CN103420989B - Benzodioxane derivative and application thereof - Google Patents

Benzodioxane derivative and application thereof Download PDF

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CN103420989B
CN103420989B CN201210150420.9A CN201210150420A CN103420989B CN 103420989 B CN103420989 B CN 103420989B CN 201210150420 A CN201210150420 A CN 201210150420A CN 103420989 B CN103420989 B CN 103420989B
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base
methyl
diox
nitrae
isosorbide
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CN103420989A (en
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张桂森
王松林
徐祥清
刘星华
林亚维
刘欣
刘笔锋
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Nhwa Pharmaceutical Corp
Huazhong University of Science and Technology
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Nhwa Pharmaceutical Corp
Huazhong University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a kind of Benzodioxane derivative and application thereof, for having compound as shown in the formula (I) or its medically acceptable salt; Find through experiment, described Benzodioxane derivative can be applicable to preparation treatment Nervous and mental diseases medicine, and extracorporeal receptor binding tests shows, derivative involved in the present invention is to SERT and 5-HT 1Aacceptor has higher avidity.Animal test results shows, and this compounds, in acute treatment, can obviously reduce the mouse dead time, and the compound that therefore the present invention relates to has the effect for the treatment of Nervous and mental diseases, especially has therapeutic action to dysthymia disorders.

Description

Benzodioxane derivative and application thereof
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of Benzodioxane derivative and the application in treatment Mental disease thereof.
Background technology
Dysthymia disorders is the fourth-largest disease in the world, World Health Organization's investigation statistics is analyzed, only existing more than 8,900 ten thousand people of global Serious depression patient in 2002, and the patients with depression in the whole world has reached 3.4 hundred million, the incidence of whole world dysthymia disorders is about 3.1%, and in developed country close to about 6%, be about 3%-5% in China's depression rate, estimate that the year two thousand twenty dysthymia disorders will rise to the 2nd of the total class of disease.
The research and development of present all effective antidepressant drugs are the clinical effective medicines of two classes found before 50 years: Iricyclic antidepressants and oxidase inhibitor.Monoamine hypothesis is thought: dysthymia disorders is because the transmission of serotonin in human body and norepinephrine produces disorderly causing.On the basis of this hypothesis, think the transmission of norepinephrine and serotonin in tricyclic drugs and oxidase inhibitor energy reinforcement.But this two classes medicine they also to choline, suprarenin and histamine effect, therefore can produce a series of side effect.
Five amine reuptake inhibitors are the topmost antidepressant drugs of recent two decades, and it develops from tricyclic drugs, more safer than tricyclic drugs, and tolerance is better, has now become the main flow antidepressant drug of Clinical practice.It suppress the re-uptake of synaptic cleft serotonin, add the concentration of synaptic cleft serotonin.Although five amine reuptake inhibitors are significantly improved compared with tricyclic antidepressant in security, in curative effect and in onset speed, there is no improvement.
Although five amine reuptake inhibitors can improve synaptic cleft 5-HT level rapidly within a few hours, activate 5-HT simultaneously 1Aautoreceptor produces negative feedback inhibition effect, causes 5-HT Neural spike train to reduce, and then suppresses even to cancel the projected area such as cortex, hippocampus 5-HT level and raises, this 5-HT 1Aautoreceptor activates the negative feedback inhibition effect caused and is considered to play keying action in antidepressant drug onset deferring procedure.Administration is after 2 ~ 6 weeks, 5-HT 1Aautoreceptor desensitizes, and 5-HT neurone recovers regular discharge, thus produces antidepressant effect.
Onset postpones not only to reduce depressive patients compliance, also add its danger property of committing suiside, and therefore newly-developed antidepressant research and development are made every effort to innovate to some extent in quickening onset speed and break through.
Summary of the invention
The object of the invention is open a kind of Benzodioxane derivative, to overcome the above-mentioned defect that prior art exists.
Another object of the present invention is and the application of the open described Benzodioxane derivative of application in preparation medicament for treatment of depression.
Benzodioxane derivative of the present invention, for a kind of 3-(2-(4-((2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl) piperazine-1-base) alkyl)-1H-indole derivatives, for having compound as shown in the formula (I) or its medically acceptable salt;
Wherein:
R 1represent hydrogen, halogen, aryl, substituted aryl, C 1-5the C of alkyl or replacement 1-5alkyl;
R 2represent hydrogen, halogen, methoxyl group, cyano group, C 1-5the C of alkyl or replacement 1-5alkyl;
N is 1 or 2;
Preferably, described C 1-5alkyl is methyl, ethyl, propyl group, butyl, n-pentyl, isopentyl or neo-pentyl;
Preferably, the C of replacement 1-5alkyl is C 1-5haloalkyl or C 1-5hydroxyalkyl, preferred trifluoromethyl or methylol;
Preferably, the substituting group of the aryl of described replacement is C 1-5alkyl, C 1-5alkoxy or halogen;
Preferably, described aryl is phenyl;
Preferably, the aryl of described replacement is chlorophenyl, difluorophenyl, aminomethyl phenyl, ethylphenyl, isopropyl phenyl or p-methoxy-phenyl;
Preferably, R 1for hydrogen, methyl or phenyl;
Preferably, R 2for hydrogen, methyl, fluorine or chlorine;
Above-mentioned Benzodioxane derivative is selected from following compound or its pharmacy acceptable salt:
Code name 1:3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
The fluoro-3-of code name 2:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
The chloro-3-of code name 3:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
Code name 4:3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-5-Methyl-1H-indole;
Code name 5:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
The fluoro-3-of code name 6:5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
The chloro-3-of code name 7:5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
Code name 8:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-5-Methyl-1H-indole;
Code name 9:3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
The fluoro-3-of code name 10:5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
The chloro-3-of code name 11:5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
Code name 12:3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-5-Methyl-1H-indole;
Code name 13:3-(3-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
The fluoro-3-of code name 14:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
The chloro-3-of code name 15:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
Code name 16:3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-5-Methyl-1H-indole;
Code name 17:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
The fluoro-3-of code name 18:5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
The chloro-3-of code name 19:5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
Code name 20:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-5-Methyl-1H-indole;
Code name 21:3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-5-Methyl-1H-indole;
The fluoro-3-of code name 22:5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
The chloro-3-of code name 23:5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
Code name 24:3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-5-Methyl-1H-indole;
Described medically acceptable salt is selected from hydrochloride, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, acetate, lactic acid salt, Citrate trianion, tartrate, maleate, fumarate, mesylate, gluconate, saccharate, benzoate, esilate, benzene sulfonate or tosilate etc.;
The compound universal synthesis method of formula (I), comprises the steps:
Step (1): by carbon tetrabromide under triphenyl phosphine catalyst, the 3-ethyl/propyl indole alcohol derivatives shown in bromination formula (A), obtains 3-bromotrifluoromethane/propyl indole analog derivative;
Formula (A) compound, prepared by the method that document Org.Lett.6 (2004) 79-82 can be adopted to report, raw material all comes from Aladdin Reagent Company;
Step (2): at room temperature stir after the benzodioxan methyl alcohol that the compound-3 shown in formula (B) replaces and Tosyl chloride are dissolved in pyridine, reaction generates sulphonate;
Compound shown in formula (B), prepared by the method that document J.Med.Chem.36 (1993) 1520-1528 can be adopted to report, raw material all comes from Aladdin Reagent Company;
Step (3): described sulphonate and piperazine are dissolved in ethanol, temperature rising reflux reacts, synthesis benzodioxan methylpiperazine analog derivative;
Step (4): benzodioxan methylpiperazine analog derivative and 3-bromotrifluoromethane/propyl indole are dissolved in acetonitrile, add salt of wormwood and potassiumiodide, backflow, obtains target product.
Such as, can as shown in following reactions steps, synthesis the compounds of this invention:
Step (1)
Step (2)
Step (3)
Step (4)
In above-mentioned reaction expression, R 1, R 2, n defined with above-mentioned.
The present invention also provides a kind of pharmaceutical composition, comprise the compound shown in formula (I) or its medically acceptable salt and pharmaceutically acceptable auxiliary material for the treatment of significant quantity, as carrier and/or vehicle etc., this pharmaceutical composition produces the compound of the present invention of antipsycholic action or the antipsychotic composition of its medically acceptable salt containing being enough to;
The pharmaceutical composition that the present invention relates to, its per unit dosage can provide the activeconstituents of about 0.01 to 1000mg.Composition is used by any suitable approach, such as capsules per os, uses with the form parenteral of injection liquid, with the form topical application of paste or lotion, with the form rectal administration of suppository, with the form applied dermally of the transfer system of paster.
Compound of the present invention or its medically acceptable salt, by the form of pharmaceutical composition, put on the patient needing treatment, these preparations should contain the active compound of the present invention of at least 0.5wt%, but can change according to specific formulation, account for unit weight 4% is easily to about 70%, in such composition.The amount of active compound should reach suitable dosage.The oral dosage of the composition that the present invention is preferential and preparation contains the active compound of the present invention of 1.0-300 milligram.
Dosage of the present invention, depends on type and the seriousness of disease or illness, also depends on the feature of object, such as general health, age, sex, body weight and drug tolerance.Technician can determine suitable dosage according to these or other factors.The effective dose of medicine for central nervous system usually used is known by the technical staff.Every TDD is usually about between 0.05mg to 2000mg.
Compound of the present invention can contain chiral centre, and can exist with different enantiomorph and diastereomer form thus.The present invention relates to all optically active isomers of the compounds of this invention and all steric isomers, as the racemic mixture of this compounds and the form of each enantiomorph and diastereomer, and the present invention relate separately to as above-mentioned define containing or use their all pharmaceutical compositions and methods for the treatment of.
In addition, derivative provided by the invention and the pharmaceutical composition be made up of derivative, can be applicable to preparation treatment or prevention Nervous and mental diseases medicine aspect, described Nervous and mental diseases is selected from mental disorder, anxiety disorder, personality disorder, dysthymia disorders, manic disorder, migraine, epilepsy or convulsive disorder, childhood disorder, Parkinson's disease, cognitive disorder, neurodegeneration, neurotoxicity and local asphyxia; Preferred dysthymia disorders.
Extracorporeal receptor binding tests shows, derivative involved in the present invention is to SERT and 5-HT 1Aacceptor has higher avidity.
Animal test results shows, and this compounds, in acute treatment, can obviously reduce the mouse dead time, and the compound that therefore the present invention relates to has the effect for the treatment of Nervous and mental diseases, especially has therapeutic action to dysthymia disorders.
Embodiment
The following examples just for the purpose of description and not as restriction of the present invention.Except as otherwise noted, all temperature are centigradetemperature (DEG C).
The embodiment of A, synthesis aspect
Embodiment 1
3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles (code name: 1)
1) triphenylphosphine of 0.025mol is dissolved in the acetonitrile of 80ml drying, drips acetonitrile (75ml) solution of 0.02mol3-(2-bromotrifluoromethane)-1H-indoles.Then, drip acetonitrile (25ml) solution of 0.027mol carbon tetrabromide, stir 3 hours at normal temperatures, except desolventizing, column chromatography, obtains pale yellow oil.
2) 1.98g (2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl alcohol is dissolved in the pyridine of 30ml drying, is cooled to 0 DEG C, adds 6.9g Tosyl chloride, stirs, and at room temperature reacts 18 hours.After having reacted, reaction solution 300ml ether dilution, with dilute hydrochloric acid washing, washing, organic over anhydrous dried over mgso, removing ether obtains white solid, and column chromatography (sherwood oil: ethyl acetate=4:1) obtains yellow oil.
3) 2.24g (2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl 4-aminomethyl phenyl sulphonate is dissolved in 20ml ethanol, add 11.9g piperazine, temperature rising reflux reacts, and reacts 36 hours, after having reacted, except desolventizing, residuum adds the sodium hydroxide solution that 50ml weight concentration is 2.5%, with chloroform extraction, organic over anhydrous dried over mgso, except desolventizing obtains yellow oily liquid, obtain faint yellow solid after cooling, fusing point: 213-216 DEG C (hydrochloride).
4) 0.4g1-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methylpiperazine is dissolved in 10ml anhydrous acetonitrile, add 0.5g3-(2-bromotrifluoromethane)-1H-indoles, 0.9g Anhydrous potassium carbonate, 0.35g potassiumiodide, temperature rising reflux, reacts 10 hours.Cooling, filter, filtrate desolventizes to obtain crude product, and crude product column chromatography (sherwood oil: ethyl acetate=1:1, volume ratio) obtains target compound.
Fusing point: 238 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ10.97(s,1H),7.63-7.02(m,5H),6.94-6.82(m,4H),4.55-4.32(m,2H),4.07-3.98(m,1H),3.74-3.29(m,12H),3.20-3.09(m,2H);
MS(ESI)m/z378.1([M+H] +)。
Embodiment 2
The fluoro-3-of 5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles (code name: 2)
3-(2-bromotrifluoromethane)-1H-indoles is changed to the fluoro-1H-indoles of 3-(2-bromotrifluoromethane)-5-, prepares target compound by the method for embodiment 1.
Fusing point: 223 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ11.10(s,1H),7.48-7.30(m,3H),6.99-6.83(m,5H),4.72-4.31(m,2H),4.08-4.00(m,1H),3.88-3.28(m,12H),3.22-3.08(m,2H)
MS(ESI)m/z396.1([M+H] +)
Embodiment 3
The chloro-3-of 5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles (code name: 3)
3-(2-bromotrifluoromethane)-1H-indoles is changed to the chloro-1H-indoles of 3-(2-bromotrifluoromethane)-5-, prepares target compound by the method for embodiment 1.
Fusing point: 225 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ11.20(s,1H),7.72-7.08(m,4H),6.96-6.85(m,4H),4.67-4.31(m,2H),4.08-4.00(m,1H),3.88-3.28(m,12H),3.20-3.12(m,2H)
MS(ESI)m/z412.0([M+H] +)。
Embodiment 4
3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-5-Methyl-1H-indole (code name: 4)
3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(2-bromotrifluoromethane)-5-Methyl-1H-indole, prepares target compound by the method for embodiment 1.
Fusing point: 226 DEG C, (hydrochloride decomposes);
1H-NMR(DMSO-d6)δ10.85(s,1H),7.41-7.18(m,3H),6.96-6.85(m,5H),4.72-4.31(m,2H),4.08-4.00(m,1H),3.88-3.28(m,12H),3.26-3.03(m,2H),2.39(s,3H);
MS(ESI)m/z392.1([M+H] +)。
Embodiment 5
3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles (code name: 5)
(2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] diox-3-base) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl alcohol, prepares target compound by the method for embodiment 1.
Fusing point: 234 DEG C, (hydrochloride decomposes);
1H-NMR(DMSO-d6)δ10.97(s,1H),7.63-7.23(m,5H),6.96-6.85(m,4H),4.49-4.41(m,1H),4.21-4.15(m,1H),3.88-3.28(m,12H),3.22-3.10(m,2H),1.37-1.20(m,3H);
MS(ESI)m/z392.1([M+H] +)
Embodiment 6
The fluoro-3-of 5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles (code name: 6)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] diox-3-bases) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to the fluoro-1H-indoles of 3-(2-bromotrifluoromethane)-5-, prepares target compound by the method for embodiment 1.
Fusing point: 232 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ11.10(s,1H),7.48-7.30(m,3H,),6.99-6.83(m,5H),4.49-4.41(m,1H),4.21-4.15(m,1H),3.88-3.28(m,12H),3.22-3.09(m,2H),1.38-1.21(m,3H);
MS(ESI)m/z411.1([M+H] +)
Embodiment 7
The chloro-3-of 5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles (code name: 7)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] diox-3-bases) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to the chloro-1H-indoles of 3-(2-bromotrifluoromethane)-5-, prepares target compound by the method for embodiment 1.
Fusing point: 234 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ11.19(s,1H),7.70-7.07(m,4H),6.93-6.81(m,4H),4.47-4.40(m,1H),4.20-4.12(m,1H),3.88-3.28(m,12H),3.16-3.02(m,2H),1.37-1.20(m,3H);
MS(ESI)m/z426.1([M+H] +)
Embodiment 8
3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-5-Methyl-1H-indole (code name: 8)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] diox-3-bases) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(2-bromotrifluoromethane)-5-Methyl-1H-indole, prepares target compound by the method for embodiment 1.
Fusing point: 221 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ10.83(s,1H),7.4-7.18(m,3H),6.99-6.83(m,5H),4.49-4.41(m,1H),4.21-4.15(m,1H),3.88-3.28(m,12H),3.19-3.08(m,2H),2.39(s,3H),1.38-1.21(m,3H);
MS(ESI)m/z406.1([M+H] +)
Embodiment 9
3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles (code name: 9)
(2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] diox-3-base) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox 3-yl) methyl alcohol, prepares target compound by the method for embodiment 1.
Fusing point: 213 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ10.98(s,1H),7.66-7.18(m,8H),7.14-6.83(m,6H),5.17-5.09(m,1H),4.83-4.63(m,1H),3.88-3.28(m,12H),3.26-3.11(m,2H);
MS(ESI)m/z454.3([M+H] +)
Embodiment 10
The fluoro-3-of 5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles (code name: 10)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [1,4] diox 3-yls) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to the fluoro-1H-indoles of 3-(2-bromotrifluoromethane)-5-and prepares target compound by the method for embodiment 1.
Fusing point: 205 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ11.10(s,1H),7.64-7.29(m,8H),7.10-6.83(m,5H),5.17-5.09(m,1H),4.83-4.63(m,1H),3.88-3.28(m,12H),3.25-3.10(m,2H);
MS(ESI)m/z472.2([M+H] +).
Embodiment 11
The chloro-3-of 5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles (code name: 11)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [1,4] diox 3-yls) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to the chloro-1H-indoles of 3-(2-bromotrifluoromethane)-5-and prepares target compound by the method for embodiment 1.
Fusing point: 219 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ11.08(s,1H),7.61-7.24(m,8H),7.11-6.82(m,5H),5.17-5.09(m,1H),4.83-4.63(m,1H),3.88-3.28(m,12H),3.26-3.11(m,2H);
MS(ESI)m/z488.2([M+H] +)
Embodiment 12
3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-5-Methyl-1H-indole (code name: 12)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [1,4] diox 3-yls) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(2-bromotrifluoromethane)-5-Methyl-1H-indole and prepares target compound by the method for embodiment 1.
Fusing point: 203 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ11.10(s,1H),7.61-7.10(m,8H),7.11-6.82(m,5H),5.17-5.09(m,1H),4.83-4.63(m,1H),3.88-3.28(m,12H),3.18-3.10(m,2H),2.38(s,3H);
MS(ESI)m/z468.3([M+H] +)
Embodiment 13
3-(3-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles (code name: 13)
3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(2-bromopropyl)-1H-indoles and prepares target compound by the method for embodiment 1.
Fusing point: 244 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ10.87(s,1H),7.54-7.02(m,5H),6.94-6.82(m,4H),4.72-4.29(m,2H),4.07-3.98(m,1H),3.74-3.29(m,10H),3.27-3.10(m,2H),2.75(t,2H,J=14.8Hz),2.16-2.04(m,2H);
MS(ESI)m/z392.1([M+H] +)
Embodiment 14
The fluoro-3-of 5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles (code name: 14)
3-(2-bromotrifluoromethane)-1H-indoles is changed to the fluoro-1H-indoles of 3-(3-bromopropyl)-5-and prepares target compound by the method for embodiment 1.
Fusing point: 252 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ10.98(s,1H),7.36-7.26(m,3H,),6.99-6.83(m,5H),4.68-4.29(m,2H),4.08-4.00(m,1H),3.74-3.22(m,10H),3.26-3.03(m,2H),2.72(t,2H,J=14.8Hz),2.13-2.01(m,2H);
MS(ESI)m/z410.1([M+H] +)
Embodiment 15
The chloro-3-of 5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles (code name: 15)
3-(2-bromotrifluoromethane)-1H-indoles is changed to the chloro-1H-indoles of 3-(3-bromopropyl)-5-and prepares target compound by the method for embodiment 1.
Fusing point: 247 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ11.10(s,1H),7.60-7.05(m,4H),6.95-6.83(m,4H),4.66-4.29(m,2H),4.06-3.99(m,1H),3.88-3.28(m,10H),3.24-3.06(m,2H),2.72(t,2H,J=14.8Hz),2.13-2.01(m,2H);
MS(ESI)m/z426.0([M+H] +)
Embodiment 16
3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-5-Methyl-1H-indole (code name: 16)
3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(3-bromopropyl)-5-Methyl-1H-indole and prepares target compound by the method for embodiment 1.
Fusing point: 244 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ10.72(s,1H),7.32-7.13(m,3H),6.96-6.85(m,5H),4.71-4.30(m,2H),4.07-3.99(m,1H),3.84-3.28(m,10H),3.24-3.12(m,2H),2.73(t,2H,J=14.8Hz),2.13-2.01(m,2H),2.39(s,3H);
MS(ESI)m/z406.1([M+H] +)
Embodiment 17
3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles (code name: 17)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] diox-3-bases) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(3-bromopropyl)-1H-indoles and prepares target compound by the method for embodiment 1.
Fusing point: 240 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ10.86(s,1H),7.54-7.07(m,4H),6.98-6.82(m,5H),4.48-4.39(m,1H),4.21-4.12(m,1H),3.88-3.28(m,10H),3.23-3.09(m,2H),2.75(t,2H,J=14.8Hz),2.15-2.01(m,2H),1.38-1.18(m,3H);
MS(ESI)m/z406.1([M+H] +)
Embodiment 18
The fluoro-3-of 5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles (code name: 18)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] diox-3-bases) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to the fluoro-1H-indoles of 3-(3-bromopropyl)-5-and prepares target compound by the method for embodiment 1.
Fusing point: 249 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ11.00(s,1H),7.37-7.26(m,3H),6.99-6.83(m,5H),4.49-4.41(m,1H),4.21-4.15(m,1H),3.88-3.28(m,10H),3.26-3.05(m,2H),2.72(t,2H,J=14.8Hz),2.14-2.02(m,2H),1.36-1.20(m,3H);
MS(ESI)m/z424.1([M+H] +)
Embodiment 19
The chloro-3-of 5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles (code name: 19)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] diox-3-bases) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to the chloro-1H-indoles of 3-(3-bromopropyl)-5-and prepares target compound by the method for embodiment 1.
Fusing point: 245 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ11.10(s,1H),7.60-7.05(m,4H),6.99-6.83(m,4H),4.47-4.41(m,1H),4.21-4.15(m,1H),3.88-3.28(m,10H),3.23-3.05(m,2H),2.73(t,2H,J=14.8Hz)，2.14-2.02(m,2H),1.38-1.21(m,3H);
MS(ESI)m/z440.1([M+H] +)
Embodiment 20
3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-5-Methyl-1H-indole (code name: 20)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] diox-3-bases) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(3-bromopropyl)-5-Methyl-1H-indole and prepares target compound by the method for embodiment 1.
Fusing point: 239 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ10.73(s,1H),7.43-7.16(m,3H,),7.05-6.83(m,5H),4.49-4.41(m,1H),4.21-4.15(m,1H),3.88-3.28(m,10H),3.29-3.03(m2H),2.73(t,2H,J=14.8Hz),2.39(s,3H),2.14-2.02(m,2H),1.38-1.21(m,3H);
MS(ESI)m/z420.1([M+H] +)
Embodiment 21
3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-5-Methyl-1H-indole (code name: 21)
(2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] diox-3-base) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl alcohol, prepares target compound by the method for embodiment 1.
Fusing point: 214 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ10.98(s,1H),7.63-7.15(m,8H),7.11-6.82(m,6H),5.17-5.09(m,1H),4.83-4.63(m,1H),3.88-3.28(m,10H),3.23-3.08(m,2H),2.74(t,2H,J=14.8Hz),2.14-2.02(m,2H);
MS(ESI)m/z468.3([M+H] +)
Embodiment 22
The fluoro-3-of 5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles (code name: 22)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [1,4] diox-3-bases) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(3-bromopropyl)-1H-indoles and prepares target compound by the method for embodiment 1.
Fusing point: 234 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ10.97(s,1H),7.61-7.24(m,8H),7.11-6.82(m,5H),5.17-5.09(m,1H),4.83-4.63(m,1H),3.88-3.28(m,10H),3.14-3.04(m,2H),2.70(t,2H,J=14.8Hz),2.10-1.96(m,2H);
MS(ESI)m/z486.3([M+H] +)
Embodiment 23
The chloro-3-of 5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles (code name: 23)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [1,4] diox-3-bases) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to the chloro-1H-indoles of 3-(3-bromopropyl)-5-and prepares target compound by the method for embodiment 1.
Fusing point: 228 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ11.08(s,1H),7.61-7.24(m,8H),7.11-6.82(m,5H),5.17-5.09(m,1H),4.83-4.63(m,1H),3.88-3.28(m,10H),3.22-3.03(m,2H),2.72(t,2H,J=14.8Hz),2.10-1.96(m,2H);
MS(ESI)m/z502.2([M+H] +)
Embodiment 24
3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-5-Methyl-1H-indole (code name: 24)
By (2,3-dihydrobenzo [b] [1,4] diox-3-bases) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [1,4] diox-3-bases) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(3-bromopropyl)-5-Methyl-1H-indole and prepares target compound by the method for embodiment 1.
Fusing point: 221 DEG C, (hydrochloride decomposes).
1H-NMR(DMSO-d6)δ10.71(s,1H),7.61-7.10(m,8H),7.11-6.82(m,5H),5.17-5.09(m,1H),4.83-4.63(m,1H),3.88-3.28(m,10H),3.22-3.10(m,2H),2.70(t,2H,J=14.8Hz)2.11-1.92(m,2H),2.38(s,3H);
MS(ESI)m/z482.3([M+H] +)
Preferred compound numbering prepared by table 1 embodiment and structural formula thereof
The embodiment of B, pharmacology aspect
Execute example 25
5HT 1Athe preparation of film
Rat breaks end, and operates on ice, gets cortex rapidly, add 3ml damping fluid (the Tris-HCl damping fluid of 0.05M, the xitix containing 0.1%, 10um Supirdyl and 4mMCaCl 2) in 4 grades of 3-4s homogenate, homogenate 4 times, then adds 5ml damping fluid, in 37 DEG C of hatching 10min, hatch rear test tube balance and adjusted weight, at 12000r, 4 DEG C of centrifugal 20min, abandon supernatant liquor, add 5ml damping fluid, mix with vortex mixer, centrifugal, in triplicate, centrifugal complete, abandon supernatant liquor ,-80 DEG C will be deposited in and store for future use.
Receptor Binding Assay material:
Isotropic substance aglucon 3h-8-OH-DPAT(67.0Ci/mmol), purchased from PerkinElmer company; 5-HT, purchased from RBI company; GF/C glass fiber filter paper, purchased from Whatman company; Tris import packing; PPO, POPOP are purchased from Shanghai reagent one factory; Fat-soluble scintillation solution.BeckmanLS-6500 type full-service fluid scintillation counter.
Experimental technique:
(1) the appropriate homogenate of film first will prepared, is uniformly dispersed with refiner, is mixed in the container of 100ml by 15 test tubes, adds the suspension that appropriate homogenate is 50ml film, for subsequent use.
(2) each reaction tubes adds film preparation thing 100 μ L respectively, homogenate 100 μ L.
(3) total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds 5-HT100 μ L(final concentration 10 -5m), each test-compound specific binding pipe (SB) adds 100 μ L test-compound (final concentrations 10 -5m);
(4) each reaction tubes adds radioligand respectively 3the each reaction tubes of H-8-OH-DPAT10 μ L(all establishes 3 parallel pipes, and during application of sample, each pipe is placed on ice);
(5) each reaction tubes 37 DEG C of temperature are incubated 10min, react complete, in conjunction with aglucon by decompression fast filtering, fully wash with ice-cold test damping fluid, by filter disc take out be put in 3ml scintillating disc, add the toluene scintillation solution of 2ml and mix;
(6) scintillation vial is put into liquid scintillation counter counting.
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%
Compound is tested at every turn and is done three parallel samples.
Experimental result is in table 2
Execute example 26
The preparation of SERT film
Rat breaks end, and operates on ice, gets cortex rapidly, add 3ml damping fluid (the Tris-HCl damping fluid of 0.05M, containing NaCl120mM, KCl5mM) in 4 grades of 3-4s homogenate, homogenate 4 times, then adds 5ml damping fluid, in 23 DEG C of hatching 10min, hatch rear test tube balance and adjusted weight, at 12000r, 4 DEG C of centrifugal 20min, abandon supernatant liquor, add 5ml damping fluid, with vortex mixer mixing, centrifugal, in triplicate, centrifugal complete, abandon supernatant liquor ,-80 DEG C will be deposited in and store for future use.
Receptor Binding Assay material:
Isotropic substance aglucon [ 3h]-paroxetine, purchased from PerkinElmer company; Paroxetine, purchased from sigma-aldrich company; GF/C glass fiber filter paper, purchased from Whatman company; Tris import packing; PPO, POPOP are purchased from Shanghai reagent one factory; Fat-soluble scintillation solution.BeckmanLS-6500 type full-service fluid scintillation counter.
Experimental technique:
(1) the appropriate homogenate of film first will prepared, is uniformly dispersed with refiner, is mixed in the container of 100ml by 15 test tubes, adds the suspension that appropriate homogenate is 50ml film, for subsequent use;
(2) each reaction tubes adds film preparation thing 100 μ L respectively, homogenate 100 μ L;
(3) total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds paroxetine100 μ L(final concentration 10 -5m), each test-compound specific binding pipe (SB) adds 100 μ L test-compound (final concentrations 10 -5m);
(4) each reaction tubes adds radioligand respectively 3the each reaction tubes of H-paroxetine10 μ L(all establishes 3 parallel pipes, and during application of sample, each pipe is placed on ice);
(5) each reaction tubes 23 DEG C of temperature are incubated 60min, react complete, in conjunction with aglucon by decompression fast filtering, fully wash with ice-cold test damping fluid, by filter disc take out be put in 3ml scintillating disc, add the toluene scintillation solution of 2ml and mix;
(6) scintillation vial is put into liquid scintillation counter counting.
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%
Compound is tested at every turn and is done three parallel samples.
Experimental result is in table 2.
Vitro Experimental Results shows that compound 1 and 6 is to two kinds of acceptor (5HT 1Aand SERT) stronger avidity.
Embodiment 27
Tail suspension test
Laboratory animal and reagent
Healthy Kunming mouse, male and female half and half, body weight (20 ± 2) g, is provided by Qinglongshan animal cultivation center, Nanjing.
Fluoxetine, sigma-aldrich company;
Experimental technique
Experiment a few days ago filters out the qualified mouse of body weight and divides into groups, mouse is put into 6min on lever by D1, the dead time of 4min after record, filter out the dead time the mouse of 60s ~ 180s and set up 60s ~ 90s, 90s ~ 120s, then 120s ~ 180s tetra-levels carry out random packet mouse at all levels, often organize 10, set up blank group, positive controls and be subject to each administration group of reagent.D2, after mouse stomach administration 1h, is put into 6min on lever by mouse, the dead time of 4min after record.
Motionless standard: what is called is motionless refers to that mouse static stopping on lever is struggled or presented the state of playing on a swing.
Obtain the mean value of each group of mouse dead time, result represents with " means standard deviation ", the result of administration group and control group is carried out t and checks whether there is antidepressant, with P<0.05 for there being significant difference to evaluate test medicine.
Experimental result is in table 2.
Observe by experiment, the compound 1 and 6 gastric infusion 80mg/kg dead time significantly reduces.Compared with blank, the dead time of compound 1 reduces 63.4%, and its action effect is better than fluoxetine, and the dead time of compound 6 reduces 54.4%, and its action effect is suitable with fluoxetine.
Table 2 compound is to the IC of each acceptor 50
Table 3 compound is on the impact of Tail suspension test dead time
Compound Dosage (mg/kg) Dead time (s)
Blank 108
Fluoxetine 80 48.8±4.2
1 80 39.5±4.2
2 80 79.9±4.7
5 80 71.1±6.2
6 80 49.2±5.3
13 80 93.2±3.5
14 80 95.5±4.4
21 80 63.0±4.1
C, composition embodiment
Embodiment 28
It is for subsequent use that supplementary material crosses 80 mesh sieves; take recipe quantity activeconstituents, Microcrystalline Cellulose, lactose, PVP K30, join in high-speed mixing granulating machine, stirring at low speed mixes; add appropriate purified water; stirring at low speed, high-speed cutting is granulated, wet granular 60 DEG C of dry 3h; the whole grain of 24 mesh sieve; add recipe quantity carboxymethylstach sodium, silicon-dioxide and Magnesium Stearate, always mix, rotary tablet machine compressing tablet.
Embodiment 29
It is for subsequent use that supplementary material crosses 80 mesh sieves; take recipe quantity activeconstituents, lactose, starch, PVP K30, join in high-speed mixing granulating machine, stirring at low speed mixes; add appropriate purified water; stirring at low speed, high-speed cutting is granulated, wet granular 60 DEG C of dry 3h; the whole grain of 24 mesh sieve; add recipe quantity silicon-dioxide and Magnesium Stearate, always mix, capsule filling machine filled capsules.

Claims (11)

1. Benzodioxane derivative, is characterized in that, for having such as formula the compound shown in (I) or its medically acceptable salt;
Wherein:
R 1represent hydrogen, halogen, aryl, substituted aryl, C 1-5the C of alkyl or replacement 1-5alkyl;
R 2represent hydrogen, halogen, methoxyl group, cyano group, C 1-5the C of alkyl or replacement 1-5alkyl;
N is 1 or 2;
The substituting group of described substituted aryl is C 1-5alkyl, C 1-5alkoxy or halogen;
Described aryl is phenyl;
The C of described replacement 1-5alkyl is C 1-5haloalkyl or C 1-5hydroxyalkyl.
2. Benzodioxane derivative according to claim 1, is characterized in that, the aryl of described replacement is chlorophenyl, difluorophenyl, aminomethyl phenyl, ethylphenyl, isopropyl phenyl or p-methoxy-phenyl.
3. Benzodioxane derivative according to claim 1, is characterized in that, described C 1-5alkyl is methyl, ethyl, propyl group, butyl, n-pentyl, isopentyl or neo-pentyl.
4. Benzodioxane derivative according to claim 1, is characterized in that, the C of described replacement 1-5alkyl is C 1-5haloalkyl is trifluoromethyl.
5. Benzodioxane derivative according to claim 1, is characterized in that, described C 1-5hydroxyalkyl is methylol.
6. Benzodioxane derivative according to claim 1, is characterized in that, R 1for hydrogen, methyl or phenyl, R 2for hydrogen, methyl, fluorine or chlorine.
7. Benzodioxane derivative according to claim 1, is characterized in that, is selected from following compound or its pharmacy acceptable salt:
Code name 1:3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
The fluoro-3-of code name 2:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
The chloro-3-of code name 3:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
Code name 4:3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-5-Methyl-1H-indole;
Code name 5:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
The fluoro-3-of code name 6:5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
The chloro-3-of code name 7:5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
Code name 8:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-5-Methyl-1H-indole;
Code name 9:3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
The fluoro-3-of code name 10:5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
The chloro-3-of code name 11:5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-1H-indoles;
Code name 12:3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) ethyl)-5-Methyl-1H-indole;
Code name 13:3-(3-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
The fluoro-3-of code name 14:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
The chloro-3-of code name 15:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
Code name 16:3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-5-Methyl-1H-indole;
Code name 17:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
The fluoro-3-of code name 18:5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
The chloro-3-of code name 19:5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
Code name 20:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-5-Methyl-1H-indole;
Code name 21:3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-5-Methyl-1H-indole;
The fluoro-3-of code name 22:5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles;
The chloro-3-of code name 23:5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-base) methyl) piperazine-1-base) propyl group)-1H-indoles.
8. the Benzodioxane derivative according to any one of claim 1 ~ 7, it is characterized in that, described medically acceptable salt is selected from hydrochloride, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, acetate, lactic acid salt, Citrate trianion, tartrate, maleate, fumarate, mesylate, gluconate, saccharate, benzoate, esilate, benzene sulfonate or tosilate.
9. a pharmaceutical composition, comprises the Benzodioxane derivative described in any one of claim 1 ~ 8 for the treatment of significant quantity.
10. the application of the Benzodioxane derivative described in any one of claim 1 ~ 8 in preparation treatment or prevention Nervous and mental diseases medicine.
11. application according to claim 10, it is characterized in that, described Nervous and mental diseases is selected from mental disorder, anxiety disorder, personality disorder, dysthymia disorders, manic disorder, migraine, epilepsy or convulsive disorder, childhood disorder, Parkinson's disease, cognitive disorder, neurodegeneration or neurotoxicity.
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