MXPA00009811A

MXPA00009811A - N-aryloxyethyl-indoly-alkylamines for the treatment of depression (5-ht1a receptor active agents)

Info

Publication number: MXPA00009811A
Application number: MXPA/A/2000/009811A
Authority: MX
Inventors: Richard Eric Mewshaw; Dahui Zhou
Original assignee: American Home Products Corporation
Priority date: 1998-04-08
Filing date: 2000-10-06
Publication date: 2002-06-05

Abstract

Compounds useful for alleviating symptoms of depression (5-HT1A receptor active agents) are provided which have formula (I), wherein:R1 is hydrogen, lower alkyl or aryl;R2 is hydrogen, lower alkyl, phenyl or substituted phenyl;X and Y are each, independently, hydrogen, lower alkyl, lower alkoxy, or halogen, or together combined with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl, dihydrofuranyl, furanyl, dioxanyl, oxazolyl or isoxazolyl group;Z is hydrogen, halogen or lower alkoxy;with the proviso that when X, Y or Z represent lower alkoxy, they are not present at the ortho position;W is hydrogen, halogen, lower alkyl, cyano or a trifluoromethyl group;and n is 2-5;or pharmaceutically acceptable salts thereof.

Description

N-ARYLOXYTHEI-INDOLYL-ALKYLAMINES FOR THE DEPRESSION TREATMENT (ACTIVE AGENTS OF THE 5-HT1A RECEPTOR) FIELD OF THE INVENTION This invention relates to compounds useful for the treatment of diseases affected by disorders of neurological systems affected by serotonin. More specifically, the present invention is directed to the aryloxyethyl-indolyl-alkylamine derivatives useful for the treatment of such diseases.

BACKGROUND OF THE INVENTION Pharmaceuticals 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 non-selective drugs affecting serotonin operated through a variety of means physiological factors that cause it to have numerous unwanted side effects.

Ref: 123325.

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 presynaptic serotonin 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 5-HT neurons, causing a damping of the therapeutic effect . Studies suggest that after several weeks of SSRI administration, a desensitization of 5-HT autoreceptors occurs allowing a complete antidepressant effect in most patients (see for example Le Poul et al., Arch. Pharmacol., 352: 141 (nineteen ninety five)). Therefore, it is believed that by canceling out this negative feedback through the use of 5-HT 1A 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 combination of 5-HT1A activity and the inhibition of 5-HT uptake within a single molecular entity can achieve a stronger and faster acting antidepressant effect. U.S. Patent No. 3,371,098 describes the sec- and tert-indolylethylamines useful as sedatives, anticonvulsants and analgesics. U.S. Patent No. 5,436,264 describes compounds similar to a. N-aryloxyalkyl-triptamine of the following formula as alpha-1-adrenergic receptor antagonists for the treatment of cardiovascular disorders.

European Patent No. 0722 941 A2 describes the preparation of a series of hetero-oxy-alkanes of the following formula for the treatment of depression and other disorders for which inhibitors of serotonin uptake are normally used.

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 compounds of the present invention are aminomethyl-benzoxezin-indoles represented by Formula I: wherein: Ri is hydrogen, lower alkyl, or aryl; R2 is hydrogen, lower alkyl, phenyl, or substituted phenyl; X and Y are each, independently, hydrogen, lower alkyl, lower alkoxy, or halogen, or together they are combined with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl group, dihydrofuranyl, furanyl, dioxanyl, oxazolyl, or isoxazolyl; Z is hydrogen, halogen, or lower alkoxy; with the proviso that when X, Y or Z represent lower alkoxy, these are not present in the ortho position; is hydrogen, halogen, lower alkoxy, lower alkyl, cyano, or a trifluoromethyl group; and n is 2-5; or the pharmaceutically acceptable salts thereof.

The present invention is further derived to pharmaceutical compounds containing such compounds, as well as to methods for alleviating the symptoms of depression, comprising administering the present compounds to a patient in need thereof.

DETAILED DESCRIPTION OF THE INVENTION Preferably, the compounds of the present invention are those represented by Formula I, wherein: Ri is hydrogen, methyl or aryl; R2 is hydrogen; X and Y are each, independently, hydrogen, halogen or lower alkoxy, or together they are combined with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyridinyl, dioxanyl, oxazolyl, furanyl or dihydrofuranyl group; Z is hydrogen, halogen or lower alkoxy; with the proviso that when X, Y or Z are lower alkoxy they are not present in the ortho position; it is hydrogen or halogen; and n is 2-4; or the pharmaceutically acceptable salts thereof. More preferably, the compounds of the present invention are selected from the following: [3- (5-fluoro-1H-indol-3-yl) -propyl] - [2- (1H-indol-4-yloxy) -ethyl] amine; [2- (1H-indol-4-yloxy) ethyl] - [3- (1 H -indo-3-yl) -propyl] -amine; [3- (1H-indol-3-yl) -butyl] - [2- (1H-indol-4-yloxy) -ethyl] -amine; [2- (2,3-dihydro-benzo [1,4] dioxin-5-yloxy) -ethyl] - [2- (lH-indol-3-yl) -ethyl] -amine; [2- (2,3-dihydro-benzo [1,4] dioxin-5-yloxy) -ethyl] - [3- (5-fluoro-lH-indol-3-yl) -propyl] -amine; [2- (6-fluorochroman-8-yloxy) -ethyl] - [2- (lH-indol-3-yl) -ethyl] -amine; 2- (6-fluorochroman-8-yloxy) -ethyl] - [3- (5-fluoro-lH-indol-3-yl) -propyl] -amine; [2- (6-fluorochornan-8-yloxy) -ethyl] - [2- (5-fluoro-lH-indol-3-yl) -ethyl] -amine; [2- (2,3-dihydro-benzofuran-7-yloxy) -ethyl] -3- (5-fluoro-1H-indol-3-yl) -propyl] -amine; 2- (benzofuran-7-yloxy) -ethyl] - [3- (5-fluoro-lH-indol-3-yl) -propyl] -amine; [2- (5-fluoro-2, 3-dihydro-7-yloxy) -ethyl] - [2- (5-fluoro-lH-indol-3-yl) -ethyl] -amine; [3- (5-fluoro-lH-indol-3-yl) -propyl] - [2- (indane-4-yloxy) -ethyl] -amine; [3- (5-fluoro-1H-indol-3-yl) -propyl] - [2- (5,6,7,8-tetrahydro-naphthalen-1-yloxy) -ethyl] -amine; [3- (1H-indol-3-yl) -propyl] - [2 - (naphthalen-1-yloxy) -ethyl] amine; [3- (1H-indol-3-yl) -propyl] - (2-phenoxy-ethyl) -amine; [3- (5-fluoro-1H-indol-3-yloxy) -propyl] - [2- (indane-5-yloxy) -ethyl] -amine; [3- (1H-indol-3-yl) -propyl] - [2- (quinolin-8-yloxy) -ethyl] -amine; [3- (5-fluoro-lH-indol-3-yl) -propyl] - [2- (2-methoxy-phenoxy) -2-phenyl-ethyl] -amine; and [3- (5-fluoro-lH-indol-3-yl) -propyl] - [2- (2-methoxy-phenoxy) -propyl] -amine. 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. It is understood that the term "halogen" includes fluorine, chlorine, bromine, and iodine. The term "substituted phenyl" is understood to include a phenyl portion substituted with an alkyl, halogen, or alkoxy group. The term "aryl" is understood to include aromatic radicals containing 6 to 12 carbon atoms. The compounds of Formula I can be advantageously used in the form of the pharmaceutically acceptable acid addition salts thereof. Such salts, which can be prepared by methods well known to those skilled in the art, can be formed with the inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylene-allylic, methanesulfonic acids , ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic , sulfuric, cyclohexylphthalamic, phosphoric and nitric. The compounds of the present invention can be prepared by any suitable method known to those skilled in the art. However, the present compounds can be advantageously prepared according to Reaction Schemes 1 to 10 described below. In the Reaction Schemes, the intermediate compounds discussed below in the present are identified in parentheses. The compound produced in each of the Schemes of Reaction 1 to 10 is identified with reference to the corresponding, appropriate example.

Reaction Scheme 1 Reaction Scheme 2 Reaction Scheme 3 Reaction Scheme 4 (20) Ex. 5 Reaction Scheme 5 Reaction Scheme 6 (29) (30) Ex. 8 (28) Ex. 9 Reaction Scheme 7 Reaction Scheme 8 Reaction Scheme 9 Reaction Scheme 10 The present invention will now be illustrated by reference to the following specific, non-limiting examples.

INTERMEDIARY 2 [2- (2-Methoxy-phenoxyethyl] -benzylcarbamic acid tert -butyl ester) To a solution of the (2-hydroxy-ethyl) -benzylcarbamic acid tert-butyl ester (3.2 g, 12.6 mmol) and 2-methoxyphenol (1.0 g, 8.4 mmol) containing triphenylphosphine (3.3 g, 12.6 mmol) in 40 ml of anhydrous tetrahydrofuran, diisopropyl azodicarboxylate (2.5 g, 12.6 mmol) was added slowly. The reaction was allowed to stir for 18 hours, then it was drained into 250 ml of methylene chloride and washed with 1 N sodium hydroxide (3 x 80 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to get a clear oil. The oil was dissolved in 70 ml of ether and hexanes were slowly added until the triphenylphosphine oxide precipitated. The solid was filtered and the solvent was removed. The thick oil was then purified by column chromatography (15% ethyl acetate-hexanes) to provide 2.57 g (57.0%) of a clear oil: MS (El) 358 m / e (M +). Elemental analysis for C2? H27N0 Calculated: C, 70.56; H, 7.61; N, 3.92 Found: C, 70.27; H, 7.58; N, 4.07 INTERMEDIARY 3 [2- (2-methoxy-phenoxy) -ethyl] -benzyl-amine To a solution of 2- (2-methoxy-phenoxy-ethyl] -benzylcarbamic acid tert-butyl ester (18.0 g, 50.4 mmol) in 350 ml of methylene chloride, 60 ml of trifluoroacetic acid was added slowly. The reaction was stirred at room temperature for 12 hours, then it was drained in 200 ml of 1 N sodium hydroxide and extracted with 3 portions of 150 ml of methylene chloride.The combined organic layers were washed with 1 N sodium hydroxide ( 2 x 150 ml) followed by 2 portions of 100 ml of water, then dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo, chromatography (5% methanol-methylene chloride) provided 12.4 g ( 96%) of a clear oil Elemental analysis for C? 6H19N02 Calculated: C, 74.19; H, 7.24; N, 5.54 Found: C, 73.91; H, 7.28; N, 5.44 The fumarate salt was prepared in ethanol: mp 121.5- 122 ° C Elemental analysis for C? 6Hi9N02 »C4H4? 4 Calculated: C, 63.56; H, 6.27; N, 3.71 Found: C, 63.35; H, 6. 16; N, 3.62 INTERMEDIARY 4 N-benzyl-3- (1H-indol-3-yl) -N- [2- (2-methoxy-phenoxy) -ethyl] -propion-amide (4a) To a solution of 3-indole-propionic acid (4.1 g, 21.7 mmol) and 1- (3-dimethyl-amino-propyl) -3-ethylcarbodiimide hydrochloride (4.4 g, 23 mmol) in 80 ml of methylene chloride, a solution of 2- (2-methoxy-phenoxy) -ethyl] -benzylamine (3 g, 11.6 mmol) in 20 ml of methylene chloride at 0 ° C was added. After 2 hours, the reaction mixture was emptied into 200 ml of water and extracted with methylene chloride (2 x 50 ml). The combined organic layers were washed with 50 ml of 1 N sodium hydroxide, followed by 2 50 ml portions of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. Chromatography (5% methanol-methylene chloride) gave 3.3 g (66.0%) of the product as a white solid: mp 46.5-47.5 ° C. MS The m / e 428 (M +).

N-benzyl-3- (lH-indol-3-yl) -N- [2- (2-methoxy-phenoxy) -ethyl] -butyr-amide (4b) Replacing 3-indolpropionic acid with 3-indolbutyric acid (1.8 g, 8.9 mmol) in (4a) above, gave N-benzyl-3- (1H-indol-3-yl) -N- [2- (2 -methoxy-phenoxy) -ethyl] butyramide (1.3 g, 78%) as a white foam. MS FAB m / e 443 (M + H) + MS FAB m / e 465 (m + Na) +.

INTERMEDIARY 5 Benzyl- [3- (1H-indol-3-yl) -propyl] - [2- (2-methoxyphenoxy) -ethyl] amine (5a) To a solution of N-benzyl-3- (1H-indol-3-yl) -N- [2- (2-methoxy-phenoxy) -ethyl] -propion-amide in 50 ml of tetrahydrofuran at room temperature was added 1.8 g of lithium-aluminum hydride. The reaction was heated to reflux for 12 hours and then allowed to cool to room temperature. The reaction was quenched with saturated ammonium chloride and the precipitated solid was filtered through celite. The solvent was concentrated in vacuo and the product was purified by chromatography (5% methanol-methylene chloride) to provide 2.0 g (86%) of the product as a yellow oil. MS The m / e 414 (M +). Elemental analysis for C27H30N2O Calculated: C, 78.23; H, 7.30; N, 6.76 Found: C, 77.53; H, 6.95; N, 6.90 Benzyl- [4- (1H-indol-3-yl) -butyl] - [2- (2-methoxy-phenoxy) -ethyl] -amine (5b) Replacing N-benzyl-3- (lH-indol-3-yl) -N- [2- (2-methoxy-phenoxy) -ethyl] -propion-amide with N-benzyl-3- (lH-indole) 3-yl) -N- [2- (2-methoxy-phenoxy) -ethyl] -butyl-amide (1.2 g, 2.7 mmol) in (5a), provided the N-benzyl-3- (lH-indole-3 -yl) -N- [2- (2-methoxy-phenoxy) -ethyl] -butyl-amide (1.06 g, 91%) as a white oil. MS The m / e 428 (M +).

INTERMEDIARY 7 -fluoro-indolyl-3-propyl bromide A solution of 3- (5-fluoro-lH-indol-3-yl) -propan-1-ol (Intermediate 6) prepared according to the procedures described in Demerson et al., J. Med. Chem., 19: 391-395 (1976) (25.4 g, 0.13 mol), carbon tetrabromide (65.5 g, 0.2 mol) and triphenylphosphine (52 g, 0.2 mol) in 156 ml of methylene chloride was allowed to stir for 2 hours. The solvent was evaporated and the product was chromatographed (30% ethyl acetate-hexanes) to provide 33.5 g (99%) of the product.

INTERMEDIARY 8 -fluoro-indolyl-3-propylazide A solution of 5-fluoro-indolyl-3-propylbromide (10.67 g, 41 mmol) and sodium azide (3.9 g, 60 mmol) in 60 ml of anhydrous N, N-dimethylformamide was allowed to stir at 60 ° C for 18 hours. The mixture was drained in 150 ml of water, extracted with 3 portions of 150 ml of methylene chloride, washed with 3 100 ml portions of water. The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (30% ethyl acetate-hexanes) provided 8.10 g (89%) of the product as a clear oil. Elemental analysis for CnHnFN3 Calculated: C, 60.54; H, 5.08; N, 25.67 Found: C, 60.62; H, 5.08; N, 25.84 INTERMEDIARY 9 -fluoro-indolyl-3-propylamine A solution of 5-fluoro-indolyl-3-propylazide (8 g, 0.037 mol) and 10% palladium on carbon in ethanol was hydrogen at 3.51 kg / cm2 (50 psi) for 16 hours. The catalyst was filtered and the solvent removed in vacuo. The celite was washed with 300 ml of methanol and the solvent was removed in vacuo. Chromatography (15% methanol-methylene chloride plus ammonium hydroxide) gave 4.33 g (61%) of the product as a yellow solid: mp 82-84.5 ° C. Elemental analysis for CnH? 3FN2 Calculated: C, 68.73; H, 6.82; N, 14.57 Found: C, 68.82; H, 6.85; N, 14.49 INTERMEDIARY 10 [3- (5-fluoro-IH indol-3-yl) -propyl] - [2- (2-methoxy-phenoxy) ethyl] -benzylamine A solution of [2- (2-methoxy-phenoxy) -ethyl] -benzylamine (1.0 g, 3.9 mol), 3- (5-fluoro-lH-indol-3-yl) -propylamine (1.4 g, 5.8 mmol) and triethylamine (0.79 g, 7.8 mmol) in 40 ml of dimethyl sulfoxide was allowed to stir for 16 hours at 100 ° C. The reaction mixture was poured into 100 ml of water and extracted with 3 100 ml portions of methylene chloride. The organic layer was washed with 3 100 ml portions of water, dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. Chromatography (30% ethyl acetate-hexanes) gave 0.94 g (58%) of the product as a yellow oil. MS The m / e 432 (M +).

INTERMEDIARY 11 2- (5-fluoro-lH-indol-3-yl) ethanol To a solution of 5-fluoro-indole-3-acetic acid (4.3 g, 0.022 mol) in 35 ml of anhydrous tetrahydrofuran was added LiAlH4 (1.0 M, 33 ml, 0.033 mol) at 0 ° C. The mixture was allowed to stir for 0.5 hours and then quenched with saturated ammonium chloride solution. The mixture was then filtered through celite. The filtrate was washed with 1 N sodium hydroxide (3 x 100 ml) and extracted with 3 100 ml portions of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, it was filtered, and the solvent was removed in vacuo. Chromatography (10% methanol-methylene chloride) gave 4.04 g (100%) of the product as an off-white solid: mp 59-61 ° C. Elemental analysis for C? 0H? 0FNO Calculated: C, 67.03; H, 5.63; N, 7.82 Found: C, 66.71; H, 5.50; N, 7.74 INTERMEDIARY 12 3- (5-fluoro-lH-indol-3-yl) -ethyl bromide To a solution of 2- (5-fluoro-lH-indol-3-yl) ethanol (4 g, 22.5 mmol) in 50 mL of methylene chloride was added carbon tetrabromide (11.2 g, 34 mmol), followed by triphenylphosphine (8.8 g, 33 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 2.5 hours.

The solvent was removed in vacuo. Chromatography (30% ethyl acetate-hexanes) provided 5.91 g (98%) of the product as a white solid: mp 58-59 ° C. Elemental analysis for C? 0H9FBrN Calculated: C, 49.61; H, 3.75; N, 5.79 Found: C, 49.29; H, 3.73; N, 5.72 INTERMEDIARY 15 2- (5-fluoro-2-methoxy-phenoxy) ethylchloride A solution of 5-fluoro-2-methoxy-phenol (4.34 g, 31 mmol) prepared according to the procedures described in Mancini et al., Synth.

Comm. , 19: 2001-2005 (1989), l-bromo-2-chloroethane (8.9 ml, 107 mmol) and potassium carbonate (14.8 g, 106 mmol) in 60 ml of 2-butanone was heated at reflux for 24 hours. The mixture was poured into 150 ml of water, extracted with 3 portions of 150 ml of methylene chloride and washed with 3 100 ml portions of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (20% ethyl acetate-hexanes) provided 4.77 g (76%) of the product as a clear oil. Elemental analysis for C9H? 0FC102 Calculated: C, 52.83; H, 4.93 Found: C, 52.79; H, 4.75 INTERMEDIARY 16 2- (5-fluoro-2-methoxy-phenoxy) ethylazide A solution of 2- (5-fluoro-2-methoxy-phenoxy) ethylchloride (3.97 g, 19 mmol) and sodium azide (2.6 g, 39 mmol) in 60 ml of anhydrous N, N-dimethyl formamide was allowed to stir at 60 ° C for 18 hours. The mixture was poured into 150 ml of water, extracted with methylene chloride (3 x 150 ml), washed with 3 100 ml portions of water. The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (20% ethyl acetate-hexanes) provided 3.75 g (92%) of the product as a clear oil. Elemental analysis for C9H? 0FN3O2 Calculated: C, 51.18; H, 4.77; N, 19.90 Found: C, 51.35; H, 4.71; N, 20.06 INTERMEDIARY 17 2- (5-fluoro-2-methoxy-phenoxy) ethylamine A solution of 2- (5-fluoro-2-methoxy-phenoxy) ethylazide (3.97 g, 0.019 mol) and triphenylphosphine (5.95 g, 0.023 mol) in 80 ml of tetrahydrofuran and 1.5 ml of water was allowed to stir for 18 minutes. hours at room temperature. The solvent was removed in vacuo. Chromatography (ethyl acetate) removed triphenylphosphine and triphenylphosphine oxide and (25-50% methanol-ethyl acetate plus ammonium hydroxide) gave 3.14 g (90%) of the product as a clear oil. MS The m / e 185 (M +).

INTERMEDIARY 18 3-indolyl-propionamide (18a) A solution of 3-indolpropionic acid (15 g, 79 mmol), 1,1 '-carbonyldiimidazole (16.7 g, 100 mmol) in 150 ml of anhydrous tetrahydrofuran was allowed to stir for 1.5 hours at room temperature. NH3 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 removed in vacuo. The white solid was collected and dried in vacuo, and 10.42 g (96%) were obtained; mp 124-125 ° C. MS The m / e 188 (M +). 3-indolyl-butyramide (18b) This compound was prepared in the manner described above for (18a), using 3-indolbutyric acid and 1,1'-carbonyldiimidazole. A yield of 96% was obtained as an off-white solid: mp 86-87 ° C.

INTERMEDIARY 19 3-indolyl-propylamine (19a) 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 tetrahydrofuran, 100 ml) slowly.The reaction mixture was heated to reflux by 3 hours, then quenched by the addition of 4 ml of water, 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 m / e 174 (M +). 3-indolyl-butylamine (19b) This compound was prepared in the manner described above for (19a) using 3-indolyl-butyramide and lithium-aluminum hydride. A yield of 75% was obtained as a yellow solid: mp 51-53 ° C.

INTERMEDIARY 20 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 added slowly. 60 mmol).

The reaction was allowed to stir for 2.5 hours at room temperature, then it was drained into 250 ml of methylene chloride, washed with 3 portions of 100 ml of water and dried over anhydrous sodium sulfate. This material was filtered and the solvent was removed in vacuo. 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 21 -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. MS The m / e 152 (M +).

INTERMEDIARY 22 - (2-Chloroethoxy) - (2,3) -dihydrobenzo [1,4] dioxane A 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, was slowly added diisopropylasidodicarbimide (DIAD) (2.0 g, 9.8 mmol). After 2 hours, another 1.5 equivalents of triphenylphosphine, DIAD, and 2-chloroethanol were added to the mixture and this 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. This material was 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? OHuC103 Calculated: C, 55.96; H, 5.17 Found: C, 55.57; H, 5.20 INTERMEDIARY 23 2- (2,3-dihydrobenzo [1,4] dioxin-5-yloxy) ethylazide A solution of 5- (2-chloroethoxy) - (2, 3) -dihydrobenzo [1,4] dioxane (4.6 g, 0.02 mol) and sodium azide (2.78 g, 0.043 mol) in 100 ml of N, N- Anhydrous dimethylformamide was allowed to stir for 18 hours at 60 ° C. The mixture was poured into 200 ml of water, extracted with 3 portions of 100 ml of methylene chloride. The organic layer was washed with 3 portions of 150 ml of water, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (20% ethyl acetate-hexanes) provided 3.43 g (72%) of the product as a clear oil. MS FAB m / e 221 (M +).

INTERMEDIARY 24 2- (2,3-dihydrobenzo [1,4] ioxin-5-yloxy) ethylamine A solution of 2- (2,3-dihydrobenzo [1,4] dioxin-5-yloxy) ethylazide (3.43 g, 0.016 mol) and triphenylphosphine (6.3 g, 0.023 mol) in 50 ml of tetrahydrofuran and 2 ml of water, it was allowed to stir for 18 hours at room temperature. The solvent was removed in vacuo. Chromatography (30% methanol-methylene chloride plus ammonium hydroxide) gave 1.93 g (62%) of the product as a yellow oil. MS FAB m / e 196 (M + H) +.

INTERMEDIARY 25 6-Fluorochroman A mixture of 6-fluoro-4-chromanone (2 g, 12 mmol) and 10% palladium on 1 g of carbon in 20 ml of concentrated hydrochloric acid and 30 ml of ethanol was hydrogenated for 20 hours. The catalyst was filtered and the solvent removed in vacuo. The residue was dissolved in 100 ml of ethyl acetate, washed with 6 portions of 200 ml of 1 N sodium hydroxide and water (3 x 150 ml), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (20% ethyl acetate-hexanes) gave 1.41 g (77%) of the product as a clear oil. MS The m / e 152 (M +).

INTERMEDIARY 26 6-fluorochroman-8-carbaldehyde To a solution of 6- fluorochroman (0.7 g, 4. 6 mmol) in 20 ml of anhydrous methylene chloride was added TiCl 4 (1.57 g, 8.3 mmol) and methyl ether of α, α'-dichloromethyl (0.53 g, 4.6 mmol) slowly at 0 ° C. The reaction was allowed to reach room temperature slowly, and stirred for 16 hours. The reaction mixture was poured into ice water, extracted with 3 portions of 100 ml of methylene chloride, washed with 5 portions of 150 ml of saturated sodium carbonate and with 3 portions of 100 ml of brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. The crude solid was collected and dried under vacuum to provide 0.75 g (90%) of the product as a yellow solid. Mp 55-57 ° C. Elemental analysis for C? 0H9FO2 Calculated: C, 66.66; H, 5.04 Found: C, 66.64; H, 4.78 INTERMEDIARY 27 6-fluoro-8-hydroxychroman To a solution of 6-fluorochroman-8-carbaldehyde (8.6 g, 48 mmol), 3-t-butyl-4-hydroxy-5-methylphenyl sulfide (100 mg) in 60 ml of anhydrous methylene chloride at 0 ° C. , 3-chloroperoxybenzoic acid (mCPBA) (12.4 g, 70 mmol) was added in portions. The reaction mixture was heated to reflux for 16 hours. The excess mCBPA was destroyed by the addition of 10% sodium sulfite. The benzoic acid was filtered and the filtrate was extracted with 3 portions of 150 ml of methylene chloride and washed with 3 portions of 150 ml of water. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the crude product (10.2 g, 52 mmol) was dissolved in ethanol-water (200 ml, 1: 1). To the above solution was added sodium hydroxide (6.2 g, 160 mmol) at 0 ° C. After 30 minutes, the ice water was removed, and the reaction mixture was allowed to stir for 3 hours at room temperature. The ethanol was then evaporated. The residue was neutralized with concentrated hydrochloric acid, extracted with 3 portions of 150 ml of methylene chloride, washed with 2 portions of 100 ml of saturated sodium bicarbonate and 2 portions of 100 ml of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (25% ethyl acetate-hexanes) gave 6.9 g (79%) of the product as a white solid: mp 62-63 ° C. Elemental analysis for C9H9F02 Calculated: C, 64.28; H, 5.39 Found: C, 64.31; H, 5.27 INTERMEDIARY 28 2- (6-fluorochroman-8-yloxy) ethylchloride A solution of 6-fluorochroman-8-carbaldehyde (5.5 g, 33 mmol), l-bromo-2-chloroethane (16.4 g, 114 mmol) and potassium carbonate (16 g, 114 mmol) in 60 mL of 2-butanone was heated to reflux for 24 hours. The mixture was poured into 150 ml of water, extracted with 3 portions of 15 ml of methylene chloride and washed with 3 100 ml portions of brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (20% ethyl acetate-hexanes) gave 5.74 g of the product as a white solid: mp 89-90 ° C. Elemental analysis for CnH? 2FC102 Calculated: C, 57.28; H, 5.24 Found: C, 57.15; H, 5.69 INTERMEDIARY 29 2- (6-fluorochroman-8-yloxy) ethylazide A solution of 2- (6-fluorochroman-8-yloxy) ethylchloride (4.13 g, 0.018 mol) and sodium azide (2.33 g, 0.036 mol) in 60 ml of anhydrous dimethylformamide was allowed to stir at 60 ° C for 18 hours. The mixture was poured into 150 ml of water, extracted with 3 portions of 150 ml of methylene chloride and washed with 3 portions of 100 ml of water. The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (20% ethyl acetate-hexanes) gave 4.12 g (97%) of the product as a clear oil. Elemental analysis for CnH? 2FN302 Calculated: C, 55.69; H, 5.10; N, 17.71 Found: C, 55.44; H, 4.97; N, 17.88 INTERMEDIARY 30 2- (6-fluorochroman-8-yloxy) ethylamine A solution of 2- (6-fluorochroman-8-yloxy) ethylazide (4.12 g, 0.017 mol) and triphenylphosphine (6.83 g, 0.026 mol) in 80 ml of tetrahydrofuran and 1.5 ml of water was allowed to stir for 18 hours at room temperature. ambient. The solvent was removed in vacuo. Chromatography (ethyl acetate) removed triphenylphosphine and triphenylphosphine oxide (40% methanol-methylene chloride plus ammonium hydroxide) gave 3.45 g (94%) of the product as a white solid: mp 68-70 ° C. Elemental analysis for CnH? 4FN02 Calculated: C, 62.55; H, 6.68; N, 6.63 Found: C, 62.18; H, 6.54; N, 6.63 INTERMEDIARY 31 7-methoxybenzofuran A solution of 7-methoxy-2-benzofurancarboxylic acid (5 g, 0.026 mol), 0.2 g of copper in 30 ml of quinoline, was heated to reflux for 2 hours. The mixture was filtered through celite. The celite was washed with ethyl acetate. The solvent was removed in vacuo. Chromatography (25% ethyl acetate-hexanes) gave 2.45 g (64%) of the product as a yellow oil. MS The m / e 148 (M +).

INTERMEDIARY 32 7-hydroxybenzofuran The 7-methoxybenzofuran (1 g, 6.7 mmol) was dissolved in 25 ml of anhydrous methylene chloride in a 100 ml round bottom flask. The flask was placed in an ice-acetone bath at -78 ° C. The flask was equipped with an air condenser. A solution of boron tribromide in methylene chloride (1 M, 10 ml) was carefully added to the stirred solution through the condenser. The reaction was maintained at -78 ° C for 6 hours and then allowed to stir at room temperature overnight. The reaction was quenched by the addition of 20 ml of water and diluted with ethyl ether. The solvent was removed in vacuo. Chromatography (25% ethyl acetate-hexanes) gave 0.47 g (52%) of the product as a light brown oil. MS The m / e 134 (M +).

INTERMEDIARY 33 2- (benz furan-7-yloxy) -ethylchloride To a solution of 7-hydroxybenzofuran (0.47 g, 3.5 mmol), triphenylphosphine (2.3 g, 8.7 mmol) and 2-chloroethanol (0.7 g, 8.7 mmol) in 50 mL of tetrahydrofuran, diisopropyl azodicarboxylate (1.8 g) was added slowly. 8.7 mmol). The reaction was stirred at room temperature for 3 hours. The tetrahydrofuran was removed in vacuo. Chromatography (25% ethyl acetate-hexanes) gave 0.58 g (84%) of the product as a yellow oil. MS The m / e 196 (M +).

INTERMEDIARY 34 2- (2,3-dihydrobenzofuran-7-yloxy) ethylchloride A solution of 2- (benzofuran-7-yloxy) -ethylchloride (0.64 g) and 10% palladium on carbon in 20 ml of acetic acid was hydrogenated under 2.81 kg / cm 2 (40 psi) pressure for 20 hours. The catalyst was filtered and the solvent removed in vacuo. Chromatography (20% ethyl acetate-hexanes) gave 0.39 g (60%) of the product as a white solid: mp 49-52 ° C. MS The m / e 198 (M +).

INTERMEDIARY 35 2- (4-fluorophenoxy) -acetaldehyde diethylacetal To a suspension of sodium hydroxide (5.4 g, 0.134 mol) in 100 ml of anhydrous dimethylformamide was added 4-fluorophenol (10 g, 0.089 mol) at 0 ° C. After the evolution of hydrogen had ceased, the bromoacetaldehyde diethylacetal (16 ml, 0.11 mol) was added. The reaction was heated to 160-170 ° C for 18 hours. The mixture was poured into ice-water, extracted with 3 portions of 150 ml of ethyl acetate, washed with 3 portions of 100 ml of 1 N sodium hydroxide and 3 portions of 100 ml of brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. Chromatography (25% ethyl acetate-hexanes) gave 16.36 g (80%) of the product as a clear oil. MS The m / e 228 (M +).

INTERMEDIARY 36 -fluorobenzofuran To a mixture of 200 ml of benzene containing polyphosphoric acid (7.9 g, 0.035 mol), the diethyl acetal of 2- (4-fluoro-phenoxy) -acetaldehyde (8 g, 0.035 mol) was added. The mixture was stirred vigorously while heating to reflux for 2.5 hours. The reaction mixture was cooled to room temperature and decanted from the polyphosphoric acid. The solvent was removed in vacuo. Chromatography (5% ethyl acetate-hexanes) gave 3.4 g (45%) of the product as a clear oil.

INTERMEDIARY 37 -fluoro-2, 3-dihydrobenzofuran A solution of 5-fluorobenzofuran and 10% palladium on carbon in 25 ml of acetic acid was hydrogenated under 3.51 kg / cm2 (50 psi) of pressure for 12 hours. The catalyst was filtered through celite, and the celite was washed with 200 ml of methylene chloride. The organic layer was washed with 3 portions of 100 ml of 1 N sodium hydroxide, 3 portions of 100 ml of brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to provide 2.59 g (85%) of the product as a clear oil.

INTERMEDIARY 38 -fluoro-2, 3-dihydrobenzofuran-7-carbaldehyde To a solution of 5-fluoro-2, 3-dihydrobenzofuran (7 g, 0.051 mol) in 40 ml of methylene chloride was added TiCl 4 (9.5 ml, 0.087 mol), followed by the methyl ether of a, a'-dichloromethyl (4.6 ml, 0.051 mol) at 0 ° C. The reaction was allowed to reach room temperature slowly and stirred overnight. The reaction mixture was slowly emptied into ice-water, extracted with methylene chloride (3 x 100 ml) and washed with saturated sodium carbonate (5 x 100 ml), and brine (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (25% ethyl acetate-hexanes) provided 3.29 g (39%) of the product as a white solid: mp 103-104 ° C. Elemental analysis for C9H7F02 Calculated: C, 65.06; H, 4.75 Found: C, 65.01; H, 4.03 INTERMEDIARY 39 -fluoro-7-hydroxy-2,3-dihydro-benzofuran To a solution of 5-fluoro-2,3-dihydrobenzofuran-7-carbaldehyde (3.29 g, 20 mmol), 3-t-butyl-4-hydroxy-5-methylphenyl sulfide (100 mg) in 40 ml of sodium chloride. Methylene at 0 ° C was added 3-chloroperoxybenzoic acid (mCPBA) (8.5 g, 30 mmol) in portions. The reaction mixture was heated to reflux for 16 hours. The excess mCBPA was destroyed by the addition of 10% sodium sulfite. The benzoic acid was filtered and the filtrate was extracted with methylene chloride (3 x 100 ml) and washed with 3 100 ml portions of water. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was dissolved in ethanol-water (100 ml, 1: 1). To the above solution, sodium hydroxide (2.11 g, 53 mmol) was added at 0 ° C. After 30 minutes, the ice bath was removed, and the reaction mixture was allowed to stir for 3 hours at room temperature. The ethanol was evaporated and the residue was neutralized with concentrated hydrochloric acid. This mixture was extracted with methylene chloride (3 x 100 ml) and washed with saturated sodium bicarbonate (2 x 100 ml) and brine (2 x 100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (30% ethyl acetate-hexanes) gave 1.62 g (50%) of the product as a white solid: mp 102.5-103.5 ° C. Elemental analysis for C8H7F02 Calculated: C, 62.34; H, 4.58 Found: C, 62.19; H, 4.59 INTERMEDIARY 40 2- (5-fluoro-2,3-dihydro-benzofuran-7-yloxy) ethylchloride A solution of 5-fluoro-7-hydroxy-2,3-dihydrobenzofuran (1.6 g, 10 mmol), l-bromo-2-chloroethane (7.8 g, 55 mmol) and K2C03 (2.2 g, 16 mmol) in 4.0 ml of 2-butanone was heated to reflux for 24 hours. The mixture was poured into 150 ml of water, extracted with methylene chloride (3 x 150 ml) and washed with brine. (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (25% ethyl acetate-hexanes) gave 2.10 g of the product as a white solid: mp 72.5-74.5 ° C. Elemental analysis for C? 0H? 0FC102 Calculated: C, 55.44; H, 4.65 Found: C, 55.37; H, 4.58 INTERMEDIARY 41 2- (5-fluoro-2,3-dihydrobenzofuran-7-yloxy) ethylazide A solution of 2- (5-fluoro-2,3-dihydro-benzofuran-7-yloxy) ethylchloride (2.05 g, 9.4 mmol) and sodium azide (1.23 g, 19 mol) in 30 ml of anhydrous dimethylformamide was allowed to stir at 60 ° C for 24 hours. The mixture was drained in 100 ml of water, extracted with methylene chloride (3 x 150 1), washed with water (3 x 100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (20% ethyl acetate-hexanes) gave 2.0 g (95%) of the product as a clear oil. MS The m / e [M + 1] +.

INTERMEDIARY 42 2- (5-fluoro-2,3-dihydrofuran-7-yloxy) ethylamine A solution of 2- (5-fluoro-2,3-dihydrobenzofuran-7-yloxy) ethylazide (1.98 g, 89 mmol) and triphenylphosphine (2.8 g, 10.6 mmol) in 50 mL of tetrahydrofuran and 1.5 mL of water was allowed to stir for 18 hours at room temperature. The solvent was removed in vacuo. Chromatography (ethyl acetate) removed triphenylphosphine and triphenylphosphine oxide (40% methanol-methylene chloride plus ammonium hydroxide) gave 2.0 g (100%) of the product as a clear oil. MS ESI m / e 198 [M + i r.

INTERMEDIARY 44 4-indanol A solution of 1 g of 2- (5-fluoro-2,3-dihydrofuran-7-yloxy) ethylamine (Intermediate 43) (Intermediate 44), prepared in the manner described by Ross et al., J. Am. Chem. Soc. , 110: 6471-6480 (1988) and 10% of palladium on carbon in 50 ml of acetic acid, was hydrogenated for 36 hours. The catalyst was filtered through celite. The celite was washed with methylene chloride. The organic layer was washed with 3 portions of 150 ml of saturated sodium carbonate, 3 portions of 150 ml of brine and dried over sodium sulfate. The solvent was removed in vacuo. Chromatography (30% ethyl acetate-hexanes) provided 0.78 g (86%) of the product as a clear oil. MS The m / e 134 (M +).

INTERMEDIARY 45 2- (indane-4-yloxy) -ethylchloride (45a) To a solution of 4-indanol (0.75 g, 5.6 mmol), triphenylphosphine (4.4 g, 16.8 mmol), 2-chloroethanol (0.7 g, 8.7 mmol) in 50 ml of tetrahydrofuran was slowly added diisopropyl azodicarboxylate (1.8 g, 8.7 g). mmol). The reaction was stirred at room temperature for 33 hours and the solvent was removed in vacuo. Chromatography (25% ethyl acetate-hexanes) gave 0.58 g (84%) of the product as a yellow oil. MS The m / e 196 (M +). 2- (5, 6, 7, 8-tetrahydronaphthalen-1-yloxy) -ethylchloride (45b) This compound was prepared in the manner described by 45 (a) above by replacing 4-indanol with 5, 6, 7, 8-tetrahydro-l-naphthol (4 g, 0.027 mol) with 46% yield (2.57 g) ) as a clear oil. Elemental analysis for C? 2H? 5C10 Calculated: C, 68.41; H, 7.17 Found: C, 68.37; H, 7.25 2- (naphthalen-1-yloxy) -ethylchloride (45c ' This compound was prepared in the manner described by 45 (a) above by replacing 4-indanol with 1-naphthol (5 g, 0.035 mol) with 82% yield (6.34 g) as a clear oil. Elemental analysis for C? 2HnC10 Calculated: C, 69.74; H, 5.37 Found: C, 69.64; H, 5.30 2-phenoxy-ethylchloride (45d) This compound was prepared in the manner described above by 45 (a) by replacement of 4-indanol with phenol (5 g, 0.053 mol) with 12% yield (1.03 g) as a clear oil. MS The m / e 156 (M +).

INTERMEDIARY 46 2- (indan-5-yloxy) -ethylchloride A solution of 5-indanol (5 g, 0.037 mol), l-bromo-2-chloroethanol (8.02 g, 0.056 mol) and potassium carbonate (7.7 g, 0.056 mol) in 40 ml of 2-butanone was heated to reflux for 18 hours. The mixture was poured into 100 ml of water, extracted with methylene chloride (3 x 150 ml) and washed with water (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (20% ethyl acetate-hexanes) gave 3.2 g (43%) of the product as a white solid: mp 45-46 ° C. Elemental analysis for CnH? 3C10 Calculated: C, 67.18; H, 6.66 Found: C, 67.03; H, 6.57 INTERMEDIARY 47 [3- (1H-indol-37U) -propyl] - (2-hydroxyethyl) amine To a solution of 3- (1H-indol-3-yl) -propylamine (3.5 g, 18.6 mmol), 2-chloro-ethanol (1 g, 12.4 mmol) in 20 ml of anhydrous dimethylsulfoxide was allowed to stir at 80 °. C for 12 hours. The mixture was drained in 100 ml of water, extracted with 3 portions of 150 ml of methylene chloride and washed with 3 100 ml portions of water. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (15% methanol-methylene chloride) gave 1.04 g (38%) of the product as a yellow oil. MS The m / e 218 (M +).

INTERMEDIARY 48 (2-hydroxy-ethyl) - [3- (1H-indol-3-yl) -propyl] -carbamic acid tert-butyl ester A solution of [3- (1H-indol-3-yl) -propyl] - (2-hydroxyethyl) amine (1.05 g, 4.5 mmol), di-ter-dicarbonate (5 g, 24 mmol) in 20 ml of Anhydrous tetrahydrofuran was heated at 80 ° C for 2 hours. The mixture was drained in 100 ml of water, extracted with 3 portions of 150 ml of methylene chloride and washed with 3 100 ml portions of water. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (5% methanol-methylene chloride) provided 0.86 g (56%) of the product as a yellow oil. MS The m / e 318 (M +).

INTERMEDIARY 49 2-chloro-l-phenylethanol A solution of 2-chloroacetophenone (5 g, 0. 032 mol), sodium borohydride (6.1 g, 0.16 mol) in 30 ml of tetrahydrofuran was allowed to stir at 60 ° C for 18 hours. The reaction was quenched with 200 ml of water and stirred for another 2 hours. The mixture was extracted with 3 portions of 100 ml of methylene chloride and washed with 3 portions of 150 ml of water. The organic layer was dried over sodium sulfate and filtered. The solvent was removed in vacuo and gave 5.07 g (100%) of the product as a clear oil. MS The m / e 156 (M +).

INTERMEDIARY 50 2- (2-methoxy-phenoxy) -2-phenyl-ethylchloride To a solution of guaiacol (2 g, 8.1 mmol), triphenylphosphine (6.4 g, 24 mmol), and 2-chloro-1-phenylethanol (3.78 g, 24 mmol) in 50 mL of tetrahydrofuran, diisopropyl azodicarboxylate was added slowly ( 4.8 g, 24 mmol). The reaction was stirred at room temperature for 2 hours. The tetrahydrofuran was removed in vacuo. Chromatography (20% ethyl acetate-hexanes) provided 3.30 g (78%) of the product as a clear oil. MS The m / e 262 (M +).

INTERMEDIARY 51 -fluoro-3- (3-p-toluenesulfonyloxypropyl) indole To a stirred solution of 3- (5-fluoro-lH-indol-3-yl) -propan-1-ol (2.90 g, 15.0 mmol) in 15.0 ml of pyridine was added p-toluenesulfonyl chloride (7.1 g, 37.5 mmol) at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was poured into 200 ml of ice-water. The aqueous solution was extracted with ethyl acetate and the combined organic extracts were washed with 1 N HCl and brine. The resulting material was dried over sodium sulfate, filtered, and the solvent was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (ethyl acetate / hexane, 3/7) to give 4.1 g (79%) of the title compound as a solid: mp 74 ° C (mp Lit. 99 ° C; EP-464604 A2).

INTERMEDIARY 52 2- (2-methoxy-phenoxypropionitrile) To a solution of guaiacol (5 g, 0.04 mol) in 20 ml of anhydrous N, N-dimethylformamide was added sodium hydride (1.16 g, 0.048 mol). The mixture was allowed to stir at room temperature for 0.5 hours, followed by the addition of 2-bromopropionitrile (8.09 g, 0.06 mol). The mixture was allowed to stir for 4 hours at room temperature and quenched with 20 ml of water. The mixture was extracted with 3 portions of 100 ml of methylene chloride, washed with 3 portions of 100 ml of water and the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. Chromatography (20% ethyl acetate-hexanes) provided 3.91 g (55%) of the product as a clear oil. MS The m / e 177 (M +).

INTERMEDIARY 53 2- (2-methoxy-phenoxy) propylamine To a solution of 2- (2-methoxy-phenoxy) -propionitrile (3.91 g, 0.022 mol) in 30 ml of anhydrous ethyl ether was added lithium-aluminum hydride. (1.0 M, 44 ml, 0.044 mol). The mixture heated to 65 ° C for 18 hours and the reaction was quenched with 3 ml of water, 3 ml of 15% NaOH and 9 ml of water. The resulting material was filtered through celite. The celite was washed with 200 ml of methanol and the solvent was removed in vacuo. Chromatography (10% methanol-methylene chloride) provided 0.26 g (7%) of the product as a yellow oil. MS The m / e 181 (M +).

EXAMPLE 1 [3- (1H-indol-3-yl) -propyl] - [2- (2-methoxy-phenoxy) -ethyl] -amine A mixture of benzyl- [3- (1H-indol-3-yl) -propyl] - [2- (2-methoxy-phenoxy) -ethyl] amine (2 g, 4.7 mmol) and 5% palladium on carbon in ethanol, was hydrogenated for 20 hours. The catalyst was filtered and the solvent removed in vacuo. Chromatography (ethyl acetate-hexanes-methanol-ammonium hydroxide: 4/4/1/1) gave 0.79 g (52%) of the product as a white solid: mp 101-102 ° C. The fumarate salt was prepared in ethanol: mp 130-130.5 ° C. Elemental analysis for C2oH24N202 * C4H4? 4 Calculated: C, 64.78; H, 6.46; N, 6.29 Found: C, 64.76; H, 6.23; N, 6.21 [4- (1H-indol-3-yl) -butyl] - [2- (2-methoxy-phenoxy) -ethyl] -amine Hydrogenation of benzyl- [4- (1H-indol-3-yl) -butyl] - [2- (2-methoxy-phenoxy) -ethyl] -amine gave 0.79 g (100%) of the product as a clear oil. The oxalate salt was prepared from isopropanol: mp 167-168 ° C. Elemental analysis for C2oH24N202 »C4H404 Calculated: C, 64.47; H, 6.59; N, 6.54 Found: C, 64.44; H, 6.52; N, 6.46 EXAMPLE 2 [3- (5-fluoro-1H-indol-3-yl) -propyl] - [2- (2-methoxy-phenoxy) ethyl] -amine A mixture of [3- (5-fluoro-lH-indol-3-yl) -propyl] - [2- (2-methoxy-phenoxy) ethyl] -benzylamine (0.94 g, 2.2 mol) and 10% palladium on 250 mg of carbon in ethanol was hydrogenated for 20 hours. The catalyst was filtered and the solvent removed in vacuo. Chromatography (10% methanol-methylene chloride) gave 0.63 g (85%) of the product as an off-white solid: mp 125-126 ° C. The oxalate salt was prepared in isopropanol: mp 146-149 ° C. Elemental analysis for C20H23FN2O2 »C2H2O4 * 0.5H20 Calculated: C, 59.85; H, 5.94; N, 6.35 Found: C, 60.13; H, 5.67; N, 6.10 EXAMPLE 3 [3- (5-fluoro-lH-.indol-3-yl) propyl] - [2- (5-fluoro-2-methoxy-phenoxy) -ethyl] -amine A solution of 2- (5-fluoro-2-methoxy-phenoxy) ethylchloride (0.3 g, 1.5 mmol), 3- (5-fluoro-lH-indol-3-yl) propylamine (0.56 g, 2.9 mmol) in 20 ml of dimethyl sulfoxide was allowed to stir for 12 hours at 90 ° C. The reaction mixture was emptied into 100 ml of water and extracted with methylene chloride (3 x 100 ml). . The organic layer was washed with water (3 x 150 ml), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (10% methanol-methylene chloride) gave 0.39 g (77%) of the product as a white solid: mp 119-122 ° C. The oxalate salt was prepared in ethanol: mp 175-177 ° C Elemental analysis for C20H22F2N2O2 * C2H2O4 Calculated: C, 58.66; H, 5.57; N, 6.22 Found: C, 58.29; H, 5.25; N, 6.07 [2- (5- fluoro-H-indol-3-yl) ethyl] - [2- (5-fluoro-2-methoxy-phenoxy) -ethyl-amine (3b) A solution of 2- (5-fluoro-2-methoxy-phenoxy) ethylamine (0.51 g, 2.8 mmol), 2- (5-fluoro-lH-indol-3-yl) ethylchloride (0.44 g, 1.8 mmol) and triethylamine (0.29 g, 3 mmol) in 20 ml of dimethyl sulfoxide was allowed to stir for 8 hours at 90 ° C. The reaction mixture was emptied into 100 ml of water and extracted with methylene chloride (3 x 100 ml). The organic layer was washed with water (3 x 150 ml), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (5% methanol-methylene chloride) provided 0.27 g (43%) of the product as a brown oil. The oxalate salt was prepared in ethanol: mp 185-188 ° C Elemental analysis for C? 9H20F2N2O2 * C2H2? 4 Calculated: C, 57.80; H, 5.08; N, 6.42 Found: C, 57.53; H, 4.95; N, 6.36 EXAMPLE 4 [2- (5-Fluoro-lH-indol-3-yl) ethyl] - [2- (5-fluoro-2-methoxy-phenoxy) -ethyl] -amine A solution of 2- (5-fluoro-2-methoxy-phenoxy) ethylamine (0.41 g, 2.2 mmol), 3- (2-bromoethyl) indole (0.25 g, 1.1 mmol) in 20 ml of dimethyl sulfoxide was left in stirring for 12 hours at 90 ° C. The reaction mixture was poured into 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, filtered and the solvent removed in vacuo. Chromatography (10% methanol-methylene chloride) provided 0.15 g (34%) of the product as a brown oil. The oxalate salt was prepared in ethanol: mp 188-189 ° C Elemental analysis for d9H21FN2O2 * C2H2O4 »0.25H20 Calculated: C, 59.04; H, 5.63; N, 6.62 Found: C, 59.68; H, 5.49; N, 6.56 EXAMPLE 5 [3- (5-fluoro-1H-indol-3-yl) propyl] - [2- (lH-indol-4-yloxy) -ethyl] -amine A solution of 2- (1H-indol-4-yloxy) ethylchloride (0.7 g, 3.6 mmol), 5-fluoro-indolyl-3-propylamine (1.0 g, 5.4 mmol) in 20 mL of dimethyl sulfoxide was allowed to stir for 12 hours at 90 ° C. The reaction mixture was poured into 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, filtered and the solvent removed in vacuo. Chromatography (5% -10% methanol-methylene chloride) provided 0.54 g (43%) of the product as a white solid: mp 70-73 ° C. The oxalate salt was prepared in ethanol: mp 183.5-185 ° C Elemental analysis for C2? H22FN30 * C2H204 Calculated: C, 62.53; H, 5.48; N, 9.51 Found: C, 62.31; H, 5.38; N, 9.35 [2- (1H-indol-4-yloxy) ethyl] - [3- (1H-indol-3-yl) -propyl] amine (5b) This compound was prepared in the manner described above for Example 5 using 2- (1H-indol-4-yloxy) ethylchloride and 3-indolyl-propylamine in 65% yield as an off-white solid: mp 109-111 ° C. The oxalate salt was prepared in isopropanol: mp 200.5-202 ° C. Elemental analysis for C2? H23N30 * C2H204 Calculated: C, 65.19; H, 5.95; N, 9.92 Found: C, 64.89; H, 6.00; N, 9.81 [3- (lH-indol-3-yl) butyl] - [2- (lH-indol-4-yloxy) ethyl] amine (5c) This compound was prepared in the manner described above for Example 5 using 2- (1H-indol-4-yloxy) ethylchloride and 3-indolyl-butylamine with 43% yield as an off-white solid: mp 70-73 ° C. The oxalate salt was prepared in ethanol: mp 183.5- 185 ° C. Elemental analysis for C22H25N30 »C2H204 Calculated: C, 62.58; H, 5.48; N, 9.52 Found: C, 62.31; H, 5.38; N, 9.35 EXAMPLE 6 [2- (2,3-dihydrobenzo [1,4] dioxin-5-yloxy) -ethyl] - [2- (lH-indol-3-yl) -ethyl] amine A solution of 2- (2,3-dihydrobenzo [1,4] dioxin-5-yloxy) -ethylamine (0.38 g, 1.9 mmol), 3- (2-bromoethyl) -indole (0.24 g, 1.1 mmol) and triethylamine (0.22 g, 2.2 mmol) in 20 ml of anhydrous dimethyl sulfoxide was left stirring for 14 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, filtered and the solvent removed in vacuo. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) gave 0.19 g (52%) as a yellow oil. The oxalate salt was prepared in ethanol: mp 197.5-198.5 ° C. Elemental analysis for C20H22N2O3 * C2H2O4 Calculated: C, 61.63; H, 5.64; N, 6.53 Found: C, 61.36; H, 5.46; N, 6.45 EXAMPLE 7 [2- (2,3-dihydro-benzo [1,4] dioxin-5-yloxy) -ethyl] - [3- (5-fluoro-lH-indol-3-yl) -propyl] -amine A solution of 5- (2-chloroethoxy) - (2,3) -dihydrobenzo [1,4] dioxane (0.75 g, 3.5 mmol), 3- (5-fluoro-lH-indol-3-yl) -propylamine ( 1.0 g, 5.2 mmol) and triethylamine (0.35 g, 3.5 mmol) in 20 ml of anhydrous dimethyl sulfoxide was allowed to stir for 14 hours at 100 ° 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, filtered and the solvent removed in vacuo.

Chromatography (5% -10% methanol-methylene chloride plus ammonium hydroxide) provided 0.10 g (52%) of the product as a yellow oil. The fumarate salt was prepared in isopropanol: mp 189.5-190.5 ° C Elemental analysis for C2? H23FN2O3 * 0.5C4H4O4 »0.5H20 Calculated: C, 64.74; H, 5.88; N, 6.54 Found: C, 64.01; H, 5.95; N, 6.36 EXAMPLE 8 [2- (6-fluoroerornan-8-yloxy) ethyl] - [2- (lH-indol-3-yl) ethyl] -amine A solution of 2- (6-fluorochroman-8-yloxy) ethylchloride (0.41 g, 2.2 mmol), 3- (2-bromoethyl) indole (0.25 g, 1.1 mmol) and triethylamine (0.23 g, 2.2 mmol) in 20 ml of 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, filtered and the solvent removed in vacuo. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) gave 0.15 g (34%) of the product as a yellow oil. The oxalate salt was prepared in ethanol: mp 213-214 ° C Elemental analysis for C2? H23FN202 * C2H204 Calculated: C, 62.11; H, 5.67; N, 6.30 Found: C, 62.26; H, 5.71; N, 6.19 EXAMPLE 9 [2- (6-fluorochroman-8-yloxy) ethyl] - [3- (5-fluoro-lH-indol-3-yl) propyl] -amine (9a) A solution of 2- (6-fluorochroman-8-yloxy) ethylchloride (0.25 g, 7.1 mmol), 3- (5-fluoro-lH-indol-3-yl) -propylamine (0.42 g, 2.2 mmol) and triethylamine ( 0.22 g, 2.2 mmol) in 20 ml of anhydrous dimethyl sulfoxide was allowed to stir for 14 hours at 90 ° C. The mixture was emptied in 100 ml of water and. it was extracted with 3 portions of 100 ml of methylene chloride. The organic layer was washed with 3 portions of 150 ml of water, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) provided 0.25 g (60%) as a white solid: mp 137-138.5 ° C. The oxalate salt was prepared in isopropanol: mp 214-215 ° C Elemental analysis for C22H24F2N202 »1.5C2H204 Calculated: C, 57.58; H, 5.22; N, 5.31 Found: C, 57.75; H, 5.07; N, 5.51 [2- (6-fluorochroman-8-yloxy) ethyl] - [2- (5-fluoro-1H-indol-3-yl) ethyl] -amine (9b) A solution of 2- (6-fluorochroman-8-yloxy) ethylchloride (0.26 g, 1.1 mmol), 2- (5-fluoro-lH-indol-3-yl) -ethylamine (0.45 g, 2.1 mmol) and triethylamine ( 0.30 ml, 2.1 mmol) in 20 ml of anhydrous dimethyl sulfoxide was allowed to stir for 14 hours at 90 ° C. The mixture was drained in 100 ml of water and extracted with methylene chloride (3 x 100 ml). The organic layer was washed with water (3 x 150 ml), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) gave 0.19 g (48%) of the product as a yellow oil. The oxalate salt was prepared in ethanol: mp 201-203 ° C Elemental analysis for C2? H22F2N202 * lC2H2? 4 Calculated: C, 59.70; H, 5.23; N, 6.05 Found: C, 59.48; H, 5.08; N, 5.88 EXAMPLE 10 [2- (2,3-dihydrobenzofuran-7-yloxy) ethyl] - [3- (5-fluoro-H-indol-3-yl) propyl] amine A solution of 2- (2,3-dihydrobenzof ran-7-yloxy) ethylchloride (0.38 g, 1.9 mmol), 3- (5-fluoro-lH-indol-3-yl) propylamine (0.93 g, 4.8 mmol), triethylamine (0.48 g, 4.8 mmol) in 20 ml of anhydrous DMSO was allowed to stir at 90 ° C for 12 hours. The mixture was drained in 100 ml of water and extracted with methylene chloride (3 x 100 ml). The organic layer was washed with water (3 x 150 ml), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) gave 0.52 g (77%) of the product as a yellow oil. The oxalate salt was prepared in ethanol: mp 158-160 ° C Elemental analysis for C2? H23FN202 »C2H204 Calculated: C, 63.82; H, 5.78; N, 5.95 Found: C, 63.45; H, 5.74; N, 5.76 EXAMPLE 11 [2- (benzofuran-7- i loxi) ethyl] - [3- (5-fluoro-lH-indol-3-yl) propyl] amine A solution of 2- (benzofuran-7-yloxy) -ethylchloride (0.58 g, 2.9 mmol), 3- (5-fluoro-lH-indol-3-yl) propylamine (1.4 g, 7.4 mmol) and triethylamine (0.74 g) , 7.4 mmol) in 20 ml of anhydrous DMSO was allowed to stir at 90 ° C for 12 hours. The mixture was drained in 100 ml of water and extracted with 3 portions of .100 ml of methylene chloride. The organic layer was washed with 3 portions of 150 ml of water, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (7% methanol-methylene chloride) provided 0.31 g (30%) of the product as a light brown oil. The oxalate salt was prepared in THF: mp 181-183 ° C Elemental analysis for C2? H2? FN202 »lC2H204 Calculated: C, 62.39; H, 5.24; N, 6.33 Found: C, 62.07; H, 5.24; N, 6.45 EXAMPLE 12 [2- (5-fluoro-2, 3-dihydro-7-yloxy) -ethyl] - [2- (5-fluoro-l-indol-3-yl) -ethyl] -amine A solution of 2- (5-fluoro-2,3-dihydrofuran-7-yloxy) -ethylamine (0.40 g, 2.1 mmol), 2- (5-fluoro-lH-indol-3-yl) -ethylamine (0.25 g) , 1.0 mmol) and triethylamine (0.29 ml, 2.1 mmol) in 20 ml of anhydrous dimethyl sulfoxide was allowed to stir for 14 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 3 100 ml portions of water, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (5% methanol-methylene chloride plus ammonium hydroxide) provided 0.2 g (54%) of the product as a yellow oil. The oxalate salt was prepared in ethanol: mp 209.5-210.5 ° C Elemental analysis for C2oH20F2N202 * 1 .5C2H20 Calculated: C, 55.98; H, 4.70; N, 5.68 Found: C, 55.53; H, 4.44; N, 5.72 EXAMPLE 13 [3- (5-fluoro-lH-indol-3-yl) -propyl] - [2- (indane-4-yloxy) -ethyl] -amine (13a) A solution of 2- (indan-4-yloxy) -ethylchloride (0.58 g, 2.9 mmol), 3- (5-fluoro-lH-indol-3-yl) -propylamine (1.4 g, 7.4 mmol) and triethylamine (1 ml, 7.4 mmol) in 20 ml of anhydrous dimethyl sulfoxide was left stirring 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 3 100 ml portions of water, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (7% methanol-methylene chloride) provided 0.31 g (30%) of the product as a brown oil. The oxalate salt was prepared in tetrahydrofuran: mp 220-222 ° C Elemental analysis for C22H25FN20 «C2H204 Calculated: C, 65.10; H, 6.15; N, 6.33 Found: C, 64.74; H, 6.14; N, 6.11 [3- (5-fluoro-lH-indol-3-yl) -propyl] - [2- (5,6,7,8-tetrahydro-naphthalen-1-yloxy) -ethyl] -amine (13b) ) This compound was prepared in the manner described above for Example 13 by the replacement of 2- (indane-4-yloxy) -ethylchloride with 2- (5,6,7,8-tetrahydronaphthalen-1-yloxy) -ethylchloride (0.6 g, 2.8 mmol) with 29% yield (0.3 g) as a yellow oil. The fumarate salt was prepared in ethanol: mp 203-205 ° C Elemental analysis for C23H27FN2O * 0.5C4H4? Calculated: C, 70.73; H, 6.89; N, 6.60 Found: C, 70.49; H, 6.87; N, 6.52 [3- (1H-indol-3-yl) -propyl] - [2- (naphthalen-1-yloxy) -ethyl] -amine (13c) This compound was prepared in the manner described above for Example 13 by the replacement of 2- (indane-4-yloxy) -ethylchloride with 2- (naphthalen-1-yloxy) -ethylchloride (0.6 g, 2.8 mmol), and - (5-fluoro-lH-indol-3-yl) -propylamine with 3- (1H-indol-3-yl) -propylamine (1.35 g, 7.2 mmol) with 85% yield (1.42 g) as a yellow solid : mp 119-120 ° C.

The fumarate salt was prepared in ethanol: mp 203-205 ° C Elemental analysis for C23H24N2 »0.5C H4? 4« 0.25H20 Calculated: C, 73.78; H, 6.56; N, 6.88 Found: C, 73.74; H, 6.47; N, 6.89 [3- (lH-indol-3-yl) -propyl] - [2-phenoxy-ethyl] -amine (13d) This compound was prepared in the manner described above for Example 13 by the replacement of 2- (naphthalen-1-yloxy) -ethylchloride with 2-phenoxy-ethylchloride (0.59 g, 3.8 mmol) in 100% yield (1.08 g) like a yellow oil. The fumarate salt was prepared in ethanol: mp 203-205 ° C Elemental analysis for C? 9H22N20 »C4H4? 4 Calculated: C, 67.30; H, 6.38; N, 6.82 Found: C, 67.01; H, 6.30; N, 6.73 EXAMPLE 14 [3- (5-fluoro-lH-indol-3-yloxy) -propyl] - [2- (indane-5-yloxy) -ethyl] -amine A solution of 2- (indan-5-yloxy) -ethylchloride (0.7 g, 3.5 mmol), 3- (5- fluoro-lH-indol-3-yl) -propylamine (1.01 g, 5.3 mmol) and triethylamine (0.53 g, 5 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 3 100 ml portions of water, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (5-10% methanol-methylene chloride) provided 0.53 g (43%) of the product as a yellow oil. The fumarate salt was prepared in ethanol: mp 179-180 ° C Elemental analysis for C22H25FN2O »0.5C4H O Calculated: C, 69.46; H, 6.68; N, 6.75 Found: C, 69.19; H, 6.67; N, 6.72 EXAMPLE 15 [3- (lH-indol-3-yl) -propyl] - [2- (quinolin-8-yloxy) ethyl] -amine To a solution of the (2-hydroxy-ethyl) - [3- (1H-indol-3-yl) -propyl] -carbamic acid tert-butyl ester (0.86 g, 2.7 mmol), triphenylphosphine (0.71 g, 2.7 mmol) ) and 8-hydroxy-quinoline (0.26 g, 2.7 mmol) in 50 ml of tetrahydrofuran was slowly added diisopropyl azodicarboxylate (0.55 g).2.7 mmol). The reaction was stirred at room temperature for 3 hours. The tetrahydrofuran was removed in vacuo. Chromatography (5% methanol-methylene chloride) gave a yellow solid, which was dissolved in 30 ml of methylene chloride. To this solution was added a solution of trifluoroacetic acid (4 ml in 10 ml of methylene chloride). The reaction mixture was allowed to stir for 2 hours at room temperature. The mixture was then quenched with saturated sodium carbonate and extracted with 3 portions of 100 ml of methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. Chromatography (10-15% methanol-methylene chloride plus ammonium hydroxide) gave 0.17 g (18%) of the product as a light yellow oil. The hydrochloride salt was prepared in ethyl acetate: mp 83-86 ° C Elemental analysis for C22H23N30 * HC1 «1.25H20 Calculated: C, 65.34; H, 6.60; N, 10.39 Found: C, 65.24; H, 6.69; N, 10.47 EXAMPLE 16[3- (5-fluoro-lH indol-3-yl) -propyl] - [2- (2-methoxy-phenoxy) -2-phenyl-ethyl] -amine A solution of 2- (2-methoxy-phenoxy) -2-phenyl-ethylchloride (0.71 g, 2.7 mmol), 2- (5- fluoro-H-indol-3-yl) -ethylamine (1.04 g, 5.4 mmol) and triethylamine (0.75 ml, 5.4 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 3 100 ml portions of water, dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. Chromatography (7% methanol-methylene chloride plus ammonium hydroxide) provided 0.15 g (13%) of the product as a yellow oil. The citrate salt was prepared in ethyl ether: mp 64.5-67 ° C Elemental analysis for C20H2oF2N202 »C6H8? 7 # l .5H20 Calculated: C, 60.27; H, 6.01; N, 4.39 Found: C, 59.96; H, 6.00; N, 4.39 EXAMPLE 17 [3- (5-fluoro-l-rindol-3-yl) -propyl] - [2- (2-methoxy-phenoxy) propyl] amine A solution of 2- (2-methoxy-phenoxy) propylamine (0.26 g, 1.2 mmol), 5-fluoro-3- (3-p-toluenesulfonyloxypropyl) indole (0.26 g, 0.81 mol) and triethylamine (0.13 g, 1.2 mmol) ) in 20 ml of anhydrous dimethyl sulfoxide was left stirring for 8 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 3 100 ml portions of water, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) gave 0.1 g (36%) of the product as a yellow oil. The oxalate salt was prepared in l-propanol: mp 143-146 ° C Elemental analysis for C20H20F2N2O2 * C2H2? 4 »lH2O Calculated: C, 59.47; H, 6.29; N, 6.03 Found. C, 59.34; H, 5.87; N, 5.96 The activity of the present compounds is demonstrated by the following standard pharmacological test procedures. The cloning by PCR 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 Chinese hamster ovary cell line expressing the human 5-HTIA receptor subtype (HT? A.CHO cells) was employed 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 pellets or buttons were taken by aliquots and placed at -80 ° C. On the day of the test, the cells were thawed on ice, and resuspended in buffer. Studies were conducted using [3 H] 8-OH-DPAT as the radioligand. The binding assay was performed on microtiter plates in 96 wells in a total final 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. The 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 at 30 minutes at room temperature, the reaction was terminated by the addition of an ice-cooled buffer and rapid filtration using a Brandel M-96 Cell Harvester (Gaithersburg, MD) through a pre-moistened GF / B filter. for 30 minutes in 0.5% polyethylenimine. 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. In summary, frontal cortical membranes prepared from male Sprague-Dawley rats were incubated with 3H-paroxetine (0.1 nM) for 60 minutes at 25 ° C. All tubes also contained either vehicle, test compound (one to eight concentrations), or a 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. Non-linear regression analysis was used to determine the IC50 values that were converted to Ki values using the method of Cheng and Prusoff, Biochem, Pharmacol. 22: 3099 (1973); Ki IC50 / ((Radioligand concentration) / 1 + KD)). The [35 S] -GTP? S binding assay was similar to that used by Lazareno and Birdsall, Br. J. Pharmacol. 109: 1120 (1993). Briefly, fragments of the 5-HTIA cloned receptor membrane (as used for the 5-HT? A receptor binding assays) were stored at -70 ° C until needed. When needed, the membranes were rapidly thawed, centrifuged at 40,000 xg for 10 minutes and resuspended at 4 ° C for 10 minutes in assay buffer (25 mM HEPES, 3 mM magnesium chloride, 100 mM sodium chloride, EDTA 1 mM, GDP 10 uM, DTT 500 mM, 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 agonist. All reactions were terminated by the addition of ice-cooled Tris buffer followed by rapid filtration using a Tom Tech® filtration device to remove bound [35S] GTP? S from the free compound. 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 mM HEPES, 5 mM theophylline and 10 μM pargyline for a period of 20 minutes at 37 ° C. Functional activity was evaluated by treatment of the cells with forskolin (final concentration of 1 uM) 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 by 20 minutes before the addition of. 8-OH-DPAT 10 nM and forskolin. The reaction was terminated by removal of the medium and addition of 0.5 ml of ice-cold assay buffer. Plates were stored at 20 ° C before the evaluation of cAMP formation by a cAMP SPA assay (Amersham). The compounds tested correspond to those prepared in Examples 1 to 17 above. The results of the procedure are described in Table 1.

TABLE 1 Example 5-HT? A ST (K ±, nM, or% GTP? S ED50 cAMP ED50 No. (Ki, nM) Inhib. - 1 μM) (EMax%) (EMax%) the 1.97 22 13.0 (80%) 1.32 (94%) lb 7.72 25 44.0 (60%) 2 1.34 0.48 41.6 (77%) 4.28 (97%) 3a 35.0 0.97 4.71 (99%) 3b 47.9 49% (100)% 4 91.4 28.0 5a 1.50 0.57 2.0 (90%) b 2.47 14 4.0 (66%) TABLE 1 (continued) Example 5-HT1A ST (Klf nM, or% GTP? S ED50 cAMP ED50 No. (Ki, nM) Inhib. @ 1 μM) (EMax%) (EMax%) 5c 4.22 18 25.8 (59%) 6 5.80 12.0 (100%) 7 0.68 0.08 15.7 (75%) 1.11 (90%) 8 8.53 4.5 36 (49%) 9a 26.6 0.84 121 (0%) 49 (0%) 9b 29.2 4.5 234 (0%) 1.63 0.74 4.72 (80%) 11 1.55 3.03 2.93 (99.9%) - 12 35.1 12.0 13a 76.9 71% 13b 170.3 40 13c 16.8 34% 13d 9.20 26% 14 158.4 56 15 0.54 24 3.0 (76%) 16 43.9 21.0 17 14.50 16.0 236 (97.5%) As demonstrated by the results described above, the compounds of the present invention are active towards 5HT1A receptors and in general elevate serotonin levels by inhibiting 5-HT transport. Accordingly, the present compounds should be useful in the treatment of disorders related to defects in the concentration of serotonin. 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, phosphate, calcium, 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 can 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 (containing particularly 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 liquid or solid composition form. 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 dosage form may 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

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, or aryl; R2 is hydrogen, lower alkyl, phenyl, or substituted phenyl; X and Y are each, independently, hydrogen, lower alkyl, lower alkoxy, or halogen, or together they are combined with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl group, dihydrofuranyl, furanyl, dioxanyl, oxazolyl, or isoxazolyl; Z is hydrogen, halogen, or lower alkoxy; with the proviso that when X, Y or Z represent lower alkoxy, these are not present in the ortho position; W is hydrogen, halogen, lower alkyl, cyano, or a trifluoromethyl group; and n is 2-5; or the pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, characterized in that: Ri is hydrogen, methyl or aryl; R2 is hydrogen; X and Y are each, independently, hydrogen, halogen or lower alkoxy, or together they are combined with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyridinyl, dioxanyl, oxazolyl, furanyl or dihydrofuranyl group; Z is hydrogen, halogen or lower alkoxy; with the proviso that when X, Y or Z represent lower alkoxy, they are not present in the ortho position; W is hydrogen or halogen; and n is 2-4; or the pharmaceutically acceptable salts thereof.

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

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

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

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

7. The compound according to claim 1, characterized in that it is [2- (2,3-dihydro-benzo [1,4] dioxin-5-yloxy) -ethyl] - [3- (5-fluoro-lH-indole- 3-yl) -propyl] -amine.

8. The compound according to claim 1, characterized in that it is [2- (6-fluorochornan-8-yloxy) -ethyl] - [2- (1H-indol-3-yl) -ethyl] -amine.

9. The compound according to claim 1, characterized in that it is [2- (6-fluorochroman-8-yloxy) -ethyl] - [3- (5-fluoro-1 H -indo-3-yl) -propyl] -amine.

10. The compound according to claim 1, characterized in that it is [2- (6-fluorochornan-8-yloxy) -ethyl] - [2- (5-fluoro-lH-indol-3-yl) -ethyl] -amine.

11. The compound according to claim 1, characterized in that it is [2- (2,3-dihydro-benzofuran-7-yloxy) -ethyl] -3- (5-fluoro-lH-indol-3-yl) -propyl] -amine

12. The compound according to claim 1, characterized in that it is [2- (benzofuran-7-yloxy) -ethyl] - [3- (5-fluoro-1H-indol-3-yl) -propyl] -amine.

13. The compound according to claim 1, characterized in that it is [2 - (5-fluoro-2,3-dihydro-benzofuran-7-yloxy) -ethyl] - [2- (5-fluoro-1H-indole-3- il) -ethyl] -amine.

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

15. The compound according to claim 1, characterized in that it is [3- (5-fluoro-1H-indol-3-yl) -propyl] - [2- (5,6,7,8-tetrahydro-naphthalene-1-) iloxy) -ethyl] -amine.

16. The compound according to claim 1, characterized in that it is [3- (1H-indol-3-yl) -propyl] - [2- (naphthalen-1-yloxy) -ethyl] -amine.

17. The compound according to claim 1, characterized in that it is [3- (lH-indol-3-yl) -propyl] _ (2-phenoxy-ethyl) -amine.

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

19. The compound according to claim 1, characterized in that it is [3 - (. LH-indol-3-yl) -propyl] - [2- (quinolin-8-yloxy) -ethyl] -amine.

20. The compound according to claim 1, characterized in that it is [3- (5-fluoro-1H-indol-3-yl) -propyl] - [2- (2-methoxy-phenoxy) -2-phenyl-ethyl] - amine.

21. The compound according to claim 1, characterized in that it is [3- (5-fluoro-l-indol-3-yl) -propyl] - [2- (2-methoxy-phenoxy) -propyl] -amine.

22. A pharmaceutical composition, comprising a compound of the formula: characterized in that Ri is hydrogen, lower alkyl, or aryl; R2 is hydrogen, lower alkyl, phenyl, or substituted phenyl; X and Y are each, independently, hydrogen, lower alkyl, lower alkoxy, or halogen, or together they are combined with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl group, dihydrofuranyl, furanyl, dioxanyl, oxazolyl, or isoxazolyl; Z is hydrogen, halogen, or lower alkoxy; with the proviso that when X, Y or Z represent lower alkoxy, these are not present in the ortho position; W is hydrogen, halogen, lower alkyl, cyano, or a trifluoromethyl group; and n is 2-5; or the pharmaceutically acceptable salts thf.

23. - Use of a compound of the formula below indicated for the manufacture of a medication to relieve the symptoms of depression: whn: Ri is hydrogen, lower alkyl, or aryl; R 2 is hydrogen ^ lower alkyl, phenyl, or substituted phenyl; • X and Y are each, independently, hydrogen, lower alkyl, lower alkoxy, or halogen, or together they combine with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl group , dihydrofuranyl, furanyl, dioxanyl, oxazolyl, or isoxazolyl; Z is hydrogen, halogen, or lower alkoxy; with the proviso that when X, Y or Z represent lower alkoxy, these are not present in the ortho position; W is hydrogen, halogen, lower alkyl, cyano, or a trifluoromethyl group; and n is 2-5; or the pharmaceutically acceptable salts thf.