JP2002510675A - N-aryloxyethyl-indolyl-alkylamines for treatment of depression (5-HT1A receptor activators) - Google Patents

Abstract

(57) Abstract: Provided are compounds (5-HT _1A receptor activators) that are effective in reducing the symptoms of depression. Such compounds have the formula (I): Wherein R ₁ 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 with the carbon atom to which they are attached, form a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl, dihydrofuranyl, furanyl, dioxanyl, oxazolyl or isoxazolyl group; Z is hydrogen, halogen Or when X, Y or Z represents lower alkoxy, they are not in the ortho position; W is hydrogen, halogen, lower alkyl, cyano or trifluoromethyl group; and n is 2-5 Or a pharmaceutically acceptable salt thereof. You.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD [0001] The present invention relates to compounds useful for treating diseases affected by disorders of the nervous system affected by serotonin. More specifically, the present invention relates to aryloxyethyl-indolyl-alkylamine derivatives useful for treating such diseases.

BACKGROUND ART Drugs that enhance the neurotransmission of serotonin (5-HT) are useful in treating many psychiatric disorders, including depression and anxiety. The first generation of non-selective compounds that affect serotonin act through a variety of physiological means, which indicates that such compounds may have numerous undesirable side effects (e.g., Dry mouth, blurred eyes, and sedation). A recently introduced compound, a selective serotonin reuptake inhibitor (SSRI), inhibits the active removal of 5-HT released at the synapse from the synaptic cleft via the presynaptic serotonin transporter. Works predominantly. This 5-HT blockade mechanism cannot adequately explain their therapeutic activity, as SSRIs require weeks to exert their full therapeutic effect. This 2-week induction, which occurs before a sufficient antidepressant effect is observed, is presumed to be due to the involvement of the 5-HT _1A autoreceptor, which suppresses the excitatory activity of 5-HT neurons causing a diminished therapeutic effect. Studies suggest that 5-HT autoreceptor desensitization occurs a few weeks after SSRI administration and produces a sufficient antidepressant effect in most patients [eg Le Poul et al., Archives of Pharmacology, 352 (Ar ch Pharmacol.. ): 141 (1995)]. It is therefore believed that overcoming this negative feedback with a 5-HT _1A antagonist will increase and accelerate the clinical antidepressant response. According to a recent study by Artigas et al. [ Trends Neurosci. , 19: 378-383 (1996)], 5- _HT1A activity and 5-HT uptake in a single molecule. In combination with the inhibition, an antidepressant effect that acts more strongly and quickly can be achieved.

[0003] The present invention relates to a new class of molecules capable of acting simultaneously with the 5-HT transporter at the 5-HT _1A autoreceptor. Such compounds are therefore
It may be useful in treating anxiety and depression and other serotonin disorders.

[0004] US Pat. No. 3,371,098 discloses sec useful as a sedative, anticonvulsant and analgesic.
-And tert-indolylethylamine are disclosed.

US Pat. No. 5,436,264 discloses N-aryloxyalkyl-tryptamine-like compounds of the following formula as α-1-adrenergic receptor antagonists for the treatment of cardiovascular disorders: .

[0006]

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[0007] EP 0722 941 A2 describes a series of heterologous compounds of the following formula for the treatment of depression and other disorders for which serotonin uptake inhibitors are commonly used.
-Preparation of oxyalkaneamines is disclosed.

[0008]

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Japanese Patent Nos. 05255302 and 09040648 disclose diseases related to the central nervous system.
The following compounds, which have been reported to be useful in treating (eg, anxiety and depression), are disclosed.

[0010]

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DISCLOSURE OF THE INVENTION The compounds of the present invention have the formula I:

[0012]

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Wherein R ₁ 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 Being a halogen or, together with the carbon atom to which they are attached, form a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl, dihydrofuranyl, furanyl, dioxanyl, oxazolyl or isoxazolyl group; Hydrogen, halogen or lower alkoxy; provided that when X, Y or Z represents lower alkoxy, they are not in the ortho position; W is hydrogen, halogen, lower alkoxy, lower alkyl, cyano or trifluoromethyl group; , N is an atom represented by 2 to 5]. Bruno methyl benzo Oki Se Jin indole or a pharmaceutically acceptable salt thereof.

The present invention further relates to pharmaceutical compositions containing such compounds, as well as methods for reducing the symptoms of depression comprising administering a compound of the present invention to a patient in need thereof.

The compounds of the present invention preferably have the formula I wherein R ₁ is hydrogen, methyl or aryl; R ₂ is hydrogen; X and Y are each independently hydrogen, halogen or lower alkoxy. Or together with the carbon atom to which they are attached, form a cyclopentyl, cyclohexyl, phenyl, pyridinyl, dioxanyl, oxazolyl, furanyl or dihydrofuranyl group; Z is hydrogen, halogen or lower alkoxy; Provided that when X, Y or Z is lower alkoxy,
They are not in the ortho position; W is hydrogen or halogen; and n is 2-
Or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are most preferably selected from the following compounds: [3- (5-Fluoro-1H-indol-3-yl) -propyl]-[2- (1H-indole-4 [2- (1H-indole-4-yloxy) ethyl]-[3- (1H-indol-3-yl) -propyl] -amine; [3- (1H-indole) -3-yl) -butyl]-[2- (1H-indol-4-yloxy) -ethyl] -amine; [2- (2,3-dihydro-benzo [1,4] dioxin-5-yloxy)- Ethyl]-[2
-(1H-indol-3-yl) -ethyl] -amine; [2- (2,3-dihydro-benzo [1,4] dioxin-5-yloxy) -ethyl]-[3
-(5-Fluoro-1H-indol-3-yl) -propyl] -amine; [2- (6-fluorochroman-8-yloxy) -ethyl]-[2- (1H-indol-3-yl)- Ethyl] -amine; [2- (6-fluorochroman-8-yloxy) -ethyl]-[3- (5-fluoro-1H-
Indole-3-yl) -propyl] -amine; [2- (6-fluorochroman-8-yloxy) -ethyl]-[2- (5-fluoro-1H-
Indole-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-1H-indole-3-yl) -propyl] -amine; [2- (5-fluoro- 2,3-dihydro-7-yloxy) -ethyl]-[2- (5-fluoro-1H-indol-3-yl) -ethyl] -amine; [3- (5-fluoro-1H-indole-3) -Yl) -propyl]-[2- (indan-4-yloxy) -ethyl] -amine; [3- (5-fluoro-1H-indol-3-yl) -propyl]-[2- (5.6) [7,7,8-Tetrahydro-naphthalen-1-yloxy) -ethyl] -amine; [3- (1H-indol-3-yl) -propyl]-[2- (naphthalen-1-yloxy)
[3- (1H-Indol-3-yl) -propyl]-(2-phenoxy-ethyl) -amine; [3- (5-fluoro-1H-indol-3-yloxy) -propyl] -[2- (Indan-5-yloxy) -ethyl] -amine; [3- (1H-indol-3-yl) -propyl]-[2- (quinolin-8-yloxy) -ethyl] -amine; [3- (5-Fluoro-1H-indol-3-yl) -propyl]-[2- (2-methoxy-phenoxy) -2-phenyl-ethyl] -amine; and [3- (5-fluoro-1H) -Indol-3-yl) -propyl]-[2- (2-methoxy-phenoxy) -propyl] amine.

As used herein, the terms “lower alkyl” and “lower alkoxy” are meant to include straight and branched carbon chains having 1-6 carbon atoms. The term "halogen" is meant to include fluorine, chlorine, bromine and iodine. The term "substituted phenyl" is meant to include phenyl moieties substituted with alkyl, halogen or alkoxy groups. The term "aryl" is meant to include C6-C12 aromatic groups.

The compounds of the formula I can be used advantageously in the form of their pharmaceutically acceptable acid addition salts. Such salts are prepared by methods known to those skilled in the art, but may be formed using either inorganic or organic acids. Such inorganic and organic acids include, for example, fumaric acid, maleic acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid, bismethylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, oxalic acid, propionic acid, tartaric acid , Salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid , Hydrochloric acid, hydrobromic acid, sulfuric acid, cyclohexylsulfamic acid,
Phosphoric acid and nitric acid.

The compounds of the present invention may be prepared by any suitable method known to those skilled in the art.
However, the compounds of the present invention may be advantageously prepared according to any one of the schemes 1 to 10 below. In these schemes, the intermediate compounds discussed below are identified in parentheses. Compounds prepared in each of Schemes 1-10 have been identified by reference to the appropriate corresponding examples.

[0020]

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[0021]

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[0022]

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[0023]

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[0024]

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[0025]

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[0026]

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[0027]

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[0028]

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[0029]

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The present invention will now be described in more detail by the following specific but non-limiting examples.

Intermediate 2 [2- (2-Methoxy-phenoxy) -ethyl)]-benzyl-carbamic acid tert-butyl ester Triphenylphosphine (3.3 in anhydrous tetrahydrofuran (40 mL)
g, 12.6 mmol) of (2-hydroxy-ethyl) -benzyl-carbamic acid
To a solution of rt-butyl ester (3.2 g, 12.6 mmol) and 2-methoxyphenol (1.0 g, 8.4 mmol) was slowly added diisopropyl azodicarboxylate (2.5 g, 12.6 mmol). added. The reaction was stirred for 18 hours, then poured into methylene chloride (250 mL), washed with 1N sodium hydroxide (3 × 80 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to a clear oil. The oil was dissolved in ether (70 mL) and hexane was added slowly until triphenylphosphine oxide precipitated. The solid was filtered and the solvent was removed. The thick oil was then purified by column chromatography (15% ethyl acetate-hexane) to give 2.57 g (57.0%) of a clear oil. MS (EI) 358 m / e (M ⁺ ). Elemental analysis (as C ₂₁ H ₂₇ NO ₄ ): Calculated: C, 70.56; H, 7.61; N, 3.92 Found: C, 70.27; H, 7.58; N , 4.07

Intermediate 3 [2- (2-Methoxy-phenoxy) -ethyl] -benzyl-amine 2- (2-methoxy-phenoxy-ethyl) -benzyl-carbamic acid tert-butyl ester in methylene chloride (350 mL) (18.0 g, 50.4 mmol) to a solution of trifluoroacetic acid (60 mL) was added slowly. After stirring the reaction at room temperature for 12 hours, it was poured into 1N sodium hydroxide (200 mL) and extracted with methylene chloride (3 × 150 mL). The combined organic layers were washed with 1N sodium hydroxide (2 × 150 m
L), then washed with water (2 × 100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo. Chromatography (5% methanol-methylene chloride) gave 12.4 g (96%) of a clear oil. Elemental analysis (as C ₁₆ H ₁₉ NO ₂ ): Calculated: C, 74.19; H, 7.24; N, 5.54 Found: C, 73.91; H, 7.28; N , 5.44 fumarate was prepared in ethanol. 121.5-122 ° C. Elemental analysis results (as C ₁₆ H ₁₉ NO ₂ · C ₄ H ₄ O ₄ ): Calculated: C, 63.56; H, 6.27; N, 3.71 Found: C, 63.35; H, 6.16; N, 3.62

Intermediate 4 N-benzyl-3- (1H-indol-3-yl) -N- [2- (2-methoxy-phenoxy) -ethyl] -propion-amide (4a) Methylene chloride (80 mL) To a solution of 3-indolepropionic acid (4.1 g, 2 1.7 mmol) and 1- (3-dimethyl-amino-propyl) -3-ethylcarbodiimide hydrochloride (4.4 g, 23 mmol) in water C., methylene chloride (20 mL
)) [2- (2-Methoxy-phenoxy) -ethyl] -benzyl-amine (3 g, 1
(1.6 mmol). After 2 hours, the reaction mixture was poured into water (200 mL) and extracted with methylene chloride (2 × 50 mL). The combined organic layers were washed with 1N sodium hydroxide (50 mL) and then with water (2 × 50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum. Chromatography
(5% methanol-methylene chloride) gave 3.3 g (66.0%) of the product as a white solid. 46.5-47.5 [deg.] C; MS EI m / e 428 (M ^<+> ). N-benzyl-3- (1H-indol-3-yl) -N- [2- (2-methoxy-phenoxy) -ethyl] -butyramide (4b) In the above (4a), 3-indolepropionic acid was converted to 3 -Indolebutyric acid (1.8 g, 8.9 mmol) was replaced with N-benzyl-3- (1H-indole-3-
Yl) -N- [2- (2-Methoxy-phenoxy) -ethyl] butyramide (1.3 g, 78%) was obtained as a white foam. MS FAB m / e 443 (M + H) ⁺ ; MS F AB m / e 465 (M + Na) ⁺ .

Intermediate 5 Benzyl- [3- (1H-indol-3-yl) -propyl]-[2- (2-methoxy-fe
Noxy) -ethyl] amine (5a) N-benzyl-3- (1H-indol-3-yl) -N- [2- (2-methoxy-phenoxy) -ethyl] in tetrahydrofuran (50 mL) at room temperature -Propionami
Lithium aluminum hydride (1.8 g) was added to the solution of the chloride. The reaction was heated at reflux for 12 hours and then cooled to room temperature. Quench the reaction with saturated ammonium chloride solution.
And the solid precipitate was filtered through celite. Concentrate the solvent under vacuum,
The product was purified by chromatography (5% methanol-methylene chloride) to give 2.0 g (86%) of the product as a yellow oil. MS EI m / e 414 (M ⁺ ). Elemental analysis results (C₂₇H₃₀N_TwoO): 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-pheno)
(Xy) -ethyl] -amine (5b) In (5a), N-benzyl-3- (1H-indol-3-yl) -N- [2- (2-meth
Toxi-phenoxy) -ethyl] -propionamide is converted to N-benzyl-3- (1H-indo
Yl-3-yl) -N- [2- (2-methoxy-phenoxy) -ethyl] -butyramide (1.2
g, 2.7 mmol) and N-benzyl-3- (1H-indol-3-yl)
-N- [2- (2-Methoxy-phenoxy) -ethyl] -butyramide (1.06 g, 91%)
Was obtained as a white oil. MS EI m / e 428 (M⁺).

Intermediate 7 5-Fluoro-indolyl-3-propyl bromide Demerson et al. Journal in methylene chloride (156 mL).
3- (5-Fluoro-1H-indol-3-yl) -propanol-1-prepared according to the method described in J. Med. Chem. , 19: 391-395 (1976) . A solution of all (intermediate 6), carbon tetrabromide (65.5 g, 0.2 mol) and triphenylphosphine (52 g, 0.2 mol) was stirred for 2 hours. The solvent was evaporated and the product was chromatographed (30% ethyl acetate-hexane) to give 3.5 g (99%) of the product.

Intermediate 8 5-Fluoro-indolyl-3-propyl azide 5-Fluoro-indolyl-3-propyl bromide (10.67 g, 41 mmol) and sodium azide in anhydrous N, N-dimethylformamide (60 mL) (
(3.9 g, 60 mmol) was stirred at 60 ° C. for 18 hours. The mixture was poured into water (150 mL), extracted with methylene chloride (3 × 150 mL) and water (3 × 100 mL).
L). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (30% ethyl acetate-hexane) gave product 8.
10 g (89%) were obtained as a clear oil. Elemental analysis (as C ₁₁ H ₁₁ FN _3): Calcd: C, 60.54; H, 5.08 ; N, 25.67 Found: C, 60.62; H, 5.08 ; N , 25.84

Intermediate 9 5-Fluoro-indolyl-3-propylamine 5-Fluoro-indolyl-3-propyl azide in ethanol (8 g, 0.
037 mol) and a solution of 10% palladium on carbon were hydrogenated at 50 psi for 16 hours. The catalyst was filtered and the solvent was removed under vacuum. Celite was washed with methanol (300 mL) and the solvent was removed under vacuum. Chromatography (15% methanol-methylene chloride + aqueous ammonia) provided 4.33 g (61%) of the product as a yellow solid. 82-84.5 ° C. Elemental analysis (as C ₁₁ H ₁₃ FN _2): Calculated: C, 68.73; H, 6.82 ; N, 14.57 Found: C, 68.82; H, 6.85 ; N , 14.49

Intermediate 10 [3- (5-Fluoro-1H-indol-3-yl) -propyl]-[2- (2-methoxy-phenoxy) -ethyl] -benzylamine [40] in dimethylsulfoxide (40 mL) 2- (2-methoxy-phenoxy) -ethyl] -benzylamine (1.0 g, 3.9 mol), 3- (5-fluoro-1H-indole-3-yl) -propylamine (1.4 g) 5.8 mmol) and triethylamine (0.79 g, 7.8 mmol) was stirred at 100 ° C. for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 100 mL), dried over anhydrous sodium sulfate, filtered,
The solvent was removed under vacuum. Chromatography (30% ethyl acetate-hexane) gave 0.94 g (58%) of the product as a yellow oil. MS EIm / e 4
32 (M ⁺ ).

Intermediate 11 2- (5-Fluoro-1H-indol-3-yl) ethanol 5-Fluoro-indole-3-acetic acid (4.3 g,
0.022 mol) at 0 ° C. in LiAlH ₄ (1.0 M, 33 mL, 0.033).
Mol) was added. After the mixture was stirred for 0.5 h, it was quenched with a saturated NH ₄ Cl solution. The mixture was then filtered through celite. The filtrate was washed with 1N NaOH (
(3 × 100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) gave 4.04 g (100%) of product.
Was obtained as an off-white solid. 59-61 ° C. Elemental analysis (as C ₁₀ H ₁₀ FNO): Calculated: C, 67.03; H, 5.63 ; N, 7.82 Found: C, 66.71; H, 5.50 ; N, 7.74

Intermediate 12 3- (5-Fluoro-1H-indol-3-yl) -ethyl bromide 2- (5-Fluoro-1H-indole-3-yl) ethanol (4 g) in methylene chloride (50 mL) , 22.5 mmol) at room temperature in carbon tetrabromide (11.2 mmol).
g, 34 mmol) followed by triphenylphosphine (8.8 g, 33 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The solvent was removed under vacuum. Chromatography (30% ethyl acetate-hexane) gave 5.91 g (98%) of the product as an off-white solid. 58-59 ° C. Elemental analysis results (as C ₁₀ H ₉ FBrN): Calculated: C, 49.61; H, 3.75; N, 5.79 Found: C, 49.29; H, 3.73; N, 5.72

Intermediate 15 2- (5-Fluoro-2-methoxy-phenoxy) ethyl chloride Synthetic product of Mancini et al. In 2-butanone (60 mL)
5-fluoro-2-methoxy-phenol (4.34 g, 31 mmol), 1-bromo-2-chloroethane prepared according to the method described in Communications ( Synth. Comm. ), 19: 2001-2005 (1989) . (8.9 mL, 107 mmol) and potassium carbonate (14.8 g, 106 mmol) were refluxed for 24 hours. The mixture was poured into water (150 mL), extracted with methylene chloride (3 × 150 mL), and brine (3 × 100 mL).
L). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (20% ethyl acetate-hexane) gave product 4.
77 g (76%) were obtained as a clear oil. Elemental analysis (as C ₉ H ₁₀ FCO ₂ ): Calculated: C, 52.83; H, 4.93 Found: C, 52.79; H, 4.75

Intermediate 16 2- (5-Fluoro-2-methoxy-phenoxy) ethyl azide 2- (5-Fluoro-2-methoxy-phenoxy) ethyl chloride (3. A solution of 97 g (19 mmol) and sodium azide (2.6 g, 39 mmol) was stirred at 60 ° C. for 18 hours. The mixture was poured into water (150 mL), extracted with methylene chloride (3 × 150 mL) and washed with water (3 × 100 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (20% ethyl acetate-hexane) provided 3.75 g (92%) of the product as a clear oil. Elemental analysis (as C ₉ H ₁₀ FN ₃ O ₂ ): Calculated: C, 51.18; H, 4.77; N, 19.90 Found: C, 51.35; H, 4.71 N, 20.06

Intermediate 17 2- (5-Fluoro-2-methoxy-phenoxy) ethylamine 2- (5-Fluoro-2-methoxy-phenoxy) ethyl azide (3. A solution of 97 g (0.019 mol) and triphenylphosphine (5.95 g, 0.023 mol) was stirred at room temperature for 18 hours. The solvent was removed under vacuum. Chromatography (ethyl acetate) removes triphenylphosphine and triphenylphosphine oxide, and (25-50% methanol-ethyl acetate + aqueous ammonia) gives 3.14 g (9.
(0%) as a clear oil. MS EI m / e 185 (M ^<+> ).

Intermediate 18 3-Indolyl-propionamide (18a) 3-indolepropionic acid (150 mL) in anhydrous tetrahydrofuran (150 mL)
15 g, 79 mmol) and 1,1'-carbonyldiimidazole (16.7 g, 1
(00 mmol) was stirred at room temperature for 1.5 hours. The solution was then blown with NH ₃ for 2.5 hours at room temperature. The solvent was removed under vacuum and the residue was ethyl acetate (500 mL
). The organic solution was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. The white solid was collected and dried under vacuum. 10.42 g (96%); mp 124-125 [deg.] C; MS EI m / e 188 (M ^<+> ). 3-Indolyl-butyramide (18b) This compound was prepared as described in (18a) above using 3-indolebutyric acid and 1,1′-carbonyldiimidazole. A 96% yield was obtained as an off-white solid. 86-87 ° C.

Intermediate 19 3-Indolyl-propylamine (19a) To a solution of 3-indolyl-propionamide (5 g, 24.7 mmol) in anhydrous tetrahydrofuran (150 mL) was added lithium aluminum hydride (1. (0M solution, 100 mL) was added slowly. After refluxing the reaction mixture for 3 hours, it was quenched at 0 ° C. by adding water (4 mL), 15% sodium hydroxide (4 mL) and water (12 mL). The mixture was filtered through celite and concentrated in vacuo. Chromatography (10% methanol-methylene chloride + aqueous ammonia) gave 4.0 g (86%) of the product as a white solid. Melting point 5
8-60.5 [deg.] C; MS EI m / e 174 (M ^{* <+>} ). 3-Indolyl-butylamine (19b) This compound was prepared as described in (19a) above using 3-indolyl-butylamide and lithium aluminum hydride. A yield of 75% was obtained as a yellow solid. Melting point 51-53 [deg.] C.

Intermediate 20 2- (1H-Indol-4-yloxy) ethyl chloride 4-Hydroxyindole (4 g) in anhydrous tetrahydrofuran (40 mL)
To a solution of 2-chloroethanol (4.83 g, 60 mmol) and triphenylphosphine (15.7 g, 60 mmol) was slowly added diisopropyl azodicarboxylate (12.1 g, 60 mmol). Was. The reaction was allowed to stand at room temperature for 2.5
After stirring for an hour, it was poured into methylene chloride (250 mL), washed with water (3 × 100 mL), and dried over anhydrous sodium sulfate. This material was filtered and the solvent was removed under vacuum. Chromatography (20% hexane-ethyl acetate) removes triphenylphosphine and (20% methylene chloride-hexane) gives 2.94 product.
g (50%) was obtained as a white solid. 69.5-72 ° C

Intermediate 21 5-Hydroxy- (2,3) -dihydrobenzo [1,4] dioxin pyrogallol (5 g, 0.04 mol) was dissolved in 2-butanone (600 mL), and potassium carbonate (1 (.82 g, 0.013 mol). While the mixture was stirred under reflux, 1,2-dibroloethane (2.48 g, 1.14 mL, 0.013 mol) was gradually added dropwise. The reaction was stirred overnight before cooling to room temperature. Mixture with water (100 mL)
And extracted with methylene chloride (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (5% methanol-methylene chloride) gave 2.74 g (45%) of the product as a clear oil. MS EI m / e 152 (M ⁺ ).

Intermediate 22 5- (2-Chloroethoxy)-(2,3) -dihydrobenzo [1,4] dioxane 5-Hydroxybenzodioxane (1) in tetrahydrofuran (50 mL)
2.0 g, 6.5 mmol), 2-chloroethanol (0.79 g, 9.9 mmol) and triphenylphosphine (2.6 g, 9.9 mmol) in a solution of diisopropylazidodicarbamide (DIAD) (0.0 g, 9.8 mmol). After 2 hours, an additional 1.5 equivalents of triphenylphosphine, DIAD and 2-chloroethanol were added and the mixture was stirred for another 2 hours. The reaction mixture was washed with water (100 mL)
And extracted with methylene chloride (100 mL). The organic layer was separated and dried over anhydrous magnesium sulfate. This material was filtered and the solvent was removed under vacuum. Chromatography (20% ethyl acetate-hexane) provided 1.7 g (76%) of the product as a white solid. 70.5-72.5 ° C. Elemental analysis (as C ₁₀ H ₁₁ ClO _3): Calculated: C, 55.96; H, 5.17 Found: C, 55.57; H, 5.20

Intermediate 23 2- (2,3-dihydrobenzo [1,4] dioxin-5-yloxy) ethyl azide 5- (2-chloroethoxy)-(2 in anhydrous N, N-dimethylformamide (100 mL) A solution of (3,3) -dihydrobenzo [1,4] dioxane (4.6 g, 0.02 mol) and sodium azide (2.78 g, 0.043 mol) was stirred at 60 ° C. for 18 hours. The mixture was poured into water (200 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (20% ethyl acetate-hexane) provided 3.43 g (72%) of the product as a clear oil. MS FAB m / e 221 (M ^<+> ).

Intermediate 24 2- (2,3-dihydrobenzo [1,4] dioxin-5-yloxy) ethylamine 2- (2,3-dihydrobenzo [1, 4] A solution of dioxin-5-yloxy) ethyl azide (3.43 g, 0.016 mol) and triphenylphosphine (6.3 g, 0.023 mol) was stirred at room temperature for 18 hours. The solvent was removed under vacuum. Chromatography (30% methanol-methylene chloride + aqueous ammonia) gave 1.93 g (62%) of the product as a yellow oil. MS FAB m / e 196 (M + H) ^<+> .

Intermediate 25 6-Fluorochroman A mixture of 6-fluoro-4-chromanone (2 g, 12 mmol) and 10% palladium on carbon (1 g) in concentrated hydrochloric acid (20 mL) and ethanol (30 mL) was added for 20 hours. Hydrogenated. The catalyst was filtered and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate (100 mL) and 1N NaOH (6 × 200 mL) and water (3 × 150 mL).
mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (20% ethyl acetate-hexane) gave product 1.41.
g (77%) was obtained as a clear oil. MS EI m / e 152 (M ⁺ ).

Intermediate 26 6-fluorochroman-8-carbaldehyde 6-fluorochroman (0.7 g, 4.6) in anhydrous methylene chloride (20 mL)
To the solution of (mmol) at 0 ° C. was added TiCl ₄ (1.57 g, 8.3 mmol) and α, α′-dichloromethyl methyl ether (0.53 g, 4.6 mmol) slowly. The reaction was slowly brought to room temperature and stirred for 16 hours. The reaction mixture was poured into ice water, extracted with methylene chloride (3 × 100 mL) and washed with saturated sodium carbonate (5 × 150 mL) and brine (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. The crude solid was collected and dried under vacuum to give 0.75 g (90%) of the product as a yellow solid. 55-57 ° C. Elemental analysis (as C ₁₀ H ₉ FO _2): Calculated: C, 66.66; H, 5.04 Found: C, 66.64; H, 4.78

Intermediate 27 6-Fluoro-8-hydroxychroman At 0 ° C., 6-fluorochroman-8-carbaldehyde (8.6 g, 48 mmol) and 3-t-butyl-in anhydrous methylene chloride (60 mL). To a solution of 4-hydroxy-5-methylphenyl sulfide (100 mg) was added 3-chloroperoxybenzoic acid (mCPBA) (12.4 g, 70 mmol) in small portions. The reaction mixture was refluxed for 16 hours. By adding 10% sodium sulfite, excess mCBP
A was destroyed. The benzoic acid was filtered and the filtrate was extracted with methylene chloride (3 × 150 mL) and washed with water (3 × 150 mL). The organic layer is dried over anhydrous sodium sulfate,
Filtered. The solvent was removed under vacuum and the crude product (10.2 g, 52 mmol) was dissolved in ethanol-water (200 mL, 1: 1). In the above solution, sodium hydroxide (
(6.2 g, 160 mmol) at 0 ° C. After 30 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. Then the ethanol was evaporated. The residue was neutralized with concentrated hydrochloric acid, extracted with methylene chloride (3 × 150 mL), and saturated sodium bicarbonate solution.
(2 × 100 mL) and brine (2 × 100 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (25% ethyl acetate-hexane) provided 6.9 g (79%) of the product as a white solid. 62-63 ° C. Elemental analysis results (as C ₉ H ₉ FO ₂ ): Calculated: C, 64.28; H, 5.39 Found: C, 64.31; H, 5.27

Intermediate 28 2- (6-fluorochroman-8-yloxy) ethyl chloride 6-fluorochroman-8-carbaldehyde (5.5 g, 33 mmol) in 1-butanone (60 mL), 1-bromo- A solution of 2-chloroethane (16.4 g, 114 mmol) and K ₂ CO ₃ (16 g, 114 mmol) was refluxed for 24 hours. The mixture was poured into water (150 mL), extracted with methylene chloride (3 × 150 mL), and washed with brine (3 × 100 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (20% ethyl acetate-hexane) gave 5.74 g of the product as a white solid. 89-90 ° C. Elemental analysis (as C ₁₁ H ₁₂ FClO _2): Calculated: C, 57.28; H, 5.24 Found: C, 57.15; H, 5.69

Intermediate 29 2- (6-fluorochroman-8-yloxy) ethyl azide 2- (6-fluorochroman-8-yloxy) ethyl chloride (4.13 g, 0.018 mmol) in anhydrous DMF (60 mL) And sodium azide (2.33
g, 0.036 mol) was stirred at 60 ° C. for 18 hours. The mixture was poured into water (150 mL), extracted with methylene chloride (3 × 150 mL) and washed with water (3 × 100 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (20% ethyl acetate-hexane) gave product 4.12.
g (97%) was obtained as a clear oil. Elemental analysis (as _{C 11 H 12 FN 3 O 2} ): Calculated: C, 55.69; H, 5.10 ; N, 17.71 Found: C, 55.44; H, 4.97 N, 17.88

Intermediate 30 2- (6-fluorochroman-8-yloxy) ethylamine 2- (6-fluorochroman-8-yloxy) ethyl azide (4.12 g in tetrahydrofuran (80 mL) and water (1.5 mL) 0.017 mol) and triphenylphosphine (6.83 g, 0.026 mol) were stirred at room temperature for 18 hours. The solvent was removed under vacuum. Chromatography (ethyl acetate) removed the triphenylphosphine and triphenylphosphine oxide and (40% methanol-methylene chloride + aqueous ammonia) gave 3.45 g (94%) of the product as a white solid. . Mp 68-70 ° C. Elemental analysis (as C ₁₁ H ₁₄ FNO _2): Calculated: C, 62.55; H, 6.68 ; N, 6.63 Found: C, 62.18; H, 6.54 ; N , 6.63

Intermediate 31 7-methoxy-2-benzofurancarboxylic acid (5 g) in 7-methoxybenzofuran quinoline (30 mL)
, 0.026 mol) and copper (0.2 g) were heated at reflux for 2 hours. The mixture was filtered through celite. Celite was washed with ethyl acetate. The solvent was removed under vacuum. Chromatography (25% ethyl acetate-hexane) gave product 2.4.
5 g (64%) were obtained as a yellow oil. MS EI m / e 148 (M ^<+> ).

Intermediate 32 7-Hydroxybenzofuran 7-Methoxybenzofuran (1 g, 6.7 mmol) was dissolved in anhydrous methylene chloride (25 mL) in a 100 mL round bottom flask. The flask was placed in an acetone-ice bath at -78 ° C. The flask was fitted with an air cooler. Through a condenser, a solution of boron tribromide in methylene chloride (1M, 10 mL) was carefully added to the stirred solution. The reaction was kept at -78 C for 6 hours and then stirred at room temperature overnight. Water (20 mL)
The reaction was quenched by adding and diluted with ethyl ether. The solvent was removed under vacuum. Chromatography (25% ethyl acetate-hexane) provided 0.47 g (52%) of the product as a light brown oil. MS EI m / e 134 (M ⁺ ).

Intermediate 33 2- (benzofuran-7-yloxy) -ethyl chloride 7-hydroxybenzofuran (0.47 g, 3.5 mmol) in tetrahydrofuran (50 mL), triphenylphosphine (2.3 g, 8.3 g). To the solution in 7 mmol) and 2-chloroethanol (0.7 g, 8.7 mmol) was added diisopropyl azodicarboxylate (1.8 g, 8.7 mmol) slowly. The reaction was stirred at room temperature for 3 hours. THF was removed under vacuum. Chromatography (25% ethyl acetate-hexane) gave 0.58 g (84%) of the product as a yellow oil. MSEI m / e 196 (M ⁺ ).

Intermediate 34 2- (2,3-dihydrobenzofuran-7-yloxy) ethyl chloride 2- (benzofuran-7-yloxy) -ethyl chloride in acetic acid (20 mL)
(0.64 g) and a solution of 10% palladium on carbon were hydrogenated at 40 psi for 20 hours. The catalyst was filtered off and the solvent was removed under vacuum. Chromatography (20% ethyl acetate-hexane) provided 0.39 g (60%) of the product as a white solid. MP 49-52 [deg.] C; MS EI m / e 198 (M ^<+> ).

Intermediate 35 2- (4-Fluorophenoxy) -acetaldehyde diethyl acetal A suspension of NaOH (5.4 g, 0.134 mol) in anhydrous DMF (100 mL) was added at 0 ° C. with 4-fluoro Phenol (10 g, 0.089 mol) was added. After H ₂ evolution ceased, bromoacetaldehyde diethyl acetal (16 mL, 0.1 mL) was added.
11 mol) was added. The reaction was heated at 160-170 C for 18 hours. The mixture was poured into ice water, extracted with ethyl acetate (3 × 150 mL) and 1N NaOH (3 × 1
00 mL) and brine (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. Chromatography (25% ethyl acetate-hexane) provided 16.36 g (80%) of the product as a clear oil. MS EI m / e 228 (M ^<+> ).

Intermediate 36 To a mixture of benzene (200 mL) containing 5-fluorobenzofuran polyphosphoric acid (7.9 g, 0.035 mol) was added 2- (4-fluoro-phenoxy) -acetaldehyde diethyl acetal (8 g, 0.035 mol). The mixture was heated to reflux for 2.5 hours with vigorous stirring. The reaction mixture was cooled to room temperature and decanted from polyphosphoric acid. The solvent was removed under vacuum. Chromatography (5% ethyl acetate-hexane) gave product 3.
4 g (45%) were obtained as a clear oil.

Intermediate 37 5-Fluoro-2,3-dihydrobenzofuran 5-Fluorobenzofuran in acetic acid (25 mL) and 10% palladium /
The solution of carbon was hydrogenated at 50 psi for 12 hours. The catalyst was filtered through celite and the celite was washed with methylene chloride (200 mL). The organic layer was washed with 1N NaOH (3
× 100 mL), brine (3 × 100 mL) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to give 2.95 g (85%) of the product as a clear oil.

Intermediate 38 5-Fluoro-2,3-dihydrobenzofuran-7-carbaldehyde To a solution of 5-fluoro-2,3-dihydrobenzofuran (7 g, 0.051 mol) in anhydrous methylene chloride (40 mL) At 0 ° C., TiCl ₄ (9.5 mL, 0.087 mol) was added followed by α, α′-dichloromethyl methyl ether (4.6 mL, 0.051 mol). The reaction was slowly brought to room temperature and stirred overnight. The reaction mixture was poured into ice water, extracted with methylene chloride (3 × 100 mL), and saturated sodium carbonate solution.
(5 × 100 mL) and brine (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (25% ethyl acetate-hexane) gave 3.29 g (39%) of the product as a white solid. Melting point 103
~ 104 ° C. Elemental analysis results (as C ₉ H ₇ FO ₂ ): Calculated: C, 65.06; H, 4.75 Found: C, 65.01; H, 4.03

Intermediate 39 5-Fluoro-7-hydroxy-2,3-dihydro-benzofuran 5-Fluoro-2,3-dihydrobenzenefuran-7-carbaldehyde (0 ° C. in anhydrous methylene chloride (40 mL) To a solution of 3.29 g (20 mmol) and 3-t-butyl-4-hydroxy-5-methylphenylsulfide (100 mg) was added a little 3-chloroperoxybenzoic acid (mCPBA) (8.5 g, 30 mmol). Were added one by one. The reaction mixture was refluxed for 16 hours. Excess mCPBA was destroyed by adding 10% sodium sulfite. The benzoic acid was filtered off and the filtrate was extracted with methylene chloride (3 × 100 mL) and washed with water (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum and the crude was dissolved in ethanol-water (100 mL, 1: 1). To the above solution was added sodium hydroxide (2.11 g, 53 mmol) at 0 ° C. After 30 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. The ethanol was evaporated and the residue was neutralized with concentrated hydrochloric acid.
The mixture was extracted with methylene chloride (3 × 100 mL) and washed with saturated sodium bicarbonate solution (2 × 100 mL) and brine (2 × 100 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (30% ethyl acetate-hexane) provided 1.62 g (50%) of the product as a white solid. Melting point 102.5-103.5 [deg.] C. Elemental analysis (as C ₈ H ₇ FO _2): Calculated: C, 62.34; H, 4.58 Found: C, 62.19; H, 4.59

Intermediate 40 2- (5-Fluoro-2,3-dihydrobenzofuran-7-yloxy) ethyl chloride 5-Fluoro-7-hydroxy-2,3-dihydro-benzofuran in 2-butanone (40 mL) (1.6 g, 10 mmol), a solution of 1-bromo-2-chloroethane (7.8 g, 55 mmol) and K ₂ CO ₃ (2.2 g, 16 mmol) were refluxed for 24 hours. The mixture was poured into water (150 mL), extracted with methylene chloride (3 × 150 mL), and washed with brine (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (25% ethyl acetate-hexane) provided 2.10 g of the product as a white solid. Melting point 72.
5-74.5 ° C. Elemental analysis (as C ₁₀ H ₁₀ FClO _2): Calculated: C, 55.44; H, 4.65 Found: C, 55.37; H, 4.58

Intermediate 41 2- (5-Fluoro-2,3-dihydrobenzofuran-7-yloxy) ethyl azide 2- (5-Fluoro-2,3-dihydro-benzofuran-7- in anhydrous DMF (30 mL) A solution of (iloxy) ethyl chloride (2.05 g, 9.4 mmol) and sodium azide (1.23 g, 19 mmol) was stirred at 60 ° C. for 24 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 150 mL).
(3 × 100 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (20% ethyl acetate-hexane) provided 2.0 g (95%) of the product as a clear oil. MS ESI m / e 241 [M + 1] ⁺ .

Intermediate 42 2- (5-Fluoro-2,3-dihydrofuran-7-yloxy) ethylamine 2- (5-fluoro-2,3-dihydrofuran in tetrahydrofuran (50 mL) and water (1.5 mL) A solution of -benzofuran-7-yloxy) ethyl azide (1.98 g, 89 mmol) and triphenylphosphine (2.8 g, 10.6 mmol) was stirred at room temperature for 18 hours. The solvent was removed under vacuum. Triphenylphosphine and triphenylphosphine oxide were removed by chromatography (ethyl acetate), and (40% methanol-methylene chloride + aqueous ammonia) gave 2.0 g (100%) of the product as a clear oil. Obtained. MS ESI m / e 198 [M
+1] ⁺ .

Intermediate 44 4-Indanol Acetic Acid (50 mL) in Ross et al., Journal of the American Chemical Society ( J. Am. Chem. Soc. ), 110: 6471-6480 (1988) The solution of 1 g of 2- (5-fluoro-2,3-dihydrofuran-7-yloxy) ethylamine (intermediate 43) (intermediate 44) and 10% palladium on carbon prepared as described in Hydrogenated for hours. The catalyst was filtered off through celite. Celite was washed with methylene chloride. The organic layer was washed with a saturated sodium carbonate solution (3 × 150 mL), brine (3 × 150 mL) and dried over sodium sulfate. The solvent was removed under vacuum. Chromatography (30% ethyl acetate-hexane) gave 0.78 g (86%) of the product as a clear oil. MS EI m / e 134 (M ⁺ ).

Intermediate 45 2- (Indan-4-yloxy) -ethyl chloride (45a) 4-indanol (0.75 g, 5.6) in tetrahydrofuran (50 mL)
Mmol), triphenylphosphine (4.4 g, 16.8 mmol) and 2-chloroethanol (0.7 g, 8.7 mmol) in a solution of diisopropyl azodicarboxylate (1.8 g, 8.7 mmol). Slowly added. The reaction was stirred at room temperature for 3 hours,
The solvent was removed under vacuum. Chromatography (25% ethyl acetate-hexane) gave 0.58 g (84%) of the product as a yellow oil. MS EI m / e 196 (M ^<+> ). 2- (5,6,7,8-tetrahydronaphthalen-1-yloxy) -ethyl chloride (45b) This compound converts 4-indanol to 5,6,7,8-tetrahydro-1-naphthol (
(4g, 0.027 mol) and was prepared as a clear oil in 46% yield (2.57g) as described in 45 (a) above. Elemental analysis (C ₁₂ as H ₁₅ ClO): Calculated: C, 68.41; H, 7.17 Found: C, 68.37; H, 7.25 2- ( naphthalen-1-yloxy) -Ethyl chloride (45c) This compound was obtained as a clear oil as described in 45 (a) above by replacing 4-indanol with 1-naphthol (5 g, 0.035 mol). Prepared at 82% (6.34 g). Elemental analysis (as C ₁₂ H ₁₁ ClO): Calculated: C, 69.74; H, 5.37 Found: C, 69.64; H, 5.30 2- phenoxy - ethyl chloride (45d) This compound was prepared by replacing 4-indanol with phenol (5 g, 0.053 mol) as a clear oil in a yield of 12 as described in 45 (a) above.
% (1.03 g). MS EI m / e 156 (M ^<+> ).

Intermediate 46 2- (Indan-5-yloxy) -ethyl chloride 5-Indanol (5 g, 0.037 mol) in 2-butanone (40 mL), 1-bromo-2-chloroethanol (8.02 g) , 0.056 mol) and potassium carbonate (7.7 g, 0.056 mol) were refluxed for 18 hours. The mixture was poured into water (100 mL), extracted with methylene chloride (3 × 150 mL) and washed with water (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (20% ethyl acetate-hexane) gave product 3.
2 g (43%) were obtained as a white solid. 45-46 ° C. Elemental analysis (as C ₁₁ H ₁₃ ClO): Calculated: C, 67.18; H, 6.66 Found: C, 67.03; H, 6.57

Intermediate 47 [3- (1H-Indol-3-yl) -propyl]-(2-hydroxyethyl) amine 3- (1H-Indol-3-yl)-in anhydrous dimethylsulfoxide (20 mL) A solution of propyl-amine (3.5 g, 18.6 mmol) and 2-chloroethanol (1 g, 12.4 mol) was stirred at 80 ° C. for 12 hours. The mixture was poured into water (100 mL), extracted with methylene chloride (3 × 150 mL) and washed with water (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (15% methanol-methylene chloride) provided 1.04 g (38%) of the product as a yellow oil. MS EI m / e 218 (M ⁺ )
.

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

Intermediate 49 2-Chloro-acetophenone (5 g, 0.1 g) in 2-chloro-1-phenylethanol tetrahydrofuran (30 mL)
(0.032 mmol) and sodium borohydride (6.1 g, 0.16 mol) were stirred at 60 ° C. for 18 hours. The reaction was quenched with water (200 mL) and stirred for another 2 hours. The mixture was extracted with methylene chloride (3 × 100 mL) and washed with water (3 × 150 mL). The organic layer was dried over sodium sulfate and filtered. The solvent was removed under vacuum to give 5.07 g (100%) of the product as a clear oil. MS
EI m / e 156 (M ⁺ ).

Intermediate 50 2- (2-Methoxy-phenoxy) -2-phenyl-ethyl chloride guaiacol (2 g, 8.1 mmol), triphenylphosphine (6.4 g, 24 mmol) in tetrahydrofuran (50 mL) and To a solution of 2-chloro-1-phenylethanol (3.78 g, 24 mmol) was added diisopropyl azodicarboxylate (4.8 g, 24 mmol) slowly. The reaction was stirred at room temperature for 2 hours. Tetrahydrofuran was removed under vacuum. Chromatography (20% ethyl acetate-hexane) gave 3.30 g (78%) of the product as a clear oil. MS EI m / e 262 (M ^<+> ).

Intermediate 51 3- (5-Fluoro-1H-indol-3-yl in 5-fluoro-3- (3-p-toluenesulfonyloxypropyl) indole pyridine (15.0 mL)
) -Propan-1-ol (2.90 g, 15.0 mmol) was added to a stirred solution at room temperature.
-Toluenesulfonyl chloride (7.1 g, 37.5 mmol) was added. After stirring at room temperature for 30 minutes, the reaction mixture was poured into 200 mL of ice water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with 1N HCl and brine. The resulting material was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum.
The crude product is subjected to silica gel column chromatography (ethyl acetate / hexane, 3/7)
To give 4.1 g (79%) of the title compound as a solid. 74 ° C (
Literature melting point 99 ° C; EP 464604 A2).

Intermediate 52 2- (2-Methoxy-phenoxy) propionitrile To a solution of guaiacol (5 g, 0.04 mol) in anhydrous N, N-dimethylformamide (20 mL) was added sodium hydride (1.16 g). , 0.048 mol). The mixture was stirred at room temperature for 0.5 hour before 2-bromopropionitrile (8.09).
g, 0.06 mol). The mixture was stirred at room temperature for 4 hours and quenched with water (20 mL). The mixture was extracted with methylene chloride (3 × 100 mL), washed with water (3 × 100 mL), the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. Chromatography (20% ethyl acetate-hexane) provided 3.91 g (55%) of the product as a clear oil. MS EI m / e 177 (M ⁺ )
.

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

Example 1 [3- (1H-Indol-3-yl) -propyl]-[2- (2-methoxy-phenoxy) -ethyl] -amine Benzyl- [3- (1H-indole-ethyl) -amine in ethanol 3-yl) -propyl]-[
2- (2-methoxy-phenoxy) -ethyl] amine (2 g, 4.7 mmol) and 5%
The palladium / carbon mixture was hydrogenated for 20 hours. The catalyst was filtered off and the solvent was removed under vacuum. Chromatography (ethyl acetate-hexane-methanol-aqueous ammonia: 4/4/1/1) gave 0.79 g (52%) of the product as a white solid. Melting point 101-102 [deg.] C. Fumarate was prepared in ethanol. 130-130.5 ° C. Elemental analysis (as _{C 20 H 24 N 2 O 2} · C 4 H 4 O 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 benzyl- [4- Hydrogenation of (1H-indol-3-yl) -butyl]-[2- (2-methoxy-phenoxy) -ethyl] -amine afforded 0.79 g (100%) of the product as a clear oil. Was. The oxalate was prepared from isopropanol. Melting point 167-
168 ° C. Elemental analysis (as _{C 20 H 24 N 2 O 2} · C 4 H 4 O 4): 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 [3- (5-Fluoro) in ethanol -1H-Indol-3-yl) -propyl
A mixture of]-[2- (2-methoxy-phenoxy) -ethyl] -benzylamine (0.94 g, 2.2 mmol) and 10% palladium on carbon (250 mg) was hydrogenated for 20 hours. The catalyst was filtered off and the solvent was removed under vacuum. Chromatography (10% ethyl acetate-methylene chloride) provided 0.63 g (85%) of the product as an off-white solid. 125-126 ° C. The oxalate was prepared in isopropanol. 146-149 ° C. Elemental analysis (as _{C 20 H 23 FN 2 O 2} · C 2 H 2 O 4 · 0.5H 2 O): Calculated: C, 59.85; H, 5.94 ; N, 6.35 Found Values: C, 60.13; H, 5.67; N, 6.10

Example 3 [3- (5-Fluoro-1H-indol-3-yl) propyl]-[2- (5-fluoro-2
-Methoxy-phenoxy) -ethyl] -amine 2- (5-Fluoro-2-methoxy-phenoxy) ethyl chloride (0.3 g, 1.5 mmol) and 3- (5-fluoro-) in dimethyl sulfoxide (20 mL). A solution of 1 H-indol-3-yl) propylamine (0.56 g, 2.9 mmol) was added to 9
Stirred at 0 ° C. for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) provided 0.39 g (77%) of the product as an off-white solid. 119-122 ° C. Oxalate was prepared in ethanol. Melting point 175-177 [deg.] C. Elemental analysis (as _{C 20 H 22 F 2 N 2} O 2 · C 2 H 2 O 4): Calculated: C, 58.66; H, 5.57 ; N, 6.22 Found: C, 58.29; H, 5.25; N, 6.07 [2- (5-Fluoro-1H-indol-3-yl) ethyl]-[2- (5-fluoro-2-methoxy-phenoxy) -ethyl ] -Amine (3b) 2- (5-Fluoro-2-methoxy-phenoxy) ethylamine (0.51 g, 2.8 mmol) in dimethylsulfoxide (20 mL), 2- (5-fluoro-1H-indole-3 A solution of -yl) ethyl chloride (0.44 g, 1.8 mmol) and triethylamine (0.29 g, 3 mmol) was stirred at 90 ° C for 8 hours. The reaction mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate, filtered,
The solvent was removed under vacuum. Chromatography (5% methanol-methylene chloride) provided 0.27 g (43%) of the product as a brown oil. Oxalate was prepared in ethanol. 185-188 ° C. Elemental analysis results (as C ₁₉ H ₂₀ F ₂ N ₂ O ₂ .C ₂ H ₂ O 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-1H-indol-3-yl) ethyl]-[2- (5-fluoro-2-methoxy-phenoxy) -ethyl] -amine in dimethyl sulfoxide (20 mL) 2- (5-Fluoro-2-methoxy-phenoxy) ethylamine (0.41 g, 2.2 mmol) and 3- (2-bromoethyl
) A solution of indole (0.25 g, 1.1 mmol) was stirred at 90 ° C for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate,
Filter and remove the solvent under vacuum. Chromatography (10% methanol-methylene chloride) provided 0.15 g (34%) of the product as a brown oil. Oxalate was prepared in ethanol. Melting point 188-189 [deg.] C. Elemental analysis results (C ₁₉ H ₂₁ FN ₂ O ₂ · C ₂ H ₂ O ₄ · 0.25 H ₂ O): 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- (1H-indole-4-yloxy) -ethyl] -amine in dimethyl sulfoxide (20 mL) A solution of 2- (1H-indol-4-yl) ethyl chloride (0.7 g, 3.6 mmol) and 5-fluoro-indolyl-3-propylamine (1.0 g, 5.4 mmol) was added at 90 ° C. Stir for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (5% to 10% methanol-methylene chloride) gave 0.54 g (43%) of the product as a white solid. 70-73 ° C. Oxalate was prepared in ethanol. 183.5-185 [deg.] C. Elemental analysis result (C ₂₁ H ₂₂ FN ₃ O · C ₂ H ₂ O ₄ ): 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 Is 2- (1H-indol-4-yloxy) ethyl chloride and 3
Prepared as an off-white solid in 65% yield using -indolyl-propylamine as described in Example 5 above. 109-111 ° C. The oxalate was prepared in isopropanol. 20.5-202 ° C. Elemental analysis _{(C 21 H 23 N 3 O} · C 2 H 2 O 4 to): Calculated: C, 65.19; H, 5.95 ; N, 9.92 Found: C, 64. 89; H, 6.00; N, 9.81 [3- (1H-indol-3-yl) butyl]-[2- (1H-indol-4-yloxy) ethyl] amine (5c) 2,2- (1H-indol-4-yloxy) ethyl chloride and 3
Prepared using -indolyl-butylamine as an off-white solid in 43% yield as described in Example 5 above. 70-73 ° C. Oxalate was prepared in ethanol. 183.5-185 [deg.] C. Elemental analysis _{(C 22 H 25 N 3 O} · C 2 H 2 O 4 to): 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-
(1H-Indol-3-yl) -ethyl] amine 2- (2,3-dihydrobenzo [1,4] dioxin-5-yloxy) ethylamine (0.38 g, 1.9) in anhydrous dimethyl sulfoxide (20 mL). Mmol), 3- (2-bromoethyl) -indole (0.24 g, 1.1 mmol) and triethylamine (0.22 g, 2.2 mmol) were stirred at 90 ° C. for 14 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate, filtered,
The solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride + aqueous ammonia) gave 0.19 g (52%) as a yellow oil. Oxalate was prepared in ethanol. 197.5-198.5 ° C. Elemental analysis _{(C 20 H 22 N 2 O} 3 · C 2 H 2 O 4 to): 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-1H-indol-3-yl) -propyl] -amine 5- (2-chloroethoxy)-(2 in anhydrous dimethyl sulfoxide (20 mL)
, 3) -Dihydrobenzo [1,4] dioxane (0.75 g, 3.5 mmol), 3- (5-fluoro-1H-indol-3-yl) -propylamine (1.0 g, 5.2 mmol) )
And a solution of triethylamine (0.35 g, 3.5 mmol) was stirred at 100 ° C. for 14 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (5% to 10% methanol-methylene chloride + aqueous ammonia) gave 0.10 g (52%) of the product as a yellow oil. The fumarate was prepared in isopropanol. 189.5-190.5 ° C
. Elemental analysis results (as C ₂₁ H ₂₃ FN ₂ O ₃ .0.5C ₄ H ₄ O ₄ .0.5H ₂ O): Calculated: C, 64.74; H, 5.88; N, 6. 54 found: C, 64.01; H, 5.95; N, 6.36.

Example 8 [2- (6-Fluorochroman-8-yloxy) ethyl]-[2- (1H-indole-3
-Yl) ethyl] -amine 2- (6-fluorochroman-8 in anhydrous dimethylsulfoxide (20 mL)
A solution of -yloxy) ethyl chloride (0.41 g, 2.2 mmol), 3- (2-bromoethyl) indole (0.25 g, 1.1 mmol) and triethylamine (0.23 g, 2.2 mmol) was prepared. Stirred at 90 ° C. for 12 hours. Mixture with water (100 mL)
And extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride + aqueous ammonia) gave 0.15 g (34%) of the product as a yellow oil. Oxalate was prepared in ethanol. 213-214 ° C. Elemental analysis results (as C ₂₁ H ₂₃ FN ₂ O ₂ .C ₂ H ₂ O ₄ ): 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-1H-indole-3-yl) propyl] -amine (9a) Anhydrous dimethyl sulfoxide (20 mL )) In 2- (6-fluorochroman-8)
-Yloxy) ethyl chloride (0.25 g, 7.1 mmol), 3- (5-fluoro-1
A solution of H-indol-3-yl) -propylamine (0.42 g, 2.2 mmol) and triethylamine (0.22 g, 2.2 mmol) was stirred at 90 ° C for 14 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride + aqueous ammonia) provided 0.25 g (60%) of the product as a white solid. 137-138.5 ° C. The oxalate was prepared in isopropanol. Melting point 214-215 [deg.] C. Elemental analysis (as _{C 22 H 24 F 2 N 2} O 2 · 1.5C 2 H 2 O 4): 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-indole-3-yl) ethyl ] -Amine (9b) 2- (6-Fluorochroman-8 in anhydrous dimethylsulfoxide (20 mL)
-Yloxy) ethyl chloride (0.26 g, 1.1 mmol), 2- (5-fluoro-1
A solution of H-indol-3-yl) -ethylamine (0.45 g, 2.1 mmol) and triethylamine (0.30 mL, 2.1 mmol) was stirred at 90 ° C for 14 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride + aqueous ammonia) gave 0.19 g (48%) of the product as a yellow oil. Oxalate was prepared in ethanol. 201-203 ° C. Elemental analysis results (as C ₂₁ H ₂₂ F ₂ N ₂ O ₂ .C ₂ H ₂ O 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
-1H-Indol-3-yl) propyl] amine 2- (2,3-dihydrobenzofuran-7-yloxy) ethyl chloride (0.38 g, 1.9 mmol) in anhydrous DMSO (20 mL), 3- (5 A solution of -fluoro-1H-indol-3-yl) propylamine (0.93 g, 4.8 mmol) and triethylamine (0.48 g, 4.8 mmol) was stirred at 90 ° C for 12 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 150 mL), dried over anhydrous sodium sulfate, filtered,
The solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride + aqueous ammonia) gave 0.52 g (77%) of the product as a yellow oil. Oxalate was prepared in ethanol. 158-160 ° C. Elemental analysis results (as C ₂₁ H ₂₃ FN ₂ O ₂ .C ₂ H ₂ O ₄ ): 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-yloxy) ethyl]-[3- (5-fluoro-1H-indol-3-yl) propyl] amine 2- (benzofuran- in anhydrous DMSO (20 mL) 7-yloxy) -ethyl chloride (0.58 g, 2.9 mmol), 3- (5-fluoro-1H-indol-3-yl) propylamine (1.4 g, 7.4 mmol) and triethylamine (0.5 mmol). (74 g, 7.4 mmol) was stirred at 90 ° C. for 12 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 ×
(150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (7% methanol-methylene chloride) provided 0.31 g (30%) of the product as a light brown oil. The oxalate was prepared in THF. Melting point 181-183C. Elemental analysis results (as C ₂₁ H ₂₁ FN ₂ O ₂ .C ₂ H ₂ O ₄ ): 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-1H-indol-3-yl) ethyl] -amine Anhydrous 2- (5-Fluoro-2,3-dihydrofuran-7-yloxy) ethylamine (0.40 g, 2.1 mmol) in dimethylsulfoxide (20 mL), 2- (5-
Fluoro-1H-indol-3-yl) -ethylamine (0.25 g, 1.0 mmol)
And a solution of triethylamine (0.29 mL, 2.1 mmol) was stirred at 90 ° C. for 14 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (5% methanol-methylene chloride + aqueous ammonia) provided 0.2 g (54%) of the product as a yellow oil. Oxalate was prepared in ethanol. Mp 209.5-210.5 ° C. Elemental analysis (as _{C 20 H 20 F 2 N 2} O 2 · 1.5C 2 H 2 O 4): 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-1H-indol-3-yl) -propyl]-[2- (indan-4-yloxy) -ethyl] -amine (13a) Anhydrous dimethylsulfoxide (20 mL) 2- (Indan-4-yloxy)
) -Ethyl chloride (0.58 g, 2.9 mmol), 3- (5-fluoro-1H-indole-3-yl) -propylamine (1.4 g, 7.4 mmol) and triethylamine (1 mL, (7.4 mmol) was stirred at 90 ° C. for 12 hours. Mix the water (1
00 mL) and extracted with methylene chloride (3 × 100 mL). Organic layer with water (
(3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. Chromatography (7% methanol-methylene chloride) provided 0.31 g (30%) of the product as a brown oil. The oxalate was prepared in tetrahydrofuran. 220-222 ° C. Elemental analysis (as _{C 22 H 25 FN 2 O ·} C 2 H 2 O 4): Calculated: C, 65.10; H, 6.15 ; N, 6.33 Found: C, 64.74 H, 6.14; N, 6.11 [3- (5-fluoro-1H-indol-3-yl) -propyl]-[2- (5,6,7,8-tetrahydro-naphthalene-1- Yloxy) -ethyl] -amine (13b) This compound converts 2- (indan-4-yloxy) -ethyl chloride to 2- (5,6,7
By replacing with 8,8-tetrahydronaphthalen-1-yloxy) -ethyl chloride (0.6 g, 2.8 mmol), the yield was 29% (0%) as a yellow oil as described in Example 13 above. .3g). Fumarate was prepared in ethanol. 203-205 ° C. Elemental analysis results (as C ₂₃ H ₂₇ FN ₂ O · 0.5C ₄ H ₄ O ₄ ): 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 converts 2- (indan-4-yloxy) -ethyl chloride to 2- (naphthalen-1-yloxy) -ethyl chloride (0.6 g, 2.8 mmol) and , 3- (5
By replacing 3-fluoro-1H-indol-3-yl) -propylamine with 3- (1H-indol-3-yl) -propylamine (1.35 g, 7.2 mmol), As described, 85% yield (1.42) as a yellow solid.
g). 119-120 ° C. Fumarate was prepared in ethanol. 203-205 ° C. Elemental analysis (as _{C 23 H 24 N 2 O ·} 0.5C 4 H 4 O 4 · 0.25H 2 O): Calculated: C, 73.78; H, 6.56 ; N, 6.88 Found: C, 73.74; H, 6.47; N, 6.89 [3- (1H-indol-3-yl) -propyl]-[2-phenoxy-ethyl] -amine (
13d) This compound was described in Example 13 above by replacing 2- (naphthalen-1-yloxy) -ethyl chloride with 2-phenoxy-ethyl chloride (0.59 g, 3.8 mmol). As a yellow oil, the yield was 100% (1.08 g).
). Fumarate was prepared in ethanol. 203-205 ° C. Elemental analysis (as _{C 19 H 22 N 2 O ·} C 4 H 4 O 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-1H-indol-3-yloxy) -propyl]-[2- (indan-5-yloxy) -ethyl] -amine in anhydrous dimethylsulfoxide (20 mL) 2- (indan-5-yloxy)
) -Ethyl chloride (0.7 g, 3.5 mmol), 3- (5-fluoro-1H-indol-3-yl) -propylamine (1.01 g, 5.3 mmol) and triethylamine (0.53 g) , 5 mmol) was stirred at 90 ° C. for 12 hours. Mix the water (1
00 mL) and extracted with methylene chloride (3 × 100 mL). Organic layer with water (
(3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. Chromatography (5-10% methanol-methylene chloride) provided 0.53 g (43%) of the product as a yellow oil. Oxalate was prepared in ethanol. Melting point 179-180 [deg.] C. Elemental analysis (as _{C 22 H 25 FN 2 O ·} 0.5C 4 H 4 O 4): Calculated: C, 69.46; H, 6.68 ; N, 6.75 Found: C, 69 .19; H, 6.67; N, 6.72

Example 15 [3- (1H-Indol-3-yl) -propyl]-[2- (quinolin-8-yl) ethyl]-
Amine (2-Hydroxy-ethyl)-[3- (1H) in tetrahydrofuran (50 mL)
-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 a solution of diisopropyl azodicarboxylate (0.55 g, 2 mmol). (0.7 mmol). The reaction was stirred at room temperature for 3 hours. Tetrahydrofuran was removed under vacuum. Chromatography
(5% methanol-methylene chloride) gave a yellow solid. This was dissolved in methylene chloride (30 mL). To this solution was added a trifluoroacetic acid solution (4 mL in 10 mL of methylene chloride). The reaction mixture was stirred at room temperature for 2 hours. The mixture was then quenched with saturated sodium carbonate solution and methylene chloride (3 × 100 mL)
Extracted. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. Chromatography (10-15% methanol-methylene chloride + aqueous ammonia) gave 0.17 g (18%) of the product as a light yellow oil. The HCl salt was prepared in ethyl acetate. 83-86 ° C. Elemental analysis (as _{C 22 H 23 N 3 O ·} HCl · 1.25H 2 O): 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-1H-indol-3-yloxy) -propyl]-[2- (methoxy-phenoxy) -2-phenyl-ethyl] -amine Anhydrous dimethyl sulfoxide (20 mL) 2- (2-methoxy-phenoxy)
) -2-Phenyl-ethyl chloride (0.71 g, 2.7 mmol), 2- (5-fluoro-
A solution of 1H-indol-3-yl) -ethylamine (1.04 g, 5.4 mmol) and triethylamine (0.75 g, 5.4 mmol) was stirred at 90 ° C. for 12 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (7% methanol-methylene chloride + aqueous ammonia) gave 0.15 g (13%) of the product as a yellow oil. Citrate was prepared in ethyl ether. 64.5-67 ° C. Elemental analysis (as _{C 20 H 20 F 2 N 2} O 2 · C 6 H 8 O 7 · 1.5H 2 O): 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-1H-indol-3-yl) -propyl]-[2- (2-methoxy-phenoxy) propyl] amine 2- (in anhydrous dimethylsulfoxide (20 mL) 2-methoxy-phenoxy
) Propylamine (0.26 g, 1.2 mmol), 5-fluoro-3- (3-p-toluenesulfonyloxypropyl) indole (0.26 g, 0.81 mmol) and triethylamine (0.13 g, (0.2 mmol) was stirred at 90 ° C. for 8 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3 × 100 mL). The organic layer was washed with water (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride + aqueous ammonia) provided 0.1 g (36%) of the product as a yellow oil. Oxalate was prepared in 1-propanol. 143-146 ° C. Elemental analysis (as _{C 20 H 20 F 2 N 2} O 2 · C 2 H 2 O 4 · H 2 O): Calculated: C, 59.47; H, 6.29 ; N, 6.03 Found Values: C, 59.34; H, 5.87; N, 5.96

The activity of the compounds of the invention is demonstrated by the following standard pharmacological tests.

PCR cloning of the human 5-HT _1A receptor subtype from a human genomic library has already been reported by Chanda et al. [Molecular.
Pharmacology ( Mol. Pharmacol. ), 43: 516 (1993)]. Through this study, we adopted the human 5-HT _1A receptor stable Chinese hamster ovary fine vesicular systems expressing subtype (5-HT _1A .CHO cells). Cells were maintained in DMEM supplemented with 10% fetal calf serum, non-essential amino acids and penicillin / streptomycin.

After growing the cells as a monolayer to 95-100% confluence, the membrane was harvested for binding studies. Gently scrape cells from culture plate, transfer to centrifuge tube,
Centrifuge in buffer (50 mM Tris; pH 7.5) (2000 rpm for 10 minutes,
(4 ° C.). The resulting pellet was aliquoted and stored at -80 ° C. On the day of the assay, cells were thawed on ice and resuspended in buffer. [ ³ H] 8-OH
Studies were performed using -DPAT as radioligand. Binding assays were performed in a 96-well microtiter plate with a final total volume of buffer of 250 μL. Competition experiments were performed using seven concentrations of unlabeled drug and a final ligand concentration of 1.5 nM. Non-specific binding was determined in the presence of 10 μM 5-HT. Saturation analysis was performed using [ ³ H] 8-OH-DPAT at concentrations ranging from 0.3 to 30 nM. After incubation at room temperature for 30 minutes, ice-cold buffer was added and the M-96 Brandel cell harvester (Gaithersburg) was added.
), Maryland), the reaction was stopped by rapid filtration through a GF / B filter presoaked in 0.5% polyethyleneimine for 30 minutes.

[0099] Chisamu (Cheetham) that used by al [neuro Pharmacology, 32 (Neu rophamacol.): 737 (1993)] using a similar protocol was measured affinity of a compound for serotonin transformer Porter . Briefly, frontal cortical membranes prepared from male Sprague-Dawley rats were incubated with ³ H-paroxetine (0.1 nM) at 25 ° C. for 60 minutes. All tubes also contained either excipients, test compounds (1-8 concentrations), or saturating concentrations of fluoxetine (10 μM) that defined specific binding. After stopping all reactions by adding ice-cold Tris buffer, the conjugate was separated from free ³ H-paroxetine by rapid filtration using a Tom Tech filtration device. The radioactivity of the conjugate was measured using Wallac 120
Quantification was performed using a 5 Beta Plate ^R counter. IC ₅₀ values were determined using non-linear regression analysis. This is the case for Cheng and Prusoff
[Biochemical Pharmacol. , 22: 3099 (19
73)]; Ki = IC50 / ((radioligand concentration) / (1 + KD)).

[ ³⁵ S] -GTPγS binding assays were performed on Lazareno and Birdsall (
Birdsall) [British Journal of Pharmacology ( Br. J. Pharmacol. ), 109: 1120 (1993)]. Briefly, membrane fragments of the 5-HT _1A cloned receptor (used in the 5-HT _1A receptor binding assay) were stored at -70 ° C until needed. When needed, the membrane was quickly thawed, centrifuged at 40,000 × g for 10 minutes, and assay buffer (25 mM HEPES, 3 mM MgCl ₂ , 100 mM NaCl, 1 mM EDTA, 10 μM GDP, 500 mM DTT, pH 8). .0) at 4 ° C for 10 minutes. These membranes were then added to [ ³⁵ S] GTPγS (1 nM) in the presence of excipients, test compounds (1-8 concentrations), or an excess of 8-OH-DPAT that defined maximal agonist response.
For 30 minutes at 30 ° C. By adding ice-cold Tris buffer, after all the reaction was stopped, filtered hastily have use a filtration apparatus Tom Tech (Tom Tech ^R), the binding ^[35 S] GTPγS from the free compound separation did. Agonists increase the amount of [ ³⁵ S] GTPγS bound, whereas antagonists do not. Bound radioactivity was counted and analyzed as described above.

The following assay was performed using 25 mM HEPES, 5 mM theophylline (theo
phylline) and DMEM containing 10 μM pargyline.
Performed by incubating at 20 ° C. for 20 minutes. Functional activity was assayed by treating cells with forskolin (final concentration 1 μM) followed immediately by treatment with test compounds (six concentrations) at 37 ° C. for an additional 10 minutes. In separate experiments, six concentrations of antagonist were pre-incubated for 20 minutes before adding 10 nM 8-OH-DPAT and forskolin. The reaction was stopped by removing the medium and adding 0.5 mL of ice-cold assay buffer. Plates were stored at −20 ° C. before assessing cAMP formation by the cAMP SPA assay (Amersham).

The compounds tested correspond to the compounds prepared in Examples 1 to 17 above. Table 1 shows the results of this method.

[0103]

[Table 1]

As shown by the above results, the compounds of the present invention are active on the 5-HT _1A receptor and generally inhibit serotonin levels by inhibiting 5-HT transport. To rise. Thus, the compounds of the present invention should be useful in treating disorders associated with deficient serotonin levels.

The compounds of the present invention may be administered orally or parenterally, as such, or in combination with conventional pharmaceutical carriers. Applicable solid carriers include one or more of which can also act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, flow agent, compression aid, binder, or tablet disintegrant. The above substances or encapsulating materials can be mentioned. In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Any solid carrier known to those skilled in the art may be used with the compounds of the present invention. Particularly suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose,
Methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs of the compounds of the invention. The compounds of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. Liquid carriers include other agents such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavors, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers or osmotic pressure regulators. Can be included. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly as described above with additives such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (monohydric alcohols and polyhydric alcohols). Alcohol, for example
Glycols and derivatives thereof, and oils such as fractionated coconut and peanut oils. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used to prepare compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The composition for oral administration may be in the form of a liquid or solid composition.

Preferably, the pharmaceutical compositions containing the compounds of the present invention are in unit dosage form, for example, as tablets or capsules. In such form, the composition is subdivided into unit doses containing appropriate quantities of a compound of the present invention. The unit dosage form can be a packaged composition, for example, packeted powders, vials, ampoules, filled syringes or liquid sachets. Alternatively, the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The therapeutically effective amount of the compound of the present invention and the dosage regimen to be administered include patient weight, age, gender and treatment status, disease severity, route and frequency of administration, and the particular compound employed. Depends on various factors and can therefore vary widely.
However, it is envisaged that the above pharmaceutical compositions may contain a compound of the present invention in a range of about 0.1 to about 2000 mg, preferably about 0.5 to about 500 mg, more preferably about 1 to about 100 mg. It is. The planned daily dose of the active compound is about 0.01 to about 100 mg / kg body weight. The daily dose can conveniently be administered 2 to 4 times a day.

The present invention may be embodied in other specific forms without departing from its spirit and essential attributes, and thus is intended to indicate the scope of this invention rather than the foregoing specification. Reference should be made to the appended claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) C07D 209/36 C07D 209/36 401/12 401/12 405/12 405/12 (81) Designated country EP ( AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE , DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Darhoy Chou United States 08904 Highland Park, NJ Donaldson Street 807 B-number F-term (reference) CC14 CC76 CC79 CC82 DD06 EE01 4C086 AA03 BA05 BA08 BA15 BC13 BC28 GA07 MA01 MA04 NA14 ZA12 4C204 CB03 DB13 EB01 FB01 GB01 GB11

Claims (23)

[Claims] 1. The formula: embedded image Wherein R ₁ 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 with the carbon atom to which they are attached, form a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl, dihydrofuranyl, furanyl, dioxanyl, oxazolyl or isoxazolyl group; Z is hydrogen, halogen, Or lower alkoxy; provided that when X, Y or Z represents lower alkoxy, they are not in the ortho position; W is hydrogen, halogen, lower alkyl, cyano or trifluoromethyl;
And n is a compound represented by the formula 2 to 5] or a pharmaceutically acceptable salt thereof. 2. R ₁ is hydrogen, methyl or aryl; R ₂ is hydrogen; X and Y are each independently hydrogen, halogen or lower alkoxy, or together with the carbon atom to which they are attached. To form a cyclopentyl, cyclohexyl, phenyl, pyridinyl, dioxanyl, oxazolyl, furanyl or dihydrofuranyl group; wherein Z is hydrogen, halogen or lower alkoxy; provided that when X, Y or Z represents lower alkoxy, 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is hydrogen or halogen; and n is 2-4. 3. The compound according to claim 1, which is [3- (5-fluoro-1H-indol-3-yl) -propyl]-[2- (1H-indol-4-yloxy) -ethyl] -amine. Compound. 4. The compound according to claim 1, which is [2- (1H-indol-4-yloxy) ethyl]-[3- (1H-indole-3-yl) -propyl] -amine. 5. The compound according to claim 1, which is [3- (1H-indol-3-yl) -butyl]-[2- (1H-indol-4-yloxy) -ethyl] -amine. 6. A [2- (2,3-dihydro-benzo [1,4] dioxin-5-yloxy) -ethyl]-[2- (1H-indol-3-yl) -ethyl] -amine. Certain claim 1
A compound as described. 7. [2- (2,3-Dihydro-benzo [1,4] dioxin-5-yloxy) -ethyl]-[3- (5-fluoro-1H-indol-3-yl) -propyl The compound according to claim 1, which is a] -amine. 8. The compound according to claim 1, which is [2- (6-fluorochroman-8-yloxy) -ethyl]-[2- (1H-indol-3-yl) -ethyl] -amine. 9. The method according to claim 1, which is [2- (6-fluorochroman-8-yloxy) -ethyl]-[3- (5-fluoro-1H-indol-3-yl) -propyl] -amine. Compound. 10. [2- (6-Fluorochroman-8-yloxy) -ethyl]-[2-
The compound according to claim 1, which is (5-fluoro-1H-indol-3-yl) -ethyl] -amine. 11. The compound of the present invention is [2- (2,3-dihydro-benzofuran-7-yloxy) -ethyl]-[3- (5-fluoro-1H-indol-3-yl) -propyl] -amine. 2. The compound according to 1. 12. The compound according to claim 1, which is [2- (benzofuran-7-yloxy) -ethyl]-[3- (5-fluoro-1H-indol-3-yl) -propyl] -amine. 13. [2- (5-Fluoro-2,3-dihydro-benzofuran-7-yloxy) -ethyl]-[2- (5-fluoro-1H-indol-3-yl) -ethyl] -amine The compound according to claim 1, which is 14. [3- (5-Fluoro-1H-indol-3-yl) -propyl]-
The compound according to claim 1, which is [2- (indan-4-yloxy) -ethyl] -amine. 15. [3- (5-Fluoro-1H-indol-3-yl) -propyl]-
The compound according to claim 1, which is [2- (5,6,7,8-tetrahydro-naphthalen-1-yloxy) -ethyl] -amine. 16. The compound according to claim 1, which is [3- (1H-indol-3-yl) -propyl]-[2- (naphthalen-1-yloxy) -ethyl] amine. 17. The compound according to claim 1, which is [3- (1H-indol-3-yl) -propyl]-(2-phenoxy-ethyl] -amine. 18. The compound according to claim 1, which is [3- (5-fluoro-1H-indol-3-yloxy) -propyl]-[2- (indan-5-yloxy) -ethyl] -amine. . 19. The compound according to claim 1, which is [3- (1H-indol-3-yl) -propyl]-[2- (quinolin-8-yloxy) -ethyl] -amine. 20. [3- (5-Fluoro-1H-indol-3-yl) -propyl]-
The compound according to claim 1, which is [2- (2-methoxy-phenoxy) -2-phenyl-ethyl] -amine. 21. [3- (5-Fluoro-1H-indol-3-yl) -propyl]-
The compound according to claim 1, which is [2- (2-methoxy-phenoxy) -propyl] amine. 22. The formula: Wherein R ₁ 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 with the carbon atom to which they are attached, form a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl, dihydrofuranyl, furanyl, dioxanyl, oxazolyl or isoxazolyl group; Z is hydrogen, halogen, Or lower alkoxy; provided that when X, Y or Z represents lower alkoxy, they are not in the ortho position; W is hydrogen, halogen, lower alkyl, cyano or trifluoromethyl;
And n is a pharmaceutical composition comprising the compound represented by 2 to 5] or a pharmaceutically acceptable salt thereof. 23. A method for alleviating the symptoms of depression in a patient in need thereof, comprising the steps of: Wherein R ₁ 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 with the carbon atom to which they are attached, form a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl, dihydrofuranyl, furanyl, dioxanyl, oxazolyl or isoxazolyl group; Z is hydrogen, halogen, Or lower alkoxy; provided that when X, Y or Z represents lower alkoxy, they are not in the ortho position; W is hydrogen, halogen, lower alkyl, cyano or trifluoromethyl;
And n is a method comprising administering a compound represented by 2 to 5] or a pharmaceutically acceptable salt thereof.