CN103420989A - Benzodioxane derivative and applications thereof - Google Patents

Benzodioxane derivative and applications thereof Download PDF

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Publication number
CN103420989A
CN103420989A CN2012101504209A CN201210150420A CN103420989A CN 103420989 A CN103420989 A CN 103420989A CN 2012101504209 A CN2012101504209 A CN 2012101504209A CN 201210150420 A CN201210150420 A CN 201210150420A CN 103420989 A CN103420989 A CN 103420989A
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methyl
diox
nitrae
isosorbide
piperazine
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CN103420989B (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 present invention discloses a benzodioxane derivative and applications thereof, and relates to a compound represented by a formula (I) or a medically acceptable salt thereof. According to the present invention, experiment results show that the benzodioxane derivative can be used for preparation of neuropsychic disease treatment drugs, in vitro receptor binding test results show that the derivative provides high affinity for SERT and 5-HT1A receptors, and animal test results show that an immobility time of mice can be significantly reduced in the acute treatment with the compound, such that the compound of the present invention provides a neuropsychic disease treatment effect, especially a depression treatment effect.

Description

Benzodioxan analog derivative and application thereof
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of benzodioxan analog derivative and the application in the 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 global Serious depression patient in 2002 has more than 8,900 ten thousand people, 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 approach 6% left and right in developed country, and 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 all effective antidepressant drugs now are based on the clinical effective medicine of two classes of finding before 50 years: Iricyclic antidepressants and oxidase inhibitor.Monoamine hypothesis is thought: dysthymia disorders is disorderly the causing of transmission generation due to serotonin in human body and norepinephrine.On the basis of this hypothesis, think the transmission of norepinephrine and serotonin in tricyclic antidepressants medicine 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 is from the tricyclic antidepressants drug development, more safer than tricyclic antidepressants medicine, and tolerance is better, have now become the main flow antidepressant drug of clinical use.It has suppressed the re-uptake of synaptic cleft serotonin, has increased the concentration of synaptic cleft serotonin.Although five amine reuptake inhibitors are compared in security and are significantly improved with tricyclic antidepressant, aspect curative effect and on onset speed, there is no improvement.
Although five amine reuptake inhibitors can improve rapidly synaptic cleft 5-HT level within a few hours, activate 5-HT simultaneously 1AAutoreceptor produces the negative feedback inhibition effect, causes that the electric discharge of 5-HT neurone reduces, and then suppresses even to cancel the projected area 5-HT levels such as cortex, hippocampus and raises, this 5-HT 1AAutoreceptor activates the negative feedback inhibition effect caused and is considered to bring into play keying action in antidepressant drug onset deferring procedure.After administration 2～6 weeks, 5-HT 1AThe autoreceptor desensitization, the 5-HT neurone recovers regular discharge, thereby produces antidepressant effect.
Onset postpones not only to reduce the depressive patients compliance, has also increased its danger property of committing suiside, so the newly-developed antidepressant research and development are made every effort to innovating to some extent and breaking through aspect quickening onset speed.
Summary of the invention
The objective of the invention is to disclose a kind of benzodioxan analog derivative, the above-mentioned defect existed to overcome prior art.
Another object of the present invention is and application discloses the application of described benzodioxan analog derivative in preparing the Cure of depression medicine.
Benzodioxan analog derivative of the present invention, for a kind of 3-, ((4-((2 for 2-, 3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl) piperazine-1-yl) alkyl)-1H-indole derivatives, for having compound or its medically acceptable salt as shown in the formula (I);
Figure BDA00001641574700021
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, preferably 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 benzodioxan analog 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-yl) methyl) piperazine-1-yl) ethyl)-the 1H-indoles;
The fluoro-3-of code name 2:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 1H-indoles;
The chloro-3-of code name 3:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 1H-indoles;
Code name 4:3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 5-Methyl-1H-indole;
Code name 5:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) 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-yl) methyl) piperazine-1-yl) 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-yl) methyl) piperazine-1-yl) ethyl)-1H-indoles;
Code name 8:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-5-Methyl-1H-indole;
Code name 9:3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 1H-indoles;
The fluoro-3-of code name 10:5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 1H-indoles;
The chloro-3-of code name 11:5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 1H-indoles;
Code name 12:3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 5-Methyl-1H-indole;
Code name 13:3-(3-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-the 1H-indoles;
The fluoro-3-of code name 14:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-the 1H-indoles;
The chloro-3-of code name 15:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-the 1H-indoles;
Code name 16:3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-the 5-Methyl-1H-indole;
Code name 17:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) 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-yl) methyl) piperazine-1-yl) 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-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles;
Code name 20:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-5-Methyl-1H-indole;
Code name 21:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-5-Methyl-1H-indole;
The fluoro-3-of code name 22:5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles;
The chloro-3-of code name 23:5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles;
Code name 24:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) 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), comprise the steps:
Step (1): by carbon tetrabromide, under triphenylphosphine catalysis, the 3-ethyl shown in bromination formula (A)/propyl indole alcohol derivatives, obtain 3-bromotrifluoromethane/propyl indole analog derivative;
Formula (A) compound, can adopt the method preparation of document Org.Lett.6 (2004) 79-82 report, and raw material all comes from Aladdin reagent company;
Step (2): the benzodioxan methyl alcohol of compound-3 replacement shown in formula (B) and Tosyl chloride at room temperature stir after being dissolved in pyridine, and reaction generates sulphonate;
Compound shown in formula (B), can adopt the method preparation of document J.Med.Chem.36 (1993) 1520-1528 report, and raw material all comes from Aladdin reagent company;
Step (3): described sulphonate and piperazine are dissolved in to ethanol, temperature rising reflux reaction, synthetic 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, reflux, and obtain target product.
For example, can be as shown in following reactions steps, synthetic the compounds of this invention:
Step (1)
Figure BDA00001641574700051
Step (2)
Figure BDA00001641574700052
Step (3)
Figure BDA00001641574700053
Step (4)
Figure BDA00001641574700054
In above-mentioned reaction expression, R 1, R 2, n defines with above-mentioned.
The present invention also provides a kind of pharmaceutical composition, comprise the compound shown in the formula (I) for the treatment of significant quantity or its medically acceptable salt and pharmaceutically acceptable auxiliary material, as carrier and/or vehicle etc., this pharmaceutical composition is to contain to be enough to produce the compound of the present invention of antipsycholic action or the antipsychotic composition of its medically acceptable salt;
The pharmaceutical composition the present invention relates to, its per unit dosage can provide approximately 0.01 to 1000mg activeconstituents.Composition can be used by any suitable approach, and for example capsule form is oral, with the form parenteral of injection liquid, uses, 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, can be by the form of pharmaceutical composition, put on the patient who needs treatment, these preparations should contain at least active compound of the present invention of 0.5wt%, but can change according to specific formulation, account for unit weight 4% to 70% being approximately easily, in such composition.The amount of active compound should reach suitable dosage.The active compound of the present invention that the composition that the present invention is preferential and the oral dosage of preparation contain the 1.0-300 milligram.
Dosage of the present invention, depend on type and the seriousness of disease or illness, also depends on the feature of object, for example general health, age, sex, body weight and drug tolerance.The technician can determine suitable dosage according to these or other factors.Usually the effective dose of medicine for central nervous system used is known by the technical staff.Every TDD usually at about 0.05mg between 2000mg.
Compound of the present invention can contain chiral centre, and can exist with different enantiomorphs and diastereomer form thus.The present invention relates to all optically active isomers and all steric isomers of the compounds of this invention, as the form of the racemic mixture of this compounds and each enantiomorph and diastereomer, and the present invention relates separately to as above-mentioned defined all pharmaceutical compositions and the methods for the treatment of that contains or use them.
In addition, derivative provided by the invention and the pharmaceutical composition formed by derivative, can be applicable to preparation treatment or prevention Nervous and mental diseases medicine aspect, described Nervous and mental diseases be selected from mental disorder, anxiety disorder, personality disorder, dysthymia disorders, manic disorder, migraine, epilepsy or spastic obstacle, the Childhood obstacle, Parkinson's disease, cognitive disorder, neurodegeneration, neurotoxicity and local asphyxia; Preferred dysthymia disorders.
Extracorporeal receptor shows in conjunction with test, and derivative involved in the present invention is to SERT and 5-HT 1AAcceptor has higher avidity.
The animal test results demonstration, this compounds, in acute treatment, can obviously reduce the mouse dead time, and the compound therefore the present invention relates to has the effect for the treatment of Nervous and mental diseases, especially dysthymia disorders is had to therapeutic action.
Embodiment
The following examples just for the purpose of description and not as restriction of the present invention.Except as otherwise noted, all temperature be centigradetemperature (℃).
The embodiment of A, synthetic aspect
Embodiment 1
3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-1H-indoles (code name: 1)
1) triphenylphosphine of 0.025mol is dissolved in the acetonitrile of 80ml drying, drips acetonitrile (75ml) solution of 0.02mol 3-(2-bromotrifluoromethane)-1H-indoles.Then, drip acetonitrile (25ml) solution of 0.027mol carbon tetrabromide, stir at normal temperatures 3 hours, except desolventizing, column chromatography, obtain faint yellow oily matter.
2) 1.98g (2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl alcohol is dissolved in the pyridine of 30ml drying, is cooled to 0 ℃, adds the 6.9g Tosyl chloride, stirs, and at room temperature reacts 18 hours.After having reacted, 300ml ether dilution for reaction solution, with dilute hydrochloric acid washing, washing, the organic layer anhydrous magnesium sulfate drying, remove ether and obtain white solid, column chromatography (sherwood oil: ethyl acetate=4:1) obtain yellow oil.
3) 2.24g (2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl 4-aminomethyl phenyl sulphonate is dissolved in 20ml ethanol, add the 11.9g piperazine, the temperature rising reflux reaction, react 36 hours, after having reacted, except desolventizing, residuum adds the sodium hydroxide solution that the 50ml weight concentration is 2.5%, uses chloroform extraction, the organic layer anhydrous magnesium sulfate drying, obtain yellow oily liquid except desolventizing, after cooling faint yellow solid, fusing point: 213-216 ° of C(hydrochloride).
4) 0.4g 1-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methylpiperazine is dissolved in the 10ml anhydrous acetonitrile, adds 0.5g3-(2-bromotrifluoromethane)-1H-indoles, the 0.9g Anhydrous potassium carbonate, and the 0.35g potassiumiodide, temperature rising reflux, react 10 hours.Cooling, filter, and 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 ° of 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/z 378.1([M+H] +)。
Embodiment 2
The fluoro-3-of 5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-1H-indoles (code name: 2)
3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(2-bromotrifluoromethane)-fluoro-1H-indoles of 5-, by the method for embodiment 1, prepares target compound.
Fusing point: 223 ° of 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/z 396.1([M+H] +)
Embodiment 3
The chloro-3-of 5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-1H-indoles (code name: 3)
3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(2-bromotrifluoromethane)-chloro-1H-indoles of 5-, by the method for embodiment 1, prepares target compound.
Fusing point: 225 ° of 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/z 412.0([M+H] +)。
Embodiment 4
3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-5-Methyl-1H-indole (code name: 4)
3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(2-bromotrifluoromethane)-5-Methyl-1H-indole, by the method for embodiment 1, prepares target compound.
Fusing point: 226 ° of 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/z 392.1([M+H] +)。
Embodiment 5
3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-1H-indoles (code name: 5)
(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl alcohol, by the method for embodiment 1, prepares target compound.
Fusing point: 234 ° of 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/z 392.1([M+H] +)
Embodiment 6
The fluoro-3-of 5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-1H-indoles (code name: 6)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] dioxs-3-yl) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(2-bromotrifluoromethane)-fluoro-1H-indoles of 5-, by the method for embodiment 1, prepares target compound.
Fusing point: 232 ° of 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/z 411.1([M+H] +)
Embodiment 7
The chloro-3-of 5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-1H-indoles (code name: 7)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] dioxs-3-yl) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(2-bromotrifluoromethane)-chloro-1H-indoles of 5-, by the method for embodiment 1, prepares target compound.
Fusing point: 234 ° of 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/z 426.1([M+H] +)
Embodiment 8
3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-5-Methyl-1H-indole (code name: 8)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] dioxs-3-yl) methyl alcohol, 3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(2-bromotrifluoromethane)-5-Methyl-1H-indole, by the method for embodiment 1, prepares target compound.
Fusing point: 221 ° of 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/z 406.1([M+H] +)
Embodiment 9
3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-1H-indoles (code name: 9)
Will (2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl alcohol be changed to (2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox 3-yl) methyl alcohol, by the method for embodiment 1, prepare target compound.
Fusing point: 213 ° of 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/z 454.3([M+H] +)
Embodiment 10
The fluoro-3-of 5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-1H-indoles (code name: 10)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [1,4] diox 3-yls) methyl alcohol, be changed to 3-(2-bromotrifluoromethane)-fluoro-1H-indoles of 5-by 3-(2-bromotrifluoromethane)-1H-indoles and prepare target compound by the method for embodiment 1.
Fusing point: 205 ° of 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/z 472.2([M+H] +).
Embodiment 11
The chloro-3-of 5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-1H-indoles (code name: 11)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [1,4] diox 3-yls) methyl alcohol, be changed to 3-(2-bromotrifluoromethane)-chloro-1H-indoles of 5-by 3-(2-bromotrifluoromethane)-1H-indoles and prepare target compound by the method for embodiment 1.
Fusing point: 219 ° of 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/z 488.2([M+H] +)
Embodiment 12
3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-5-Methyl-1H-indole (code name: 12)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [1,4] diox 3-yls) methyl alcohol, be changed to 3-(2-bromotrifluoromethane)-5-Methyl-1H-indole by 3-(2-bromotrifluoromethane)-1H-indoles and prepare target compound by the method for embodiment 1.
Fusing point: 203 ° of 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/z 468.3([M+H] +)
Embodiment 13
3-(3-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles (code name: 13)
3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(2-bromopropyl)-1H-indoles and by the method for embodiment 1, prepares target compound.
Fusing point: 244 ° of 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/z 392.1([M+H] +)
Embodiment 14
The fluoro-3-of 5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles (code name: 14)
3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(3-bromopropyl)-fluoro-1H-indoles of 5-and by the method for embodiment 1, prepares target compound.
Fusing point: 252 ° of 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/z 410.1([M+H] +)
Embodiment 15
The chloro-3-of 5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles (code name: 15)
3-(2-bromotrifluoromethane)-1H-indoles is changed to 3-(3-bromopropyl)-chloro-1H-indoles of 5-and by the method for embodiment 1, prepares target compound.
Fusing point: 247 ° of 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/z 426.0([M+H] +)
Embodiment 16
3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) 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 by the method for embodiment 1, prepares target compound.
Fusing point: 244 ° of 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/z 406.1([M+H] +)
Embodiment 17
3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles (code name: 17)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] dioxs-3-yl) methyl alcohol, be changed to 3-(3-bromopropyl)-1H-indoles by 3-(2-bromotrifluoromethane)-1H-indoles and prepare target compound by the method for embodiment 1.
Fusing point: 240 ° of 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/z 406.1([M+H] +)
Embodiment 18
The fluoro-3-of 5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles (code name: 18)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] dioxs-3-yl) methyl alcohol, be changed to 3-(3-bromopropyl)-fluoro-1H-indoles of 5-by 3-(2-bromotrifluoromethane)-1H-indoles and prepare target compound by the method for embodiment 1.
Fusing point: 249 ° of 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/z 424.1([M+H] +)
Embodiment 19
The chloro-3-of 5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles (code name: 19)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] dioxs-3-yl) methyl alcohol, be changed to 3-(3-bromopropyl)-chloro-1H-indoles of 5-by 3-(2-bromotrifluoromethane)-1H-indoles and prepare target compound by the method for embodiment 1.
Fusing point: 245 ° of 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/z 440.1([M+H] +)
Embodiment 20
3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-5-Methyl-1H-indole (code name: 20)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-methyl benzo [b] [1,4] dioxs-3-yl) methyl alcohol, be changed to 3-(3-bromopropyl)-5-Methyl-1H-indole by 3-(2-bromotrifluoromethane)-1H-indoles and prepare target compound by the method for embodiment 1.
Fusing point: 239 ° of 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(m 2H),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/z 420.1([M+H] +)
Embodiment 21
3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-5-Methyl-1H-indole (code name: 21)
Will (2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl alcohol be changed to (2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl alcohol, by the method for embodiment 1, prepare target compound.
Fusing point: 214 ° of 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/z 468.3([M+H] +)
Embodiment 22
The fluoro-3-of 5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles (code name: 22)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [1,4] dioxs-3-yl) methyl alcohol, be changed to 3-(3-bromopropyl)-1H-indoles by 3-(2-bromotrifluoromethane)-1H-indoles and prepare target compound by the method for embodiment 1.
Fusing point: 234 ° of 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/z 486.3([M+H] +)
Embodiment 23
The chloro-3-of 5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles (code name: 23)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [1,4] dioxs-3-yl) methyl alcohol, be changed to 3-(3-bromopropyl)-chloro-1H-indoles of 5-by 3-(2-bromotrifluoromethane)-1H-indoles and prepare target compound by the method for embodiment 1.
Fusing point: 228 ° of 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/z 502.2([M+H] +)
Embodiment 24
3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-5-Methyl-1H-indole (code name: 24)
By (2,3-dihydrobenzo [b] [1,4] dioxs-3-yl) methyl alcohol is changed to (2,3-dihydro-2-phenyl benzo [b] [1,4] dioxs-3-yl) methyl alcohol, be changed to 3-(3-bromopropyl)-5-Methyl-1H-indole by 3-(2-bromotrifluoromethane)-1H-indoles and prepare target compound by the method for embodiment 1.
Fusing point: 221 ° of 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/z 482.3([M+H] +)
Preferred compound numbering and structural formula thereof prepared by table 1 embodiment
Figure BDA00001641574700161
Figure BDA00001641574700171
Figure BDA00001641574700181
The embodiment of B, pharmacology aspect
Execute example 25
5HT 1AThe preparation of film
The rat broken end, operation, get rapidly cortex on ice, adds 3ml damping fluid (the Tris-HCl damping fluid of 0.05M, xitix, 10um Supirdyl and 4mM CaCl containing 0.1% 2) in 4 grades of 3-4s homogenate, homogenate 4 times, then add the 5ml damping fluid, in 37 ℃ of hatching 10min, hatched rear test tube and adjusted weight with balance, at 12000r, 4 ℃ of centrifugal 20min, abandon supernatant liquor, adds the 5ml damping fluid, with vortex mixer, mix, centrifugal, triplicate, centrifugal complete, abandon supernatant liquor, will be deposited in-80 ℃ and store for future use.
The receptors bind experiment material:
The isotropic substance aglucon 3H-8-OH-DPAT(67.0Ci/mmol), purchased from PerkinElmer company; 5-HT, purchased from RBI company; The 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.Beckman LS-6500 type full-service fluid scintillation counter.
Experimental technique:
(1) first by the appropriate homogenate for film prepared, with refiner, be uniformly dispersed, 15 test tubes are blended in the container of 100ml, add appropriate homogenate to be the suspension of 50ml film, standby.
(2) each reaction tubes adds respectively film preparation thing 100 μ L, homogenate 100 μ L.
(3) total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds 5-HT 100 μ L(final concentrations 10 -5M), each test-compound specific binding pipe (SB) adds 100 μ L test-compound (final concentrations 10 -5M);
(4) each reaction tubes adds respectively radioligand 3H-8-OH-DPAT 10 each reaction tubess of μ L(are all established 3 parallel pipes, and during application of sample, each pipe is placed on ice);
(5) 37 ℃ of temperature of each reaction tubes are incubated to 10min, react complete, in conjunction with aglucon by the decompression fast filtering, with ice-cold test damping fluid, fully wash, filter disc taking-up is put in the 3ml scintillating disc, add the toluene scintillation solution of 2ml and mix;
(6) scintillation vial is put into to the liquid scintillation counter counting.
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) * 100%
Three parallel samples are done in the each experiment of compound.
Experimental result is in Table 2
Execute example 26
The preparation of SERT film
The rat broken end, operation, get rapidly cortex on ice, adds 3ml damping fluid (the Tris-HCl damping fluid of 0.05M, containing NaCl 120mM, KCl 5mM) in 4 grades of 3-4s homogenate, homogenate 4 times, then add the 5ml damping fluid, in 23 ℃ of hatching 10min, hatched rear test tube and adjusted weight with balance, at 12000r, 4 ℃ of centrifugal 20min, abandon supernatant liquor, adds the 5ml damping fluid, with vortex mixer, mix, centrifugal, triplicate, centrifugal complete, abandon supernatant liquor, will be deposited in-80 ℃ and store for future use.
The receptors bind experiment material:
The isotropic substance aglucon [ 3H]-paroxetine, purchased from PerkinElmer company; Paroxetine, purchased from sigma-aldrich company; The 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.Beckman LS-6500 type full-service fluid scintillation counter.
Experimental technique:
(1) first by the appropriate homogenate for film prepared, with refiner, be uniformly dispersed, 15 test tubes are blended in the container of 100ml, add appropriate homogenate to be the suspension of 50ml film, standby;
(2) each reaction tubes adds respectively film preparation thing 100 μ L, homogenate 100 μ L;
(3) total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds paroxetine 100 μ L(final concentrations 10 -5M), each test-compound specific binding pipe (SB) adds 100 μ L test-compound (final concentrations 10 -5M);
(4) each reaction tubes adds respectively radioligand 3H-paroxetine 10 each reaction tubess of μ L(are all established 3 parallel pipes, and during application of sample, each pipe is placed on ice);
(5) 23 ℃ of temperature of each reaction tubes are incubated to 60min, react complete, in conjunction with aglucon by the decompression fast filtering, with ice-cold test damping fluid, fully wash, filter disc taking-up is put in the 3ml scintillating disc, add the toluene scintillation solution of 2ml and mix;
(6) scintillation vial is put into to the liquid scintillation counter counting.
Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) * 100%
Three parallel samples are done in the each experiment of compound.
Experimental result is in Table 2.
The experiment in vitro result shows compound 1 and 6 couples of 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, provided by Qinglongshan animal cultivation center, Nanjing.
Fluoxetine, sigma-aldrich company;
Experimental technique
Experiment a few days ago filters out mouse the grouping that body weight is qualified, D1 is put into 6min on lever by mouse, the dead time of 4min after record, filter out the dead time the mouse of 60s～180s and set up 60s～90s, 90s～120s, tetra-levels of 120s～180s then mouse at all levels to be carried out to random packet, every group 10, set up blank group, positive controls and be subject to each administration group of reagent.D2, after mouse stomach administration 1h, be 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 struggles or present the state of playing on a swing.
Obtain the mean value of respectively organizing the mouse dead time, result means with " means standard deviation ", the result of administration group and control group are carried out to the t check and to estimate tested medicine, whether have antidepressant, with P<0.05 for significant difference is arranged.Experimental result is in Table 2.
Observe by experiment, compound 1 and 6 gastric infusion 80mg/kg dead times significantly reduce.With blank, compare, 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 and fluoxetine are suitable.
The IC of table 2 compound to each acceptor 50
Figure BDA00001641574700211
The impact of table 3 compound on the 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
Tablet:
Figure BDA00001641574700221
It is standby that supplementary material is crossed 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, 60 ℃ of dry 3h of wet granular; the whole grain of 24 mesh sieves; add recipe quantity carboxymethylstach sodium, silicon-dioxide and Magnesium Stearate, total mixed, the rotary tablet machine compressing tablet.
Embodiment 29
It is standby that supplementary material is crossed 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, 60 ℃ of dry 3h of wet granular; the whole grain of 24 mesh sieves; add recipe quantity silicon-dioxide and Magnesium Stearate, total mixed, the capsule filling machine filled capsules.

Claims (15)

1. the benzodioxan analog derivative, is characterized in that, for having compound or its medically acceptable salt as shown in the formula (I);
Figure DEST_PATH_FDA00001842037800011
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.
2. benzodioxan analog derivative according to claim 1, is characterized in that, the substituting group of described substituted aryl is C 1-5Alkyl, C 1-5Alkoxy or halogen.
3. benzodioxan analog derivative according to claim 1, is characterized in that, described aryl is phenyl.
4. benzodioxan analog derivative according to claim 2, is characterized in that, described aryl is phenyl.
5. benzodioxan analog 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.
6. benzodioxan analog 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.
7. benzodioxan analog derivative according to claim 1, is characterized in that, the C of described replacement 1-5Alkyl is C 1-5Haloalkyl or C 1-5Hydroxyalkyl.
8. benzodioxan analog derivative according to claim 7, is characterized in that, the C of described replacement 1-5Alkyl is C 1-5Haloalkyl is trifluoromethyl.
9. benzodioxan analog derivative according to claim 7, is characterized in that, described C 1-5Hydroxyalkyl is methylol.
10. benzodioxan analog derivative according to claim 1, is characterized in that R 1For hydrogen, methyl or phenyl, R 2For hydrogen, methyl, fluorine or chlorine.
11. the benzodioxan analog derivative, 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-yl) methyl) piperazine-1-yl) ethyl)-the 1H-indoles;
The fluoro-3-of code name 2:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 1H-indoles;
The chloro-3-of code name 3:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 1H-indoles;
Code name 4:3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 5-Methyl-1H-indole;
Code name 5:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) 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-yl) methyl) piperazine-1-yl) 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-yl) methyl) piperazine-1-yl) ethyl)-1H-indoles;
Code name 8:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-5-Methyl-1H-indole;
Code name 9:3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 1H-indoles;
The fluoro-3-of code name 10:5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 1H-indoles;
The chloro-3-of code name 11:5-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 1H-indoles;
Code name 12:3-(2-(4-((2,3-dihydro-2-phenyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) ethyl)-the 5-Methyl-1H-indole;
Code name 13:3-(3-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-the 1H-indoles;
The fluoro-3-of code name 14:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-the 1H-indoles;
The chloro-3-of code name 15:5-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-the 1H-indoles;
Code name 16:3-(2-(4-((2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-the 5-Methyl-1H-indole;
Code name 17:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) 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-yl) methyl) piperazine-1-yl) 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-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles;
Code name 20:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-5-Methyl-1H-indole;
Code name 21:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-5-Methyl-1H-indole;
The fluoro-3-of code name 22:5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles;
The chloro-3-of code name 23:5-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-1H-indoles;
Code name 24:3-(2-(4-((2,3-dihydro-2-methyl benzo [b] [Isosorbide-5-Nitrae] diox-3-yl) methyl) piperazine-1-yl) propyl group)-5-Methyl-1H-indole.
12. according to the described benzodioxan analog derivative of claim 1～11 any one, 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.
13. a pharmaceutical composition, comprise that the described benzodioxan class of claim 1～12 any one for the treatment of significant quantity spreads out.
14. the application of the described benzodioxan analog derivative of claim 1～12 any one in preparation treatment or prevention Nervous and mental diseases medicine.
15. application according to claim 14, it is characterized in that, described Nervous and mental diseases be selected from mental disorder, anxiety disorder, personality disorder, dysthymia disorders, manic disorder, migraine, epilepsy or spastic obstacle, the Childhood obstacle, Parkinson's disease, cognitive disorder, neurodegeneration, neurotoxicity or local asphyxia.
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