Calc. For C 58.70, H 5.68, Cl 6.66, N 7.90%.

Found: C 58.67, H 5.77, Cl 6.67, N 7.85%.

Example 7

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

The title compound is derived from 5-fluoro-3- (4-mesyl-oxybutyl) -1,3-dihydro-2H-indol-2-one and 1- (pyridin-2-yl) -piperazine Prepared according to Method B / l.

M.p .: 132-134 ° C. (hexane-ethyl acetate).

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

¹ H-NMR (CDCl ₃ , TMS, 400 MHz): 1.47-1.35 (2H, m), 1.59-1.52 (2H, m), 2.03-1.95 (2H, m), 2.36 (2H, t, J = 7.6 Hz), 2.52 (4H, t, J = 5.1 Hz), 3.48 (1H, t, J = 5.9 Hz), 3.53 (4H, t, J = 5.0 Hz), 6.64-6.59 (2H, m), 6.81 ( 1H, dd, J = 4.3, 8.5 Hz), 6.91 (1H, dt, J = 2.6, 9.2 Hz), 6.97 (1H, dd, J = 2.0, 7.9 Hz), 7.47 (1H, dt, J = 2.0, 7.1 Hz), 8.18 (1H, double doublet of doublets, J = 0.9, 2.0 Hz), 9.00 (1H, s) ppm.

¹³ C-NMR (CDC1 ₃ , TMS, 101 MHz): 23.6, 26.7, 30.2, 45.1, 46.4, 53.0, 58.3, 107.0, 110.1 (d, J = 8.0 Hz), 112.1 (d, J = 24.4 Hz), 113.2, 114.1 (d, J = 23.3 Hz), 131.3 (d, J = 7.6 Hz), 137.4, 137.5, 147.9, 159.0 (d, J = 239.9 Hz), 159.5, 180.2 ppm.

Elemental Analysis for Formula C ₂₁ H ₂₅ FN ₄ 0 (368.46):

Calculated: C 68.46, H 6.84, N 15.21%.

Found: C 68.34, H 7.04, N 14.86%.

Example 8

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

Treatment of the title compound starting from 6-fluoro-3- (4-mesyloxybutyl) -1,3-dihydro-2H-indol-2-one and 1- (pyridin-2-yl) -piperazine Prepared according to Method B by applying Method 1.

M.p .: 136-137 ° C. (hexane-ethyl acetate).

IR (KBr): 3294, 1726 (C = O), 1689 cm ^-1 .

¹ H-NMR (CDC1 ₃ , TMS, 400 MHz): 1.43-1.38 (2H, m), 1.67 (2H, br s), 1.97 (2H, q, J = 7.4 Hz), 2.55 (2H, br s) , 2.74 (4H, br s), 3.42 (1H, t, J = 5.9 Hz), 3.68 (4H, br s), 6.73-6.63 (4H, m), 7.13 (1H, dd, J = 5.3, 8.2 Hz ), 7.48 (1H, dt, J = 2.0, 7.8 Hz), 8.20-8.17 (1H, m), 8.97 (1H, s) ppm.

¹³ C-NMR (CDC1 ₃ , TMS, 101 MHz): 23.3, 25.6, 30.1, 44.3, 45.3, 52.5, 57.9, 98.4 (d, J = 27.1 Hz), 107.2, 108.5 (d, J = 22.1 Hz), 113.8, 124.7 (d, J = 3.1 Hz), 124.9 (d, J = 9.9 Hz), 137.6, 142.9 (d, J = 12.2 Hz), 147.9, 159.0, 162.6 (d, J = 244.5 Hz), 180.4 ppm .

Elemental Analysis for Formula C ₂₁ H ₂₅ FN ₄ 0 (368.46):

Calculated: C 68.46, H 6.84, N 15.21%.

Found: C 68.14, H 6.83, N 15.03%.

Example 9

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

The title compound was subjected to Treatment Method 3 starting from 3- (4-mesyloxybutyl) -1,3-dihydro-2H-indol-2-one and 1- (3-methoxyphenyl) -piperazine Prepared according to Method B.

M.p .: 208-211 ° C.

IR (KBr): 3160, 2579, 2456, 1707 (C = O) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 1.36-1.24 (2H, m), 1.95-1.72 (4H, m), 3.09-3.00 (2H, m), 3.16 (2H, t, J = 11.9 Hz), 3.46 (1H, t, J = 6.1 Hz), 3.47 (2H, t, J = 10.4 Hz), 3.73 (3H, s), 3.78 (2H, d, J = 13.0 Hz), 10.4 ( 1 H, s), 11.1 (1 H, br s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 22.7, 23.1, 29.6, 45.0, 45.4, 50.5, 50.6, 55.1, 55.2, 102.1, 105.2, 108.3, 109.2, 121.2, 124.0, 127.6, 129.5, 129.8, 142.7, 150.9, 160.2, 178.7 ppm.

Elemental Analysis for Formula C ₂₅ H ₃₁ N ₃ 0 ₆ (469.54):

Calculated: C 63.95, H 6.65, N 8.95%.

Found: C 63.80, H 6.81, N 8.81%.

Example 10

3- (4- [4- (7-chloro-2,3-dihydrobenzo [1,4] dioxin-5-yl) -piperazin-1-yl] -butyl} -5-fluoro-1 , 3-dihydro-2H-indol-2-one

The title compound was converted to 3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1- (7-chloro-2,3-dihydro Prepared according to Method B by applying Treatment Method 1 starting from benzo [1,4] dioxin-5-yl) -piperazine.

M.p .: 146-148 ° C. (hexane-ethyl acetate).

IR (KBr): 2946, 1720 (C = O), 752 cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 1.34-1.17 (2H, m), 1.43-1.34 (2H, m), 1.99-1.78 (2H, m), 2.42 (4H, br s) , 2.93 (4H, br s), 3.48 (1H, t, J = 5.6 Hz), 4.23 (4H, s), 6.42 (1H, d, J = 2.5 Hz), 6.56 (1H, d, J = 2.4 Hz ), 6.79 (1H, dd, J = 4.5, 8.5 Hz), 6.99 (1H, dt, J = 2.7, 9.1 Hz), 7.16 (1H, dd, J = 1.8, 8.2 Hz), 10.34 (1H, s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 23.1, 26.3, 29.5, 45.8 (d, J = 1.9 Hz), 49.9, 52.8, 52.9, 57.7, 63.9, 64.1, 109.8 (d, J = 8.0 Hz), 110.54, 110.6, 112.0 (d, J = 24.4 Hz), 113.8 (d, J = 22.9 Hz), 124.3, 131.8 (d, J = 8.4 Hz), 135.1, 139.1 (d, J = 1.9 Hz ), 142.7, 144.4, 158.0 (d, J = 235.7 Hz), 178.9 ppm.

Elemental Analysis for Formula C ₂₄ H ₂₇ ClFN ₃ 0 ₃ (459.95):

Calc. For C 62.67, H 5.92, Cl 7.71, N 9.14%.

Found: C 62.26, H 5.88, Cl 7.53, N 8.93%.

Example 11

3- (4- [4- (5-chloro-2-methoxyphenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one monohydrochloride

The title compound starts from 3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indol-2-one and 1- (5-chloro-2-methoxyphenyl) -piperazine Was prepared according to Method B by applying Treatment Method 2.

M.p .: 91-94 ° C.

IR (KBr): 2583, 1708 (C = O) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 1.34-1.23 (2H, m), 1.92-1.70 (4H, m), 3.15-3.00 (6H, m), 3.59-3.40 (5H, m ), 3.78 (3H, s), 6.84 (1H, d, J = 7.7 Hz), 6.90 (1H, d, J = 2.5 Hz), 6.95 (1H, dt, J = 1.0, 7.4 Hz), 6.98 (1H , d, J = 8.7 Hz), 7.04 (1H, dd, J = 2.5, 8.7 Hz), 7.17 (1H, t, J = 7.7 Hz), 7.27 (1H, d, J = 7.2 Hz), 10.4 (1H , s), 11.06 (1H, broad singlet) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 22.7, 23.1, 29.6, 45.0, 46.6, 50.9, 55.2, 55.9, 109.4, 113.4, 118.3, 121.4, 122.7, 124.2, 124.7, 127.8, 129.7, 140.8, 142.9, 150.8, 178.9 ppm.

Elemental Analysis for Formula C ₂₃ H ₂₉ C1 ₂ N ₃ 0 ₂ (450.41):

Calc. For C 61.33, H 6.49, Cl 15.74, N 9.33%.

Found: C 59.48, H 6.71, Cl 15.47, N 8.96%.

Example 12

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

The title compound was collected from 3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1- (3-methoxyphenyl) -piperazine. Prepared according to Method B by starting Treatment Method 3.

M.p .: 211-214 ° C.

IR (KBr): 3226, 1708 (C = 0) cm ^-1 .

¹ H-NMR (DMSO-d ₆ , TMS, 400 MHz): 1.28-1.15 (2H, m), 1.68-1.64 (2H, m), 1.94-1.76 (2H, m), 2.9 (2H, t, J = 7.8 Hz), 3.18 (4H, s), 3.37 (4H, s), 3.49 (1H, t, J = 5.6 Hz), 3.72 (3H, s), 6.43 (1H, d, J = 8.0 Hz), 6.56 (1H, d, J = 8.1 Hz), 6.51 (1H, s), 6.82 (1H, dd, J = 4.4, 8.3 Hz), 7.20-7.12 (2H, m), 9.2-7.6 (2H, br s ), 10.43 (1H, s) ppm.

¹³ C-NMR (DMSO-d ₆ , TMS, 101 MHz): 22.6, 23.6, 29.3, 45.6, 45.9, 50.9, 55.1, 55.5, 59.9, 102.2, 105.3, 108.5, 109.9 (d, J = 8.0 Hz), 112.1 (d, J = 24.4 Hz), 114.0 (d, J = 23.3 Hz), 130.0, 131.6 (d, J = 8.4 Hz), 139.2 (d, J = 1.5 Hz), 151.3, 158.1 (d, J = 235.7 Hz), 160.5, 164.5, 178.8 ppm.

Elemental Analysis for Formula C ₂₅ H ₃₀ FN ₃ 0 ₆ (487.53):

Calculated: C 61.59, H 6.20, N 8.62%.

Found: C 59.70, H 6.33, N 8.35%.

Claims (17)

3-alkyl indol-2-one derivative of formula (I) or a pharmaceutically acceptable acid addition salt thereof:

Where R ¹ and R ² are independently hydrogen, halogen, alkyl or alkoxy having 1 to 7 carbon atom (s), or trifluoromethyl; R ³ is hydrogen; Q is nitrogen, R ⁴ and R ⁵ are independently hydrogen, halogen, trifluoromethyl, straight or branched chain alkyl or alkoxy having 1 to 7 carbon atom (s), and R ⁶ is hydrogen, halogen, 1 Alkyl or alkoxy having from 7 to 7 carbon atom (s), or R ⁴ and R ⁵ together form ethylenedioxy; Q is a CH group, R ⁴ and R ⁵ together form ethylenedioxy and R ⁶ is halogen or alkoxy having 1 to 7 carbon atom (s), or Q is a CH group and R ⁴ , R ⁵ and R ⁶ are independently alkyl or alkoxy or halogen having 1 to 7 carbon atom (s); m is 1, 2, 3 or 4. Q is nitrogen; R ¹ and R ² are independently hydrogen, halogen, alkyl having 1 to 7 carbon atom (s) or alkoxy or trifluoromethyl; R ³ represents hydrogen; R ⁴ and R ⁵ are independently hydrogen, halogen, trifluoromethyl, straight or branched chain alkyl or alkoxy having 1 to 7 carbon atom (s), and R ⁶ is hydrogen, halogen, 1 to 7 carbon atoms Alkyl or alkoxy with (s), or R ⁴ and R ⁵ together form ethylenedioxy; 3-alkyl indol-2-one derivative wherein m is 1, 2, 3 or 4 or a pharmaceutically acceptable acid addition salt thereof. R ¹ and R ² are independently hydrogen, halogen, alkyl or alkoxy or trifluoromethyl having 1 to 7 carbon atom (s), R ³ is hydrogen; Q is a CH group and R ⁴ and R ⁵ together form ethylenedioxy and R ⁶ is halogen or alkoxy having 1 to 7 carbon atom (s), or Q is a CH group, R ⁴ , R ⁵ and R ⁶ are independently halogen or alkyl or alkoxy or halogen having 1 to 7 carbon atom (s), 3-alkyl indol-2-one derivative wherein m is 1, 2, 3 or 4 or a pharmaceutically acceptable acid addition salt thereof. 3- [4- (4-pyridin-2-yl-piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one or a pharmaceutically acceptable acid addition salt thereof. 3- {4- [4- (7-chloro-2,3-dihydrobenzo [1,4] dioxin-5-yl) -piperazin-1-yl] -butyl} -1,3-dihydro -2H-indole-2-one or a pharmaceutically acceptable acid addition salt thereof. 5-Fluoro-3- [4- (4-pyridin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one or a pharmaceutically acceptable thereof Acid addition salts. 6-fluoro-3- [4- (4-pyridin-2-yl-piperazin-1-yl) -butyl] -1,3-dihydro-2H-indol-2-one or a pharmaceutically acceptable thereof Acid addition salts. 3- {4- [4- (3-methoxyphenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one or a pharmaceutically acceptable acid addition thereof salt. 3- {4- [4- (7-chloro-2,3-dihydrobenzo [1,4] dioxine-5-yl) -piperazin-1-yl] -butyl} -5-fluoro-1 , 3-dihydro-2H-indol-2-one or a pharmaceutically acceptable acid addition salt thereof. 3- {4- [4- (5-chloro-2-methoxyphenyl) -piperazin-1-yl] -butyl} -1,3-dihydro-2H-indol-2-one or a pharmaceutically thereof Acceptable acid addition salts. 5-Fluoro-3- {4- [4- (3-methoxyphenyl) -piperazin-l-yl] -butyl} -1,3-dihydro-2H-indol-2-one or a pharmaceutical thereof Acceptable acid addition salts. As active ingredient one or more compounds of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable acid addition salt thereof, together with one or more conventional carrier (s) or adjuvant (s) Pharmaceutical composition comprising. The method of claim 12, wherein the anxiety syndrome, in particular generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social phobia, agoraphobia, phobia associated with a particular situation, stress disorder, post traumatic stress disorder, post traumatic memory disorder, cognitive impairment, central Suitable for treating or preventing sexual dysfunction of nervous system origin, depression, schizophrenia, mental decline due to neurodegeneration, Alzheimer's disease, stroke, dementia, and also central nervous system and psychosomatic disorders, including gastrointestinal diseases, and cardiovascular diseases, especially hypertension Pharmaceutical composition characterized in that. (a) a compound of formula II, wherein L is hydroxy, arylsulfonyl chloride or straight or branched chain alkylsulfonyl chloride having 1 to 7 carbon atom (s) in the presence of an organic base; , Preferably reacting with methylsulfonyl chloride, and thus obtaining the compound of formula (II), wherein L is aryl- or alkylsulfonyloxy, in the presence of an acid binder React with derivatives, (b) a process for preparing a compound of formula (I), comprising reacting a compound of formula (V) with a compound of formula (VI) in the presence of a strong base:

Where L in formula (VI) is a leaving group, preferably chlorine or bromine, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ and Q are as defined in claim 1, m is 1, 2, 3 or 4. Use of a 3-alkyl-indol-2-one derivative of formula (I) according to any one of claims 1 to 11 as a medicament. 12. Mixing the at least one compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof according to any one of claims 1 to 11 with a pharmaceutical carrier and optionally other auxiliaries so that the mixture is in the form of a herbal form. Including, anxiety syndromes, especially generalized anxiety disorders, panic disorders, obsessive compulsive disorder, social phobia, agoraphobia, phobias associated with certain situations, stress disorders, post-traumatic stress disorders, post-traumatic memory disorders, cognitive disorders, central nervous system origin Pharmaceutical compositions suitable for treating or preventing sexual dysfunction, depression, schizophrenia, mental decline due to cerebral cell fusion, Alzheimer's disease, stroke, dementia, and central nervous system and psychosomatic disorders, including gastrointestinal and cardiovascular diseases, in particular hypertension How to manufacture. Anxiety syndromes, especially generalized anxiety disorders, panic disorders, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition containing at least one compound of formula (I) or a pharmaceutically acceptable organic or inorganic acid addition salt thereof , Obsessive-compulsive disorder, social phobia, agoraphobia, phobias associated with a specific situation, stress disorder, post-traumatic stress disorder, post-traumatic memory disorder, cognitive impairment, sexual dysfunction of central nervous system origin, depression, schizophrenia, mental decline due to neurodegeneration , Alzheimer's disease, stroke, dementia, as well as methods of treating or preventing central nervous system and psychosomatic disorders, including gastrointestinal and cardiovascular diseases, in particular hypertension.