MXPA00009808A - N-aryloxyethyl-indoly-alkylamines for the treatment of depression - Google Patents

Abstract

Compounds effective in treating disorders of the serotonin-affected neurological systems are provided, such compounds having formula (I), wherein:R1 is hydrogen, lower alkyl, phenyl, or substituted phenyl;X and Y together complete a lactam, imidazole, imidazolone, or thioimidazolone ring;Z is hydrogen, halogen, or lower alkoxy;W is hydrogen, halogen, lower alkoxy, lower alkyl, cyano, or a trifluoromethyl group;and n=2 to 5;or pharmaceutically acceptable salts thereof.

Description

N-ARYLOXYTHYL-INDOLYL-ALKYLAMINES FOR THE TREATMENT OF DEPRESSION FIELD OF THE INVENTION This invention relates to compounds useful for the treatment of diseases affected by disorders of neurological systems affected by serotonin, such as depression and anxiety. More specifically, this invention relates to various N-aryloxyethyl-indolyl-alkylamines useful for the treatment of such diseases.

BACKGROUND OF THE INVENTION Pharmaceutical products that improve the transmission of serotonin (5-HT) are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective drugs that affect serotonin operated through a variety of physiological functions that cause it to possess numerous unwanted side effects, such as blurred vision, dry mouth, and sedation. The most drugs Ref: 123324 recently introduced selective serotonin reuptake inhibitors (SSRIs), act predominantly by inhibiting 5-HT, which is released at the synapse, from being actively removed from the synaptic cleft by a serotonin presynaptic transport carrier . 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 that 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 effect therapeutic. Studies suggest that after several weeks of SSRI administration, a desensitization of 5-HT autoreceptors occurs allowing a complete antidepressant effect in most patients. Therefore, it is believed that by canceling this negative feedback through the use of 5-HT1A antagonists, the clinical antidepressant response could potentially be increased and accelerated. Recent studies by Artigas et al., Trends Neurosci. , 19: 378-383, (1996) suggest that a Japanese Patent Nos. 05255302 and 09040648 describe the following compounds that are reported as useful for the treatment of diseases related to the central nervous system such as anxiety and depression.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a new class of molecules that have the ability to act concomitantly in the autoreceptors of 5-HT1A and with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.

The compounds of the present invention are N-aryloxyethyl-indolyl-alkylamines represented by Formula I: wherein: Ri is hydrogen, lower alkyl, phenyl, or substituted phenyl; X and Y together complete a lactam, imidazole, imidazolone, or thioimidazolone ring; Z is hydrogen, halogen, or lower alkoxy; W is hydrogen, halogen, lower alkoxy, lower alkyl, cyano, or a trifluoromethyl group; and n = 2 or 5; or the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION Preferably, the compounds of the present invention are those represented by Formula I, wherein: Ri is hydrogen; X and Y together complete an imidazole or thioimidazolone ring; Z is halogen or hydrogen; W is halogen or hydrogen; and n = 2 to 3; or the pharmaceutically acceptable salts thereof. More preferably, the compounds of the present invention are selected from the following: [2- (3H-benzoimidazol-4-yloxy) -ethyl] - [3- (lH-indol-3-yl) -propylamine; 4- . { 2- [3-lH-indol-3-yl) -propylamine] -ethoxy} -l, 3-dihydrobenzoimidazol-2-one; 4- . { 2- [3-lH-indol-3-yl) -propylamino] -ethoxy} -1, 3-dihydrobenzoimidazole-2-thione; [2- (3H-benzoimidazol-4-yloxy) -ethyl] - [3- (5-fluoro-lH-indol-3-yl) -propyl] -amine; [2- (6-chloro-lH-benzoimidazol-4-yloxy) -ethyl] - [3- (5-fluoro-lH-indol-3-yl)] - propyl] -amine; and 7-fluoro-4-. { 2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -1, 3-dihydro-indol-2-one. As used herein, the terms "lower alkyl" and "lower alkoxy" are understood to include linear and branched carbon chains containing 1 to 6 carbon atoms. The term "halogen" is understood to include fluorine, chlorine, bromine and iodine. The "substituted phenyl" may include substitution with the halogen, lower alkyl, lower alkoxy and cyano groups. The compounds of Formula I can also be advantageously used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, which can be prepared by methods well known to those skilled in the art, are formed with the inorganic or organic acids, for example; fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylene-allylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, indobenzoic, glutamic, benzenesulphonic, hydrochloric, hydrobromic, sulfuric, cyclohexyl sulphonic, phosphoric and nitric. The compounds of the present invention can be prepared by any suitable method known to those of skill in the art. However, the compounds can be sold according to any of Reaction Schemes 1 to 4 below. In the Reaction Schemes, the intermediate compounds exemplified hereinafter are identified in parentheses. The compound produced in each of Schemes 1 to 4 is identified by reference to the appropriate Example. However, it is understood that each of Reaction Schemes 1 to 4 is applicable to the genus of Formula I.

Reaction Scheme 1 Reaction Scheme 2 Reaction Scheme 3 Reaction Scheme 4 The present invention will now be illustrated by reference to the following specific, non-limiting examples.

INTERMEDIARY 1 3-indolyl-propionamide A solution of the 3-indolpropionic acid (15 g, 79 mmol) and 1,1 '-carbonyl-diimidazole (16.7 g, 100 mmol) in 150 ml of anhydrous tetrahydrofuran was allowed to stir for 1.5 hours at room temperature. Ammonia was then bubbled through the solution for 2.5 hours at room temperature. The solvent was removed in vacuo, and the residue was dissolved in 500 ml of ethyl acetate. The organic solution was washed with 3 portions of 150 ml of water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. The white solid was collected and dried in vacuo, 10.42 g (96%) were obtained; mp 124-125 ° C. MS The m / e 188 (M +).

INTERMEDIARY 2 3-indolyl-propylamine To a solution of 3-indolyl-propionamide (5 g, 24.7 mmol) in 150 ml of anhydrous tetrahydrofuran was added lithium aluminum hydride (1.0 M solution in 100 ml of tetrahydrofuran) slowly. The reaction mixture was heated to reflux for 3 hours, and then quenched sequentially with 4 ml of water, with 4 ml of 15% sodium hydroxide, and 12 ml of water at 0 ° C. The mixture was filtered through celite and concentrated in vacuo. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) gave 4.0 g (86%) of the product as a white solid: mp 58-60.5 ° C; MS The m / e 174 (M +).

INTERMEDIARY 3 2- (2-chloro-ethoxy) -6-nitro-phenylamine A suspension containing 2-amino-3-nitrophenol (32.0 g, 0.208 mol), 1,2-dichloroethane (260.0 g, 2.65 mol), potassium carbonate (35.0 g, 0.252 mol) and 750 ml of 2-butanone were added. heated to reflux for 24 hours. The mixture was cooled and filtered and the solids were washed with ethyl acetate. The filtrate was concentrated to an oily residue which was dissolved in 500 ml of ethyl acetate. The organic layer was washed with 250 ml of 1 N sodium hydroxide, with 500 ml of water and 2 portions of 500 ml of brine, and then dried over anhydrous magnesium sulfate. Concentration of the filtered solution and trituration of the residue with hexanes gave 37.8 g (84.6%) of the product as an orange solid: mp 71-73 ° C; MS The m / e 216 (M +). Elemental analysis for C8H9C1N203 Calculated: C, 44.36; H, 4.19; N, 12.93 Found: C, 44.45; H, 4.02; N, 12.97 INTERMEDIARY 4 2- . { 2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -6-nitro-phenylamine A solution containing 2- (2-chloro-ethoxy) -6-nitro-phenylamine (4.1 g, 19 mmol) and 3- (lH-indol-3-yl) -propi-lamine (7.1 g, 40.8 mmol) in 50 g. ml of anhydrous dimethyl sulfoxide was heated at 60 ° C for 12 hours. 200 ml of ethyl acetate were added and the mixture was washed with 3 portions of 200 ml of saturated sodium bicarbonate and 200 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product. Purification by chromatography (ethyl acetate: hexanes: methanolic ammonia 2 N = 25: 25: 1 yielded 4.6 g (68.9% of the product as a yellowish red viscous oil, MS m / e 354 (Mt). for C19H22N4O3 »0.4H2O» 0. lC4H8O2 »0.0.5CH2C12 Calculated: C, 62.35; H, 6.38; N, 14.95 Found: C, 62.38; H, 6.30; N, 14.90 INTERMEDIARY 5 3- . { 2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -benzene-1, 2-diamine To a solution of 2-. { 2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} 6-Nitro-phenylamine (1.9 g, 5.39 mmol) in 40 ml of ethanol was added 5% palladium on carbon (0.5 g) under nitrogen atmosphere. The resulting suspension was hydrogenated under 40 psi for 4 hours. The catalyst was removed by filtration and the ethanol was evaporated to give the crude product. Purification by chromatography (2 N methanolic ammonia 3-10% in methylene chloride) gave 1.57 g (90.6%) of the product as a brown oil. AH NMR (400 MHZ, DMSO-d6), d 1.79 (2H, q, J = 7.2 Hz); 2.62 (2H, t, J = 7.1 Hz); 2.71 (2H, t, J = 7.2 Hz); 2.83 (2H, t, J = 5.2 Hz); 4.09 (2H, broad); 4.43 (2H, broad); 6.19 (1H, t, J = 8.0 Hz); 6.33 (1H, t, J = 7.9 Hz); 6.94 (1H, t, J = 7.0 Hz); 7.03 (1H, t, J = 7.2 Hz); 7.08 (1H, d J = 2.0 Hz); 7.29 (2H, d, J = 7.4 Hz); 7.31 (2H, d, J = 7.4 Hz); 10.7 (1H, broad).

INTERMEDIARY 6 N- [2- (2-amino-3-nitro-phenoxy) -ethyl] -2,2, 2-trifluoro-N- [3- (lH-indol-3-yl) -propyl] -acetamide To a solution containing triethylamine (3.15 ml, 22.6 mmol) and 2-. { 2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -6-Nitro-phenylamine (4.0 g, 11.3 mmol) in 60 ml of methylene chloride at 60 ° C, trifluoroacetic anhydride (1.88 ml, 13.3 mmol) was added slowly. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was partitioned between 100 ml of ethyl acetate and 100 ml of saturated sodium bicarbonate. The organic layer was separated and washed with 100 ml of water and 100 ml of brine, and then dried over anhydrous magnesium sulfate. Concentration to give the crude product, followed by purification by chromatography, gave 3.5 g (69.1%) of the product as a reddish orange viscous oil; MS The m / e 450 (My.

INTERMEDIARY 7 N- [2- (2,3-diamino-phenoxy) -ethyl] -2,2,2-trifluoro-N- [3-lH-indol-3-yl] -propyl] -acetamide To a solution containing N- [2- (2-amino-3-nitro-phenoxy) -ethyl] -2,2, 2-tri? Uoro-N- [3- (1H-indol-3-yl) -propyl ] -acetamide (3.86 g, 8.57 mmol) in 40 ml of ethanol under nitrogen atmosphere added 10% palladium on carbon (1 g). The mixture was hydrogenated at 40 psi for 6 hours. The catalyst was filtered, washed with ethanol and the filtrate was concentrated to give the desired crude product. Purification by chromatography (40% ethyl acetate-hexanes) gave 2.8 g (78.8%) of the product as a viscous brown oil; MS The m / e 420 (My.

INTERMEDIARY 8 2,2,2-trifluoro-N- [3- (1H-indol-3-yl) -propyl] -N- [2- (2-oxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] - acetamide A mixture of N- [2- (2, 3-diamino-phenoxy) -eti1-2, 2,2-trifluoro-N- [3- (1H-indol-3-yl) -propyl] -acetamide (0.5 g) , 1.19 mmol) and carbonyldi imidazole (0.39 g, 2.38 mmol) in 50 ml of anhydrous tetrahydrofuran was stirred at 23 ° C for 5 hours. The reaction mixture was poured into water and extracted with 2 250 ml portions of ethyl acetate. The organic layer was washed with 2 portions of 250 ml of water and 200 ml of brine and dried over anhydrous magnesium sulfate. The resulting product was concentrated to give the crude product. The Purification by chromatography (60% ethyl acetate-hexanes) followed by crystallization from ethyl acetate-hexanes gave 0.44 g (82.9%) of the product as a yellowish solid: mp 180-181 ° C; The m / e 446 (M *) Elemental analysis for C22H2 F.N4O3 Calculated: C, 59.19; H, 4.74; N, 12.55 Found: C, 58.95; H, 4.82; N, 12.71 INTERMEDIARY 9 2,2, 2-trifluoro-N- [3- (1H-indol-3-yl) -propyl] -N- [2- (2-thioxo-2,3-dihydro-lH-benzoimidazol-4-yloxy) ethyl] 'acetamide This compound was prepared in the manner described above for Intermediate 8, using thiocarbonyldiimidazole to provide a product as a yellow solid: mp 120-121 ° C; MS (+) FAB m / e 463 (M + 1) +. Elemental analysis for C22H2? F3N.O2S * 0.33C 4H? 0O Calculated: C, 57.40; H, 4.99; N, 11.50 Found: C, 57.42; H, 4.93; N, 11.33 INTERMEDIARY 10 2- (2- [3- (5-fluoro-lH-indol-3-yl) -propylamino] ethoxy.} - 6-ni trophiene lamina A solution of 2- (2-chloro-ethoxy) -6-nitro-phenylamine (0.5 g, 2.3 mmol), 3- (5-fluoro-lH-3-yl) -propylamine (1.1 g, 5.7 mmol) and triethylamine (0.58 g, 5.7 mmol) in 20 ml of anhydrous dimethyl sulfoxide was allowed to stir for 12 hours at 90 ° 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, dried over anhydrous sodium sulfate and filtered and the solvent was removed in vacuo. Chromatography (5% methanol-methylene chloride plus ammonium hydroxide) provided 0.67 g (78%) of the product as a yellow oil; MS (El) 358 m / e (M +).

INTERMEDIARY 11 3- . { 2- [3- (5- Fluoro-1H-indol-3-yl) -propylamino] -ethoxy} -benzene-1,2-diamine A mixture of 2-. { 2- [3- (5-fluoro-lH-indol-3-yl) -propylamino] -ethoxy} - 6-N-trophhenylamine (0.65 g, 1.7 mmol) and 10% palladium on carbon in ethanol was hydrogenated for 3 hours. The catalyst was filtered and the solvent removed in vacuo. Chromatography (10% methanol-methylene) provided 0.49 g (82%) of the product as a light brown oil; MS (El) 358 m / e (M +).

INTERMEDIARY 12 2- (2-chloro-ethoxy) -4-chloro-6-nitro-phenylamine A solution of 2- (2-chloro-ethoxy) -6-nitro-phenylamine (30.0 g, 0.14 mol), N-chlorosuccinimide and acetonitrile (1.3 liters) was heated to reflux for 4 hours. The mixture was concentrated in vacuo and the residue was diluted with 500 ml of ethyl acetate. The organic layer was washed with 2 portions of 250 ml of water and 250 ml of brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo to give an orange solid residue. Crystallization from ethyl acetate-hexanes gave 33.5 g (95.3%) of the product as an orange solid: mp 109-110 ° C; MS (El) 250/252/254 m / e (M +). Elemental analysis for CTHeCl2N203 Calculated: C, 38.27; H, 3.21; N, 11.16 Found: C, 38.15; H, 3.10; N, 10.96 INTERMEDIARY 13 3- . { 2- [3- (5-Fluoro-lH-indol-3-yl) -propylamino] -ethoxy} -benzene-5-chloro-l, 2-dia ina A mixture of 2- (2-chloro-ethoxy) -4-chloro-6-nitro-phenylamine (0.65 g, 1.7 mmol) and 5% platinum on carbon sulfide in ethanol was hydrogenated for 1 hour. The catalyst was filtered and the solvent removed in vacuo. Chromatography (15% methanol-methylene chloride plus ammonium hydroxide) gave 0.59 g (80%) of the product as a yellow oil; MS (El) 376 m / e (M).

INTERMEDIARY 14 2, 6-dibromo-4-fluorophenol To a solution of 4-fluorophenol (25 g, 0.22 mol) in 200 ml of acetic acid at room temperature was slowly added dropwise bromine (78 g, 0.49 mol) while stirring mechanically. After 1 hour the reaction mixture was poured into 1.5 liters of ice water, followed by 100 ml of saturated aqueous sodium bisulfate. The solid precipitate was filtered and dried to provide 51.8 g (86.0%) of a white solid: mp 54-55 ° C; NMR aH (CDC13) d 5.69 (1H s, OH), 7.25 (2H d, J = 7.5 Hz); MS The m / e 268/270/272 (M +). Elemental analysis for C6H3Br2FO Calculated: C, 26.70; H, 1.12 Found: C, 26.64; H, 1.07 INTERMEDIARY 15 1- (2-chloroethoxy) -2,6-dibromo-4-fluorobenzene A mixture of 2,6-dibromo-4-fluoro-phenol (55 g, 0.20 mol), potassium carbonate (60 g, 0.43 mol), l-bromo-2-chloroethane (32.5 g, 0.23 mol) and 500 ml of 2-butanone was heated to reflux for 2 hours and allowed to cool to room temperature. The solids were filtered and the solvent was removed in vacuo to provide an oil. The oil was dissolved in 300 ml of diethyl ether and washed with water, dried over anhydrous magnesium sulfate, treated with charcoal, and filtered through silica gel to provide 65.9 g (97.2%) of the product as an oil: MS The m / e 330/332/334/336 (M *); H NMR (CDCl 3) d 3.89 (2H t, J = 6.1 Hz), 4.23 (2H, t, J = 6.1 Hz), 7.28 (2H d, J = 7.5 Hz).

INTERMEDIARY 16 1- (2-chloroethoxy) 2,6-dibromo-4-fluoro-3-nyl trobenzene To a solution of 1- (2-chloroethoxy) -2,6-dibromo-4-fluorobenzene (65.8 g, 0.20 mol) in 165 ml of concentrated sulfuric acid maintained at room temperature using a water bath, a solution was added slowly of nitric acid in sulfuric acid (10 ml of nitric acid in 165 ml of sulfuric acid). The reaction was allowed to stir at room temperature for 1 hour and then it was emptied into 1.5 liters of ice and extracted with 2 portions of 300 ml of methylene chloride. The combined organic layers were washed with 150 ml of aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate, filtered, and the solvent removed in vacuo to provide 73.3 g. (97.1%) of a white crystalline solid: mp 56-57 ° C; MS The m / e 375/377/379/381; NMR: H (CDC13) d 3.91 (2H t, J = 5.9 Hz), 4.29 (2H d, J = 5.9 Hz), 7.54 (8.1 Hz).

Elemental analysis for C8H5Br2ClFN03 Calculated: C, 25.46; H, 1.34; N, 3.71 Found: C, 25.46; H, 1.20; N, 3.51 INTERMEDIARY 17 1- (2-chloroethoxy) -4-fluoro-3-aminobenzene A solution of 1- (2-chloroethoxy) -2,6-dibromo-4-fluoro-3-nitrobenzene (73.2 g, 0.19 mol) in 1.1 liter of ethanol containing 7.3 g of 10% palladium on carbon was hydrogenated 40 psi for 5 days. The catalyst was filtered and the solvent was removed. The residue was dissolved in 300 ml of diethyl ether and washed with 200 ml of saturated aqueous sodium carbonate. The organic layer was separated and washed with water, dried over anhydrous magnesium sulfate and filtered. The solvent was removed to provide an oil, which solidified to provide 32.5 g (90.0%) of the product as a dark solid: mp 42-43 ° C; MS The m / e 189/191 (M +); NMR] H (CDC13) d 3.40-3.60 (2H, broad s, NH2), 3.77 (2H d, J = 6 Hz), 4.14 (2H d, J = 6 Hz), 6.19-6.23 (1H, m), 6.36 (1H dd, J = 7.3 Hz), 6.88 (1H dd, J = 11.9 z).

Elemental analysis for C8H9C1FN0 Calculated: C, 50.68; H, 4.78; N, 7.39 Found: C, 50.46; H, 4.66; N, 7.46 INTERMEDIARY 18 4- (2-Chloroethoxy) -7-fluoro-3-thiomethyl-1,3-dihydro-indol-2-one To a solution of ethyl (ethylthio) acetate (7.2 g, 53.4 mmol) in 200 ml of anhydrous methylene chloride at -78 ° C was added sulfuryl chloride (8.1 g, 59.7 mmol). The mixture was stirred for 20 minutes. A solution of 1- (2-chloroethoxy) -4-fluoro-3-aminobenzene (10.0 g, 52.8 mmol) and Proton Sponge (13.9 g) in 100 mL of methylene chloride was stirred for 2 hours, followed by the addition of triethylamine (6.5 g, 64.5 mmol). The temperature was maintained at -78 ° C and the reaction mixture was allowed to stir for 1 hour. After warming to room temperature, the mixture was poured into 200 ml of brine and dried over anhydrous magnesium sulfate, filtered, and the solvent was removed to provide an oil. 75 ml of acetic acid was added to the oil and the mixture was allowed to stand for 18 hours. The solvent was then removed in vacuo. The residue was partitioned between 400 ml of diethyl ether and 150 ml of 2.5 N aqueous hydrochloric acid. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered, and the solvent was removed to provide a solid. Trituration of the solid with a small amount of 30 ml of diethyl ether gave 8.8 g (60.5%) of the product as a yellow solid: mp 140-141 ° C; MS m / e 275/277 (My; 1H NMR (CDC13) d 2.14 (3H, s), 3.79-3.87 (2H, m), 4.25-4.33 (2H, m), 4.35 (1H, s), 6.51 (1H, dd, J = 9.1, 3.3 Hz), 6.99 (1H, app.t, J = 9.1 Hz), 8.09 (1H, s) Elemental analysis for CpHuClFN02S Calculated: C, 47.92; H, 4.02; N, 5.08 Found: C, 47.67; H, 3.85; N, 4.85 INTERMEDIARY 19 7-fluoro-3-thiomethyl- -. { 2- [3- (1H-indol-3-yl) -propyl'-amino] -ethyl} -1, 3-dihydro-indol-2-one A solution of 4- (2-chloroethoxy) -7-f luoro-3-thiomethyl-1,3-dihydro-indol-2-one (1.48 g, 5.4 mmol) and 3- (lH-indol-3-yl) -propi lamina (3.19 g, 18.3 mmol) in 20 ml of anhydrous dimethyl sulfoxide was left stirring for 5 hours at 95-105 ° C and another 3 hours at 115 ° 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 40 ml of saturated sodium carbonate and 3 portions of 100 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. Chromatography (5% methanol-methylene chloride provided 1.34 g (52%) of the product as a brown oil.

EXAMPLE 1 [2- (3H-benzoimidazol-4-yloxy) -ethyl] - [3- (lH-indol-3-yl) -propyl] -amine A solution of 3-. { 2- [3- (1H-indol-3-yl) -propylamino] -ethoxy} -benzene-1,2-diamine (0.75 g, 2.3 mmol) dissolved in 15 ml of formic acid (98%) was heated at 104 ° C for 6 hours. After standing overnight at 25 ° C, the excess formic acid was removed by vacuum distillation. 100 ml of water and 100 ml of ethyl acetate were added thereto. The ethyl acetate layer was separated and washed once with 50 ml of water, once with 75 ml of brine and dried over anhydrous magnesium sulfate. The concentration of the solvent gave 0.7 g of the product as a brown solid. Purification by chromatography (2N ammonia in methanol: methylene chloride = 20: 1.5) and crystallization from ethyl acetate-. ethanol gave 0.345 g (44.8%) of the product as a white solid: mp 121-124 ° C decomposes. The hydrochloride salt was prepared in ethanol: mp 256-258 ° C decomposes. Elemental analysis for C20H22N4O »2HCl» 0.25H20 Calculated: C, 58.33; H, 6.00; N, 13.60 Found: C, 58.25; H, 5.92; N, 13.38 EXAMPLE 2 4-. { 2- [3-lH-indol-3-yl) -propylamino] -ethoxy} -l, 3- dihydrobenzoimidazol-2-one A suspension of potassium carbonate (1.0 g, 7.4 mmol) and 2, 2, 2- tri-fluoro-N- [3- (lH-indol-3-yl) -propyl] -N- [2- (2-oxo -2, 3-dihydro-lH-benzoimidazol-4-yloxy) -ethyl] acetimide (0.41 g, 0.92 mmol) in methanol-tetrahydrofuran (10 mL, 1: 1) and 3 mL of water was heated to reflux for 3 hours. The solvent was evaporated and the residue was dissolved in 100 ml of ethyl acetate and washed with 80 ml of water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude solid product. Crystallization from ethyl acetate-hexanes gave 0.25 g (77.7%) or the product as a yellow solid: pf 130 ° C; MS The m / e 350 (M +). The hydrochloride salt was prepared in ethyl acetate: mp 222.5-224 ° C Elemental analysis for C20H22N? 2 »HCl Calculated: C, 60.55; H, 6.18; N, 13.85 Found: C, 60.75; H, 6.08; N, 13.69 EXAMPLE 3 4-. { 2- [3-lH-indol-3-yl) -propylamino] -ethoxy} -l, 3- dihydrobenzoimidazole-2-thione This compound was prepared in the manner described in Example 2, using 2,2,2-trifluoro-N- [3- (1H-indol-3-yl) -propyl] -N- [2- (2-thioxo- 2, 3-dihydro-lH-benzo-imidazol-4-yloxy) ethyl] -acetamide gave a product as a white solid. The hydrochloride salt was prepared in ethyl acetate: mp > 260 ° C. Elemental analysis for C2oH22N4OS »HCl * 0.25H20 Calculated: C, 58.96; H, 5.81; N, 13.75 Found: C, 58.94; H, 5.74; N, 13.51 EXAMPLE 4 [2- (3H-benzoimidazol-4-yloxy) -ethyl] - [3- (5-fluoro-lH-indol-3-yl) -propyl] -amine A solution of 3-. { 2- [3- (5-Fluoro-1H-indol-3-yl) -propylamino] -ethoxy} -benzene-1,2-diamine (0.49 g) in 30 ml of formic acid was allowed to warm to reflux for 4 hours. The mixture was poured into sodium hydroxide (1 N, 150 ml) and extracted with 3 100 ml portions of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-methylene chloride) gave 0.25 g (50%) of the product as an off-white solid: mp 93-95 ° C. The oxalate salt was prepared in ethanol: mp 185-187 ° C Elemental analysis for C20H2 FN40 * 2C2H204 Calculated: C, 54.13; H, 4.73; N, 10.52 Found: C, 53.98; H, 4.74; N, 10.49 EXAMPLE 5 [2- (5-chloro-lH-benzoimidazol-4-yloxy) -ethyl] - [3- (5-fluoro-lH-indol-3-yl)] - propyl] -amine This compound was prepared in the manner described in Example 4, using 3-. { 2- [3- (5-fluoro-lH-indol-3-yl) -propylamino] -ethoxy} -benzene-1,2-diamine with 3-. { 2- [3- (5-fluoro-lH-indol-3-yl) -propylamino] -ethoxy} -benzene-5-chloro-l, 2-diamine to give the product in 76% yield (0.22 g) as a white solid: mp 96-99 ° C The oxalate salt was prepared in ethanol: mp 185-187 ° C. Elemental analysis for C20H21 FN40 »2C2H204« 2H20 Calculated: C, 47.81; H, 4.68; N, 9.29 Found: C, 47.85; H, 4.26; N, 7.92 EXAMPLE 6 7-fluoro-4-. { 2- [3-lH-Indo-1-3-yl) -propylamino] -ethoxy} - 1, 3-dihydro-indol-2-one A mixture of 7-fluoro-3-thiomethyl-4-. { 2- [3- (lH-indol-3-yl) -propyl-amino] -ethyl} -1,3-dihydro-indole-2-one (1.34 g, 3.5 mmol) and Raney's nickel in 160 ml of ethanol was allowed to stir for 5 hours. The catalyst was filtered and the solvent removed in vacuo. Chromatography (10% methanol-methylene) provided 0.24 g (19%) of the product as an oil. MS (El) 358 m / e (M +). The fumarate salt was prepared in ethanol: mp 189-190 ° C. Elemental analysis for C2? H2? FN3? 2 »C2H4? 4 Calculated: C, 62.11; H, 5.42; N, 8.69 Found: C, 62.16; H, 5.45; N, 8.59 The activity of the present compounds was demonstrated by the following standard pharmacological test procedure. PCR cloning of the human 5-HT-A receptor subtype from a human genomic library has been previously described by Chanda et al., Mol. Pharmacol. 43: 516 (1993). A stable line of hamster ovary cells that expresses the subtype of the 5-HT ?. human (h5-HTiA.CHO cells) was used throughout this study. Cells were maintained in DMEM supplemented with 10% fetal calf serum, non-essential amino acids and penicillin / streptomycin. The cells were grown 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 buttons or concentrates were taken as an aliquot and placed at -80 ° C. On the day of the test, the cells were thawed on ice, and they were resuspended in shock absorber. 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 of buffer. The competition experiments were performed by using 7 concentrations of unlabeled drug and a final ligand concentration of 1.5 nM. A non-specific binding was determined in the presence of 10 μM 5HT. The saturation analysis was conducted by the use of [3 H] 8-OH-DPAT at concentrations in the range of 0.3-30 nM. After an incubation of 30 minutes at room temperature, the reaction was terminated by the addition of ice-cooled buffer and rapid filtration using a Brandel M-96 Cell Harvester (Gaithersburg, MD) through a GF / B filter pre-wetted for 30 minutes in 0.5% polyethylenimine. A protocol similar to that used by Cheetham et al., Neurophar acol 32: 737 (1993) was used to determine the affinity of the compounds for the serotonin transporter. Briefly, the frontal cortical membranes prepared from male Sprague-Dawley rats were incubated with 3 H-paroxet ina (0.1 nM) for 60 minutes at 25 ° C. All tubes also contained either the vehicle, the test compound (one to eight concentrations), or a saturation concentration of fluoxetine (10 μM) to define the specific binding. All reactions are terminated by the addition of ice-cooled Tris buffer followed by rapid filtration using a Tom Tech filtration device to separate bound JH-paroxetine from free. The bound radioactivity was quantified using a Wallac 1205 Beta Píate® counter. Non-linear regression analysis was used to determine the IC50 values which 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 [35S] -GTP? S binding assay was similar to that used by Lazareno and Birdsall, Br. J. Pharmacol. 109: 1120 (1993). Briefly, membrane fragments of the cloned 5-HT? A receptor (as used for the 5-HTIA receptor binding assays) were stored at -70 ° C until needed. When necessary, the membranes were thawed rapidly, centrifuged at 40,000 xg for 10 minutes and resuspended at 4 ° C for 10 minutes in the assay buffer (25 mM HEPES, 3 mM magnesium chloride, 100 mM sodium chloride, 1 mM EDTA, 10 μM GDP, 500 mM DTT, pH 8.0). These membranes were then incubated for 30 minutes at 30 ° C with [35 S] GTPγS (1 nM) in the presence of the vehicle, the test compound (one to eight concentrations), or excess of 8-OH-DPAT to define the maximum response of the agonist. 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 [35S] GTP? S from free. The agonists produce an increase in the amount of [35S] GTP? S bound, whereas the antagonists do not produce an 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 M 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 antagonist concentrations were preincubated for 20 minutes before the addition of 10 nM 8-OH-DPAT and forskolin. The reaction was terminated by removing the medium and adding 0.5 ml of ice-cold assay buffer. Plates were stored at -20 ° C before the evaluation of cyclic AMP formation (cAMP) with a SPA assay of cAMP (Amersham). The compounds tested correspond to those prepared in Examples 1 to 6 above. The results of the procedure are described in Table 1.

TABLE 1 As demonstrated by the results described above, the compounds of the present invention are active towards 5-HT? A receptors and generally elevate 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 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 encapsulating material. In the powders, the carrier is a finely divided solid that 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 the 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 waxes, and resins of ion exchange Liquid carriers can be used to prepare 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, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (which particularly contains additives as described above, for example, cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their 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 of sterile liquid form 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 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 may be packaged compositions, for example, packaged powders, ampoules, flasks, prefilled syringes, or sacks containing liquids. Alternatively, the unit dose form can be, for example, a capsule or a tablet itself, or this may be the appropriate number of any such compositions in package form. The therapeutically effective amount of the compounds of this invention that 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 2000 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 a day. 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 foregoing specification, as indicating the scope of the 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 (10)

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 is hydrogen, lower alkyl of 1 to 6 carbon atoms, phenyl or phenyl substituted by halogen, lower alkyl of 1 to 6 carbon atoms, lower alkoxy of 1 to 6 carbon atoms or cyano; X and Y simply complete a lactam, imidazole, imidazolone, or thioimidazolone ring; Z is hydrogen, halogen or lower alkoxy of 1 to 6 carbon atoms; W is hydrogen, halogen, lower alkoxy of 1 to 6 carbon atoms, lower alkyl of 1 to 6 carbon atoms, cyano, or a trifluoromethyl group; and n = 2 to 5; or the pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, characterized in that: Ri is hydrogen; X and Y together complete an imidazole or thioimidazolone ring; Z is halogen or hydrogen; W is halogen or hydrogen; and n = 2 to 3; or the pharmaceutically acceptable salts thereof.

3. The compound according to claim 1, characterized in that it is [2- (3H-benzoimidazol-4-yloxy) -ethyl] - [3- (lH-indol-3-yl) -propylamine.

4. The compound according to claim 1, characterized in that it is 4-. { 2- [3-lH-indol-3-yl) -propylamino] -ethoxy} -l, 3-dihydrobenzoimidazol-2-one.

5. The compound according to claim 1, characterized in that it is 4-. { 2- [3-lH-indol-3-yl) -propylamino] -ethoxy} -l, 3-dihydrobenzoimidazol-2-thione.

6. The compound according to claim 1, characterized in that it is [2- (3H-benzoimidazol-4-yloxy) -ethyl] - [3- (5-fluoro-lH-indol-3-yl)] - propyl] -amine .

7. The compound according to claim 1, characterized in that it is [2- (6-chloro-lH-benzoimidazol-4-yloxy) -ethyl] - [3- (5-fluoro-lH-indol-3-yl)] - propi 1] -amine.

8. The compound according to claim 1, characterized in that it is 7-fluoro-4- [(2- [3-lH-indol-3-yl) -propylamino] -ethoxy} -l, 3-dihydro-indol-2-one.

9. A pharmaceutical composition, characterized in that it comprises a compound of the formula: wherein: Ri is hydrogen, lower alkyl of 1 to 6 carbon atoms, phenyl or phenyl substituted by halogen, lower alkyl of 1 to 6 carbon atoms, lower alkoxy of 1 to 6 carbon atoms or cyano; X and Y with incompletely complete a lactam, imidazole, imidazolone, or thioimidazolone ring; Z is hydrogen, halogen, or lower alkoxy of 1 to 6 carbon atoms; W is hydrogen, halogen, lower alkoxy of 1 to 6 carbon atoms, lower alkyl of 1 to 6 carbon atoms, cyano, or a trifluoromethyl group; and n = 2 to 5; or the pharmaceutically acceptable salts thereof.

10. Use a compound of the formula below for the manufacture of a medication to relieve the symptoms of depression. wherein: Ri is hydrogen, lower alkyl of 1 to 6 carbon atoms, phenyl or phenyl substituted by halogen, lower alkyl of 1 to 6 carbon atoms, lower alkoxy of 1 to 6 carbon atoms or cyano; X and Y together complete a lactam, imidazole, imidazolone, or thioimidazolone ring; Z is hydrogen, halogen, or lower alkoxy of 1 to 6 carbon atoms; W is hydrogen, halogen, lower alkoxy of 1 to 6 carbon atoms, lower alkyl of 1 to 6 carbon atoms, cyano, or a trifluoromethyl group; and n = 2 to 5; or the pharmaceutically acceptable salts thereof.