CN1304403A - N-aryloxyethyl-indoly-alkylamines for treatment of depression (5-HT1A receptor active agents) - Google Patents

N-aryloxyethyl-indoly-alkylamines for treatment of depression (5-HT1A receptor active agents) Download PDF

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CN1304403A
CN1304403A CN99807013A CN99807013A CN1304403A CN 1304403 A CN1304403 A CN 1304403A CN 99807013 A CN99807013 A CN 99807013A CN 99807013 A CN99807013 A CN 99807013A CN 1304403 A CN1304403 A CN 1304403A
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R·E·穆肖
周大卉
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Wyeth LLC
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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

The N-aryloxy ethyl-indyl-alkylamine (5-HT1A receptor activator) that is used for the treatment of dysthymia disorders
Invention field
The present invention relates to be used for the treatment of because the compound of the disease that the neurological disorder that influenced by serotonin causes.More particularly, the present invention relates to can be used for treating the aryloxy ethyl-indyl-alkylamine derivative of this class disease.
Background of invention
The medicine that strengthens serotonin (5-HT) neurotransmission can be used for treating many mental disorderes, comprises dysthymia disorders and anxiety disorder.The non-selective compound that influences serotonin of the first-generation works by multiple physiological response, and this causes that this compound has many undesirable pair of effects, for example dry, blurred vision and because the sedative effect that the activity of many acceptors is caused.The compound of introducing is a selectivity serotonin reuptake inhibitors (SSRIs) recently, mainly initiatively removes from synaptic cleft by presynaptic serotonin transport vehicle by the 5-HT that is suppressed at cynapse place release and works.Because SSRIs needs several weeks before giving full play to curative effect, this 5-HT blocking mechanism can not illustrate their therapeutic activity fully.By inference, being arranged the inductive phase in two weeks before observing antidepressant curative effect completely, is owing to relate to the 5-HT1A autoreceptor that suppresses to provide the 5-HT neuronal activity, causes weakening of curative effect.Studies show that to give SSRI after several weeks that the desensitization of 5-HT autoreceptor makes and produced antidepressant curative effect completely in most patient, referring to Le Poul etc., Arch.Pharmacol., 352:141 (1995).Therefore, be sure of to strengthen and quicken 5HT1A antagonist that clinical antidepressant replys and can eliminate this negativity and feed back by using.Artigas etc., Trends Neurosci., 19:378-383, the recent research of (1996) thinks, 5-HT1A combination active and that suppress the 5-HT picked-up can reach stronger and onset antidepressant effect faster in single molecular entity.
The molecule that the present invention relates to that a new class works to the 5-HT1A autoreceptor and work with the 5-HT translocator.Therefore, this compounds might be used for the treatment of anxiety disorder or dysthymia disorders, and the treatment of other serotonin disorder.
United States Patent (USP) the 3rd, 371 discloses the second month in a season and uncle's indole amine as tranquilizer, anticonvulsive drug and anodyne for No. 098.
United States Patent (USP) the 5th, 436 discloses the following formula N-aryloxy alkyl tryptamines sample compound that is used for the treatment of cardiovascular disorder as α-1-adrenergic receptor antagonist No. 264:
Figure A9980701300071
EP 0722941 A2 discloses the preparation method who is used for the treatment of dysthymia disorders and a series of assorted-oxygen alkanamine compound of the following formula of the disease of other common use serotonin uptake inhibitors:
Figure A9980701300072
Japanese Patent 05255302 and 09040648 discloses following compound, and this compounds can be used for treatment and central nervous system diseases associated such as anxiety disorder and dysthymia disorders according to reports:
Figure A9980701300073
Summary of the invention
Compound of the present invention is aminomethyl benzoxezine benzazolyl compounds or its pharmacy acceptable salt of being represented by the formula I: Wherein: R 1Be hydrogen, low alkyl group or aryl; R 2It is the phenyl of hydrogen, low alkyl group, phenyl or replacement; Each independently is hydrogen, low alkyl group, lower alkoxy or halogen for X and Y, perhaps forms cyclopentyl, cyclohexyl, phenyl, pyrryl, pyranyl, pyridyl, dihydrofuran base, furyl, alkyl dioxin, oxazolyl Huo isoxazolyl with the carbon atom that they connected; Z is hydrogen, halogen or lower alkoxy; Condition is for when X, Y or Z represent lower alkoxy, and they do not appear at the ortho position; W is hydrogen, halogen, lower alkoxy, low alkyl group, cyano group or trifluoromethyl; With n be 2-5.
The invention still further relates to the medicinal compound that contains this compounds and comprise the method for the patient who needs this treatment compound of the present invention with alleviate depression disease.The detailed description of the invention
The preferred compound of the present invention is those compounds by the representative of formula I, wherein: R 1Be hydrogen, methyl or aryl; R 2Be hydrogen; Each independently is hydrogen, halogen or lower alkoxy for X and Y, perhaps forms cyclopentyl, cyclohexyl, phenyl, pyridyl, alkyl dioxin, oxazolyl, furyl or dihydrofuran base with the carbon atom that they connected; Z is hydrogen, halogen or lower alkoxy; Condition is for when X, Y or Z are lower alkoxy, and they do not appear at the ortho position; W is a hydrogen or halogen; With n be 2-4; Or its pharmacy acceptable salt.
The preferred compound of the present invention is selected from following compounds: [3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(1H-indoles-4-base oxygen base)-ethyl]-amine; [2-(1H-indoles-4-base oxygen base) ethyl]-[3-(1H-indol-3-yl)-propyl group]-amine; [3-(1H-indol-3-yl)-butyl]-[2-(1H-indoles-4-base oxygen base)-ethyl]-amine; [2-(2,3-dihydro-benzo [1,4] dioxin (dioxin)-5-base oxygen base)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amine; [2-(2,3-dihydro-benzo [1,4] dioxin-5-base oxygen base)-ethyl]-[3-(5-fluoro-1H-indol-3-yl)-propyl group]-amine; [2-(6-fluoro chroman-8-base oxygen base)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amine; [2-(6-fluoro chroman-8-base oxygen base) ethyl]-[3-(5-fluoro-1H indol-3-yl)-propyl group]-amine; [2-(6-fluoro chroman-8-base oxygen base)-ethyl]-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-amine; [2-(2,3-dihydro-cumarone-7-base oxygen base)-ethyl]-[3-(5-fluoro-1H-indol-3-yl)-propyl group]-amine; [2-(cumarone-7-base oxygen base)-ethyl]-[3-(5-fluoro-1H-indol-3-yl)-propyl group]-amine; [2-(5-fluoro-2,3-dihydro-7-base oxygen base)-ethyl]-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-amine; [3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(indane-4-base oxygen base)-ethyl]-amine; [3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(5,6,7,8-tetrahydrochysene-naphthalene-1-base oxygen base)-ethyl]-amine; [3-(1H-indol-3-yl)-propyl group]-[2-(naphthalene-1-base oxygen base)-ethyl]-amine; [3-(1H-indol-3-yl)-propyl group]-(2-phenoxy group-ethyl)-amine; [3-(5-fluoro-1H-indol-3-yl-oxygen base)-propyl group]-[2-(indane-5-base oxygen base)-ethyl]-amine; [3-(1H-indol-3-yl)-propyl group]-[2-(quinoline-8-base oxygen base)-ethyl]-amine; [3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(2-methoxyl group-phenoxy group)-2-phenyl-ethyl]-amine; [3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(2-methoxyl group-phenoxy group)-propyl group]-amine.
Here used term " low alkyl group " and " lower alkoxy " mean and comprise straight chain and the side chain carbochain that contains 1-6 carbon atom.Term " halogen " means and comprises fluorine, chlorine, bromine and iodine.Term " substituted-phenyl " means and comprises the phenyl moiety that replaces with alkyl, halogen or alkoxyl group.Term " aryl " means and comprises the aryl that contains 6-12 carbon atom.
Formula 1 compound can advantageously use with the form of its pharmaceutically-acceptable acid addition.The available inorganic or organic acid of this class salt (available method known to those skilled in the art preparation), for example: fumaric acid, toxilic acid, phenylformic acid, xitix, pounce on acid, succsinic acid, the dimethylene Whitfield's ointment, methylsulfonic acid, ethane disulfonic acid, acetate, oxalic acid, propionic acid, tartrate, Whitfield's ointment, citric acid, glyconic acid, lactic acid, oxysuccinic acid, the acid of bolt for fastening a door from outside peach, styracin, citraconic acid, aspartic acid, stearic acid, palmitinic acid, methylene-succinic acid, oxyacetic acid, para-amino benzoic acid, L-glutamic acid, Phenylsulfonic acid, hydrochloric acid, Hydrogen bromide, sulfuric acid, ring ethylamino sulfonic acid, phosphoric acid and nitric acid form.
The compounds of this invention can be by prepared by any suitable process well known by persons skilled in the art.Yet this compound can be advantageously according to any one preparation among the scheme 1-10 proposed below.In this scheme, the midbody compound of Tao Luning marks parenthetic hereinafter.Compound to each generation among the scheme 1-10 is determined with reference to suitable, respective embodiments.
Scheme 1 Embodiment 1 scheme 2
Figure A9980701300121
Scheme 3
Figure A9980701300131
Scheme 4
Figure A9980701300132
Scheme 5
Figure A9980701300141
Scheme 6
Figure A9980701300151
Scheme 7
Figure A9980701300161
Scheme 8 Scheme 9 Embodiment 15 schemes 10
Now, by the present invention being described with reference to following specific, unrestriced embodiment.
Intermediate 2
[2-(2-methoxyl group-phenoxy group-ethyl)]-benzyl-t-butyl carbamate
To in anhydrous tetrahydro furan (40ml), containing triphenyl phosphine (3.3g, 12.6mmol) (2-hydroxyl-ethyl)-benzyl-t-butyl carbamate (3.2g, 12.6mmol) and 2-methoxyphenol (1.0g, 8.4mmol) solution in slowly add the diisopropyl azo-2-carboxylic acid (2.5g, 12.6mmol).Reactant was stirred 18 hours, pour then that (clarifying oil is filtered and be condensed into to 3 * 80ml) washings through anhydrous magnesium sulfate drying, in the methylene dichloride (250mg) and with 1N sodium hydroxide into.This oil is dissolved in the ether (70ml), slowly adds hexane and precipitate up to triphenyl phosphine oxide.Cross filter solid and remove solvent.Obtain 2.57g (57.0%) clarifying oil: MS (EI) 358m/e (M through this dense thick oil of column chromatography (15% ethyl acetate-hexane) purifying +).C 21H 27NO 4Ultimate analysis
Calculated value: C, 70.56; H, 7.61; N, 3.92
Measured value: C, 70.27; H, 7.58; N, 4.07
Intermediate 3
[2-(2-methoxyl group-phenoxy group)-ethyl]-benzyl-amine
(18.0g slowly adds trifluoroacetic acid (60ml) to 2-in being dissolved in methylene dichloride (350ml) (2-methoxyl group-phenoxy group-ethyl)-benzyl-carboxylamine tertiary butyl ester in solution 50.4mmol).At room temperature stirred this reactant 12 hours, and poured into then in the 1N sodium hydroxide (200ml) also with methylene dichloride (3 * 150ml) extractions.(organic layer that 2 * 150ml) washings merge, (2 * 100ml) washings through anhydrous magnesium sulfate drying, are filtered solvent removed in vacuo to water then with 1N sodium hydroxide.Chromatography (5% methyl alcohol-methylene dichloride) obtains clarifying oily 12.4g (96%).C 16H 19NO 2Ultimate analysis
Calculated value: C, 74.19; H, 7.24; N, 5.54
Measured value: C, 73.91; H, 7.28; N, 5.44 prepare fumarate in ethanol: mp 121.5-122 ℃: C 16H 19NO 2C 4H 4O 4Ultimate analysis
Calculated value: C, 63.56; H, 6.27; N, 3.71
Measured value: C, 63.35; H, 6.16; N, 3.62
Intermediate 4
N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxyl group-phenoxy group)-ethyl]-propionic acid amide (4a)
Under 0 ℃, 3-indolepopionic acid (4.1g in being dissolved in methylene dichloride (80ml), 21.7mmol) and 1-(3-dimethyl-amino-propyl group)-3-ethyl-carbodiimide hydrochloride (4.4g, add [2-(2-methoxyl group-phenoxy group)-ethyl]-benzyl amine (3g, solution 11.6mmol) that is dissolved in the methylene dichloride (20ml) in solution 23mmol).After two hours, this reaction mixture is poured in the water (200ml), used methylene dichloride (2 * 50ml) extractions then.With the organic layer that 1N sodium hydroxide (50ml) washing merges, (2 * 50ml) wash water subsequently.Through the anhydrous sodium sulfate drying organic layer, filter solvent removed in vacuo.Chromatography (5% methyl alcohol-methylene dichloride) obtains 3.3g (66.0%) white solid product: mp 46.5-47.5 ℃.MS?EI?m/e?428(M +)。
N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxyl group-phenoxy group)-ethyl]-butyramide (4b)
Usefulness 3-indolebutyric acid in above (4a) (1.8g, 8.9mmol) replacement 3-indolepopionic acid obtains N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxyl group-phenoxy group)-ethyl into white foam] butyramide (1.3g; 78%) in.MS?FAB?m/e?443(M+H) +；MS?FAB?m/e?465(M+Na) +。
Intermediate 5
Benzyl-[3-(1H-indol-3-yl)-propyl group]-[2-(2-methoxyl group-phenoxy group)-ethyl] amine (5a)
At room temperature, the N-benzyl-3-in being dissolved in tetrahydrofuran (THF) (50ml) (1H-indoles-3 base)-N-[2-(2-methoxyl group-phenoxy group)-ethyl]-add lithium aluminium hydride (1.8g) in the solution of propionic acid amide.This reactant is heated to backflow reaches 12 hours, be cooled to room temperature then.With saturated ammonium chloride quencher reactant, through the diatomite filtration solid precipitation.Concentrated solvent under the vacuum through chromatography (5% methyl alcohol-methylene dichloride) purified product, obtains 2.0g (86%) yellow oil product.MSEI?m/e?414(M +)。C 27H 30N 2The O ultimate analysis
Calculated value: C, 78.23; H, 7.30; N, 6.76
Measured value: C, 77.53; H, 6.95; N, 6.90
Benzyl-[4-(1H-indol-3-yl)-butyl]-[2-(2-methoxyl group-phenoxy group)-ethyl]-amine (5b)
In (5a), use N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxyl group-phenoxy group)-ethyl]-butyramide (1.2g, 2.7mmol) replacement N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxyl group-phenoxy group)-ethyl]-propionic acid amide, obtain N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxyl group-phenoxy group)-ethyl for white oily matter]-butyramide (1.06g, 91%).MS?EIm/e?428(M +)。
Intermediate 7
5-fluoro-indyl-3-propyl bromide
To be dissolved in the methylene dichloride (156ml) according to Demerson etc., J.Med.Chem., 3-(5-fluoro-1H-indol-3-yl)-third-1-alcohol (intermediate 6) (25.4g of the method preparation that proposes among the 19:391-395 (1976), 0.13mol), carbon tetrabromide (65.5g, 0.2mol) and triphenyl phosphine (52g, 0.2mol) solution stirring is two hours.Evaporating solvent, chromatography (30% ethyl acetate-hexane) purified product obtains the product of 33.5g (99%).
Intermediate 8
5-fluoro-indyl-3-propyl group trinitride
To be dissolved in anhydrous N, the 5-fluoro-indyl in the dinethylformamide (60ml)-3-propyl bromide (10.67g, 41mmol) and sodiumazide (3.9g, solution 60mmol) stirred 18 hours down at 60 ℃.Mixture is poured in the water (150ml), with methylene dichloride (3 * 150ml) extractions, water (3 * 100ml) washings.Through the dried over sodium sulfate organic layer, filter, remove under the vacuum and desolvate.Chromatography (30% ethyl acetate-hexane) obtains the product of 8.10g (89%), is clarifying oil.C 11H 11FN 3Ultimate analysis
Calculated value: C, 60.54; H, 5.08; N, 25.67
Measured value: C, 60.62; H, 5.08; N, 25.84
Intermediate 9
5-fluoro-indyl-3-propylamine
5-fluoro-indyl-3-propyl group trinitride that will be in ethanol (8g, 0.037mol) and the hydrogenation 16 hours under 50psi of 10% beryllium palladium carbon solution.Filter out catalyzer, vacuum is gone down and is desolventized.Desolvate with removing under methyl alcohol (300ml) washing diatomite and the vacuum.Chromatography (15% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains 4.33g (61%) product, is yellow solid: mp 82-84.5 ℃.C 11H 13FN 2Ultimate analysis
Calculated value: C, 68.73; H, 6.82; N, 14.57
Measured value: C, 68.82; H, 6.85; N, 14.49
Intermediate 10
[3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(2-methoxyl group-phenoxy group)-ethyl]-benzyl amine
[2-(2-methoxyl group-phenoxy group)-ethyl]-benzyl-amine (1.0g that will be in methyl-sulphoxide (40ml), 3.9mol), 3-(5-fluoro-1H-indol-3-yl)-propylamine (1.4g, 5.8mmol) and triethylamine (0.79g, solution 7.8mmol) stirred 16 hours down at 100 ℃.This reaction mixture is poured in the water (100ml) also with methylene dichloride (3 * 100ml) extractions.(3 * 100ml) washing organic layers through anhydrous sodium sulfate drying, filter water, remove under the vacuum and desolvate.Layer folding (30% ethyl acetate-hexane) obtains 0.94g (58%) product, is yellow oil.MS?EI?m/e?432(M +)。
Intermediate 11
2-(5-fluoro-1H-indol-3-yl) ethanol
Under 0 ℃, (4.3g adds LiAIH in solution 0.022mol) to the 5-fluoro-indole-3-acetic acid in being dissolved in anhydrous THF (35ml) 4(1.0M, 33ml, 0.033mol).Stir this mixture 0.5 hour, and used saturated NH then 4The quencher of Cl solution.By this mixture of diatomite filtration.(3 * 100ml) wash this filtrate, and with ethyl acetate (3 * 100ml) extractions with the NaOH of 1N.Through this organic layer of anhydrous sodium sulfate drying, filter solvent removed in vacuo.Chromatography (10% methyl alcohol-methylene dichloride) obtains the product of 4.04g (100%), is pale solid: mp 59-61 ℃.C 10H 10The ultimate analysis of FNO
Calculated value: C, 67.03; H, 5.63; N, 7.82
Measured value: C, 66.71; H, 5.50; N, 7.74
Intermediate 12
3-(5-fluoro-1H-indol-3-yl)-monobromoethane
At room temperature, the 2-in being dissolved in methylene dichloride (50ml) (5-fluoro-1H-indol-3-yl) ethanol (4g, 22.5mmol) add in the solution carbon tetrabromide (11.2g, 34mmol), add subsequently triphenyl phosphine (8.8g, 33mmol).At room temperature stirred this reaction mixture 2.5 hours.Remove under the vacuum and desolvate.Chromatography (30% ethyl acetate-hexane) obtains the product of 5.91g (98%), is pale solid: mp 58-59 ℃.
C 10H 9The ultimate analysis of FBrN
Calculated value: C, 49.61; H, 3.75; N, 5.79
Measured value: C, 49.29; H, 3.73; N, 5.72
Intermediate 15
2-(5-fluoro-2-methoxyl group-phenoxy group) ethyl chloride
To be dissolved in the 2-butanone (60ml) according to Mancini etc., Svnth.Cormm., 5-fluoro-2-methoxyl group-phenol (4.34g of the method preparation that proposes among the 19:2001-2005 (1989), 31mmol), 1-bromo-2-ethylene dichloride (8.9ml, 107mmol) and salt of wormwood (14.8g, 106mmol) solution refluxed 24 hours.This mixture is poured in the water (150ml), with methylene dichloride (3 * 150ml) extractions and with salt solution (3 * 100ml) wash.Through the dried over sodium sulfate organic layer, filter, remove under the vacuum and desolvate.Chromatography (20% ethyl acetate-hexane) obtains the product of 4.77g (76%), is clarifying oil.C 9H 10FCIO 2Ultimate analysis
Calculated value: C, 52.83; H, 4.93
Measured value: C, 52.79; H, 4.75
Intermediate 16
2-(5-fluoro-2-methoxyl group-phenoxy group) ethyl trinitride
To be dissolved in anhydrous N, the 2-in the N-dimethylformamide (60ml) (5-fluoro-2-methoxyl group-phenoxy group) ethyl chloride (3.97g, 19mmol) and sodiumazide (2.6g, solution 39mmo1) stirred 18 hours down at 60 ℃.This mixture is poured in the water (150ml), with methylene dichloride (3 * 150ml) extractions, water (3 * 100ml) washings.Through the dried over sodium sulfate organic layer, filter, remove under the vacuum and desolvate.Chromatography (20% ethyl acetate-hexane) obtains the product of 3.75g (92%), is clarifying oil.C 9H 10FN 3O 2Ultimate analysis
Calculated value: C, 51.18; H, 4.77; N, 19.90
Measured value: C, 51.35; H, 4.71; N, 20.06
Intermediate 17
2-(5-fluoro-2-methoxyl group-phenoxy group) ethamine
To be dissolved in 2-(5-fluoro-2-methoxyl group-phenoxy group) ethyl trinitride in tetrahydrofuran (THF) (80ml) and the water (1.5ml) (3.97g, 0.019mol) and triphenyl phosphine (5.95g, solution 0.023mol) at room temperature stirred 18 hours.Remove under the vacuum and desolvate.Chromatography (ethyl acetate) is removed the product that triphenyl phosphine and triphenyl phosphine oxide and (25-50% methyl alcohol-ethyl acetate hydro-oxidation ammonium) obtain 3.14g (90%), is clarifying oil.MS?EI?m/e?185(M +)。
Intermediate 18
3-indyl-propionic acid amide (18a)
(15g, 79mmol) and 1, (16.7g, solution 100mmol) at room temperature stirred 1.5 hours 1 '-carbon back diimidazole will to be dissolved in 3-indolepopionic acid in the anhydrous tetrahydro furan (150ml).Then, at room temperature, with NH 3Feed solution foaming 2.5 hours.Remove under the vacuum and desolvate, residue is dissolved in the ethyl acetate (500ml).Water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 150ml) washing organic solutions.Collect and under vacuum drying obtain 10.42g, the white solid of (96%): mp 124-125 ℃.MS?EI?m/e?188(M +)。
3-indyl-butyramide (18b)
With the mode described in above (18a), use 3-indolebutyric acid and 1,1 '-carbonyl dimidazoles prepares this compound.Obtain yield and be 96% pale solid product; Mp 86-87 ℃.
Intermediate 19
3-indyl-propylamine (19a)
3-indyl-propionic acid amide in being dissolved in anhydrous tetrahydro furan (150ml) (5g, (1.0M is dissolved in the solution in the tetrahydrofuran (THF) 24.7mmol) slowly to add lithium aluminium hydride in the solution; 100ml).Reflux this reaction mixture 3 hours makes its quencher by adding water (4ml), 15% sodium hydroxide (4ml) and water (12ml) then under 0 ℃.Concentrate by this mixture of diatomite filtration and under vacuum.Chromatography (10% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains the product of 4.0g (86%), is white solid: mp 58-60.5 ℃.MS?EI?m/e?174(M +)。
3-indyl-butylamine (19b)
With above (19a) described mode, use 3-indyl-butyramide and lithium aluminium hydride to prepare this compound.Obtain yield and be 75% product, be yellow solid: mp 51-53 ℃.
Intermediate 20
2-(1H-indoles-4-base oxygen base) ethyl chloride
4-oxyindole in being dissolved in anhydrous tetrahydro furan (40ml) (4g, 30mmol), ethylene chlorhydrin (4.83g, 60mmol), triphenyl phosphine (15.7g, 60mmol) slowly add in the solution diisopropyl azo-2-carboxylic acid (12.1g, 60mmol).At room temperature stirred this reactant 2.5 hours, and poured into then in the methylene dichloride (250ml), water (3 * 100ml) washing and through anhydrous sodium sulfate drying.Filter this material, remove under the vacuum and desolvate.Chromatography (20% hexane-ethyl acetate) is removed triphenyl phosphine, and (20% methylene dichloride-hexane) obtains 2.94g, and (50%) product is white solid: mp69.5-72 ℃.
Intermediate 21
5-hydroxyl-(2,3)-dihydrobenzo [1,4] dioxine
Pyrogallol in being dissolved in 2-butanone (600ml) (5g, add in 0.04mol) salt of wormwood (1.82g, 0.013mol).This mixture is stirred in backflow down, and slow simultaneously dropping glycol dibromide (2.48g, 1.14ml, 0.013mol).Stir this reactant and spend the night, be cooled to room temperature then.This mixture is poured in the water (100ml) also with methylene dichloride (200ml) extraction.Through the anhydrous sodium sulfate drying organic layer, filter, remove under the vacuum and desolvate.Chromatography (5% methyl alcohol-methylene dichloride) obtains the product of 2.74g (45%), is clarifying oil.MS?EI?m/e?152(M +)。
Intermediate 22
5-(2-chloro oxyethyl group)-(2,3)-dihydrobenzo [1,4] diox
5-hydroxy benzo diox (1.0g in being dissolved in tetrahydrofuran (THF) (50ml), 6.5mmol) and ethylene chlorhydrin (0.79g, 9.9mmol), triphenylphosphine (2.6g, 9.9mmol) slowly add in the solution diethyl propyl group azido-two carbimides (diisopropyl azidodicarbimide) (DIAD) (2.0g, 9.8mmol).After 2 hours, add triphenylphosphine, DIAD and the ethylene chlorhydrin of other 1.5eq, and then stirred this mixture 2 hours.Reaction mixture is poured in the water (100ml), with methylene dichloride (100ml) extraction.Separate organic layer and through anhydrous magnesium sulfate drying.Filter this material, remove under the vacuum and desolvate.Chromatography (20% ethyl acetate-hexane) obtains the product of 1.7g (76%), is white solid: mp 70.5-72.5 ℃.C 10H 11ClO 3Ultimate analysis
Calculated value: C, 55.96; H, 5.17
Measured value: C, 55.57; H, 5.20
Intermediate 23
2-(2,3-dihydrobenzo [1,4] dioxin-5-base oxygen base) ethyl trinitride
To be dissolved in anhydrous N, the 5-in N-dimethyl-methane amide (100ml) (2-chloro oxyethyl group)-(2,3)-dihydrobenzo [1,4] diox (and 4.6g, 0.02mol) and sodiumazide (2.78g, solution 0.043mol) stirred under 60 ℃ of temperature 18 hours.This mixture is poured in the water (200ml), with methylene dichloride (3 * 100ml) extractions.(3 * 150ml) wash this organic layer to water, through anhydrous sodium sulfate drying, filter solvent removed in vacuo.Chromatography (20% ethyl acetate-hexane) obtains 3.43g (72%) product, is clarified oil: MS FAB m/e 221 (M +).
Intermediate 24
2-(2,3-dihydrobenzo [1,4]-dioxin-5-base oxygen base) ethamine
At room temperature, stir 2-(2, the basic oxygen base of 3-dihydrobenzo [1,4] dioxin-5-) the ethyl trinitride be dissolved in tetrahydrofuran (THF) (50ml) and the water (2ml) (3.43g, 0.016mol) and triphenyl phosphine (6.3g, solution 0.023mol) 18 hours.Solvent removed in vacuo.Chromatography (30% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains the product of 1.93g (62%), is yellow oily.MS?FAB?m/e196(M+H) +。
Intermediate 25
6-fluoro chroman
To be dissolved in 6-fluoro-4-benzodihydropyrone in concentrated hydrochloric acid (20ml) and the ethanol (30ml) (2g, 12mmol) and the mixture hydrogenation of 10% palladium on carbon (1g) 20 hours.Filter out catalyzer and solvent removed in vacuo.Resistates is dissolved in the ethyl acetate (100ml), with 1N NaOH (6 * 200ml) and water (3 * 150ml) washings through anhydrous sodium sulfate drying, are filtered also solvent removed in vacuo.Chromatography (20% ethyl acetate-hexane) obtains the product of 1.41g (77%), is clarifying oil: MS EI m/e 152 (M +).
Intermediate 26
6-fluoro chroman-8-aldehyde
Under 0 ℃, (0.7g 4.6mmol) slowly adds TiCI to the 6-fluoro chroman in being dissolved in anhydrous methylene chloride (20ml) in the solution 4(1.57g, 8.3mmol) and α, α '-dichloromethyl methyl ether (0.53g, 4.6mmol).Make this reactant slowly reach room temperature and stirred 16 hours.This reaction mixture is poured in the frozen water, with methylene dichloride (3 * 100ml) extractions, with saturated yellow soda ash (5 * 150ml) and salt solution (3 * 100ml) wash.Organic layer filters solvent removed in vacuo through anhydrous sodium sulfate drying.Collect the crude product solid, drying obtains the product of 0.75g (90%) under vacuum, is yellow solid: mp 55-57 ℃.
C 10H 9FO 2Ultimate analysis
Calculated value: C, 66.66; H, 5.04
Measured value: C, 66.64; H, 4.78
Intermediate 27
6-fluoro-8-hydroxychroman
Under 0 ℃, 6-fluoro chroman in being dissolved in anhydrous methylene chloride (60ml)-8-aldehyde (8.6g, 48mmol), add in 3-tertiary butyl-4-hydroxy-5-aminomethyl phenyl sulfide (100mg) solution in batches 3-chloro peroxybenzoic acid (mCPBA) (12.4g, 70mmol).Make this reaction mixture refluxed 16 hours.Make excessive mCBPA invalid by adding 10% S-WAT.Filter this phenylformic acid, with methylene dichloride (3 * 150ml) extraction filtrates and water (3 * 150ml) washings.Organic layer is through anhydrous sodium sulfate drying and filtration.Remove under the vacuum and desolvate, (10.2g 52mmol) is dissolved in the alcohol-water (200ml, 1: 1) with rough product.In above-mentioned solution, add under 0 ℃ sodium hydroxide (6.2g, 160mmol).After 30 minutes, remove ice bath, at room temperature stirred reaction mixture is 3 hours.Ethanol evaporation.Resistates neutralizes with concentrated hydrochloric acid, with methylene dichloride (3 * 150ml) extractions, with saturated sodium bicarbonate (2 * 100ml) and salt solution (2 * 100ml) wash.Organic layer filters and solvent removed in vacuo through dried over sodium sulfate.Chromatography (25% ethyl acetate-hexane) obtains the product of 6.9g (79%), is white solid: mp 62-63 ℃.
C 9H 9FO 2Ultimate analysis
Calculated value: C, 64.28; H, 5.39
Measured value: C, 64.31; H, 5.27
Intermediate 28
2-(6-fluoro chroman-8-base oxygen base) ethyl chloride
To be dissolved in 6-fluoro chroman-8-aldehyde in the 2-butanone (60ml) (5.5g, 33mmol), 1-bromo-2-ethylene dichloride (16.4g, 114mmol) and K 2CO 3(16g, 114mmol) solution refluxed 24 hours.This mixture is poured in the water (150ml), and (3 * 150ml) extractions are with salt solution (3 * 100ml) washings with methylene dichloride.Organic layer filters solvent removed in vacuo through dried over sodium sulfate.Chromatography (20% ethyl acetate-hexane) obtains the 5.74g product, is white solid: mp 89-90 ℃.C 11H 12FClO 2Ultimate analysis
Calculated value: C, 57.28; H, 5.24
Measured value: C, 57.15; H, 5.69
Intermediate 29
2-(6-fluoro chroman-8-base oxygen base) ethyl trinitride
To be dissolved in 2-in the dry DMF (60ml) (6-fluoro chroman-8-base oxygen base) ethyl chloride (4.13g, 0.018mol) and sodiumazide (2.33g, 0.036mol) solution is 60 ℃ of stirrings 18 hours down.This mixture is poured in the water (150ml), with methylene dichloride (3 * 150ml) extractions and water (3 * 100ml) washings.Organic layer filters solvent removed in vacuo through dried over sodium sulfate.Chromatography (20% ethyl acetate-hexane) obtains 4.12g (97%) product, is clarified oil.C 11H 12FN 3O 2Ultimate analysis
Calculated value: C, 55.69; H, 5.10; N, 17.71
Measured value: C, 55.44; H, 4.97; N, 17.88
Intermediate 30
2-(6-fluoro chroman-8-base oxygen base) ethamine
Under room temperature, will be dissolved in 2-in tetrahydrofuran (THF) (80ml) and the water (1.5ml) (6-fluoro chroman-8-base oxygen base) ethyl trinitride (4.12g, 0.017mol) and triphenyl phosphine (6.83g, solution stirring 0.026mol) 18 hours.Solvent removed in vacuo.Chromatography (ethyl acetate) is removed the product that triphenyl phosphine and triphenyl phosphine oxide and (40% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtain 3.45g (94%), is white solid: mp 68-70 ℃.C 11H 14FNO 2Ultimate analysis
Calculated value: C, 62.55; H, 6.68; N6.63
Measured value: C, 62.18; H, 6.54; N, 6.63
Intermediate 31
7-methoxyl group benzo furans
To be dissolved in 7-methoxyl group-2-benzofurancarboxylic acid in the quinoline (30ml) (5g, 0.026mol) and the heating 2 hours under refluxing of the solution of copper (0.2g).With this mixture process diatomite filtration.Diatomite washs with ethyl acetate.Solvent removed in vacuo.The product that chromatography (25% ethyl acetate-hexane) obtains 2.45g (64%) is a yellow oil: MS EI m/e 148 (M +).
Intermediate 32
The 7-hydroxyl benzofuran
(1g 6.7mmol) is dissolved in and is contained at the bottom of the 100ml garden in the anhydrous methylene chloride (25ml) in the flask with 7-methoxyl group benzo furans.Flask is placed-78 ℃ of acetone ice baths.This flask is equipped with atmospheric condenser.(1M is 10ml) in the solution of this stirring carefully to add the boron tribromide solution that is dissolved in the methylene dichloride through condenser.This reactant was placed 6 hours down at-78 ℃, at room temperature stirred then and spend the night.Through adding entry (20ml) quencher reaction and diluting with ether.Solvent removed in vacuo.The product that chromatography (25% ethyl acetate-hexane) obtains 0.47g (52%) is bright brown oil: MS EI m/e 134 (M +).
Intermediate 33
2-(cumarone-7-base oxygen base)-ethyl chloride
7-hydroxyl benzofuran in being dissolved in tetrahydrofuran (THF) (50ml) (0.47g, 3.5mmol), triphenyl phosphine (2.3g, 8.7mmol) and ethylene chlorhydrin (0.7g, 8.7mmol) slowly add in the solution diisopropyl azo-2-carboxylic acid (1.8g, 8.7mmol).This reactant was at room temperature stirred 3 hours.Remove THF under the vacuum.The product that chromatography (25% ethyl acetate-hexane) obtains 0.58g (84%) is a yellow oil: MS EI m/e 196 (M +).
Intermediate 34
2-(2,3-Dihydrobenzofuranes-7-base oxygen base) ethyl chloride
To be dissolved in the hydrogenation 20 hours under 40psi of 2-in the acetate (20ml) (cumarone-7-base oxygen base)-ethyl chloride (0.64g) and 10% palladium on carbon solution.Catalyzer is filtered out, remove under the vacuum and desolvate.Chromatography (20% ethyl acetate-hexane) obtains the product of 0.39g (60%), is white solid: mp 49-52 ℃.MS?EI?m/e?198(M +)。
Intermediate 35
2-(4-fluorinated phenoxy) acetal
Under 0 ℃, the NaOH in being dissolved in dry DMF (100ml) (5.4g, and adding 4-fluorophenol in suspension 0.134mol) (10g, 0.089mol).After H2 stops to discharge, and the adding bromacetal (16ml, 0.11mol).This reactant was heated 18 hours in 160-170 ℃.This mixture is poured in the frozen water, and (3 * 150ml) extractions are with 1N NaOH (3 * 100ml) and salt solution (3 * 100ml) washings with ethyl acetate.Organic layer is through anhydrous sodium sulfate drying and filtration.Remove under the vacuum and desolvate.Chromatography (25% ethyl acetate-hexane) obtains the product of 16.36g (80%), is clarified oil.MS?EI?m/e?228(M +)。
Intermediate 36
5-fluoro cumarone
To contain Tripyrophosphoric acid (7.9g, add in benzene 0.035mol) (200ml) mixture 2-(4-fluoro-phenoxy group)-acetal (8g, 0.035mol).This mixture of vigorous stirring is heated to simultaneously and refluxed 2.5 hours.This reaction mixture is cooled to room temperature and from Tripyrophosphoric acid, inclines to.Remove under the vacuum and desolvate.Chromatography (5% ethyl acetate-hexane) obtains the product of 3.4g (45%), is clarifying oil.
Intermediate 37
5-fluoro-2, the 3-Dihydrobenzofuranes
With the hydrogenation 12 hours under 50psi of acetate (25ml) solution of 5-fluoro cumarone and 10% palladium on carbon.Go out catalyzer by diatomite filtration, (200ml) washs this diatomite with methylene dichloride.Organic layer with 1N NaOH (3 * 100ml), (3 * 100ml) washings are through anhydrous sodium sulfate drying for salt solution.Obtain the product of 2.59g (85%) except that desolvating under the vacuum, be clarifying oil.
Intermediate 38
5-fluoro-2,3-Dihydrobenzofuranes-7-aldehyde
Under 0 ℃, the 5-fluoro-2 in being dissolved in anhydrous methylene chloride (40ml), (7g adds TiCI in solution 0.051mol) to the 3-Dihydrobenzofuranes 4(9.5ml 0.087mol), adds α subsequently, and α '-dichloromethyl ether (4.6ml, 0.051mol).Making this reactant slowly reach room temperature and stir spends the night.In the slow impouring frozen water of this reaction mixture, with methylene dichloride (3 * 100ml) extractions, with saturated yellow soda ash (5 * 100ml) and salt solution (3 * 100ml) wash.Organic layer is through anhydrous sodium sulfate drying and filtration.Chromatography (25% ethyl acetate-hexane) obtains the product of 3.29g (39%), is white solid: mp 103-104 ℃.C 9H 7FO 2Ultimate analysis
Calculated value: C, 65.06; H, 4.75
Measured value: C, 65.01; H, 4.03
Intermediate 39
5-fluoro-7-hydroxyl-2,3-dihydro-cumarone
Under 0 ℃, 5-fluoro-2 in being dissolved in anhydrous methylene chloride (40ml), 3-Dihydrobenzofuranes-7-aldehyde (3.29g, 20mmol) and in 3-t-butyl-4-hydroxy-5-methyl base phenyl sulfide (100mg) solution gradation add 3-chloro peroxybenzoic acid (mCPBA) (8.5g, 30mmol).With this reaction mixture refluxed 16 hours.The S-WAT of adding 10% lost efficacy excessive mCBPA.Filter out phenylformic acid, with methylene dichloride (3 * 100ml) extraction filtrates and water (3 * 100ml) washings.Organic layer is through anhydrous sodium sulfate drying and filtration.Remove under the vacuum and desolvate, rough product is dissolved in the alcohol-water (100ml, 1: 1).Under 0 ℃, in above solution, add sodium hydroxide (2.11g, 53mmol).After 30 minutes, remove ice bath, this reaction mixture was at room temperature stirred 3 hours.Ethanol evaporation is used in the concentrated hydrochloric acid and resistates.With methylene dichloride (3 * 100ml) extract this mixture and with saturated sodium bicarbonate (2 * 100ml) and salt solution (2 * 100ml) wash.Organic layer filters through dried over sodium sulfate, removes under the vacuum and desolvates.Chromatography (30% ethyl acetate-hexane) obtains the product of 1.62g (50%), is white solid: mp102.5-103.5 ℃.C 8H 7FO 2Ultimate analysis
Calculated value: C, 62.34; H, 4.58
Measured value: C, 62.19; H, 4.59
Intermediate 40
2-(5-fluoro-2,3-dihydro-cumarone-7-base oxygen base) ethyl chloride
To be dissolved in the 5-fluoro-7-hydroxyl-2 in the 2-butanone (40ml), 3-dihydro-cumarone (1.6g, 10mmol), 1-bromo-2-ethylene dichloride (7.8g, 55mmol) and K 2CO 3(2.2g, solution 16mmol) refluxed 24 hours.This mixture is poured in the water (150ml), with methylene dichloride (3 * 150ml) extractions and with salt solution (3 * 100ml) wash.Organic layer filters through anhydrous sodium sulfate drying, removes under the vacuum and desolvates.Chromatography (25% ethyl acetate-hexane) obtains the product of 2.10g, is white solid: mp72.5-74.5 ℃.C 10H 10FClO 2Ultimate analysis
Calculated value: C, 55.44; H, 4.65
Measured value: C, 55.37; H4.58
Intermediate 41
2-(5-fluoro-2,3-dihydro-cumarone-7-base oxygen base) ethyl trinitride
To be dissolved in 2-in the dry DMF (30ml) (5-fluoro-2,3-dihydro-cumarone-7-base oxygen base) ethyl chloride (2.05g, 9.4mmol) and sodiumazide (1.23g, solution 19mol) is 60 ℃ of stirrings 24 hours down.This mixture is poured in the water (100ml), with methylene dichloride (3 * 150ml) extractions and water (3 * 100ml) washings.Organic layer filters through dried over sodium sulfate, removes under the vacuum and desolvates.Chromatography (20% ethyl acetate-hexane) obtains the product of 2.0g (95%), is clarified oil.MSESI?m/e?241[M+1] +。
Intermediate 42
2-(5-fluoro-2,3 dihydro furan-7-base oxygen base) ethamine
To be dissolved in 2-in tetrahydrofuran (THF) (50ml) and the water (1.5ml) (5-fluoro-2,3-Dihydrobenzofuranes-7-base oxygen base) ethyl trinitride (1.98g, 89mmol) and triphenyl phosphine (2.8g, solution 10.6mmol) at room temperature stirred 18 hours.Solvent removed in vacuo.Chromatography (ethyl acetate) is removed the product that triphenyl phosphine and triphenyl phosphine oxide and (40% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtain 2.0g (100%), is clarified oil.MS?ESI?m/e?198[M+1] +。
Intermediate 44
The 4-indanol
To be dissolved in 1g in the acetate (50ml) according to Ross etc., J.Am.Chem.Soc., the solution hydrogenation of (5-fluoro-2,3 dihydro furan-7-base oxygen base) ethamine (intermediate 43) (intermediate 44) of the 2-of disclosed method preparation among the 110:6471-6480 (1988) and 10% palladium on carbon 36 hours.Go out catalyzer by diatomite filtration, with this diatomite of washed with dichloromethane.Organic layer with saturated yellow soda ash (3 * 150ml) and salt solution (3 * 150ml) washing, through dried over sodium sulfate.Remove under the vacuum and desolvate.Chromatography (30% ethyl acetate-hexane) obtains the product of 0.78g (86%), is clarified oil.MS?EI?m/e?134(M +)。
Intermediate 45
2-(indane-4-base oxygen base)-ethyl chloride (45a)
4-indanol in being dissolved in tetrahydrofuran (THF) (50ml) (0.75g, 5.6mmol), triphenyl phosphine (4.4g, 16.8mmol) and ethylene chlorhydrin (0.7g, slowly add in solution 8.7mmol) diisopropyl azo-2-carboxylic acid (1.8g, 8.7mmol).This reactant was at room temperature stirred 3 hours, remove under the vacuum and desolvate.Chromatography (25% ethyl acetate-hexane) obtains the product of 0.58g (84%), is yellow oil.MS?EI?m/e?196(M +)。
2-(5,6,7, the basic oxygen base of 8-tetraline-1)-ethyl chloride (45b)
With the method for describing among above 45 (a), by by 5,6,7, (4g 0.027mol) replaces the 4-indanol to 8-tetrahydrochysene-1-naphthols, prepares this compound, and yield is the clarified oil of 46% (2.57g).C 12H 15The ultimate analysis of ClO
Calculated value: C, 68.41; H, 7.17
Measured value: C, 68.37; H, 7.25
2-(naphthalene-1-base oxygen base)-ethyl chloride (45c)
With the method for describing among above 45 (a), by (5g 0.035mol) replaces the 4-indanol to prepare this compound, and yield is the clarified oil of 82% (6.34g) by the 1-naphthols.C 12H 11The ultimate analysis of ClO
Calculated value: C, 69.74; H, 5.37
Measured value: C, 69.64; H, 5.30
2-phenoxy group-ethyl chloride (45d)
With the method for describing among above 45 (a), by (5g 0.053mol) replaces the 4-indanol to prepare this compound, and yield is the clarified oil of 12% (1.03g) by phenol.MS?EI?m/e156(M +)。
Intermediate 46
2-(indane-5-base oxygen base)-ethyl chloride
To be dissolved in 5-indanol in the 2-butanone (40ml) (5g, 0.037mol), 1-bromo-ethylene chlorhydrin (8.02g, 0.056mol) and salt of wormwood (7.7g, solution 0.056mol) refluxed 18 hours.This mixture is poured in the water (100ml), with ethylene dichloride (3 * 150ml) extractions and water (3 * 100ml) washings.Organic layer filters through anhydrous sodium sulfate drying, removes under the vacuum and desolvates.Chromatography (20% ethyl acetate-hexane) obtains the product of 3.2g (43%), is white solid: mp45-46 ℃.C 11H 13The ultimate analysis of ClO
Calculated value: C, 67.18; H, 6.66
Measured value: C, 67.03; H, 6.57
Intermediate 47
[3-(1H-indol-3-yl)-propyl group]-(2-hydroxyethyl) amine
To be dissolved in 3-(1H-indol-3-yl)-propyl group-amine in the anhydrous dimethyl sulfoxide (20ml) (3.5g, 18.6mmol), (1g, solution 12.4mmol) stirred 12 hours down at 80 ℃ ethylene chlorhydrin.This mixture is poured in the water (100ml), with methylene dichloride (3 * 150ml) extractions and water (3 * 100ml) washings.Organic layer filters through anhydrous sodium sulfate drying, removes under the vacuum and desolvates.Chromatography (15% methyl alcohol-methylene dichloride) obtains the product of 1.04g (38%), is yellow oil.MS?EIm/e?218(M +)。
Intermediate 48
(2-hydroxyl-ethyl)-[3-(1H-indol-3-yl)-propyl group]-carboxylamine-tertiary butyl ester
To be dissolved in [3-(1H-indol-3-yl)-propyl group]-(2-hydroxyethyl) amine in the anhydrous tetrahydro furan (20ml) (1.05g, 4.5mmol) and tert-Butyl dicarbonate (5g, solution 24mmol) was in 80 ℃ of heating 2 hours.This mixture is poured in the water (100ml), with methylene dichloride (3 * 150ml) extractions and water (3 * 100ml) washings.Organic layer filters through anhydrous sodium sulfate drying, removes under the vacuum and desolvates.Chromatography (5% methyl alcohol-methylene dichloride) obtains the product of 0.86g (56%), is yellow oil.MS?EI?m/e?318(M +)。
Intermediate 49
2-chlorophenyl ethanol
To be dissolved in 2-chloro-acetophenone in the tetrahydrofuran (THF) (30ml) (5g, 0.032mol) and sodium borohydride (6.1g, solution 0.16mol) stirred 18 hours down at 60 ℃.Water (200ml) made this reactant quencher and restir 2 hours.((3 * 150ml) wash this mixture for 3 * 100ml) extractions and water with methylene dichloride.Organic layer is through dried over sodium sulfate and filtration.Obtain the product of 5.07g (100%) except that desolvating under the vacuum, be clarified oil.MS?EI?m/e?156(M +)。
Intermediate 50
2-(2-methoxyl group-phenoxy group)-2-phenyl-ethyl chloride
Hydroxyanisole in being dissolved in tetrahydrofuran (THF) (50ml) (2g, 8.1mmol), triphenylphosphine (6.4g, 24mmol) and 2-chloro-1-phenylethyl alcohol (3.78g, slowly add in solution 24mmol) diisopropyl azo-2-carboxylic acid (4.8g, 24mmol).This reactant was at room temperature stirred 2 hours.Remove tetrahydrofuran (THF) under the vacuum.Chromatography (20% ethyl acetate-hexane) gets the product of 3.30g (78%), is clarified oil.MS?EI?m/e?262(M +)。
Intermediate 51
5-fluoro-3-(3-P-tosyloxy propyl group) indoles
At room temperature, the 3-of the stirring in being dissolved in pyridine (15.0ml) (5-fluoro-1H-indol-3-yl)-third-1-alcohol (2.90g, and adding P-toluene sulfonyl chloride in solution 15.0mmol) (7.1g, 37.5mmol).After at room temperature stirring 30 minutes, this reaction mixture is poured in the 200ml frozen water.With this aqueous solution of ethyl acetate extraction, be somebody's turn to do the organic extract that merges with HCI and the salt water washing of 1N.The material that obtains filters concentrated solvent under the vacuum through anhydrous sodium sulfate drying.Rough product obtains 4.1g (79%) title compound through silica gel column chromatography (ethyl acetate/hexane, 3/7) purifying, is 74 ℃ of solid: mp (99 ℃ of Lit.mp; EP 464604 A2).
Intermediate 52
2-(2-methoxyl group-phenoxy group) propionitrile
To being dissolved in anhydrous N, the hydroxyanisole in the dinethylformamide (20ml) (5g, 0.04mol) add in the solution sodium hydride (1.16g, 0.048mol).This mixture was at room temperature stirred 0.5 hour, add then 2-bromo propionitrile (8.09g, 0.06mol).At room temperature stir this mixture 4 hours and water (20ml) and make its quencher.(3 * 100ml) extract this mixture, and (3 * 100ml) washings, organic layer is through anhydrous sodium sulfate drying and filtration for water with methylene dichloride.Remove under the vacuum and desolvate.Chromatography (20% ethyl acetate-hexane) obtains the product of 3.91g (55%), is clarified oil.MS?EI?m/e?177(M +)。
Intermediate 53
2-(2-methoxyl group-phenoxy group) propylamine
2-in being dissolved in anhydrous diethyl ether (30ml) (2-methoxyl group-phenoxy group) propionitrile (3.91g, 0.022mol) add in the solution lithium aluminium hydride (1.0M, 44ml, 0.044mol).In 65 ℃ of heating this mixtures 18 hours, water (3ml), 15%NaOH (3ml) and water (9ml) quencher reactant, the material that obtains passes through diatomite filtration.(200ml) washs this diatomite with methyl alcohol, removes under the vacuum and desolvates.Chromatography (10% methyl alcohol-methylene dichloride) obtains the product of 0.26g (7%), is yellow oil.MS?EI?m/e?181(M +)。
Embodiment 1
[3-(1H-indol-3-yl)-propyl group]-[2-(2-methoxyl group-phenoxy group)-ethyl]-amine
To be dissolved in benzyl-[3-(1H-indol-3-yl)-propyl group]-[2-(2-methoxyl group-phenoxy group)-ethyl] amine in the ethanol (2g, 4.7mmol) and the mixture hydrogenation of 5% palladium on carbon 20 hours.Filter out catalyzer, remove under the vacuum and desolvate.Chromatography (ethyl acetate-hexane-methanol-hydrogen ammonium oxide: 4/4/1/1) obtain 0.79g (52%) product, be white solid: mp 101-102 ℃.In ethanol, prepare fumarate: mp 130-130.5 ℃.C 20H 24N 2O 2C 4H 4O 4Ultimate analysis
Calculated value: C, 64.78; H, 6.46; N, 6.29
Measured value: C, 64.76; H6.23; N, 6.21
[4-(1H-indol-3-yl)-butyl]-[2-(2-methoxyl group-phenoxy group)-ethyl]-amine
Benzyl-[4-(1H-indol-3-yl)-butyl]-[2-(2-methoxyl group-phenoxy group)-ethyl]-amine hydrogenation is obtained the product of 0.79g (100%), is clarified oil.In Virahol, prepare oxalate: mp167-168 ℃.C 20H 24N 2O 2C 4H 4O 4Ultimate analysis
Calculated value: C, 64.47; H, 6.59; N, 6.54
Measured value: C, 64.44; H, 6.52; N, 6.46
Embodiment 2
[3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(2-methoxyl group-phenoxy group) ethyl]-amine
To be dissolved in [3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(2-methoxyl group-phenoxy group) ethyl]-benzylamine in the ethanol (0.94g, 2.2mol) and the mixture hydrogenation of 10% palladium on carbon (250mg) 20 hours.Filter catalyzer, remove under the vacuum and desolvate.Chromatography (10% methyl alcohol-methylene dichloride) obtains the product of 0.63g (85%), is pale solid: mp 125-126 ℃.In Virahol, prepare oxalate: mp 146-149 ℃.C 20H 23FN 2O 2C 2H 2O 40.5H 2The ultimate analysis of O
Calculated value: C, 59.85; H, 5.94; N.6.35
Measured value: C, 60.13; H, 5.67; N, 6.10
Embodiment 3[3-(5-fluoro-1H-indol-3-yl) propyl group]-[2-(5-fluoro-2-methoxyl group-phenoxy group)-ethyl]-amine
To be dissolved in 2-(5-fluoro-2-methoxyl group-phenoxy group) ethyl chloride in the methyl-sulphoxide (20ml) (0.3g, 1.5mmol) and 3-(5-fluoro-1H-indol-3-yl) propylamine (0.56g, solution 2.9mmol) stirred 12 hours down at 90 ℃.This reaction mixture is poured in the water (100ml) also with methylene dichloride (3 * 100ml) extractions.(through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 150ml) washings through water for organic layer.Chromatography (10% methyl alcohol-methylene dichloride) obtains the product of 0.39g (77%), is white solid: mp 119-122 ℃.
Preparation oxalate mp is 175-177 ℃ in ethanol.C 20H 22F 2N 2O 2C 2H 2O 4Ultimate analysis
Calculated value: C, 58.66; H, 5.57; N, 6.22
Measured value: C, 58.29; H, 5.25; N6.07
[2-(5-fluoro-1H-indol-3-yl) ethyl]-[2-(5-fluoro-2-methoxyl group-phenoxy group)-ethyl]-amine (3b)
To be dissolved in 2-(5-fluoro-2-methoxyl group-phenoxy group) ethamine (0.51g in the methyl-sulphoxide (20ml), 2.8mmol), 2-(5-fluoro-1H-indol-3-yl) ethyl chloride (0.44g, 1.8mmol) and triethylamine (0.29g, solution 3mmol) stirred 8 hours down at 90 ℃.This reaction mixture is poured in the water (100ml), through methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 150ml) washings.Chromatography (5% methyl alcohol-methylene dichloride) obtains the product of 0.27g (43%), is brown oil.In ethanol, prepare oxalate: mp185-188 ℃.C 19H 20F 2N 2O 2C 2H 2O 4Ultimate analysis
Calculated value: C, 57.80; H, 5.08; N, 6.42
Measured value: C, 57.53; H, 4.95; N, 6.36
Embodiment 4[2-(5-fluoro-1H-indol-3-yl) ethyl]-[2-(5-fluoro-2-methoxyl group-phenoxy group)-ethyl]-amine
To be dissolved in 2-(5-fluoro-2-methoxyl group-phenoxy group) ethamine in the methyl-sulphoxide (20ml) (0.41g, 2.2mmol) and 3-(2-bromotrifluoromethane) indoles (0.25g, solution 1.1mmol) stirred 12 hours down at 90 ℃.This reaction mixture poured in the water (100ml) and through methylene dichloride (3 * 100ml) extractions.(3 * 150ml) washing organic layers through anhydrous sodium sulfate drying, filter water, remove under the vacuum and desolvate.Chromatography (10% methyl alcohol-methylene dichloride) obtains the product of 0.15g (34%), is brown oil.
In ethanol, prepare oxalate: mp 188-189 ℃.C 19H 21FN 2O 2C 2H 2O 40.25H 2The ultimate analysis of O
Calculated value: C, 59.04; H, 5.63; N, 6.62
Measured value: C, 59.68; H, 5.49; N, 6.56
Embodiment 5
[3-(5-fluoro-1H-indol-3-yl) propyl group]-[2-(1H-indoles-4-base oxygen base)-ethyl]-amine
To be dissolved in 2-in the methyl-sulphoxide (20ml) (1H-indoles-4-base oxygen base) ethyl chloride (0.7g, 3.6mmol) and 5-fluoro-indyl-3-propylamine (1.0g, 5.4mmol) solution stirred 12 hours down at 90 ℃.This reaction mixture is poured in the water (100ml) through methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 150ml) washings.Chromatography (5%-10% methyl alcohol-methylene dichloride) obtains the product of 0.54g (43%), is white solid: mp 70-73 ℃.In ethanol, prepare oxalate: mp 183.5-185 ℃.C 21H 22FN 3OC 2H 2O 4Ultimate analysis
Calculated value: C, 62.53; H, 5.48; N, 9.51
Measured value: C, 62.31; H, 5.38; N, 9.35
[2-(1H-indoles-4-base oxygen base) ethyl]-[3-(1H-indol-3-yl)-propyl group] amine (5b)
Method so that top embodiment 5 describes prepares this compound with 2-(the basic oxygen base of 1H-indoles-4-) ethyl chloride and 3-indyl-propylamine, obtains yield and be 65% pale solid: mp109-111 ℃.In Virahol, prepare oxalate: mp200.5-202 ℃.C 21H 23N 3OC 2H 2O 4Ultimate analysis
Calculated value: C, 65.19; H, 5.95; N, 9.92
Measured value: C, 64.89; H, 6.00; N, 9.81
[3-(1H-indol-3-yl) butyl]-[2-(1H-indoles-4-base oxygen base) ethyl] amine (5c)
Method with above embodiment 5 describes prepares this compound with 2-(the basic oxygen base of 1H-indoles-4-) fluoroethane and 3-indyl-butylamine, obtains yield and be 43% pale solid: mp 70-73 ℃.In ethanol, prepare oxalate: mp 183.5-185 ℃.C 22H 25N 3OC 2H 2O 4Ultimate analysis
Calculated value: C, 62.58; H, 5.48; N, 9.52
Measured value: C, 62.31; H, 5.38; N, 9.35
Embodiment 6[2-(2,3-dihydrobenzo [1,4] dioxin-5-base oxygen base)-ethyl]-[2-(1H-indol-3-yl)-ethyl] amine
To be dissolved in the 2-(2 in the anhydrous dimethyl sulfoxide (20ml), 3-dihydrobenzo [1,4] dioxin-5-base oxygen base) ethamine (0.38g, 1.9mmol), 3-(2-bromoethyl)-indoles (0.24g, 1.1mmol) and triethylamine (0.22g, 2.2mmol) solution stirred 14 hours down at 90 ℃.This mixture is poured in the water (100ml) also with methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and straight empty removing down desolvated by 3 * 150ml) washings.Chromatography (10% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains the product of 0.19g (52%), is yellow oil.In ethanol, prepare oxalate: mp 197.5-198.5 ℃.C 20H 22N 2O 3C 2H 2O 4Ultimate analysis
Calculated value: C, 61.63; H, 5.64; N, 6.53
Measured value: C, 61.36; H, 5.46; N, 6.45
Embodiment 7
[2-(2,3-dihydro-benzo [1,4] dioxin-5-base oxygen base)-ethyl]-[3-(5-fluoro-1H-indol-3-yl)-propyl group]-amine
To be dissolved in the 5-(2-chloro oxyethyl group)-(2 in the anhydrous dimethyl sulfoxide (20ml), 3)-dihydrobenzo [1,4]-diox (0.75g, 3.5mmpl), 3-(5-fluoro-1H-indol-3-yl)-propylamine (1.0g, 5.2mmol) and triethylamine (0.35g, 3.5mmol) solution stirred 14 hours down at 100 ℃.This mixture is poured in the water (100ml), with methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 150ml) washings.Chromatography (5%-10% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains the product of 0.10g (52%), is yellow oil.In Virahol, prepare fumarate: mp 189.5-190.5 ℃.C 21H 23FN 2O 30.5C 4H 4O 40.5H 2The ultimate analysis of O
Calculated value: C, 64.74; H, 5.88; N, 6.54
Measured value: C, 64.01; H, 5.95; N, 6.36
Embodiment 8[2-(6-fluoro chroman-8-base oxygen base) ethyl]-[2-(1H-indol-3-yl) ethyl]-amine
To be dissolved in 2-(the 6-fluoro chroman-8-base oxygen base) ethyl chloride (0.41g in the anhydrous dimethyl sulfoxide (20ml), 2.2mmol), 3-(2-bromoethyl) indoles (0.25g, 1.1mmol) and triethylamine (0.23g, 2.2mmol) solution stirred 12 hours down at 90 ℃.This reaction mixture is poured in the water (100ml), with methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 150ml) washings.Chromatography (10% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains the product of 0.15g (34%), is yellow oil.In ethanol, prepare oxalate: mp 213-214 ℃.C 21H 23FN 2O 2C 2H 2O 4Ultimate analysis
Calculated value: C, 62.11; H, 5.67; N, 6.30
Measured value: C, 62.26; H, 5.71; N, 6.19
Embodiment 9
[2-(6-fluoro chroman-8-base oxygen base) ethyl]-[3-(5-fluoro-1H-indol-3-yl) propyl group]-amine (9a)
To be dissolved in 2-(the 6-fluoro chroman-8-base oxygen base) ethyl chloride (0.25g in the anhydrous dimethyl sulfoxide (20ml), 7.1mmol), 3-(5-fluoro-1H-indol-3-yl)-propylamine (0.42g, 2.2mmol) and triethylamine (0.22g, 2.2mmol) solution stirred 14 hours down at 90 ℃.This mixture is poured in the water (100ml), with methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 150ml) washings.Chromatography (10% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains the product of 0.25g (60%), is white solid: mp137-138.5 ℃.In Virahol, prepare oxalate: mp 214-215 ℃.C 22H 24F 2N 2O 21.5C 2H 2O 4Ultimate analysis
Calculated value: C, 57.58; H, 5.22; N, 5.31
Measured value: C, 57.75; H, 5.07; N, 5.51
[2-(6-fluoro chroman-8-base oxygen base) ethyl]-[2-(5-fluoro-1H-indol-3-yl) ethyl]-amine (9b)
To be dissolved in 2-(the 6-fluoro chroman-8-base oxygen base) ethyl chloride (0.26g in the anhydrous dimethyl sulfoxide (20ml), 1.1mmol), 2-(5-fluoro-1H-indol-3-yl) ethamine (0.45g, 2.1mmol) and triethylamine (0.30ml, 2.1mmol) solution stirred 14 hours down at 90 ℃.This mixture is poured in the water (100ml), with methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 150ml) washings.Chromatography (10% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains the product of 0.19g (48%), is yellow oil.In ethanol, prepare oxalate: mp201-203 ℃.C 21H 22F 2N 2O 21C 2H 2O 4Ultimate analysis
Calculated value: C, 59.70; H, 5.23; N, 6.05
Measured value: C, 59.48; H, 5.08; N, 5.88
Embodiment 10
[2-(2,3-Dihydrobenzofuranes-7-base oxygen base) ethyl]-[3-(5-fluoro-1H-indol-3-yl) propyl group] amine
To be dissolved in the 2-(2 among the anhydrous DMSO (20ml), 3-Dihydrobenzofuranes-7-base oxygen base) ethyl chloride (0.38g, 1.9mmol), 3-(5-fluoro-1H-indol-3-yl) propylamine (0.93g, 4.8mmol) and triethylamine (0.48g, 4.8mmol) solution stirred 12 hours down at 90 ℃.This mixture is poured in the water (100ml), with methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 150ml) washings.Chromatography (10% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains the product of 0.52g (77%), is yellow oil.In ethanol, prepare oxalate: mp 158-160 ℃.C 21H 23FN 2O 2C 2H 2O 4Ultimate analysis
Calculated value: C, 63.82; H, 5.78; N, 5.95
Measured value: C, 63.45; H, 5.74; N, 5.76
Embodiment 11
[2-(cumarone-7-base oxygen base) ethyl]-[3-(5-fluoro-1H-indol-3-yl) propyl group] amine
To be dissolved in 2-(cumarone-7-base oxygen base)-ethyl chloride (0.58g among the anhydrous DMSO (20ml), 2.9mmol), 3-(5 fluoro-1H-indol-3-yl) propylamine (1.4g, 7.4mmol) and triethylamine (0.74g, 7.4mmol) solution stirred 12 hours down at 90 ℃.This mixture is poured in the water (100ml), with methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 150ml) washings.Chromatography (7% methyl alcohol-methylene dichloride) obtains the product of 0.31g (30%), is shallow brown oil.In THF, prepare oxalate: mp 181-183 ℃.C 21H 21FN 2O 21C 2H 2O 4Ultimate analysis
Calculated value: C, 62.39; H, 5.24; N, 6.33
Measured value: C, 62.07; H, 5.24; N, 6.45
Embodiment 12[2-(5-fluoro-2,3-dihydro-7-base oxygen base)-ethyl]-[2-(5-fluoro-1H-indol-3-yl) ethyl]-amine
To be dissolved in 2-(the 5-fluoro-2 in the anhydrous dimethyl sulfoxide (20ml), 3-dihydrofuran-7-base oxygen base) ethamine (0.40g, 2.1mmol), 2-(5-fluoro-1H-indol-3-yl)-ethamine (0.25g, 1.0mmol) and triethylamine (0.29ml, 2.1mmol) solution stirred 14 hours down at 90 ℃.This mixture is poured in the water (100ml), with methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 100ml) washings.Chromatography (5% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains the product of 0.2g (54%), is yellow oil.In ethanol, prepare oxalate: mp 209.5-210.5 ℃.C 20H 20F 2N 2O 21.5C 2H 2O 4Ultimate analysis
Calculated value: C, 55.98; H, 4.70; N, 5.68
Measured value: C, 55.53; H, 4.44; N, 5.72
Embodiment 13
[3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(indane-4-base oxygen base)-ethyl]-amine (13a)
To be dissolved in 2-(indane-4-base oxygen base)-ethyl chloride (0.58g in the anhydrous dimethyl sulfoxide (20ml), 2.9mmol), 3-(5-fluoro-1H-indol-3-yl)-propylamine (1.4g, 7.4mmol) and triethylamine (1ml, 7.4mmol) solution stirred 12 hours down at 90 ℃.This mixture is poured in the water (100ml), with methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 100ml) washings.Chromatography (7% methyl alcohol-methylene dichloride) obtains the product of 0.31g (30%), is brown oil.In tetrahydrofuran (THF), prepare oxalate: mp 220-222 ℃.C 22H 25FN 2OC 2H 2O 4Ultimate analysis
Calculated value: C, 65.10; H, 6.15; N, 6.33
Measured value: C, 64.74; H, 6.14; N, 6.11
[3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(5,6,7,8-tetraline-1-base oxygen base)-ethyl]-amine (13b)
With the method that above embodiment 13 describes, (0.6g 2.8mmol) replaces 2-(indane-4-base oxygen base)-ethyl chloride, prepares this compound, and obtaining yield is 29% (0.3g) yellow oil with 2-(5,6,7,8-tetraline-1-base oxygen base)-ethyl chloride.In ethanol, prepare fumarate: mp 203-205 ℃.C 23H 27FN 2O0.5C 4H 4O 4Ultimate analysis
Calculated value: C, 70.73; H, 6.89; N, 6.60
Measured value: C, 70.49; H, 6.87; N, 6.52
[3-(1H-indol-3-yl)-propyl group]-[2-(naphthalene-1-base oxygen base)-ethyl]-amine (13c)
With above embodiment 13 described methods, with 2-(naphthalene-1-base oxygen base)-ethyl chloride (0.6g, 2.8mmol) replacement 2-(indane-4-base oxygen base)-ethyl chloride, and with 3-(1H-indol-3-yl)-propylamine (1.35g, 7.2mmol) replace 3-(5-fluoro-1H-indol-3-yl)-propylamine to prepare this compound, obtain the yellow solid that yield is 85% (1.42g): mp 119-120 ℃.In ethanol, prepare fumarate: mp 203-205 ℃.C 23H 24N 2O0.5C 4H 4O 40.25H 2The ultimate analysis of O
Calculated value: C, 73.78; H, 6.56; N, 6.88
Measured value: C, 73.74; H, 6.47; N, 6.89
[3-(1H-indol-3-yl)-propyl group]-[2-phenoxy group-ethyl]-amine (13d)
With the method that above embodiment 13 describes, (0.59g 3.8mmol) replaces 2-(naphthalene-1-base oxygen base)-ethyl chloride to prepare this compound, obtain the yellow oil that yield is 100% (1.08g) with 2-phenoxy group-ethyl chloride.In ethanol, prepare fumarate: mp 203-205 ℃.C 19H 22N 2OC 4H 4O 4Ultimate analysis
Calculated value: C, 67.30; H, 6.38; N, 6.82
Measured value: C, 67.01; H, 6.30; N, 6.73
Embodiment 14[3-(5-fluoro-1H-indol-3-yl oxygen base)-propyl group]-[2-(indane-5-base oxygen base)-ethyl]-amine
To be dissolved in 2-(indane-5-base oxygen base)-ethyl chloride (0.7g in the anhydrous dimethyl sulfoxide (20ml), 3.5mmol), 3-(5-fluoro-1H-indol-3-yl)-propylamine (1.01g, 5.3mmol) and triethylamine (0.53g, 5mmol) solution stirred 12 hours down at 90 ℃.This mixture is poured in the water (100ml), with methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 100ml) washings.Chromatography (5-10% methyl alcohol-methylene dichloride) obtains the product of 0.53g (43%), is xanchromatic oil.In ethanol, prepare fumarate: mp 179-180 ℃.C 22H 25FN 2O0.5C 4H 4O 4Ultimate analysis
Calculated value: C, 69.46; H, 6.68; N, 6.75
Measured value: C, 69.19; H, 6.67; N, 6.72
Embodiment 15
[3-(1H-indol-3-yl)-propyl group]-[2-(quinoline-8-base oxygen base) ethyl]-amine
(2-hydroxyl-ethyl) in being dissolved in tetrahydrofuran (THF) (50ml)-[3-(1H-indol-3-yl)-propyl group]-carboxylamine-tertiary butyl ester (0.86g, 2.7mmol), triphenyl phosphine (0.71g, 2.7mmol) and 8-hydroxyl-quinoline (0.26g, 2.7mmol) slowly add in the solution diisopropyl azo-2-carboxylic acid (0.55g, 2.7mmol).Stirred this reactant 3 hours under the room temperature.Remove tetrahydrofuran (THF) under the vacuum.Chromatography (5% methyl alcohol-methylene dichloride) obtains yellow solid, and this solid is dissolved in the methylene dichloride (30ml).In this solution, add trifluoroacetic acid solution (4ml is dissolved in the 10ml methylene dichloride).At room temperature this reaction mixture was stirred 2 hours.Then, (3 * 100ml) extract this reactant with the saturated sodium carbonate quencher and with methylene dichloride.Organic layer is through anhydrous sodium sulfate drying and filtration.Remove under the vacuum and desolvate.Chromatography (10-15% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains the product of 0.17g (18%), is flaxen oil.In ethyl acetate, prepare hydrochloride: mp 83-86 ℃.C 22H 23N 3OHCI1.25H 2The ultimate analysis of O
Calculated value: C, 65.34; H, 6.60; N, 10.39
Measured value: C, 65.24; H, 6.69; N, 10.47
Embodiment 16[3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(2-methoxyl group-phenoxy group)-2-phenyl-ethyl]-amine
To be dissolved in 2-(2-methoxyl group-phenoxy group)-2-phenyl-ethyl chloride (0.71g in the anhydrous dimethyl sulfoxide (20ml), 2.7mmol), 2-(5-fluoro-1H-indol-3-yl)-ethamine (1.04g, 5.4mmol) and triethylamine (0.75ml, 5.4mmol) solution stirred 12 hours down at 90 ℃.This mixture is poured in the water (100ml), with methylene dichloride (3 * 100ml) extractions.(3 * 100ml) washing organic layers through anhydrous sodium sulfate drying, filter water, remove under the vacuum and desolvate.Chromatography (7% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains the product of 0.15g (13%), is yellow oil.In ether, prepare Citrate trianion: mp 64.5-67 ℃.C 20H 20F 2N 2O 2C 6H 8O 71.5H 2The ultimate analysis of O
Calculated value: C, 60.27; H, 6.01; N, 4.39
Measured value: C, 59.96; H, 6.00; N, 4.39
Embodiment 17
[3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(2-methoxyl group-phenoxy group)-propyl group] amine
To be dissolved in 2-(2-methoxyl group-phenoxy group) propylamine (0.26g in the anhydrous dimethyl sulfoxide (20ml), 1.2mmol), 5-fluoro-3-(3-P-tosyloxy propyl group) indoles (0.26g, 0.81mol) and triethylamine (0.13g, 1.2mmol) solution stirred 8 hours down at 90 ℃.This mixture is poured in the water (100ml), with methylene dichloride (3 * 100ml) extractions.The organic layer water (through anhydrous sodium sulfate drying, filter, and removes under the vacuum and desolvate by 3 * 10ml) washings.Chromatography (10% methyl alcohol-methylene dichloride hydro-oxidation ammonium) obtains the product of 0.1g (36%), is yellow oil.In the 1-propyl alcohol, prepare oxalate: mp 143-146 ℃.C 20H 20F 2N 2O 2C 2H 2O 41H 2The ultimate analysis of O
Calculated value: C, 59.47; H, 6.29; N, 6.03
Measured value: C, 59.34; H, 5.87; N, 5.96
The activity of this compound confirms by following standard pharmacology test method.
Human 5-HT from the people's gene storehouse 1AThe PCR of receptor subtype clone is before this by Chanda etc., Mol.Pharmacol., and 43:516 (1993) describes.A kind of stable, express human 5-HT 1AChinese hamster ovary line (the 5-HT of receptor subtype 1A.CHO cell) be used for the whole process of this research.Cell is remained among the DMEM that is supplemented with 10% foetal calf serum, non-essential amino acid and penicillin/streptomycin.
Before the results film is used in conjunction with research, makes cell grow to 95-100% and merge as the individual layer thing.Cell is scraped from culture plate gently, be transferred in the centrifuge tube, by at damping fluid (50mM Tris; PH7.5) centrifugal in (2000rpm 10 minutes, 4 ℃) washed twice.Resulting precipitation is divided into equal portions, places down in-80 ℃.Measuring day, cell is being melted on ice, be suspended in again in the slow middle liquid.With [ 3H] 8-OH-DPAT studies as radioligand.This combination is determined on the 96 hole microtiter plates that last cumulative volume is 250 μ L damping fluids to be carried out.Use the experiment that is at war with of the part of medicine that the end of 7 concentration marks and 1.5nM final concentration.In the presence of 10 μ M 5HT, measure non-specific binding.By use [ 3H] 8-OH-DPAT carries out saturation analysis in the concentration range of 0.3-30nM.After at room temperature hatching 3 minutes, (Gaithersburg MD), filters fast by 30 minutes GF/B filter membrane of preimpregnation in 0.5% polymine by adding ice-cold damping fluid termination reaction and using M-96 Brandel cell harvester.
Use and Cheetham etc., Neuropharmacol.32:737, (1993) similarly scheme measure the avidity of compound to serotonin transporter.Briefly, by the preceding cortex film of male Sprague-Dawley rat preparation with 3H-Paroxetine (0.1nM) was hatched 60 minutes at 25 ℃.All test tubes also contain the fluoxetine (10 μ M) of vehicle, test compound (1-8 concentration) or saturation concentration so that determine the specificity combination.Stop all reactions by adding ice-cold Tris damping fluid, filter fast (so that make bonded with the TomTech filtration unit subsequently 3The H Paroxetine separates with free 3H Paroxetine).With Wallac 1205 BetaPlate Counter carries out quantitatively the bonded radioactivity.Use nonlinear regression analysis to determine IC 50Value, with Cheng and Prusoff., Biochem.Pharmacol., 22:3099, (1973) disclosed method converts thereof into the Ki value; Ki=IC 50/ ((radioligand concentration)/(1+KD)).
[ 35S]-GTP γ S in conjunction with measure with by Lazareno and Birdsall, Br.J.Pharmacol., 109:1120, (1993) disclosed mensuration is similar.Briefly, will clone the segmental 5-HT of receptor membrane IA(be used for 5-HT IAReceptors bind is measured) be stored under-70 ℃ when needs.When needs, this film is thawed rapidly, 40, under the 000xg centrifugal 10 minutes and under 4 ℃, be suspended in again test slow in liquid (25mM HEPES, 3mM MgCI 2, 100mM NaCI, 1mM EDTA, 10uM GDP, 500mM DTT, pH8.0) in 10 minutes.Then, with these films in the presence of vehicle, test compound (1-8 concentration) or excessive 8-OH-DPAT, with [ 35S] GTPgS (1nM) was hatched under 30 ℃ 30 minutes together so that definite maximum agonist response.Respond by adding ice-cold Tyis damping fluid termination institute, use TomTech subsequently Filtration unit filters rapidly, so as with bonded [ 35S] GTPgS and free compound separation.Agonist generation combination [ 35S] increase of GTPgS amount, and antagonist does not produce the increase in conjunction with the aspect.Counting is in conjunction with radioactivity and as above analysis.
By being hatched at 37 ℃ with the DMEM of the eutonyl that contains 25mMHEPES, 5mM theophylline and 10 μ M, described cell carried out following test in 20 minutes.By handling described cell, immediately use test compound (6 concentration) to handle cell again and assessed its functionally active in 10 minutes at 37 ℃ with forskolin (1 μ M ultimate density).In separating experiment, before adding 10nM 8-OH-DPAT and forskolin with the antagonist preincubate of 6 concentration 20 minutes.Stop described reaction by removing medium and adding the ice-cold assay buffer of 0.5ml.Dull and stereotyped-20 ℃ of storages down before forming with assessment cAMP by cAMP SPA test (Amersham).
The compound of corresponding above embodiment 1-17 preparation detects described compound.The test result of described method is listed in the table 1.
Table 1 embodiment numbers 5-HT 1AST (Ki, nM, GTP γ S ED 50CAMP ED 50
(Ki; nM ) ％,1μM ) ( EMax％ ) ( EMax％ ) 1a 1.97 22 13.0 ( 80％ ) 1.32 ( 94％ ) 1b 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％ ) --5b 2.47 14 4.0 ( 66％ ) --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％ ) 10 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％ ) --
Confirm that by the above result who provides the present composition has active and general by suppressing the level of 5-HT transhipment raising serotonin to the 5HTIA acceptor.Therefore, The compounds of this invention can be used for the treatment with the not enough diseases related of serotonin concentration.
The compounds of this invention can oral or parenteral admin, can be separately or with the pharmaceutical carrier mixing administration of routine.Use solid carrier can comprise one or more material, they can be used as seasonings, lubricant, solubilizing agent, suspension agent, weighting agent, glidant (glidants), compression aid, tackiness agent or tablet disintegrant or coating material.For powder, carrier is a solid (mixing with activeconstituents in small, broken bits) in small, broken bits.For tablet, active ingredient with have essential compressible carrier and mix in the proper ratio, and be pressed into required shape and size.Powder and tablet preferably contain high to 99% activeconstituents.Solid carrier known to any those skilled in the art can be used for compound of the present invention.Specially suitable solid carrier comprises, for example calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidone, low-melting wax and ion exchange resin.
Can use liquid vehicle in solution, suspension, emulsion, syrup and the elixir of preparation The compounds of this invention.The compounds of this invention solubilized or be suspended in pharmaceutically acceptable liquid vehicle for example in water, organic solvent, both mixture or pharmaceutically acceptable oil or fat.This liquid vehicle can contain other suitable medicinal additive for example solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweeting agent, seasonings, suspension agent, thickening material, tinting material, viscosity modifier, stablizer or Osmolyte regulator.The example that is used for the suitable liquid vehicle of oral and parenteral admin comprises that water (especially contains for example derivatived cellulose of aforesaid additive, the preferably carboxymethyl cellulose sodium solution), alcohols (comprising monohydroxy-alcohol and polyvalent alcohol, for example dibasic alcohol) and their derivative and oil (for example fractionated coconut oil and peanut oil).For parenteral admin, carrier is for example ethyl oleate and Wickenol 101 of oily ester also.Sterile liquid carrier is used to prepare the composition of parenteral admin.
For the liquid pharmaceutical composition of sterile solution or suspension can be by for example intramuscular, intraperitoneal or subcutaneous injection use.Sterile solution also can intravenous administration.Being used for liquid preparations for oral administration can be the liquid or solid composition forms.
The medicinal compositions that contains The compounds of this invention is preferably unit dosage form for example tablet or capsule.In these formulations, said composition can be further divided into the unitary dose that contains an amount of The compounds of this invention.This unit dosage form is for example packaged powders, glass tube vial, ampoule, the syringe that is full of in advance or contain the sachet of liquid of packaged composition.Perhaps, described unit dosage form can be for example independent capsule or any this based composition with packaged form of tablet or suitable quantity.
The treatment significant quantity and the dosage that give The compounds of this invention depend on multiple factor, comprise the severity of weight in patients, age, sex and medical conditions, disease, the approach of administration and the particular compound of number of times and use etc., thereby alter a great deal.But can be sure of that the scope that described medicinal compositions can contain The compounds of this invention is about 0.1 to about 2000mg, preferably about 0.5 to about 500mg, more preferably about 1 to about 100mg.The plan per daily dose of active compound is about 0.01 to about 100mg/kg body weight.This per daily dose divides two to four administrations easily every day.
Under the situation of corresponding spirit and fundamental characteristics without prejudice to the present invention and its, the present invention can other specific forms show, and the scope of the invention that shows should be with reference to incidental claims, rather than above specification sheets.

Claims (23)

1. following formula: compound or its pharmacy acceptable salt: Wherein: R 1Be hydrogen, low alkyl group or aryl; R 2It is the phenyl of hydrogen, low alkyl group, phenyl or replacement; Each independently is hydrogen, low alkyl group, lower alkoxy or halogen for X and Y, perhaps forms cyclopentyl, cyclohexyl, phenyl, pyrryl, pyranyl, pyridyl, dihydrofuran base, furyl, alkyl dioxin, oxazolyl Huo isoxazolyl with the carbon atom that they connected; Z is hydrogen, halogen or lower alkoxy; Condition is that they do not occur at the ortho position when X, Y or Z represent lower alkoxy; W is hydrogen, halogen, low alkyl group, cyano group or trifluoromethyl; With n be 2-5.
2. the compound of claim 1 or its pharmacy acceptable salt, wherein: R 1Be hydrogen, methyl or aryl; R 2Be hydrogen; Each independently is hydrogen, halogen or lower alkoxy for X and Y, perhaps forms cyclopentyl, cyclohexyl, phenyl, pyridyl, alkyl dioxin, oxazolyl, furyl or dihydrofuran base with the carbon atom that they connected; Z is hydrogen, halogen or lower alkoxy; Condition is for when X, Y or Z represent lower alkoxy, and they do not appear at the ortho position; W is a hydrogen or halogen; With n be 2-4.
3. the compound of claim 1 is [3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(1H-indoles-4-base oxygen base)-ethyl]-amine.
4. the compound of claim 1 is [2-(1H-indoles-4-base oxygen base) ethyl]-[3-(1H-indol-3-yl)-propyl group]-amine.
5. the compound of claim 1 is [3-(1H-indol-3-yl)-butyl]-[2-(1H-indoles-4-base oxygen base)-ethyl]-amine.
6. the compound of claim 1 is [2-(2,3-dihydro-benzo [1,4] dioxin (dioin)-5-base oxygen base)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amine.
7. the compound of claim 1, for [2-(2,3-dihydro-benzo [1,4] dioxin-5-base oxygen base-ethyl]-[3-(5-fluoro-1H-indol-3-yl)-propyl group]-amine.
8. the compound of claim 1 is [2-(6-fluoro coumaran-8-base oxygen base)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amine.
9. the compound of claim 1 is [2-(6-fluoro coumaran-8-base oxygen base)-ethyl]-[3-(5-fluoro-1H-indol-3-yl)-propyl group]-amine.
10. the compound of claim 1 is [2-(6-fluoro coumaran-8-base oxygen base)-ethyl]-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-amine.
11. the compound of claim 1 is [2-(2,3-dihydro-cumarone-7-base oxygen base)-ethyl]-[3-(5-fluoro-1H-indol-3-yl)-propyl group]-amine.
12. the compound of claim 1 is [2-(cumarone-7-base oxygen base)-ethyl]-[3-(5-fluoro-1H-indol-3-yl)-propyl group]-amine.
13. the compound of claim 1 is [2-(5-fluoro-2,3-two-hydrogen-cumarone-7-base oxygen base)-ethyl]-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-amine.
14. the compound of claim 1 is [3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(indane-4-base oxygen base)-ethyl]-amine.
15. the compound of claim 1 is [3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(5,6.7.8-tetrahydrochysene-naphthalene-1-base oxygen base)-ethyl]-amine.
16. the compound of claim 1 is [3-(1H-indol-3-yl)-propyl group]-[2-(naphthalene-1-base oxygen base)-ethyl]-amine.
17. the compound of claim 1 is [3-(1H-indol-3-yl)-propyl group]-(2-phenoxy group-ethyl)-amine.
18. the compound of claim 1 is [3-(5-fluoro-1H-indol-3-yl oxygen base)-propyl group]-[2-(indane-5-base oxygen base)-ethyl]-amine.
19. the compound of claim 1 is [3-(1H-indol-3-yl)-propyl group]-[2-(quinoline-8-base oxygen base)-ethyl]-amine.
20. the compound of claim 1 is [3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(2-methoxyl group-phenoxy group)-2-phenyl-ethyl]-amine.
21. the compound of claim 1 is [3-(5-fluoro-1H-indol-3-yl)-propyl group]-[2-(2-methoxyl group-phenoxy group)-propyl group]-amine.
22. contain the medicinal compositions of following formula: compound or its pharmacy acceptable salt: Wherein: R 1Be hydrogen, low alkyl group or aryl; R 2It is the phenyl of hydrogen, low alkyl group, phenyl or replacement; Each independently is hydrogen, low alkyl group, lower alkoxy or halogen for X and Y, perhaps forms cyclopentyl, cyclohexyl, phenyl, pyrryl, pyranyl, pyridyl, dihydrofuran base, furyl, alkyl dioxin, oxazolyl Huo isoxazolyl with the carbon atom that they connected; Z is hydrogen, halogen or lower alkoxy; Condition is for when X, Y or Z represent lower alkoxy, and they do not appear at the ortho position; W is hydrogen, halogen, low alkyl group, cyano group or trifluoromethyl; With n be 2-5.
23. alleviate the method for the patient's who needs treatment depressive symptom, comprise the following formula: compound or its pharmacy acceptable salt that give this patient's antidepressant significant quantity:
Figure A9980701300051
Wherein: R 1Be hydrogen, low alkyl group or aryl; R 2It is the phenyl of hydrogen, low alkyl group, phenyl or replacement; Each independently is hydrogen, low alkyl group, lower alkoxy or halogen for X and Y, perhaps forms cyclopentyl, cyclohexyl, phenyl, pyrryl, pyranyl, pyridyl, dihydrofuran base, furyl, alkyl dioxin, oxazolyl Huo isoxazolyl with the carbon atom that they connected; Z is hydrogen, halogen or lower alkoxy; Condition is for when X, Y or Z represent lower alkoxy, and they do not appear at the ortho position; W is hydrogen, halogen, low alkyl group, cyano group or trifluoromethyl; With n be 2-5.
CN99807013A 1998-04-08 1999-04-07 N-aryloxyethyl-indoly-alkylamines for treatment of depression (5-HT1A receptor active agents) Pending CN1304403A (en)

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