CN1304409A - Indol-3-Yl-cyclohexyl amide derivatives for treatment of depression (5-HT1 receptor antagonists) - Google Patents

Indol-3-Yl-cyclohexyl amide derivatives for treatment of depression (5-HT1 receptor antagonists) Download PDF

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CN1304409A
CN1304409A CN99807010A CN99807010A CN1304409A CN 1304409 A CN1304409 A CN 1304409A CN 99807010 A CN99807010 A CN 99807010A CN 99807010 A CN99807010 A CN 99807010A CN 1304409 A CN1304409 A CN 1304409A
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hydrogen
phenyl
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R·E·穆肖
P·周
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Wyeth LLC
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Abstract

The invention provides compounds effective in treating disorders of the serotonin-affected neurological symptoms (5-HT1A receptor active), such compounds having formula (I), wherein: R1 and R5 are each, independently, hydrogen, halogen, lower alkoxy, lower alkyl, cyano, or trifluoromethyl; R2 and R4 are each, independently, hydrogen, lower alkyl, phenyl, or substituted phenyl; R3 is hydrogen or lower alkyl; and X and Y are each, independently, O, NR6, or CH2, wherein R6 is hydrogen, lower alkyl, phenyl, or substituted phenyl; or pharmaceutically acceptable salts thereof.

Description

Indol-3-yl-the cyclohexylamine derivant (5-HT1 receptor antagonist) that is used for the treatment of dysthymia disorders
Invention field
The compound that the present invention relates to can be used for treating because of being subjected to the disease of the neurological disorder that thrombotonin influences, as dysthymia disorders and anxiety disorder.More particularly, the present invention relates to can be used for treating the various indoles 3-base-cyclohexylamine derivants of this type of disease.
Background of invention
The medicinal compound that strengthens thrombotonin (serotonin) transmission can be used for treating many abalienations and comprises dysthymia disorders and anxiety disorder.The non-selective drug effect that influences thrombotonin of the first-generation makes it have many unwanted side effects such as blurred vision, dry and calmness in different physiological roles.The compound of up-to-date introduction is selective serotonin reuptake inhibithors (SSRI), and its main effect is to suppress initiatively to remove the serotonin that discharges in cynapse from synaptic cleft by presynaptic serotonin transport vehicle.Because SSRI needs several time-of-weeks could bring into play their therapeutic action fully, such serotonin blocking mechanism can not be explained its therapeutic activity fully.By inference, the described two all inducing actions that exist before observing complete antidepressant effect are that it is active that this autoreceptor suppresses the neuronic discharge of serotonin, causes weakening of curative effect owing to relate to the 5-HT1A autoreceptor.Studies show that most patient is taken SSRI after several weeks, the desensitization that produces the serotonin autoreceptor is brought into play the antidepressive effect fully.Therefore, think that controlling reverse feedback with the 5-HT1A antagonist will increase and quicken clinical antidepressive curative effect.Artgas etc., Trends Neurosci., the suggestion of the current research of 19:378-383 (1996), 5-HT1A active with suppress being absorbed in associating in the unit molecule entity and can obtaining stronger, antidepressant curative effect faster of serotonin.
United States Patent (USP) the 3rd, 058 discloses the preparation method of the compound with following molecular formula, and has thought that this compound has analgesic activities for No. 980.
PCT patent WO discloses the preparation method of the compound with following molecular formula for 89-07596A number, and this compounds has activity in various central nervous system disorders, comprises dysthymia disorders and schizophrenia.
At last, United States Patent (USP) the 4th, 612 discloses the compound with following molecular formula, has thought that it might be used as anti-worry and antihypertensive drug for No. 312.
Summary of the invention
The present invention be directed to novel molecular, it can act on 5-HT1A autoreceptor and 5-HT translocator simultaneously.Therefore, this compounds might be used for the treatment of dysthymia disorders and the imbalance of other serotonins.
Compound of the present invention is indol-3-yl-encircle sulfonamide derivatives or its pharmacy acceptable salt with formula I representative:
Wherein:
R 1And R 5Independent separately is hydrogen, halogen, lower alkoxy, low alkyl group, cyano group or trifluoromethyl;
R 2And R 4Independent separately is the phenyl of hydrogen, low alkyl group, phenyl or replacement;
R 3Be hydrogen or low alkyl group; Simultaneously
X and Y independently are O, NR separately 6Or CH 2, wherein
R 6It is the phenyl of hydrogen, low alkyl group, phenyl or replacement.Detailed description of the present invention
Compound of the present invention is preferably compound or its pharmacy acceptable salt by the representative of molecular formula I, wherein:
R 1And R 5Independent separately is hydrogen or halogen;
R 2And R 4The hydrogen of respectively doing for oneself;
R 3Be hydrogen; Simultaneously
X and Y are independent respectively to be O or NR 6, R wherein 6Represent hydrogen.
More particularly, compound of the present invention is selected from following compound:
(3,4-dihydro-benzo [1,4] oxazine-2-ylmethyl)-[cis-4-(5-fluoro-1H-indol-3-yl)-hexamethylene] amine;
(3,4-dihydro-benzo [1,4] oxazine-2-ylmethyl)-[trans-4-(5-fluoro-1H-indol-3-yl)-hexamethylene] amine;
(3,4-dihydro-benzo [1,4] oxazine-3-ylmethyl)-[cis-4-(5-fluoro-1H-indol-3-yl)-hexamethylene] amine; With
(3,4-dihydro-benzo [1,4] oxazine-3-ylmethyl)-[trans-4-(5-fluoro-1H-indol-3-yl)-hexamethylene] amine.
Term used herein " low alkyl group " and " lower alkoxy " are meant and comprise normal carbon chain and the branched chain that contains 1-6 carbon atom.Term " halogen " is meant and comprises fluorine, chlorine, bromine and iodine." phenyl of replacement " can comprise by the replacement of halogen, low alkyl group, lower alkoxy and cyano group.
Formula I compound also can use with the form of pharmaceutically-acceptable acid addition, and described acid salt has available free alkali.This type of salt can prepare with the known method in this area, available organic acid or mineral acid form, for example: fumaroyl, maleic acid, M-nitro benzoic acid, xitix, pamoic acid, succsinic acid, the dimethylene Whitfield's ointment, methylsulfonic acid, ethane disulfonic acid, acetate, oxalic acid, propionic acid, tartrate, Whitfield's ointment, citric acid, gluconic acid, lactic acid, oxysuccinic acid, mandelic acid, styracin, citraconic acid, aspartic acid, stearic acid, palmitinic acid, methylene-succinic acid, oxyacetic acid, p-aminobenzoic acid, L-glutamic acid, Phenylsulfonic acid, hydrochloric acid, Hydrogen bromide, sulfuric acid, the cyclohexyl thionamic acid, phosphoric acid and nitric acid.
Compound of the present invention can be by any appropriate method preparation well known by persons skilled in the art.Yet this compound can be according to any method preparation in the 1-3 scheme that proposes below.In these schemes, midbody compound is as an example discerned with bracket below.The compound that produces in each scheme is by differentiating with reference to suitable embodiment.
The compound of molecular formula I prepares according to the overall order of pointing out among the scheme 1-3 that proposes below usually.In each scheme, the midbody compound that below exemplifies is discerned with bracket.The compound that produces in each 1-3 scheme is differentiated by the suitable embodiment of reference.
Scheme one Scheme two
Scheme three
Figure A9980701000091
The present invention will be by following detailed non-limiting example explanation.
Intermediate 1
4-(5-fluoro-1H-3-indyl)-hexamethylene-3-alkene-ketone ketene acetal
(5.4g, 0.04mol), 1, (12.5g 0.08mol) places 60ml 2N potassium hydroxide methanol solution to 4-cyclohexanedione one ketene acetal with the 5-fluoro indole.Reaction mixture is heated to backflow 4 hours.Make the reactant cooling, the filtering separation product is also used methanol wash, obtains 10.1g (93%) white solid product: fusing point 153-155 ℃.
Intermediate 2
4-(5-fluoro-1H-3-indyl)-pimelinketone ketene acetal
(2.7g is 0.01mol) with the mixture hydrogenation of 10% palladium carbon (1.2g) in ethanol (200ml) 4 days to make 4-(5-fluoro-1H-3-indyl)-hexamethylene-3-alkene-ketone ketene acetal.The elimination catalyzer, concentrated filtrate.The described product of vacuum-drying obtains 2.8g (100%) white solid product: fusing point 183-185 ℃.
Intermediate 3
4-(5-fluoro-1H-3 indyl)-pimelinketone
With 4-(5-fluoro-1H-3 indyl)-(2.8g, 0.01mol) solution at room temperature stirred 16 hours pimelinketone ketene acetal in 200ml (1: 1) tetrahydrofuran (THF)-hydrochloric acid (1N).Mixture is concentrated to half of original volume.Use the ethyl acetate extraction aqueous solution.Organic extract salt water washing, dry (anhydrous sodium sulphate) and filtration then.Crude product obtains 2.1g (91%) yellow solid product: fusing point 112-114 ℃ with flash chromatography (hexane solution of 40% ethyl acetate) purifying.
Intermediate 4
2,3-dihydro-2H-benzo [1,4] oxazine-2-carboxylic esters
With Anhydrous potassium carbonate (15.2g, 0.108mol) add the 2-amino phenol (10.0g, in acetone 0.089mol) (100ml) solution, then under reflux temperature with 2, (23.6g 0.092mol) adds the 3-dibromo ethyl propionate in four batches.Stirred 24 hours under the reaction mixture refluxed, then cooling.Solid is leached concentrated filtrate.Residue is used extracted with diethyl ether then with cold 1N sodium hydroxide solution dissolving.The organic extract salt water washing that merges, dry (anhydrous sodium sulphate) filters, and concentrates.After chromatography (ethyl acetate/hexane: 1/2) obtain 6.25g (34.4%) brown oily product:
Intermediate 5
3,4-2 hydrogen-2H benzo-[1,4] oxazine-2 base)-methyl alcohol
At room temperature, 2, [(11.9g slowly adds 2M lithium borohydride (15ml) solution to 1,4] oxazine-2-carboxylic acid, ethyl ester to 3-dihydro-2H-benzo in anhydrous tetrahydro furan 19.0mmol) (200ml) solution.Reaction stirred 1 hour slowly adds the methyl alcohol stopped reaction then.After 2 hours, slowly add water (100ml), (4 * 100ml) extract reaction mixture with ethyl acetate.Separate organic layer, use anhydrous magnesium sulfate drying, filter solvent removed in vacuo.(ethyl acetate/hexane/methyl alcohol: 3/6/1) purification obtains the oily product of 1.96g (62%): MS (EI) m/e165 (M+) with chromatography.
Intermediate 6
2-methylol-2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester
3,4-dihydro-2H-benzo [1,4] oxazine-2-yl)-(10.7g in anhydrous tetrahydro furan 65.0mmol) (200ml) solution, slowly adds tetrahydrofuran (THF) (40ml) solution of two-tertiary butyl-supercarbonate (62g) to methyl alcohol.After 4 hours, make its cool to room temperature in reflux, pour into then in the water (100ml) also with ether (3 * 100ml) extractions.(anhydrous sodium sulfate drying is used in 2 * 50ml) washings to the organic layer water, filters, and final solvent is removed under vacuum.Chromatography (ethyl acetate/hexane: 1/2) obtain 12.9g (75%) white solid product: fusing point 93.5-94.5 ℃; MS (EI) m/e 265 (M+).
C 14H 19NO 4Ultimate analysis:
Calculated value: C, 63.38:H, 7.22:N, 5.28
Measured value: C, 63.53:H, 7.32:N, 5.38
Intermediate 7
The tertiary butyl-2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylicesters-2-methyl tosylate
With 2-methylol-2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylic acid tert-butyl ester (and 80mg, 0.3mmol) and anhydrous pyridine (15ml) solution of Tosyl chloride (86mg) at room temperature stir and spend the night.Reaction mixture is used methylene dichloride (3 * 20ml) extractions then with 1N hydrochloric acid (20ml) stopped reaction.(2 * 20ml) wash organic layer, and the organic layer anhydrous sodium sulfate drying filters then, and solvent is removed under vacuum with 1N hydrochloric acid.With chromatography (ethyl acetate/hexane: 1/2) the viscous crude shape product of acquisition 120mg (94%): MS (FAB) m/e 419 (M+Na).
C 21H 25NO 6The ultimate analysis of S:
Calculated value: C, 60.13; H, 6.01; N, 3.34
Measured value: C, 60.13; H, 6.11; N, 3.56
Intermediate 8
The tertiary butyl-2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylicesters-2-triazo-methane thing
With the tertiary butyl-2,3-dihydro-2H-benzo [1,4] oxazine 4-carboxylicesters-2-methyl tosylate (and 14.2g, 33.9mmol) and sodiumazide (4.4g, anhydrous dimethyl formamide 67.7mmol) (150ml) solution be heated to 60 ℃ 20 hours.This reaction mixture is poured in the water (150ml), and (3 * 150ml) extract with methylene dichloride.The organic layer anhydrous sodium sulfate drying that merges filters, and solvent is removed under vacuum then.Chromatography (hexane) is purified and is obtained 8.7g (88%) white solid product: fusing point 82-83 ℃.
C 14H 18N 4O 3Ultimate analysis:
Calculated value: C, 57.92; H, 6.25; N, 19.30.
Measured value: C, 58.07; H, 6.21; N, 19.03.
Intermediate 9
The tertiary butyl-2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylicesters
-2-methylamine
Make the tertiary butyl-2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylicesters-2-triazo-methane thing (and 6.25g, 21.6mmol) and moisture (4ml) tetrahydrofuran (THF) (150ml) solution of triphenyl phosphine (6.4g) at room temperature stirred 18 hours.Solvent is removed under vacuum.Residue is dissolved in the ether (100ml).After adding hexane (50ml), the sedimentary triphenyl phosphine oxide of filtering.Concentrated filtrate, residue is purified by chromatography (methylene dichloride of 5% methyl alcohol), obtains 7.2g product (containing the small amounts triphenyl phosphine): MS (FAB) m/e 265 (M+H +).
Intermediate 10 (tertiary butyl-3,4-dihydro-benzo [1,4] oxazine-4-carboxylicesters-2-methyl)-[cis-4-(5-fluoro-1H-
Indol-3-yl)-cyclohexyl]-amine
Make 4-(5-fluoro-1H-indol-3-yl)-pimelinketone (0.74g, 3.2mmol), the tertiary butyl-2,3-dihydro-2H-benzo [1,4] oxazine-4-carboxylicesters-2-methylamine (0.80g, 3.02mmol), nitrilotriacetic base sodium borohydride (1.0g, 4.5mmol) and acetate (0.18ml, 3.2mmol) 1,2-ethylene dichloride (14ml) solution at room temperature stirred 1.5 hours.Reaction stops with 1N sodium hydroxide, extracts with dichloromethyl then.The organic extract that merges is through the salt water washing, and dry (anhydrous sodium sulphate) filtered and concentrated.(ethyl acetate/hexane: 3/7 to 5/5) obtain the 1.40g title compound, this compound is the mixture of cis/trans, need not to do further separation during use by chromatography.
Embodiment 1 (3,4-dihydro-benzo [1,4] oxazine-2-ylmethyl)-[cis-4-(5-fluoro-1H-indol-3-yl)-hexamethylene]-amine and (3,4-dihydro-benzo [1,4] oxazine-2-ylmethyl)-[trans-4-(5-fluoro-1H-indol-3-yl)-
Hexamethylene]-amine
At room temperature, trifluoroacetic acid (5ml) is added cis/trans-(tert-butyl-3,4-dihydro-benzo [1,4] oxazine-4-carboxylicesters-2-methyl)-4-[5-fluoro-1H-indol-3-yl)-hexamethylene]-dichloromethane solution (15ml) of amine in.At room temperature, stirred reaction mixture removed and desolvates after 2 hours.In residue, add a spot of methyl alcohol, this solution is adjusted to pH value＞9 with the 2N sodium hydroxide solution.Contain the water section dichloromethane extraction.The organic extract that merges is through the salt water washing, and anhydrous sodium sulfate drying filters and concentrates.Product is through chromatography (ethyl acetate/methanol/ammoniacal liquor: 99/1/0.5) purify, obtain 0.41g (35%) cis-isomeride white solid: fusing point 65-67.The hydrochloride of preparation syn-isomerism body in ethyl acetate: 120 ℃ of fusing points (decomposition)
C 23H 26FN 3The ultimate analysis of O2HCl:
Calculated value: C, 61.06; H, 6.24; N, 9.29.
Measured value: C, 61.06; H, 6.40; N, 8.71.
Be isolated as the trans-isomer(ide) of white solid with 19% productive rate (0.22g): 66-68 ℃.Anti-type isomerism body hydrochloride prepares in ethyl acetate: 155 ℃ of fusing points (decomposition).
C 23H 26FN 3OHCL0.75H 2The ultimate analysis of O0.33EtOH:
Calculated value: C, 63.71; H, 6.85; N, 9.16.
Measured value: C, 63.40; H, 6.70; N, 8.97.
Embodiment 2 (3,4-dihydro-benzo [1,4] oxazine-3-ylmethyl)-[cis-4-(5-fluoro-1H-indol-3-yl)-hexamethylene]-amine and (3,4-dihydro-benzo [1,4] oxazine-3-ylmethyl)-[trans-4-(5-fluoro-1H-indol-3-yl)-
Hexamethylene]-amine
With 4-(5-fluoro-1H-indol-3-yl)-pimelinketone (0.578g, 2.5mmol), the 3-aminomethyl-1,2,4-benzoxazine (0.411g, 2.5mmol), nitrilotriacetic sodium borohydride (0.78g, 3.5mmol) and acetate (0.14ml, 2.5mmol) 1,2-ethylene dichloride (11ml) solution at room temperature stirred 5 hours.With 1N sodium hydroxide quencher reaction, extract with dichloromethyl.The organic extract that merges is through the salt water washing, and anhydrous sodium sulfate drying filters and concentrates.With chromatography (ethyl acetate/methanol/ammoniacal liquor: 99/1/0.5) purified product, the oily cis-isomeride of acquisition 0.63g (66%).The fumarate of cis-isomeride prepares in Virahol: fusing point 208-209 ℃.
C 23H 26FN 3O0.5C 4H 4O 40.3H 2The ultimate analysis of O0.24i-PrOH:
Calculated value: C, 67.55; H, 6.73; N, 9.19.
Measured value: C, 67.75; H, 6.69; N, 8.99.
Separating acquisition with 33% productive rate (0.32g) is the trans-isomer(ide) of oily matter.The fumarate of trans-isomer(ide) prepares in Virahol: fusing point 275-277 ℃ (decomposition).
C 23H 26FN 3O0.5C 4H 4O 40.3H 2The ultimate analysis of O:
Calculated value: C, 67.79; H, 6.51; N, 9.49.
Measured value: C, 67.58; H, 6.47; N, 9.18.
Confirm the activity of The compounds of this invention with following standard pharmacological test method.
Chanda etc. in the past, Mol Pharmacol., 43:516 (1993) have described PCR human cloning 5-HT from the Human genome library 1AReceptor subtype.In whole research, use expressing human 5-HT 1AStable Chinese hamster ovary line (the 5-HT of receptor subtype 1AChinese hamster ovary celI).Cell is kept cultivation in the DMEM that is added with 10% foetal calf serum, non-essential amino acid and penicillin/streptomycin.
When cell grew to 95-100% and is fused to monolayer cell, the collecting cell film was used in conjunction with research.Cell is wiped off from culture plate lightly, it is transferred in the centrifuge tube, and at damping fluid (50mM Tris; PH 7.5) in centrifugal (2000rpm, 10 minutes, 4 ℃) washed twice.The precipitation that obtains Deng branch also places under-80 ℃.When analyzing, cell is thawed on ice, be suspended in the damping fluid again.With [ 3H] 8-OH-DPAT studies as radioligand.Carry out in the final damping fluid cumulative volume of 250 μ l of binding analysis in 96 hole microtiter plates.Unexpectedly the experiment of striving property uses the unmarked medicine of 7 concentration and the whole ligand concentration of 1.5mmol to carry out.Under the situation that has 10 μ M serotonins, measure non-specific binding.Saturation analysis concentration be 0.3-30nM's [ 3H] 8-OH-DPAT carries out.After at room temperature cultivating 30 minutes then, add ice-cold damping fluid termination reaction, and (Gaithersburg filters fast by the GF/B filter membrane that soaked 30 minutes with 0.5% polymine in advance MD) with M-96 Brandel CellHarvester.
With being similar to Cheetham etc., Neuropharmacol., the used method of 32:737 (1993), the avidity of mensuration compound and serotonin transporter.In brief, under 25 ℃, will from the preceding cortex film of the female mouse of Spague-Dawely preparation with 3H-paroxetine (paroxetine) is incubation 60 minutes (0.1nM).All test tubes also contain solvent, test compounds (1 to 8 concentration) or saturation concentration fluoxetine (10 μ M) to determine the specificity combination.All reactions all add ice-cold Tris damping fluid termination reaction, filter fast with Tom Tech filtration unit then, from free 3The H-paroxetine is isolated bonded 3The H-paroxetine.The radioactivity of binding substances Wallac 1205 Beta Plate The counter quantitative assay.Earlier obtain IC with nonlinear regression analysis 50Value, again with its value Cheng and Prusoff, Biochem.Pharmacol, the method for 22:3099 (1973) converts the Ki value to, Ki=IC50/ ((radioligand concentration)/(1+KD)).
[ 35S]-GTP γ S binding analysis and Lazareno and Birdsall, the method that Br.J.Pharmacol.109:1120 (1993) uses is similar.In brief, with 5-HT 1AClone's receptor membrane fragment is (as 5-HT 1AReceptor binding assay) be stored in-70 ℃ standby.When needing, film is thawed rapidly, with 40,000 * g centrifugal 10 minutes, then at analysis buffer (25mM HEPES, 3mM magnesium chloride, 100mM sodium-chlor, 1mM ethylenediamine tetraacetic acid (EDTA), 10 μ M guanosine diphosphate (GDP)s, the 500mM dithiothreitol (DTT) is pH8.0) in 4 ℃ of resuspensions 10 minutes.Then these films 30 ℃ down with [ 35S] GTPgS (1nM) incubation 30 minutes, and in the presence of solvent, test compounds (1 to 8 concentration) or excessive 8-OH-DPDA, to determine maximum stirring effect.All reactions are all passed through to add ice-cold Tris damping fluid termination reaction, filter fast with the TomTech filtration unit then, from dissociate [ 35S] GTPgS isolate bonded [ 35S] GTPgS.The agonist increase [ 35S] the GTPgS binding capacity, and antagonist does not increase combination.Count and analyze the bonded radioactivity as previously discussed.
By cell was cultivated 20 minutes at 37 ℃ with the DMEM that comprises 25mM HEPES, 5mM theophylline and 10 μ M Supirdyl, carry out following analysis.Functionally active is estimated by the cell of handling, and cell is handled through forskolin (1 μ M final concentration), immediately uses test compounds (6 concentration) to handle under 37 ℃ 10 minutes again.In other experiment, the antagonist of 6 kinds of concentration is pre-the cultivation 20 minutes before adding 10nM 8-OH-DPAT and forskolin.Reaction stops by the ice-cold analysis buffer of removing substratum and adding 0.5ml.Before the formation of analyzing (Amersham) evaluation cAMP by cAMP SPA, microtiter plate is stored in-20 ℃.
The test result of the compound of embodiment 1 and embodiment 2 provides in following table:
Embodiment Ki(nM)ST[ 3H] paroxetine Ki(nM)5HT1A[ 3H]DPAT
1 (cis) ????44 ????2432
1 (trans) ????24 ????44％,1μM
2 (cis) ????34％,1μM ????9％,1μM
2 (trans) ????10 ????20％,1μM
The compounds of this invention can give with pure compound or in conjunction with conventional pharmaceutical carrier orally give or parenteral.The solid carrier that is suitable for can comprise one or more materials, and they can be used as seasonings, lubricant, solubilizing agent, suspension agent, weighting agent, glidant, compression auxiliary, tackiness agent, tablet disintegrant or encapsulate capsule material.When pulvis, described carrier is a kind of solid of fine refinement, and it mixes with the activeconstituents that becomes more meticulous.During tablet, activeconstituents mixes with the carrier with necessary compression property of suitable proportion, and is compressed into needed shape and size.Pulvis and tablet preferably comprise the activeconstituents up to 99%.Any solid well known by persons skilled in the art carries and can be applied to compound of the present invention.Especially the solid carrier of Shi Heing comprises for example calcium phosphate, Magnesium Stearate, talcum powder, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidone, low melt wax and ion exchange resin.
Liquid vehicle can be used to prepare solution, suspension agent, emulsion, syrup and the elixir of The compounds of this invention.Compound of the present invention can dissolve or be suspended in pharmaceutically acceptable liquid vehicle, for example water, organic solvent, both mixture or pharmaceutically acceptable oil or fat.Liquid vehicle can comprise other suitable medicinal additive, for example solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweeting agent, seasonings, suspension agent, thickening material, pigment, viscosity modifier, stablizer or osmotic pressure regulator.Be fit to suitable example oral and parenteral liquid vehicle and comprise that water (especially comprises as above for example derivatived cellulose of additive, carboxymethylcellulose sodium solution preferably), alcohols (comprising monohydroxy-alcohol and polyvalent alcohol, for example ethylene glycol) and their derivative and oil (for example fractionated Oleum Cocois and peanut oil).For parenteral admin, described carrier also can be grease for example ethyl oleate and isopropyl myristate.Sterile liquid carrier is used for the sterile liquid build composition of parenteral admin.
For the liquid pharmaceutical composition of sterile solution or suspension can be by using such as intramuscular, intraperitoneal or subcutaneous injection.Sterile solution also can lead to intravenous administration.The composition of orally give both can be an also solids composition form of forms of liquid compositions.
The medicinal compositions that comprises The compounds of this invention is unit dosage, for example tablet or capsule preferably.With this form, described composition can contain the unitary dose segmentation of an amount of The compounds of this invention.Described unit dosage can packaged composition, such as the syringe of parcel pulvis, bottle, ampoule, pre-can or contain the wafer of liquid.In other words, described unit dosage can be as capsule or tablet itself, perhaps its any this based composition of the packaged form of proper amt.
The The compounds of this invention that is given the treatment significant quantity depend on different factors with dosage, comprise patient's body weight, age, sex and healthy state, the severity of the state of an illness, approach and the frequency and the employed particular compound of administration, therefore the possibility variation range is very wide.Yet, think scope that described medicinal compositions contains The compounds of this invention from about 0.1 to about 2000mg, preferable range is about 0.5 to about 500mg, most preferred range is about 1 to arrive about 100mg.The per daily dose of the active ingredient agent of design is about 0.01-100mg/kg body weight.One day dosage can be divided into and giving easily for 2-4 time every day.
The present invention can not depart from other specific form performance of its essence and base attribute, therefore, and the scope of the invention that should point out with reference to appended claims, rather than above-mentioned specifying.

Claims (8)

1. the compound of following formula or its pharmacy acceptable salt:
Figure A9980701000021
Wherein:
R 1And R 5Independent separately be hydrogen, halogen, lower alkoxy, low alkyl group, cyano group or
Trifluoromethyl;
R 2And R 4Independent separately is the phenyl of hydrogen, low alkyl group, phenyl or replacement;
R 3Be hydrogen or low alkyl group; And
X and Y independently are O, NR separately 6Or CH 2, wherein
R 6Phenyl for hydrogen, low alkyl group, phenyl or replacement.
2. according to compound or its pharmacy acceptable salt of claim 1, wherein: R 1And R 5Independent separately is hydrogen, halogen; R 2And R 4Be respectively hydrogen; R 3Be hydrogen; And X and Y independently are O or NR separately 6, R wherein 6Be hydrogen.
3. according to the compound of claim 1, it is (3,4-dihydro-benzo [1,4] oxazine-2-ylmethyl)-[cis-4-(5-fluoro-1H-indol-3-yl)-hexamethylene]-amine.
4. according to the compound of claim 1, it is (3,4-dihydro-benzo [1,4] oxazine-2-ylmethyl)-[trans-4-(5-fluoro-1H-indol-3-yl)-hexamethylene]-amine.
5. according to the compound of claim 1, it is (3,4-dihydro-benzo [1,4] oxazine-3-ylmethyl)-[cis-4-(5-fluoro-1H-indol-3-yl)-hexamethylene]-amine.
6. according to the compound of claim 1, it is (3,4-dihydro-benzo [1,4] oxazine-3-ylmethyl)-[trans-4-(5-fluoro-1H-indol-3-yl)-hexamethylene]-amine.
7. the medicinal compositions that contains following formula: compound or its pharmacy acceptable salt: Wherein: R 1And R 5Independent separately is hydrogen, halogen, lower alkoxy, low alkyl group, cyano group or trifluoromethyl; R 2And R 4Independent separately is the phenyl of hydrogen, low alkyl group, phenyl or replacement; R 3Be hydrogen or low alkyl group; And X and Y are independent respectively to be O, NR 6Or CH 2, R wherein 6Phenyl for hydrogen, low alkyl group, phenyl or replacement.
8. one kind alleviates the method that it needs patient's depressive symptom, and this method comprises following formula: compound or its pharmacy acceptable salt that described patient is given the antidepressant significant quantity:
Figure A9980701000032
Wherein: R 1And R 5Independent separately is hydrogen, halogen, lower alkoxy, low alkyl group, cyano group or trifluoromethyl; R 2And R 4Independent separately is the phenyl of hydrogen, low alkyl group, phenyl or replacement; R 3Be hydrogen or low alkyl group; And X and Y independently are O, NR separately 6Or CH 2, R wherein 6Phenyl for hydrogen, low alkyl group, phenyl or replacement.
CN99807010A 1998-04-08 1999-04-07 Indol-3-Yl-cyclohexyl amide derivatives for treatment of depression (5-HT1 receptor antagonists) Pending CN1304409A (en)

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US6911445B2 (en) * 2002-09-12 2005-06-28 Wyeth Antidepressant cycloalkylamine derivatives of heterocycle-fused benzodioxans
US7041697B2 (en) 2002-09-12 2006-05-09 Wyeth Antidepressant cycloalkylamine derivatives of 2,3-dihydro-1,4-benzodioxan
US7276603B2 (en) * 2003-05-02 2007-10-02 Wyeth Benzofuranyl-and benzothienyl-piperazinyl quinolines and methods of their use

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