MXPA01010677A - Azaindole derivatives for the treatment of depression - Google Patents

Abstract

Compounds useful in the treatment of diseases affected by disorders of the serotonin-affected neurological systems, such as depression and anxiety, are provided having formula (I) wherein:R 1 and R 2 form a carbocyclic or heterocyclic ring of 5 to 7 atoms, wherein said ring may be saturated or unsaturated;and X is independently hydrogen, cyano, carbamoyl, halogen or alkoxy;or pharmaceutically acceptable salts thereof.

Description

DERIVATIVES OF AZAINDOL FOR THE TREATMENT OF DEPRESSION FIELD OF THE INVENTION This invention relates to compounds that are useful for the treatment of diseases affected by disorders of neurological systems affected by serotonin, such as depression and anxiety. More specifically, the present invention is directed to the dihydroisoquinolinyl indole derivatives useful in the treatment of such disorders.

BACKGROUND OF THE INVENTION Pharmaceutical compositions that enhance the neurotransmission of serotonin (5-HT) are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of the non-selective drugs that affect serotonin, operated through a variety of physiological means that caused them to have numerous unwanted side effects. The most recently prescribed drugs, selective serotonin reuptake inhibitors (SSRIs), act predominantly by inhibiting 5-HT, which is released at the synapse, from being actively removed from the body.

Ref. 133482 synaptic cleft via a serotonin transport carrier, presynaptic. Since SSRIs require several weeks before they exert their full therapeutic effect, this mechanism of 5-HT blockade can not fully explain its therapeutic activity. It is speculated that this induction of two weeks, which occurs before a complete antidepressant effect is observed, is due to the involvement of the 5-HT1A autoreceptors that suppress the firing activity of the 5-HT neurons, causing a damping of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, desensitization of 5-HT autoreceptors occurs allowing a complete antidepressant effect in most patients (see, for example, LePaul et al., Arch. Pharmacol., 352 : 141 (1995)). Therefore, it is believed that by canceling out this negative feedback through the use of 5HT1A antagonists, the clinical antidepressant response could potentially be increased and accelerated. Recent studies by Artigas et al., Trends Neurosci. , 19: 378-383 (1996) suggested that a combination of 5HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust antidepressant effect and faster action.

European Patent Application No. 0714894A1 describes the preparation of the following compounds as 5HT1A agonists for the treatment of migraine headaches) ("> \ wherein: A-B is -CH-CH2 or -C = CH-; X is hydrogen, halo, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, benzyloxy, hydroxyl or carboxamido; And it's oxygen, sulfur or a bond; n is 1-4; and Ar is 1-naphthyl, 2-naphthyl, phenyl or phenyl, monosubstituted with a substituent selected from the group consisting of halo, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, benzyloxy of 1 to 4 carbon, hydroxyl or trifluoromethyl atoms. U.S. Patent No. 5,627,196 describes the compounds of the following formula that have effects on serotonin-related systems. where r is 0-4; s is 0-1; and D is a residue that combines with the carbon atoms to which it is attached to complete a pyrrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl group; X is hydrogen, phenyl, hydroxyl or methoxy, with the proviso that X is hydrogen or phenyl where r is 0; and R is -NH-Ri, Malleron et al, J. Med. Chem. 36: 1194-1202 (1983)) describes the indole derivatives as inhibitors of serotonin uptake having the basic formula: where A can be: Thus, according to the present invention, the compounds of Formula I are provided: wherein: Ri and R2 form a carbocyclic or heterocyclic ring of 5 to 7 atoms, wherein the ring may be saturated or unsaturated; and X is independently hydrogen, cyano, carbamoyl, halogen or alkoxy; or the pharmaceutically acceptable salts thereof. Preferred compounds of the present invention are preferably those of the formula I, wherein: Ri and R2 form a carboxyl or heterocyclic ring of 5 to 6 atoms; and X is hydrogen; or the pharmaceutically acceptable salts thereof. More preferably, the compounds of the present invention are selected from the following: 3-. { l- [2- (2,3-Dihydro-benzo [1,4] dioxin-5-yloxy) -ethyl] -1,2,3,6-tetrahydro-pyridin-4-yl} -lH-pyrrolo [2,3-b] pyridine; 3-. { 1- [2- (1H-indol-4-yloxy) -ethyl] -1,2,3,6-tetrahydro-pyridin-4-yl} -lH-pyrrolo [2, 3-b] pyridine; and 5-. { 2- [4- (lH-pyrrolo [2,3-b] -pyridin-3-yl) -3,6-dihydro-2H-pyridin-1-yl] -ethoxy} -quinoline. As used herein, the term "alkoxy" is understood to include linear and branched carbon chains containing from 1 to 6 carbon atoms. The term "halogen" is understood to include fluorine, chlorine, bromine and iodine. The term "heterocyclic ring" means saturated or unsaturated rings containing one or more heteroatoms, preferably selected from oxygen, nitrogen and sulfur. Preferred examples contain 5 or 6 atoms, particular examples being 1,4-dioxane, pyrrole and pyridine. The term "carbocyclic ring" means saturated or unsaturated carbon rings such as aryl or cycloalkyl, preferably containing 5 or 6 carbon atoms. The compounds of Formula I can also be used in the form of a pharmaceutically acceptable acid addition salt, which has the utility of the free base. Such salts, prepared by methods well known in the art, are formed with inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylene-salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric acids , salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, - benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexyl sulfamic, phosphoric and nitric. The compounds of the present invention can be prepared by any suitable method which will be recognized by those skilled in the art. However, the present compounds can be advantageously prepared according to the following Reaction Scheme I.

Reaction scheme 1 Ex.

The processes for the preparation of the compounds of the formula I form a further aspect of the present invention. The specific exemplification of the production of the representative compounds of this invention is provided in the following procedures.

INTERMEDIARY 1 3- (1,2,3,6-tetrahydro-pyridin-4-yl.}. -lH-pyrrolo [2,3-b] pyridine 7-Azanindole (10 g, 85 mmol), 4-piperidone (34 g, 0.22 mol) and potassium hydroxide (16.83 g, 0.3 mol) were heated at reflux in 150 ml of methanol overnight. The reaction was cooled, filtered and concentrated to give an orange suspension. The suspension was then extracted with methylene chloride and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to provide 14.2 g (84%) of the product as a solid: mp 195-199 ° C.

INTERMEDIARY 2 5-hydroxy- (2,3) -dihydrobenzo [1,4] dioxin Pyrogallol (5 g, 0.04 mol) was dissolved in 600 ml of 2-butanone to which potassium carbonate (1.82 g, 0.013 mol) was added. The mixture was stirred at reflux while 1,2-dibromoethane (2.48 g, 1.14 ml, 0.013 mol) was slowly added dropwise. The reaction was allowed to stir overnight and then cooled to room temperature. The mixture was drained in 100 ml of water and extracted with 200 ml of methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. Chromatography (5% methanol-methylene chloride) provided 2.74 g (45%) of the product as a clear oil. Mass Spectrum (MS) The m / e 152 (M +) INTERMEDIARY 3 5- (2-Chloroethoxy) - (2,3) -dihydrobenzo- [1,4] dioxane To the solution of 5-hydroxybenzodioxane (1.0 g, 6.5 mmol) and 2-chloroethanol (0.79 g, 9.9 mmol), triphenylphosphine (2.6 g, 9.9 mmol) in 50 ml of tetrahydrofuran, diisopropylasidodicarbimide (DIAD) (2.0 g, 9.8 mmol) was slowly added. After 2 hours, another 1.5 equivalents of triphenylphosphine, DIAD, and 2-chloroethanol were added, and the reaction was stirred for another 2 hours. The reaction mixture was emptied into 100 ml of water, and extracted with 100 ml of methylene chloride. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo. Chromatography (20% ethyl acetate-hexanes) gave 1.7 g (76%) of the product as a white solid: mp 70.5-72.5 ° C. Elemental analysis for C? 0HnClO3 Calculated C, 55.96; H, 5.17 Found C, 55.57; H, 5.20 INTERMEDIARY 4 2- (lH-indol-4-yloxy) ethylchloride To a solution of 4-hydroxyindole (4 g, 30 mmol), 2-chloroethanol (4.83 g, 60 mmol), triphenylphosphine (15.7 g, 60 mmol) in 40 mL of anhydrous tetrahydrofuran, diisopropyl azodicarboxylate (12.1 g) was slowly added. 60 mmol). The reaction was allowed to stir for 2.5 hours at room temperature, then it was evacuated in 250 ml of methylene chloride, washed with 3 portions of 100 ml of water and dried over anhydrous sodium sulfate, filtered and the solvent was removed to empty. Chromatography (20% hexanes-ethyl acetate) to remove the triphenylphosphine (20% methylene chloride-hexanes) yielded 2.94 g (50%) of the product as a white solid: mp 69.5-72 ° C.

INTERMEDIARY 5 5- (2-chloroethoxy) -quinoline A 3-neck, 100 ml, oven-dried flask was cooled under a nitrogen atmosphere. 5-Hydroxyquinoline (2 g, 14 mmol) was added as well as triphenylphosphine (5.42 g, 21 mmol) suspended in 50 ml of anhydrous tetrahydrofuran. 2-Chloroethanol (1.3 ml, 21 mmol) was added slowly to the above reaction mixture by means of a syringe, followed by the addition of DEAD (2.98 ml, 21 mmol) by means of a syringe. A second quantity of 1.5 equivalents of 2-chloroethanol, triphenylphosphine and DEAD was added. The reaction mixture was poured into 100 ml of water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography (20% ethyl acetate-hexanes) provided 2.31 g (82%) of the product as a solid: mp 75-78 ° C.

EXAMPLE 1 3-. { l- [2- (2,3-Dihydro-benzo [1,4] dioxin-5-yloxy) -ethyl] -1,2,3,6-tetrahydropyridin-4-yl} -lH-pyrrolo [2, 3-b] pyridine; A solution of 5- (2-chloroethoxy) - (2,3) -dihydrobenzo [1,4] dioxane (0.5 g, 23 mmol), 3- (1,2,3,6-tetrahydropyridin-4-yl) - lH-pyrrolo [2, 3-b] pyridine (0.56 g, 28 mmol) and triethylamine (0.65 ml, 46 mmol) in 20 ml of anhydrous dimethyl sulfoxide was allowed to stir for 4 hours at room temperature. 105 ° C. The mixture was drained in 100 ml of water, and extracted with 3 100 ml portions of methylene chloride. The organic layer was washed with 3 portions of 150 ml of water, with sodium bicarbonate and dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. Chromatography (10% methanol-methylene chloride) provided 0.80 g (92%) of the product as a yellow oil. The oxalate salt was prepared in ethanol: mp 164- 167 ° C. Elemental analysis for C22H23N3O3 »2C2H2? 4 * 0.7H20 Calculated: C, 54.77, H, 5.02; N, 7.37 Found: C, 54.77; H, 4.97; N, 7.23 EXAMPLE 2 3-. { 1- [2- (1H-indol--yloxy) -ethyl] -1,2,3,6-tetrahydro-pyridin-4-yl} -lH-pyrrolo [2, 3-b] iridine; A solution of 2- (1H-indol-4-yloxy) ethylchloride (0.5 g, 26 mmol), 3- (1, 2, 3, 6-tetrahydropyridin-4-yl) -1H-pyrrolo [2, 3-b ] pyridine (0.61 g, 31 mmol) and triethylamine (0.71 ml, 52 mmol) in 20 ml of anhydrous dimethyl sulfoxide was allowed to stir for 4 hours at 80 ° C. The mixture was then emptied and extracted with 3 100 ml portions of ethyl acetate. The organic layer was washed with 3 portions of 100 ml of water, with sodium bicarbonate and dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. Chromatography (10% methanol-methylene chloride) provided 0.95 g (97%) of product as a green oil. The oxalate salt was prepared in ethanol: mp 106-109 ° C. Elemental analysis for C22H22N40 »2C2H204 Calculated: C, 57.99, H, 4.87; N, 10.40 Found: C, 57.62; H, 5.03; N, 10.36 EXAMPLE 3 5-. { 2- [4- (lH-pyrrolo [2, 3-b] pyridin-3-yl) 3,6-dihydro-2H-pyridin-1-yl] ethoxy} quinoline A solution of 5- (2-chloroethoxy) quinoline (0.5 g, 24 mmol), 3- (1, 2, 3, 6-tetrahydropyridin-4-yl) lH-pyrrolo [2, 3-b] pyridine (0.58 g) , 20 mmol) and triethylamine (0.67 ml, 48 mmol) in 20 ml of anhydrous dimethyl sulfoxide was allowed to stir for 4 hours at 80 ° C. The mixture was poured into water diluted with sodium hydroxide solution and extracted with 3 100 ml portions of ethyl acetate. The organic layer was washed with 3 100 ml portions of water, with sodium bicarbonate and dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo to give a pale yellow solid, which was triturated with ethanol ethyl ether to provide a pale yellow solid: mp 202-205 ° C. The oxalate salt was prepared in ethanol: mp 202-205 ° C Elemental analysis for C23H22N4O »C2H2O4 * 0.5H20 Calculated: C, 72.80, H, 6.11; N, 14.77 Found: C, 72.71; H, 5.97; N, 15.37 The activity of the present compounds is demonstrated by the following pharmacological test procedures, standards. PCR cloning of the human 5-HTIA receptor subtype from a human genomic library has been previously described by Chanda et al., Mol. Pharmacol. , 43: 516 (1993). A stable Chinese hamster ovary cell line expressing the subtype of the human 5-HT? A receptor (5-HT? A-CH0 cells) was employed throughout this study. The cells were maintained in DMEM supplemented with 10% fetal calf serum, non-essential amino acids and penicillin / streptomycin. The cells were developed to a confluence of 95-100% as a monolayer before the membranes were harvested for binding studies. The cells were gently scraped from the culture plates, transferred to centrifuge tubes, and washed twice by centrifugation (2000 rpm for 10 minutes, 4 ° C) in buffer (50 mM Tris, pH 7.5). The resulting concentrates were diluted in aliquots and maintained at -80 ° C. On the day of the assay, the cells were thawed on ice, and resuspended in buffer. The studies were conducted using [3 H] 8-OH-DPAT as the radioligand. The binding assay was performed in 96-well microtiter plates in a final total volume of 250 μl buffer. The comparison experiments were performed by using 7 concentrations of the unlabeled drug and a final ligand concentration of 1.5 nM. The non-specific binding was determined in the presence of 10 μM 5HT. Saturation analysis was conducted by using [3H] 8-OH-DPAT at concentrations in the range of 0.3 to 30 nM. After a 30-minute incubation at room temperature, the reaction was terminated by the addition of ice-cooled buffer and rapid filtration using a M-96 Brandel Cell Harvester (Gaithersburg, MD) through a pre-wetted GF / B filter. 30 minutes in 0.5% polyethyleneimine. A protocol similar to that used by Cheetham et al., Neuropharmacol. , 32: 737 (1993) was used to determine the affinity of the compounds for the serotonin transporter. Briefly, frontal cortical membranes prepared from male Sprague-Dawley rats were incubated with 3 H-paroxetine (0.1 nM) for 60 minutes at 25 ° C. All tubes also contained either vehicle, test compound (one to eight concentrations), or saturation concentration of fluoxetine (10 μM) to define the specific binding. All reactions were terminated by the addition of ice-cooled Tris buffer followed by rapid filtration using a Tom Tech filtration device to separate bound 3H-paroxetine from free. The bound radioactivity was quantified using a Wallac 1205 Beta Píate® counter. The non-linear regression analysis was used to determine the IC50 values that were converted to Ki values using the method described in Cheng and Prusoff, Biochem. Pharmacol., 22: 3099 (1973) (Ki = IC50 / ((Radioligand conc.) / (1 + KD)). The binding assay [35S] -GTP? S was similar to that used by Lazareno and Birdsall, Br J. Pharmacol., 109: 1120 (1993) In summary, the membrane fragments of the cloned 5-HT? A receptor (as used for the 5-HTXA receptor binding assays) were stored at -70 ° C. it was necessary, the membranes were rapidly thawed, centrifuged at 40,000 xg for 10 minutes and resuspended at 4 ° C for 10 minutes in a test buffer (25 mM HEPES, 3 mM magnesium chloride, 100 mM sodium chloride, 1 mM EDTA , GDP 10 μM, DTT 500 mM, pH 8.0) These membranes were then incubated for 30 minutes at 30 ° C with [35 S] GTPgS (1 nM) in the presence of the vehicle, the test compound (one to eight concentrations), or 8-OH-DPAT in excess to define the maximum response of the agonist All reactions were terminated by the addition of ice-cooled Tris buffer, followed by to rapid filtration using a Tom Tech® filtration device to separate bound [35S] GTPgS from free. The agonists produced an increase in the amount of [35S] GTPgS bound, whereas the antagonists produced no increase in the bond. The bound radioactivity was counted and analyzed as described above. The following assays were performed by incubating the cells with DMEM containing 25 mM HEPES, 5 mM theophylline, and 10 μM pargyline for a period of 20 minutes at 37 ° C. Functional activity was evaluated by treating the cells with forskolin (final concentration of 1 μM) followed immediately by the test compound (6 concentrations) for an additional 10 minutes at 37 ° C. In separate experiments, 6 concentrations of the antagonist were preincubated for 20 minutes before the addition of 10 nM 8-OH-DPAT and forskolin. The reaction was terminated by removing the media and adding 0.5 ml of the ice-cooled assay buffer. Plates were stored at -20 ° C prior to the evaluation of cyclic AMP formation (cAMP) by a cAMP SPA assay (Amersham).

Example No. 5-HT1A ST (Ki, nM) GTP? S ED50 cAMP ED50 (Ki, nM) (% Emax) (Emax) 1 43.9 18.0 (30%) 2 10.9 1.46 38.9 (9.0%) 12.4 (0%) 3 71.6 6.89 181 (0%) 90.1 (0%) As demonstrated by the results described above, the compounds of the present invention are active toward 5HTiA receptors and in general raise serotonin levels by inhibiting 5-HT transport. Accordingly, the present compounds should be useful in the treatment of disorders related to defects in serotonin concentration. The compounds of the formula I for use in the methods of treatment or therapy form additional aspects of the present invention. The compounds of this invention can be administered orally or parenterally, either pure or in combination with conventional pharmaceutical carriers. Applicable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending, fillers, glidants, compression aids, binders or tablet disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Any of the solid carriers known to those skilled in the art can be used with the compounds of this invention. Particularly suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting point waxes and exchange resins. ionic. The liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs of the compounds of this invention. The compounds of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colorants, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (containing particularly additives as described above, cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and its derivatives and oils (for example, fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used for example by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compositions for oral administration can be either in the form of liquid or solid composition. Preferably, the pharmaceutical compositions containing the compounds of this invention are in the unit dosage form, for example, tablets or capsules.

In such form, the compositions can be subdivided into unit doses containing appropriate amounts of the present compounds. The unit dosage forms can be packaged compositions, for example, packaged powders, flasks, ampoules, pre-filled syringes or sacks containing liquids. Alternatively, the unit dosage form may be, for example, a capsule or tablet itself, or it may be the appropriate number of any such compositions in package form. The therapeutically effective amount of the compounds of this invention is administered and the dosage regimen depends on a variety of factors, including the weight, age, sex, and medical condition of the subject, the severity of the disease, the route and the frequency of administration, and the specific compound employed, and can thus vary widely. However, it is believed that the pharmaceutical compositions may contain the compounds of this invention in the range of about 0.1 to about 2,000 mg, preferably in the range of about 0.5 to about 500 mg and more preferably between about 1 and about 100 mg. The projected daily doses of the active compound are from about 0.01 to about 100 mg / kg of body weight. The daily dose can be conveniently administered two to four times per day. Pharmaceutical compositions comprising compounds of the formula I and a pharmaceutically acceptable carrier form a further aspect of the present invention. The present invention may be exemplified in other specific forms, without departing from the spirit and essential attributes thereof, and accordingly, reference should be made to the appended claims, rather than to the above specification, as indicated by the scope of the invention. invention.

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

Claims (12)

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

1. A compound of the formula: characterized in that: Ri and R2 form a carbocyclic or heterocyclic ring of 5 to 7 atoms, wherein the ring may be saturated or unsaturated; and X is independently hydrogen, cyano, carbamoyl, halogen or alkoxy; or the pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, characterized in that: Ri and R2 form a heterocyclic ring of 5 to 6 atoms, and X is hydrogen; or the pharmaceutically acceptable salts thereof.

3. The compound according to claim 1, characterized in that it is 3-. { l- [2- (2,3-Dihydro-benzo [1,4] dioxin-5-yloxy) -ethyl] -1,2,3,6-tetrahydro-pyridin-4-yl} -lH-pyrrolo [2, 3-b] pyridine.

4. The compound according to claim 1, characterized in that it is 3-. { 1- [2- (1H-indol-4-yloxy) -ethyl] -1,2,3,6-tetrahydro-pyridin-4-yl} -1H-pyrrolo [2, 3-b] pyridine.

5. The compound according to claim 1, characterized in that it is 5-. { 2- [4- (lH-pyrrolo [2, 3-b] -pyridin-3-yl) -3,6-dihydro-2H-pyridin-1-yl] -ethoxy} -quinoline.

6. A pharmaceutical composition, characterized in that it comprises a compound of the formula: wherein: Ri and R2 form a carbocyclic or heterocyclic ring of 5 to 7 atoms, where the ring can be saturated or unsaturated; and X is independently hydrogen, cyano, carbamoyl, halogen or alkoxy; or the pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

7. A compound of the formula wherein: Ri and R2 form a carbocyclic or heterocyclic ring of 5 to 7 atoms, wherein the ring may be saturated or unsaturated; and X is independently hydrogen, cyano, carbamoyl, halogen or alkoxy; or the pharmaceutically acceptable salts thereof; for use in therapy.

8. A compound according to claim 7, wherein the use is for the treatment of diseases affected by disorders of neurological systems affected by serotonin.

9. The use of a compound of the formula: wherein: Ri and R2 form a carbocyclic ring of 5 to 7 carbon atoms, wherein the ring may be saturated or unsaturated; and may contain one or more heteroatoms and X is independently hydrogen, cyano, carbamoyl, halogen or alkoxy; or the pharmaceutically acceptable salts thereof for the manufacture of a medicament for working the depression in a patient in need thereof.

10. A process for the preparation of the compounds of the formula: wherein: Ri and R2 form a carbocyclic or heterocyclic ring of 5 to 7 atoms, wherein the ring may be saturated or unsaturated; and X is independently hydrogen, cyano, carbamoyl, halogen or alkoxy; or the pharmaceutically acceptable salts thereof; characterized the process because it comprises the reaction of a compound of the formula: where Rx and R2 are as previously defined and Hal is a halogen, with a compound of the formula: where X is as previously defined; and optionally forming a pharmaceutically acceptable salt thereof.

11. The process according to claim 10, characterized in that the compound of the formula: where X is as previously defined, it is prepared by the reaction of the compound of the formula: with piperidin-4-one.

12. The process according to claim 10, characterized in that the compound of the formula: where Ri, R2 and Hal are as previously defined, is prepared by the reaction of: with a corresponding haloalcanol,