CN106279153A - Substituted benzazolyl compounds and using method thereof and purposes - Google Patents

Substituted benzazolyl compounds and using method thereof and purposes Download PDF

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Publication number
CN106279153A
CN106279153A CN201610473748.2A CN201610473748A CN106279153A CN 106279153 A CN106279153 A CN 106279153A CN 201610473748 A CN201610473748 A CN 201610473748A CN 106279153 A CN106279153 A CN 106279153A
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compound
base
present
annular atoms
group
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CN106279153B (en
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金传飞
高金恒
张英俊
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The present invention relates to a substituted benzazolyl compounds of class and using method thereof and purposes, and comprise the medical composition and its use of this compounds；Described compound or pharmaceutical composition can be used for suppressing 5 hydroxytryptamine reuptake.The method that the invention still further relates to prepare this compounds and pharmaceutical composition, and they purposes in pivot nervous system dysfunction in the treatment.

Description

Substituted benzazolyl compounds and using method thereof and purposes
Technical field
The invention belongs to technical field of pharmaceuticals, be particularly used for treat central nervous system dysfunction compound, Compositions and using method thereof and purposes.Especially, of the present invention can be as serotonin reuptake inhibitor Benzazolyl compounds.
Background technology
5-hydroxy tryptamine, a kind of neurotransmitter transmitting signal in brain and nervous system, at central nervous system (CNS) In dysfunction, especially anxiety, depression, invade and get excited in emotion, play important role.Antagonism or exciting certain class The 5-hydroxytryptamine receptor of type can regulate and control central nervous system dysfunction effectively.Up to now, at least 14 kinds of 5-hydroxyl colors Amine receptor is identified.These receptors can be divided into different family, is denoted as 5-HT respectively1、5-HT2、5-HT3、5-HT4、5-HT5、5-HT6 And 5-HT7, the different subtype in each race is then distinguished with a, b and c etc..
In all indications relevant to 5-hydroxy tryptamine dysfunction, depression is most important, because defending according to the world Raw Organization, depression has become the mankind's the fourth-largest burden disease.Expecting the year two thousand twenty, the disability of depression adjusts the life-span Annual meeting leaps to the second of all diseases.(Bromet E,Andrade LH,Hwang I,et al.,Cross-national epidemiology of DSM-IV major depressive episode.BMCMed.2011,9:90)。
In history, the Drug therapy of dysthymic disorder starts from the 1950's, including tricyclic antidepressant (TCAs) and Oxidase inhibitor (MAOIs), these medicines are mainly by neurotransmitter (dopamine, norepinephrine and 5-hydroxyl color Amine) blocking effect play curative effect.But, the non-selective and less desirable side effect to target limits making of they With.To the eighties in 20th century, the appearance of selective serotonin reuptake inhibitor (SSRIs), change this situation.With TCAs compares, and this kind of curative effect of medication is suitable, but side effect is little, though excessive use, the least (Sarko of toxicity of generation J.Andidepressant,old and new.Areview of their adverse effects and toxicity in overdose.Emerg Med Clin North Am,2000；18(4):637-54).
The invention provides some noval chemical compounds with serotonin reuptake transporter inhibitory activity, possess the most clinical answering Use prospect.Compared with existing similar compound, the compound of the present invention has more preferable drug effect, medicine for character and/or toxicity Characteristic.
Abstract of invention
Hereinafter some aspects of the present invention are only summarized, it is not limited to this.These aspects and other parts are later There is more complete explanation.All lists of references in this specification are incorporated in this by entirety.Work as the disclosure of the specification With quote document variant time, be as the criterion with the disclosure of the specification.
The present invention relates to the substituted benzazolyl compounds that a class is novel, it has stronger knot with 5-HT transporter (SERT) Close affinity, energy Selective depression 5-HT reuptake, such that it is able to be used for preparing treatment central nervous system (CNS) dysfunction Medicine, and the compounds of this invention stable in properties, safety is good, has pharmacodynamics and pharmacokinetic advantage, the best Good brain/blood plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability etc., therefore has Standby preferable potential applicability in clinical practice.
Compound of the present invention inhibitory action selective to serotonin reuptake transporter, may be used for preparing treatment maincenter Nervous system (CNS) dysfunction, the such as medicine of depression, anxiety neurosis, bipolar disorders.
The present invention also provides for preparing the method for this compounds and the pharmaceutical composition containing this compounds.
On the one hand, the present invention relates to a kind of compound, it is compound shown in the compound shown in formula (I) or formula (I) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein, each Q, R1、Ry、R2、R3, m, n and r there is implication as described in the present invention.
In one embodiment, Q is CH or N.
In one embodiment, each R1And RyIndependently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、C1-C6Alkyl, C1-C6Haloalkyl, C1-C6Alkoxyl or C1-C6Halogenated alkoxy, wherein said C1-C6Alkyl, C1-C6Haloalkyl, C1-C6 Alkoxyl and C1-C6Halogenated alkoxy is individually optionally by one or more RxReplaced；With each RxHave as described in the present invention Implication.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-C (=O) NH2、- COOH ,-C (=O) CH3、C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxyl, C1-C6Halo Alkoxyl, C3-C8Cycloalkyl, the heterocyclic radical of 3-10 annular atoms composition, C6-C10Aryl or the heteroaryl of 5-10 annular atoms composition Base, wherein said-C (O) CH3、C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxyl, C1-C6 Halogenated alkoxy, C3-C8Cycloalkyl, the heterocyclic radical of 3-10 annular atoms composition, C6-C10Aryl and 5-10 annular atoms composition Heteroaryl is individually optionally by one or more RxReplaced；With each RxThere is implication as described in the present invention.
In one embodiment, each R3Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、C1-C6Alkyl, C2-C6 Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxyl, C1-C6Halogenated alkoxy, C3-C8Cycloalkyl, 3-10 ring are former Molecular heterocyclic radical, C6-C10Aryl or the heteroaryl of 5-10 annular atoms composition, wherein said C1-C6Alkyl, C2-C6Alkene Base, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxyl, C1-C6Halogenated alkoxy, C3-C8Cycloalkyl, 3-10 annular atoms The heterocyclic radical of composition, C6-C10The heteroaryl of aryl and 5-10 annular atoms composition is individually optionally by one or more RxTaken Generation；With each RxThere is implication as described in the present invention.
In one embodiment, each RxIndependently be D, F, Cl, Br, I ,-NO2、-CN、-N3、-NH2,-OH ,-SH, oxo (=O), C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxyl, C1-C4Halogenated alkoxy, C1- C4Alkylamino, C1-C4Alkylthio group, NH2-(C1-C4Alkylidene)-, HO-(C1-C4Alkylidene)-, HS-(C1-C4Alkylidene)-, (C1- C4Alkoxyl)-(C1-C4Alkylidene)-, (C1-C4Alkylamino)-(C1-C4Alkylidene)-, (C1-C4Alkylthio group)-(C1-C4Alkylene Base)-, C3-C6Cycloalkyl, (C3-C6Cycloalkyl)-(C1-C4Alkylidene)-, the heterocyclic radical of 3-7 annular atoms composition, (3-7 ring Former molecular heterocyclic radical)-(C1-C4Alkylidene)-, phenyl, phenyl-(C1-C4Alkylidene)-, 5-6 annular atoms composition miscellaneous Aryl or (heteroaryl of 5-6 annular atoms composition)-(C1-C4Alkylidene)-.
In one embodiment, m is 0,1,2 or 3.
In one embodiment, n is 0,1,2,3 or 4.
In one embodiment, r is 0,1,2,3,4 or 5.
In another embodiment, each R1And RyIndependently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、C1-C4Alkyl, C1-C4Haloalkyl, C1-C4Alkoxyl or C1-C4Halogenated alkoxy, wherein said C1-C4Alkyl, C1-C4Haloalkyl, C1-C4 Alkoxyl and C1-C4Halogenated alkoxy is individually optionally by one or more RxReplaced；With each RxHave as described in the present invention Implication.
In yet another embodiment, each R1And RyIndependently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2, methyl, second Base, n-pro-pyl, isopropyl, methoxyl group, ethyoxyl, n-pro-pyl epoxide, isopropyl epoxide ,-CF3Or-OCF3。
In another embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-C (=O) NH2、- COOH ,-C (=O) CH3、C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxyl, C1-C4Halo Alkoxyl, C3-C6Cycloalkyl, the heterocyclic radical of 5-6 annular atoms composition, phenyl or the heteroaryl of 5-6 annular atoms composition, wherein Described-C (=O) CH3、C1-C4Alkyl, C2-C4Thiazolinyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxyl, C1-C4Halo Alkoxyl, C3-C6The heteroaryl of cycloalkyl, the heterocyclic radical of 5-6 annular atoms composition, phenyl and 5-6 annular atoms composition is independently appointed Selection of land is by one or more RxReplaced；With each RxThere is implication as described in the present invention.
In yet another embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-C (=O) NH2、- COOH ,-C (=O) CH3, methyl, ethyl, n-pro-pyl, isopropyl, methoxyl group, ethyoxyl, n-pro-pyl epoxide, isopropyl epoxide ,- CF3、-CH2CF3、-OCF3、-OCH2CF3Or-OCH2CF2CHF2。
In another embodiment, each R3Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2, methyl, ethyl, just Propyl group, isopropyl, methoxyl group, ethyoxyl, n-pro-pyl epoxide, isopropyl epoxide ,-CF3、-CH2CF3、-OCF3、-OCH2CF3、- OCH2CF2CHF2Or phenyl.
In one embodiment, compound of the present invention, it is to have the compound of one of following structure or have One of the following stereoisomer of compound of structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug:
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises chemical combination disclosed by the invention Thing.
In one embodiment, the pharmaceutical composition that the present invention relates to, comprise further pharmaceutically acceptable excipient, Carrier, adjuvant or their combination in any.
In one embodiment, the pharmaceutical composition that the present invention relates to, comprise treatment central nervous system's merit further The medicine of energy obstacle；Wherein, the medicine of described treatment central nervous system dysfunction be antidepressant drug, anxiolytic drugs, As the salts medicine of mood stabilizers, atypical antipsychotic drug, antiepileptic, antiparkinsonism drug, work Medicine, central nervous stimulant, nicotinic antagonists or their combination in any for selective serotonin reuptake inhibitor.
In another embodiment, the present invention treats the medicine of central nervous system dysfunction is amitriptyline (amitriptyline), desipramine (desipramine), mirtazapine (mirtazapine), amfebutamone (bupropion), reboxetine (reboxetine), fluoxetine (fluoxetine), trazodone (trazodone), Sertraline (sertraline), duloxetine (duloxetine), fluvoxamine (fluvoxamine), midalcipran (milnacipran), left-handed midalcipran (levomilnacipran), desmethylvenlafaxine (desvenlafaxine), Wella Oxazolone (vilazodone), venlafaxine (venlafaxine), dapoxetine (dapoxetine), nefazodone (nefazodone), femoxetine (femoxetine), Clomipramine (clomipramine), citalopram (citalopram), escitalopram (escitalopram), paroxetine (paroxetine), lithium carbonate (lithium Carbonate), buspirone (buspirone), olanzapine (olanzapine), Quetiapine (quetiapine), risperidone (risperidone), Ziprasidone (ziprasidone), Aripiprazole (aripiprazole), cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl (perospirone), clozapine (clozapine), modafinil (modafinil), mecamylamine (mecamylamine), card Ergota woods (cabergoline), diamantane (obsolete) (adamantane), imipramine (imipramine), pramipexole (pramipexole), thyroxine (thyroxine), dextromethorphan (dextromethorphan), quinidine (quinidine), naltrexone (naltrexone), samidorphan, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), pipamperone (pipamperone), dimension for smooth (vestipitant), Chlordiazepoxide (chlordiazepoxide), perphenazine (perphenazine) or their combination in any.
On the other hand, the present invention relates to compound disclosed by the invention or the compositions purposes in preparing medicine, wherein, Described medicine is used for preventing, treating or alleviate central nervous system dysfunction.Such as, in one embodiment, described medicine For preventing, treat or alleviate mammalian central nervous system dysfunction, in another embodiment, described medicine is used for Prevent, treat or alleviate the central nervous system dysfunction of people.
In one embodiment, described central nervous system dysfunction refers to depression, anxiety neurosis, mania, essence God's Split disease, bipolar disorders, sleep disorder, obsessive idea and behavior disorder, panic disorder, posttraumatic stress disorder, motion barrier Hinder, sexual dysfunction, musculoskeletal pain obstacle, cognitive disorder, dysmnesia, parkinson, Huntington's disease, terror Disease, substance abuse or addiction, drug addiction withdrawal symptom or premenstrualtension syndrome.
On the other hand, the present invention relates to compound disclosed by the invention or the compositions purposes in preparing medicine, described Medicine is used for suppressing serotonin reuptake transporter.
On the other hand, the present invention relates to the preparation of compound shown in formula (I), separation and the method for purification.
Biological results shows, the compound that the present invention provides can press down as preferable selectivity serotonin reuptake transporter Preparation.
Any embodiment of the either side of the present invention, can be combined with other embodiment, as long as they are not There will be contradiction.Additionally, in any embodiment of either side of the present invention, it is real that arbitrary technical characteristic goes for other Execute this technical characteristic in scheme, as long as they do not have contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and Content in terms of him will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed and chemical formula explanation.This Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many similar with the described herein or method of equivalent and material can be used in reality Trample the present invention.The present invention is not limited to method described herein and material.At the document combined, patent and similar material one Or many different from the application or conflicting in the case of (include but not limited to defined term, term application, described Technology, etc.), be as the criterion with the application.
It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity, Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated this by reference Bright.
Unless otherwise indicated, it should apply following definition used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John wiley & sons, the description in New York:2007, entire contents is incorporated herein by.
Context except as otherwise noted or has significantly conflict, article used herein " ", " one (kind) " " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.Such as, " component " refers to one or more component, it is possible to have more than one Component be taken into account in the embodiment of described embodiment and use or use.
Term used in the present invention " study subject " refers to animal.The most described animal is mammal, including people Class.Study subject, the most also refer to primate (the such as mankind, sex), cattle, sheep, goat, horse, dog, cat, rabbit, Rat, mice, fish, bird etc..In one embodiment, described study subject is primate.In another embodiment, Described study subject is people.
Term used in the present invention " patient " refers to people's (including adult and child) or other animals.Implement at some In scheme, " patient " refers to people.
Term " stereoisomer " refers to have identical chemical constitution, but atom or group spatially arrangement mode is different Compound.Stereoisomer includes that enantiomer, diastereomer, conformer (rotamer), geometry are different Structure body (cis/trans) isomer, atropisomer, etc..
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc,New York,1994.Many organic compound exist with optical active forms, and i.e. they have and make the flat of linearly polarized light The ability that face rotates.When describing optically active compound, prefix D and L or R and S is used to represent that molecule is about one Individual or the absolute configuration of mulitiple chiral centers.Prefix d and l or (+) and (-) are to revolve for linearly polarized light caused by appointed compound Turn symbol, wherein (-) or l represent that compound is left-handed.Prefix for (+) or the compound of d be dextrorotation.A kind of concrete Stereoisomer is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50 of enantiomer: 50 mixture are referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or three-dimensional special During the opposite sex, may occur in which this situation.
Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can be enriched with raceme or enantiomer Presented in, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer Excess.
According to starting material and the selection of method, the compounds of this invention can with in possible isomer or they Mixture, the such as form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) is deposited ?.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent to prepare, or use routine techniques to tear open Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing dibasic cycloalkanes in compound Base, the substituent group of cycloalkyl may have cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or the purest geometric isomer, enantiomer, diastereomer, such as, by chromatography and/or fractional crystallization Method.
By known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art The method being familiar with splits into optical antipode, e.g., by separating its diastereoisomeric salt obtained.Racemic product Thing can also be separated by chiral chromatogram, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomer can be prepared by asymmetric synthesis, such as, refers to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
What term " tautomer " or " tautomeric form " referred to have different-energy can be by low energy barrier (low Energy barrier) constitutional isomer of mutual inversion of phases.If tautomerism is possible (as in the solution), then can reach The chemical equilibrium of tautomer.Such as, (also referred to as proton translocation makes a variation proton tautomer (protontautomer) mutually Structure body (prototropic tautomer)) include being migrated the mutual inversion of phases carried out by proton, such as keto-enol isomerization and Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to so some compounds, raw material, compositions and/or dosage form, and they are rationally doctor Learn in the range of judging, it is adaptable to patient tissue contacts and without excessive toxicity, zest, allergy or with reasonably profit Other problems that benefit/Hazard ratio is symmetrical and complication, and it is effective to given application.
Term " optionally " or " optionally " refer to the event described subsequently or situation can but not necessarily occur, and this is retouched State and include situation that wherein said event or situation occur and wherein its absent variable situation.Such as, " optional key " refers to This key can exist or can not exist, and this description includes singly-bound, double or triple bonds.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as General formula compound above, or the compounds comprised as example special inside embodiment, subclass and the present invention.
Term " optionally by .... replaced ", can with term " unsubstituted or quilt ... .. is replaced " exchange make With, the most described structure is unsubstituted or is replaced by one or more substituent groups of the present invention, of the present invention takes Dai Ji includes, but are not limited to D, F, Cl, N3,-CN ,-OH ,-SH ,-NH2, alkyl, alkoxyl, alkylthio group, alkylamino, cycloalkyl, Heterocyclic radical, aryl, heteroaryl etc..
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the present invention " each ... to independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used To refer in different groups, do not affect mutually between concrete option expressed between same-sign, it is also possible to represent in phase In same group, do not affect mutually between concrete option expressed between same-sign.
It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise Content.
Term " unsaturated " or " undersaturated " represent that part is containing one or more degrees of unsaturation.
At each several part of this specification, the come into the open substituent group of compound of the present invention is open according to radical species or scope.Special Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term “C1-C6Alkyl " refer in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
At each several part of the present invention, describe connection substituent group.When this structure clearly needs linking group, for this Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connected or arylene group.
Term " halogen " and " halo " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)。
Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1-20 carbon atom, saturated straight chain or Side chain univalent hydrocarbyl group, wherein, the substituent group institute that described alkyl group can optionally be described by one or more present invention Replace.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4 Individual carbon atom；The most in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group comprises, but does not limit In, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), etc..
Saturated two obtained by two hydrogen atoms are removed in term " alkylidene " expression from saturated straight or branched hydrocarbon Valency hydrocarbyl group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylidene Group contains 1-6 carbon atom；In another embodiment, alkylidene group contains 1-4 carbon atom；In another embodiment In, alkylidene group contains 1-3 carbon atom；The most in one embodiment, alkylidene group contains 1-2 carbon atom.So Example include methylene (-CH2-), ethylidene (-CH2CH2-), isopropylidene (-CH (CH3)CH2-) etc..
Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which insatiable hunger And site, i.e. there is a carbon-to-carbon sp2Double bond, wherein, described alkenyl group can optionally be retouched by one or more present invention The substituent group stated is replaced, and it includes " cis " and the location of " trans ", or " E " and the location of " Z ".In an embodiment In, alkenyl group comprises 2-6 carbon atom；In another embodiment, alkenyl group comprises 2-4 carbon atom.Alkenyl group Example include, but is not limited to, vinyl (-CH=CH2), pi-allyl (-CH2CH=CH2) etc..
Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which insatiable hunger And site, i.e. there is carbon-to-carbon sp tri-key, wherein, described alkynyl group can optionally be retouched by one or more present invention The substituent group stated is replaced.In one embodiment, alkynyl group comprises 2-6 carbon atom；In another embodiment, alkynyl Group comprises 2-4 carbon atom.The example of alkynyl group includes, but is not limited to, acetenyl (-C ≡ CH), propargyl (-CH2C ≡ CH), 1-propinyl (-C ≡ C-CH3) etc..
Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.An embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.Described alkoxy base can be the most one or more The substituent group that the present invention describes is replaced.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1-propoxyl group (n-PrO, n-propoxyl group ,-OCH2CH2CH3), 2-propoxyl group (i-PrO, i-propoxyl group ,-OCH (CH3)2), 1-butoxy (n-BuO, n-butoxy ,-OCH2CH2CH2CH3), 2-methyl-l-propoxyl group (i-BuO, i-fourth oxygen Base ,-OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH3)CH2CH3), 2-methyl-2-propoxyl group (t- BuO, t-butoxy ,-OC (CH3)3), etc..
Term " alkylamino " or " alkyl amino " include " N-alkyl amino " and " N, N-dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group, and wherein alkyl group has implication as described in the present invention.Close Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N-first ammonia Base, N-ethylamino, N, N-dimethylamino, N, N-lignocaine etc..Described alkylamino radicals is optionally by one or more Substituent group described by invention is replaced.
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents that alkyl, thiazolinyl or alkoxy base are by one Individual or multiple halogen atoms are replaced, and wherein alkyl, thiazolinyl and alkoxy base have implication as described in the present invention, such Example comprises, but is not limited to, trifluoromethyl, trifluoromethoxy etc..
Term " cycloalkyl " represents containing 3-12 ring carbon atom, unit price or the saturated monocycle of multivalence, dicyclo or three rings System.In one embodiment, cycloalkyl comprises 3-10 ring carbon atom；In another embodiment, cycloalkyl comprises 3-8 Ring carbon atom；In yet another embodiment, cycloalkyl comprises 3-6 ring carbon atom.The example of cycloalkyl includes, but does not limit In, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, etc..Described group of naphthene base can optionally be sent out by one or more Bright described substituent group is replaced.
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising the monocycle of 3-12 annular atoms, double Ring or three-ring system, an annular atoms is selected from nitrogen, sulfur and oxygen atom up to less for its medium ring, and ring can be fully saturated or comprise One or more degrees of unsaturation, but an armaticity ring all can not have.Unless otherwise indicated, heterocyclic radical can be carbon back or nitrogen Base, and-CH2-group can be optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S-oxide. The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of heterocyclic radical include, but not limited to Oxyranyle, Azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazoles Alkyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy ring Amyl group, two sulfur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranose, 4H-pyranose, tetrahydro thiapyran base, piperidyl, Morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkyl, homopiperazine base, homopiperidinyl, oxa-ring Heptane base, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulfur azepineBase, 2-oxa--5-azabicyclo [2.2.1] Hept-5-base, etc..-CH in heterocyclic radical2-group is included, but not limited to 2-oxo-pyrrolidine by-C (=O)-substituted example Base, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3,5-dioxy piperazine piperidinyl, hybar X base, etc..In heterocyclic radical, sulfur is former The oxidized example of son includes, but not limited to sulfolane base, thio-morpholinyl 1,1-dioxide, etc..Described heterocyclic radical base Group is optionally replaced by one or more substituent groups described in the invention.
Term " hetero atom " refers to O, S, N, P and Si, including the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that in heterocycle, the hydrogen on nitrogen-atoms is replaced, such as, N is (as 3, in 4-dihydro-2 h-pyrrole base N), NH (NH as in pyrrolidinyl) or NR (NR as in the substituted pyrrolidinyl of N-).
Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, double Ring and the carbocyclic ring system of three rings, at least one of which ring is aromatic.Aromatic yl group is usual, but necessarily by aryl base The armaticity ring of group is connected with parent molecule.Term " aryl " can exchange with term " aromatic rings " or " aromatic ring " and use.Aryl The example of group can include phenyl, naphthyl, anthracene, etc..Described aromatic yl group can be optionally by one or more present invention Described substituent group is replaced.
Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, Dicyclo and three-ring system, at least one of which ring is aromatic, and at least one ring comprises one or more hetero atom.Heteroaryl Base group is usual, but is necessarily connected with parent molecule by the armaticity ring of heteroaryl groups.Term " heteroaryl " is permissible Exchange with term " hetero-aromatic ring " or " heteroaromatics " and use.Described heteroaryl groups is optionally by one or more present invention Described substituent group is replaced.In one embodiment, 5-10 unit heteroaryl comprises 1,2,3 or 4 and is independently selected from O, S and N Hetero atom；In another embodiment, heteroaryl groups is the 5-6 unit heteroaryl of lower level.
The example of heteroaryl groups includes, but is not limited to, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazole radicals, 4-imidazole radicals, 5-imidazole radicals, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-azoles Base, N-pyrrole radicals, 2-pyrrole radicals, 3-pyrrole radicals, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, 2-pyrimidine radicals, 4-pyrimidine radicals, 5- Pyrimidine radicals, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazole radical (such as 5-tetrazole radical), triazole Base (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3- Di azoly, 1,2,5-di azoly, 1,2,4-di azoly, 1,2,3-triazolyl, 1,2,3-thio biphosphole base, 1,3,4-sulfur For di azoly, 1,2,5-thio biphosphole bases, pyrazinyl, 1,3,5-triazines base, etc.；Also include following dicyclo, but never limit In these dicyclos: benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2-indyl), purine radicals, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), Imidazo [1,2-a] pyridine radicals, pyrazolo [1,5-a] pyridine radicals, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazine Base, [1,2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] Pyridine radicals, etc..
As described in the invention, substituent group draws the member ring systems formed on a ring being bonded the center of receiving (such as formula a institute Show) represent substituent group on ring any may replace or any rational position can be carried out replace.Such as, formula a represents A and B On ring, any position that may be replaced all can be replaced base R and replaces, as shown in formula b, formula c, formula d, formula e, formula f, formula g and formula h.
The when that term " blocking group " or " PG " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent group be used for block or protect the functional of hydroxyl, suitable blocking group to include trialkylsilkl, acetyl group, benzene Formoxyl and benzyl." carboxy protective group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general Carboxyl-protecting group includes-CH2CH2SO2Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxy Ylmethyl, 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro second Base, etc..Document refers to for the description that blocking group is general: Greene et al., Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991 and Kocienski et al., Protecting Groups,Thieme,Stuttgart,2005。
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo. Such conversion is hydrolyzed in blood by prodrug or is that precursor structure is affected through enzymatic conversion in blood or tissue.This Bright prodrug compounds can be ester, and in existing invention, ester can have phenyl ester class, aliphatic as prodrug (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention one Compound comprises hydroxyl, i.e. can be acylated the compound obtaining prodrug form.Other prodrug form includes Phosphate ester, if these phosphate compounds are that the di on parent obtains.About complete the begging for of prodrug Discuss and be referred to documents below: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol.14, A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery, 2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates, J.Med.Chem., 2008,51,2328-2345, every document is incorporated herein by this.
" metabolite " refers to that concrete compound or its salt is in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound Solving, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes compound Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine On, acceptable salt is known to us at art, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginate, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, Camphora sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, bitterness Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that suitable alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The quaternary ammonium salt that the compound of the group of comprised N is formed.Water solublity or oil-soluble or dispersion product can be turned into by quaternary ammonium With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt farther includes to fit When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, sulphuric acid Compound, phosphoric acid compound, nitric acid compound, C1-C8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethanolamine or its mixture.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
When described solvent is water, it is possible to use term " hydrate ".In one embodiment, a compounds of this invention Molecule can combine with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule Can combine with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention divides Son can combine with the hydrone less than, such as semihydrate.It should be noted that hydrate of the present invention remains with non- The biological effectiveness of the described compound of hydrated form.
Any disease or disease " treated " in term as used in the present invention, and some embodiment middle fingers improve disease wherein Disease or disease (i.e. slow down or stop or palliate a disease or the development of its at least one clinical symptoms).In other embodiments In, " treatment " refers to relax or improve at least one body parameter, including the body parameter may not discovered by patient.At another In a little embodiments, " treatment " refers to (such as stablize perceptible symptom) from health or physiologically (such as stablize health Parameter) or above-mentioned two aspect regulation disease or diseases.In other embodiments, " treat " and refer to prevention or postpone disease or disease The outbreak of disease, occur or deteriorate.
Term " therapeutically effective amount " refers to when delivering medicine to main body to treat disease, and the component of compound is enough to this disease Sick treatment onset." therapeutically effective amount " can be along with compound, disease and the order of severity, and has the bar of main body to be treated Part, the age, body weight, sex etc. and change.
The benzazolyl compounds that the present invention relates to, its pharmaceutically acceptable salt, pharmaceutical preparation and combinations thereof thing, can serve as Selective serotonin reuptake inhibitor, to mankind's central nervous system dysfunction, such as depression, anxiety neurosis, two-phase The treatment of obstacle has potential purposes.
Unless otherwise mentioned, all suitable isotope changes of the compound of the present invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicates, then this structure All stereoisomers all consider within the present invention, and be included in the invention as present invention compound of coming into the open.When Spatial chemistry is expressed the real wedge shape line (solidwedge) of particular configuration or time dotted line indicates, then the stereoisomer of this structure This clearly and is defined.
Within the nitrogen oxides of the compounds of this invention is also contained in the scope of the present invention.Can be by often using at an elevated temperature With oxidant (such as hydrogen peroxide), in the presence of the acid of such as acetic acid, aoxidize corresponding nitrogen-containing basic material, or pass through With acid reaction excessively in applicable solvent, such as, react with peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or Chloroform or dichloromethane react with 3-chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.
Compound shown in formula (I) can exist in a salt form.In one embodiment, described salt refers to pharmaceutically can connect The salt being subject to.Term " pharmaceutically acceptable " refers to that material or compositions must be with other compositions comprising preparation and/or use it The mammal for the treatment of is chemically and/or compatible in toxicology.In another embodiment, described salt is not necessarily and pharmaceutically may be used The salt accepted, could be for compound shown in preparation and/or purification formula (I) and/or is used for separating compound shown in this formula (I) The intermediate of enantiomer.
The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes. It is said that in general, such salt can free acid form Yu stoichiometry by making these compounds suitable alkali (as Na, Ca, The hydroxide of Mg or K, carbonate, bicarbonate etc.) reaction, or by making free alkali form and the chemistry of these compounds The suitable acid reaction of metered amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in the case of suitably, need to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook: character, select and apply (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.
Any structural formula that the present invention is given be also intended to represent these compounds not by isotope enrichment form and with The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, the present invention relates to prepare the intermediate of compound shown in formula (I).
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or combinations thereof.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.
The pharmaceutical composition of the compounds of this invention, preparation and administration
The present invention provides a kind of pharmaceutical composition, including compound shown in formula (I) or its single stereoisomer, isomery The raceme of body or non-racemic mixture or its pharmaceutically acceptable salt or solvate.In one embodiment of the present invention In formula, described pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient further, and optionally Ground, other treatment and/or prevention composition.
Suitably carrier, adjuvant and excipient agent be well known to those skilled in the art and be described in detail in such as Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al., Remington:The Science and Practice of Pharmacy (2000) Lippincott, Williams& Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, in Chicago.
It will also be appreciated that some compound of the present invention can exist in a free form for treating, if or suitably Can be presented in its pharmaceutically acceptable derivates.Some nonrestrictive enforcements of pharmaceutically acceptable derivant Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Compound of the present invention or its metabolite or any other adduct of residue or derivant are provided indirectly.
Pharmaceutical composition disclosed by the invention can prepare and be packaged as (bulk) in bulk form, wherein can extract safely and effectively The compounds of this invention of amount, then gives patient with powder or syrup form.Or, pharmaceutical composition disclosed by the invention can be made Standby and be packaged as unit dosage forms, the most discrete the most each unit contains the compounds of this invention of safe and effective amount.When with Time prepared by unit dosage forms, pharmaceutical composition disclosed by the invention generally can contain, such as, 0.5mg to 1g or 1mg to 700mg or The compound disclosed by the invention of 5mg to 100mg.
The present invention " pharmaceutically acceptable excipient " used means relevant to form of administration or pharmaceutical composition concordance Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient must become with other of pharmaceutical composition when mixing Split-phase is held, and can be substantially reduced the present invention and come into the open the interaction of effect of compound and causing not during to avoid being administered patient It it is the interaction of pharmaceutically acceptable pharmaceutical composition.Additionally, every kind of excipient must be pharmaceutically acceptable, example As, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected concrete dosage form.Additionally, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, binding agent, Disintegrating agent, lubricant, fluidizer, granulating agent, coating materials, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweeting agent, rectify Taste agent, odor mask, coloring agent, anticaking agent, wetting agent, chelating agen, plasticiser, viscosifier, antioxidant, preservative, stable Agent, surfactant and buffer agent.Technical staff it can be appreciated that, some pharmaceutically acceptable excipient can provide more than one Function, and alternative function is provided, this depend on preparation exists which there is in how many these excipient and preparation other Excipient.
Technical staff grasps the knowledge and skills of this area, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are the obtainable resource of a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and be used for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
Pharmaceutical composition disclosed by the invention uses technology well known by persons skilled in the art and method to prepare.This area The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to prepare the technique of pharmaceutical composition, described pharmaceutical composition comprises the present invention Come into the open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combinations thereof, and this technique includes that mixing is each Plant composition.Comprise the present invention to come into the open the pharmaceutical composition of compound, can mix under such as ambient temperature and atmospheric pressure and make Standby.
Compound disclosed by the invention is usually formulated as being adapted to pass through the dosage form that patient is administered by required approach.Example As, dosage form includes that those are suitable for the dosage form of following route of administration: (1) oral administration, such as tablet, capsule, caplet agent, ball Agent, containing tablet, powder, syrup, elixir, suspensoid, solution, Emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspensoid and redissolution powder；(3) transdermal administration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) suck, such as aerosol, solution and dry powder doses；(6) topical, such as ointment, ointment, lotion, molten Liquor, paste, spray, foam and gel.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention is permissible It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. The most in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
The present invention provide pharmaceutical composition can with compressed tablet, develop sheet, can chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.
The pharmaceutical composition that the present invention provides can provide with soft capsule or hard capsule, and it can be by gelatin, methyl fibre Prepared by dimension element, starch or calcium alginate.
The pharmaceutical composition that the present invention provides can provide with liquid and semisolid dosage form, including Emulsion, solution, suspendible Agent, elixir and syrup.
Time suitably, can be by the dosage unit preparations microencapsulation of oral administration.Can also be prepared into extending or dimension Hold the compositions of release, such as by by microparticle material coating or be embedded in polymer, wax or the like.
The combination of oral medication that the present invention provides can also carry with the form of liposome, micelle, microsphere or nanometer system Supply.Micelle dosage form can be prepared by the method that U.S.Pat.No.6,350,458 describes.
The pharmaceutical composition that the present invention provides can provide with non-effervescent or the granule of effervescent and powder, to reconstruct Liquid dosage form.The pharmaceutically acceptable carrier used in non-effervescent granule or powder and excipient can include dilution Agent, sweeting agent and wetting agent.The pharmaceutically acceptable carrier and the excipient that use in effervescent granule or powder can wrap Include organic acid and carbon dioxide source.
Coloring agent and flavoring agent can be used in all above-mentioned dosage forms.
Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.
The present invention provide pharmaceutical composition can be configured to immediately or Modified release dosage forms, including postpone-, slow release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
The pharmaceutical composition that the present invention provides can be common with other active component without compromising on intended therapeutical effect Preparation, or with supplement the material co-formulation of intended effect.
The pharmaceutical composition that the present invention provides can be by injection, infusion or implantation parenteral, for local or complete Body is administered.As the present invention use parenteral include intravenous, intra-arterial, intraperitoneal, sheath in, in ventricle, in urethra, breast In bone, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical composition that the present invention provides can be configured to be suitable to any dosage form of parenteral, including solution, mixes Suspension, Emulsion, micelle, liposome, microsphere, nanometer system and being suitable to makes consolidating of solution or suspension the most in a liquid Bodily form formula.Such dosage form can be prepared according to the conventional method known to the skilled person in pharmaceutical science field and (sees Remington:The Science and Practice of Pharmacy, ibid).
The pharmaceutical composition that the present invention provides can be configured to single dose or multiple dose administration.Described single-dose preparations is wrapped It is contained in ampulla, bottle or syringe.Described multiple dose parenteral administration must comprise the anti-micro-of antibacterial or fungistatic concentrations Biological agent.All of parenteral administration must be all aseptic, as known in the art with practice.
On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable to any dose to patient's inhalation Type, such as dry powder doses, aerosol, suspensoid or liquid composite.
The pharmaceutical composition being suitable for transdermal administration can be prepared as discontinuous paster agent, it is intended that keeps with the epidermis of patient It is in close contact the time of an elongated segment.Such as, delivering active ingredients from paster agent can be permeated by ion, as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for the pharmaceutical composition of topical can be formulated into ointment, ointment, suspensoid, lotion, powder, Solution, paste, gel, spray, aerosol or oil preparation.
The compounds of this invention and the purposes of compositions
Above-claimed cpd and pharmaceutical composition that the present invention provides can be used for preparation and move for preventing, treat or alleviate suckling Thing, including the medicine of the central nervous system dysfunction of the mankind, it is also possible to be used for suppressing serotonin reuptake transporter for preparation Medicine.
Specifically, in the compositions of the present invention, the amount of compound can the most optionally suppress 5-hydroxyl The reuptake of tryptamines, the compound of the present invention can be the most depressed as treatment mankind central nervous system (CNS) dysfunction Disease, the medicine of anxiety neurosis.
The compound of the present invention can apply to, but is not limited to, and uses the compound of the present invention or the effective of compositions Patient is administered by amount prevents, treats or alleviates central nervous system dysfunction disease.Described in response to 5-hydroxy tryptamine The central nervous system dysfunction disease of receptor modulators, farther includes but is not limited to, depression, and anxiety neurosis is manic Disease, schizophrenia, sleep disorder, bipolar disorders, obsessive idea and behavior disorder, panic disorder, posttraumatic stress disorder, fortune Dynamic obstacle, sexual dysfunction, musculoskeletal pain obstacle, cognitive disorder, dysmnesia, parkinson, Huntington's disease, probably It is afraid of disease, substance abuse or addiction, drug addiction withdrawal symptom and premenstrualtension syndrome etc..
The compound of the present invention and pharmaceutical composition, in addition to useful to human treatment, apply also for veterinary treatment and dote on Mammal in the animal on thing, the animal of introduced variety and farm.The example of other animal includes horse, Canis familiaris L. and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.
In one embodiment, Therapeutic Method disclosed by the invention includes giving safe and effective amount to patient in need The compounds of this invention or comprise the pharmaceutical composition of the compounds of this invention.Each embodiment disclosed by the invention includes by having The patient needed gives the present invention of safe and effective amount and comes into the open compound or comprise the present invention and come into the open the pharmaceutical composition of compound, The method treating disease mentioned above.
In one embodiment, the present invention comes into the open compound or to comprise the come into the open pharmaceutical composition of compound of the present invention permissible It is administered by any applicable route of administration, including Formulations for systemic administration and topical.
In one embodiment, the present invention comes into the open compound or to comprise the come into the open pharmaceutical composition of compound of the present invention permissible Once daily, or according to dosage regimen, at the appointed time in section, be administered several times in different time intervals.Such as, often It is administered once, twice, three times or four times.Can be administered until reaching what the therapeutic effect wanted or maintain indefinitely was wanted Therapeutic effect.The present invention comes into the open compound or comprise the come into the open appropriate dosage regimen of pharmaceutical composition of compound of the present invention and depend on In the pharmacokinetic property of this compound, such as, absorbing, be distributed and the half-life, these can be by determination of technical staff.Additionally, The present invention comes into the open compound or comprise the present invention and come into the open the appropriate dosage regimen of pharmaceutical composition of compound, including implementing the party The persistent period of case, depend on the disease being treated, the order of severity of disease being treated, the age of patient under consideration and health shape Condition, the character of the medical history of patient under consideration, simultaneously therapy, therapeutic effect of wanting etc. are in technical staff's knowledge and experience scope Interior factor.Such technical staff be also to be understood that for the individual patient reaction to dosage regimen, or elapses over time When individual patient needs change, in order to be sufficiently accurate it may be desired to adjust the dosage regimen of matters.
Present invention compound of coming into the open can, or be administered before it or afterwards with one or more other therapeutic agents simultaneously. The compounds of this invention can be administered by identical or different route of administration respectively with other therapeutic agents, or therewith with medicine group Solvate form is administered.
Additionally, compound disclosed by the invention can be administered with prodrug forms.In the present invention, the present invention comes into the open compound " prodrug " when being that patient is administered, finally can discharge the present invention in vivo and come into the open the functional derivatives of compound.In the past When medicine form gives compound disclosed by the invention, those skilled in the art can implement the one in following manner and more than: (a) The internal onset time of modification compound；The internal acting duration of (b) modification compound；(c) modification compound internal Conveying or distribution；The internal dissolubility of (d) modification compound；And (e) overcomes the side effect or other difficult points that compound faced. For preparing the typical functional derivatives of prodrug, be included in internal chemically or the mode of the enzyme compound that cracks Variant.Comprise and prepare these variants of phosphate, amide, ester, monothioester, carbonate and carbaminate to people in the art It is well-known from the point of view of Yuan.
General synthesis step
For describing the present invention, it is listed below embodiment.But it is to be understood that the invention is not restricted to these embodiments, simply The method putting into practice the present invention is provided.
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment are used for being further illustrated by this The content of invention.
The professional of art is it will be appreciated that chemical reaction described in the invention can be used to prepare perhaps suitably Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention , or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applicable to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, the most not through being further purified, unless other aspects show during use.General reagent is western Gansu Province chemical industry from Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemistry in morning Chemical reagent work, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao purchase Can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide and N, N- Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopy uses Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer record.1H H NMR spectroscopy is with CDC13、 DMSO-d6、CD3OD or acetone-d6For solvent (in units of ppm), mark as reference with TMS (0ppm) or chloroform (7.26ppm) Accurate.When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant, represents with hertz (Hz).
The condition determination of Algorithm (MS) data is: Agilent 6120 level Four bar HPLC-M (pillar model: Zorbax SB-C18,2.1x30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Phase: 5%-95% is (containing 0.1% first in flowing The CH of acid3CN) at (H containing 0.1% formic acid2O) ratio in, uses electron spray ionisation (ESI), under 210nm/254nm, uses UV detects.
Pure compound uses Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (pillar type Number: NOVASEP 50/80mm DAC), detect at 210nm/254nm UV.
The use of brief word below runs through the present invention:
AcOH、HOAc、CH3COOH acetic acid
BOC, Boc tert-butoxycarbonyl
CH2Cl2, DCM dichloromethane
CDCl3Deuterochloroform
CD3OD deuterated methanol
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
EDTA ethylenediaminetetraacetic acid
Et3N, TEA triethylamine
EtOAc, EA ethyl acetate
G gram
H hour
HCl hydrogen chloride
NaCl sodium chloride
KCl potassium chloride
MgSO4 magnesium sulfate
MeCN、CH3CN acetonitrile
ML, ml milliliter
PE petroleum ether (60-90 DEG C)
RT, rt, r.t. room temperature
Rt retention time
TFA trifluoroacetic acid
Tris-HCl tri-(methylol) aminomethane-hydrochloric acid
BSA bovine serum albumin
Pd2(dba)3Three (dibenzalacetone) two palladium
X-phos 2-dicyclohexyl phosphorus-2,4,6-tri isopropyl biphenyl
PCC pyridinium chloro-chromate
Following synthetic schemes describes the preparation present invention and comes into the open the step of compound, unless otherwise indicated, the most each R1And R2 There is definition of the present invention.
Intermediate synthetic schemes 1:
Midbody compound (9) can be prepared by the method described in intermediate synthetic schemes 1: first, aniline (1) with 3-chlorpromazine chloride react under the effect of alkali obtain compound (2), then compound (2) through friedel-crafts acylation reaction, Cyclization obtain compound (3)；Compound (3) react with lawesson reagent again after NBS bromo obtain compound (5)；Compound (5) With hydrazide kind compound (6) at suitable solvent, as in the tert-butyl alcohol cyclization obtain compound (7), then compound (7) and piperazine Piperazine-1-tert-butyl group formic acid esters carries out palladium catalysed cross coupling reaction under the effect of alkali, obtain compound (8)；Finally, compound (8) In the ethyl acetate solution of hydrogen chloride deprotection obtain midbody compound (9)。
Synthetic schemes 1:
Compound (16) can be prepared by the method described in synthetic schemes 1: first, 6-caprolactone (10) at sulfur Acid catalysis under there is alcoholysis, then through PCC aoxidize, obtain compound (11)；Compound (11) again with phenylhydrazine compounds (12) in alcohols solvent, carry out Fischer ring closure reaction as in ethanol, isopropanol or the tert-butyl alcohol, obtain compound (13)；Then Compound (13) and reducing agent, such as Lithium Aluminium Hydride, in suitable temperature, as at 40～120 DEG C reaction obtain compound (14)；? After, by compound (14Hydroxyl in) is activated obtain compound (15), compound (15) again with compound (9) in alkalescence condition Lower generation nucleophilic substitution obtain target compound (16)。
Synthetic schemes 2:
Compound (16) can also be prepared by the method described in synthetic schemes 2: first, by compound (17) with 4-chlorobutanoylchloride carries out friedel-crafts acylation reaction, generate compound (18), then compound (18) at suitable solvent, such as uncle In butanol or isopropanol, react with the reducing agent such as sodium borohydride or Lithium Aluminium Hydride obtain compound (14), finally, by compound (14Hydroxyl in) is activated obtain compound (15), compound (15) again with compound (9) there is nucleophilic in the basic conditions Substitution reaction obtain target compound (16)。
Synthetic schemes 3:
Compound (22) can be prepared by the method described in synthetic schemes 3: first, in suitable temperature, as At 40～120 DEG C, by 3,4-dihydro-2H-pyrans (19) and phenylhydrazine compounds (12) carry out Fischer ring closure reaction generationization Compound (20), then, by compound (20Hydroxy activated in), obtain compound (21), final compound (21) and compound (9) in the basic conditions occur nucleophilic substitution obtain target compound (22)。
The compound, pharmaceutical composition and the application thereof that there is provided the present invention below in conjunction with embodiment are further described.
Embodiment 1 3-(4-(4-(4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-base) fourth Base)-1H-indole-5-formonitrile HCN
Step 1) synthesis of 3-(4-chlorobutyryl)-1H-indole-5-formonitrile HCN
At 0 DEG C, 4-chlorobutanoylchloride (9.60g, 68.00mmol) is added drop-wise to containing aluminum chloride (9.00g, 68.00mmol) Dichloromethane (90mL) solution in, mixed liquor stirred after 30 minutes, continue wherein dropping 5-cyanoindole (8.10g, Dichloromethane (800mL) solution 57.00mmol).Reactant liquor is warming up to room temperature, after stirring 2 hours, is poured slowly into by reactant liquor In the mixture of ice/concentrated hydrochloric acid (50g/50mL), the most at room temperature continue stirring 20 hours.By gained mixture sucking filtration, and Successively with water (10mL) and ethyl acetate (10mL) washing filter cake, obtaining title compound after filtration cakes torrefaction is yellow solid (8.90g, 63.1%).
LC-MS(ESI,pos.ion)m/z:247.1(M+1).
Step 2) synthesis of 3-(4-hydroxybutyl)-1H-indole-5-formonitrile HCN
3-(4-chlorobutyryl)-1H-indole-5-formonitrile HCN (0.49g, 2.00mmol) is dissolved in isopropanol (20mL), molten Liquid is cooled to 0 DEG C, is dividedly in some parts sodium borohydride (0.23g, 6.00mmol) the most wherein.Reactant liquor is heated to 80 DEG C, stirs 6 After hour, it is cooled to 0 DEG C, is subsequently adding saturated aqueous sodium carbonate (1mL) cancellation reaction.By mixture sucking filtration, filtrate decompression Concentrating, it is white that gained residue obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification Color solid (343mg, 80.0%).
LC-MS(ESI,pos.ion)m/z:215.2(M+1).
Step 3) synthesis of 4-(5-cyano-1 H-indol-3-base) butyl 4-toluene sulfonic acide ester
3-(4-hydroxybutyl)-1H-indole-5-formonitrile HCN (0.41g, 1.90mmol) is dissolved in dichloromethane (20mL), It is added thereto to triethylamine (0.3mL, 2.28mmol) and paratoluensulfonyl chloride (0.43g, 2.28mmol) successively.Reactant liquor is in room After the lower stirring reaction of temperature 4 hours, (100mL) cancellation that adds water is reacted.Separatory, organic facies anhydrous sodium sulfate is dried, and filters, and subtracts Pressure concentrates, and gained residue obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification is White solid (0.56g, 80.0%).
LC-MS(ESI,pos.ion)m/z:369.2(M+1).
Step 4) synthesis of 3-chloro-N-Phenylpropionamide
Aniline (5.00g, 53.69mmol) is joined in oxolane (250mL), and sub-cooled is to 0 DEG C, then depends on Secondary it is slowly added dropwise pyridine (6.49mL, 80.54mmol) and 3-chlorpromazine chloride (6.15mL, 64.43mmol).Reactant liquor is warming up to After reaction being stirred at room temperature 12 hours, decompression is distilled off solvent, then adds water in gained residue (100mL), and uses acetic acid Ethyl ester (50mL × 3) extracts.Merging organic facies, be dried with anhydrous sodium sulfate, filter, filtrate reduced in volume obtains title compound For white solid (8.52g, 86.4%).
MS(ESI,pos.ion)m/z:184.0(M+1)；
1H NMR(400MHz,DMSO-d6) δ (ppm): 10.05 (s, 1H), 7.61 (d, J=7.6Hz, 2H), 7.30 (t, J =8.0Hz, 2H), 7.04 (t, J=7.2Hz, 1H), 3.88 (t, J=6.4Hz, 2H), 2.82 (t, J=6.4Hz, 2H).
Step 5) synthesis of 3,4-dihydroquinoline-2 (1H)-one
Chloro-for 3-N-Phenylpropionamide (4.00g, 21.78mmol) and aluminum chloride (14.52g, 108.91mmol) are added To DMAC N,N' dimethyl acetamide (30ml).After reactant liquor is warmed up to 140 DEG C of reactions 4 hours, it is cooled to room temperature and adds frozen water (20mL) cancellation reaction, then gained mixture ethyl acetate (20mL × 3) extracts.Merge organic facies, use anhydrous sodium sulfate It is dried, filters, and concentrating under reduced pressure, gained residual obtains through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification Title compound is white solid (2.73g, 85.0%).
MS(ESI,pos.ion)m/z:148.2(M+1)；
1HNMR(600MHz,DMSO-d6) δ (ppm): 10.05 (s, 1H), 7.14 (d, J=7.2Hz, 1H), 7.12 (t, J= 7.8Hz, 1H), 6.89 (td, J=7.8,0.6Hz, 1H), 6.85 (d, J=7.8Hz, 1H), 2.85 (t, J=7.8Hz, 2H), 2.43 (t, J=7.8Hz, 2H).
Step 6) synthesis of 6-bromo-3,4-dihydroquinoline-2 (1H)-one
By 3,4-dihydroquinoline-2 (1H)-one (2.73g, 18.55mmol) is dissolved in N,N-dimethylacetamide (30mL), And in ice-water bath, it is slowly added dropwise the DMAC N,N' dimethyl acetamide (10mL) of N-bromo-succinimide (3.30g, 18.55mmol) Solution.Reactant liquor continues stirring reaction in ice-water bath and is warming up to room temperature reaction 12 hours after 6 hours.After reaction terminates, to instead Answer in mixture add water (50mL), and extract by ethyl acetate (50mL × 3).Merge organic facies, be dried with anhydrous sodium sulfate, mistake Filter, and concentrating under reduced pressure, gained residue obtains titled through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purification Compound is white solid (3.86g, 92.1%).
MS(ESI,pos.ion)m/z:226.2(M+1)；
1H NMR(400MHz,DMSO-d6) δ (ppm): 10.16 (s, 1H), 7.36 (s, 1H), 7.30 (dd, J=8.4, 2.0Hz, 1H), 6.79 (d, J=8.4Hz, 1H), 2.87 (t, J=7.2Hz, 2H), 2.43 (t, J=7.2Hz, 2H).
Step 7) synthesis of 6-bromo-3,4-dihydroquinoline-2 (1H)-thioketone
By bromo-for 6-3,4-dihydroquinoline-2 (1H)-one (2.50g, 11.06mmol) and lawesson reagent (6.71g, 16.60mmol) joining in toluene (20mL), reactant liquor temperature rising reflux is cooled to room temperature after reacting 2 hours, and decompression is spin-dried for It is red solid (2.52g, 94.0%) to title compound.
MS(ESI,pos.ion)m/z:242.1(M+1).
Step 8) synthesis of 7-bromo-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline
By bromo-for 6-3,4-dihydroquinoline-2 (1H)-thioketone (500mg, 2.06mmol) and formylhydrazine (161mg, 2.68mmol) join in the tert-butyl alcohol (10mL), reactant liquor be warming up to 110 DEG C reaction 12 hours after be cooled to room temperature, then to Wherein add water (20mL), and extract by ethyl acetate (30mL × 3).Merge organic layer, be dried with anhydrous sodium sulfate, filter, And concentrating under reduced pressure, gained residue obtains title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=30/1) purification For light yellow solid (430mg, 83.3%).
MS(ESI,pos.ion)m/z:250.2(M+1)；
1H NMR(600MHz,DMSO-d6) δ (ppm): 9.25 (s, 1H), 7.73 (d, J=8.4Hz, 1H), 7.69 (s, 1H), 7.61 (d, J=8.4Hz, 1H), 3.08 (t, J=7.2Hz, 2H), 3.04 (t, J=7.2Hz, 2H).
Step 9) conjunction of 4-(4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate Become
By bromo-for 7-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline (430mg, 1.72mmol), piperazine under nitrogen protection Piperazine-1-t-butyl formate (350mg, 1.89mmol), Pd2(dba)3(155mg,0.17mmol)、X-phos(162mg, 0.34mmol) joining in toluene (20mL) with sodium tert-butoxide (330mg, 3.44mmol), it is anti-that reactant liquor is warming up to 120 DEG C of stirrings Be cooled to room temperature, and concentrating under reduced pressure after answering 20 hours, gained residue through silica gel column chromatography (methylene chloride/methanol (v/v)= 50/1) purification obtains title compound is light yellow solid (430mg, 70.4%).
MS(ESI,pos.ion)m/z:256.3(M+1-Boc)；
1HNMR(600MHz,DMSO-d6) δ (ppm): 9.13 (s, 1H), 7.59 (d, J=9.0Hz, 1H), 7.02 (d, J= 1.8Hz, 1H), 6.95 (dd, J=9.0,2.4Hz, 1H), 3.45 (brs, 4H), 3.12 (t, J=4.8Hz, 4H), 3.04 (t, J =7.8Hz, 2H), 2.95 (t, J=7.8Hz, 2H), 1.42 (s, 9H).
Step 10) 3-(4-(4-(4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-base) fourth Base) synthesis of-1H-indole-5-formonitrile HCN
By 4-(4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate (300mg, 0.84mmol) join in the ethyl acetate solution (4M, 3mL) of hydrogen chloride, and at room temperature stirring reaction 1 hour after, decompression It is spin-dried for.The solid of gained is dissolved in acetonitrile (15mL), and is sequentially added into 4-(5-cyano-1 H-indol-3-base) butyl 4-first Base benzene sulfonate (342mg, 0.93mmol), potassium carbonate (175mg, 1.27mmol) and potassium iodide (14mg, 0.08mmol), then After reactant liquor being warming up to back flow reaction 20 hours, it is cooled to room temperature, and concentrating under reduced pressure.Residue is through silica gel column chromatography (oil Ether/ethyl acetate (v/v)=1/1) to obtain title compound be white solid (200mg, 52.5%) to purification.
MS(ESI,pos.ion)m/z:452.5(M+1)；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.37(s,1H),9.11(s,1H),8.07(s,1H),7.56(d, J=9.0Hz, 1H), 7.50 (d, J=8.4Hz, 1H), 7.40 (dd, J=8.4,1.2Hz, 1H), 7.33 (d, J=1.2Hz, 1H), 6.97 (d, J=2.4Hz, 1H), 6.90 (dd, J=9.0,2.4Hz, 1H), 3.13 (brs, 4H), 3.03 (t, J= 7.2Hz, 2H), 2.94 (t, J=7.2Hz, 2H), 2.73 (t, J=7.2Hz, 2H), 2.47 (brs, 4H), 2.35 (t, J= 7.2Hz,2H),1.68-1.63(m,2H),1.53-1.48(m,2H).
Embodiment 2 3-(3-(4-(4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-base) third Base)-1H-indole-5-formonitrile HCN
Step 1) synthesis of 3-(3-hydroxypropyl)-1H-indole-5-formonitrile HCN
4-cyanophenylhydrazine hydrochlorate (3.53g, 20.8mmol) is dissolved in dilute sulfuric acid (4%, 50mL) and N, N-dimethyl In the mixed solvent of acetamide (10mL), drip 3 wherein, 4-dihydro-2H-pyrans (1.90mL, 20.80mmol).Reactant liquor It is heated to 100 DEG C, after stirring 20 hours, is cooled to room temperature, and extracts by ethyl acetate (50mL × 3).The organic facies merged is used Water (50mL × 3) washs, and is then dried with anhydrous sodium sulfate, filters, and concentrating under reduced pressure, and gained residue is through silica gel column chromatography It is white solid (1.46g, 35.0%) that (petrol ether/ethyl acetate (v/v)=2/1) purification obtains title compound.
LC-MS(ESI,pos.ion)m/z:201.1(M+1).
Step 2) synthesis of 3-(5-cyano-1 H-indol-3-base) propyl group 4-toluene sulfonic acide ester
3-(3-hydroxypropyl)-1H-indole-5-formonitrile HCN (1.00g, 5.00mmol) is dissolved in dichloromethane (20mL), It is added thereto to triethylamine (0.8mL, 6.00mmol) and paratoluensulfonyl chloride (1.14g, 6.00mmol) successively.Reactant liquor is in room After the lower stirring reaction of temperature 4 hours, (100mL) cancellation that adds water is reacted.Separatory, organic facies anhydrous sodium sulfate is dried, and filters, and subtracts Pressure concentrates, and gained residue obtains title compound through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification is White solid (1.33g, 75.0%).
LC-MS(ESI,pos.ion)m/z:355.1(M+1).
Step 3) 3-(3-(4-(4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-base) third Base) synthesis of-1H-indole-5-formonitrile HCN
By 4-(4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate (300mg, 0.84mmol) join in the ethyl acetate solution (4M, 3mL) of hydrogen chloride, and be stirred at room temperature reaction 1 hour after, decompression rotation Dry.The solid of gained is dissolved in acetonitrile (15mL), and is sequentially added into 3-(5-cyano-1 H-indol-3-base) propyl group 4-methyl Benzene sulfonate (330mg, 0.93mmol), potassium carbonate (175mg, 1.27mmol) and potassium iodide (14mg, 0.08mmol).Then will Reactant liquor rises high-temperature, and back flow reaction, after 20 hours, is cooled to room temperature, and concentrating under reduced pressure.Residue is through silica gel column chromatography (oil Ether/ethyl acetate (v/v)=1/1) to obtain title compound be white solid (210mg, 56.9%) to purification.
MS(ESI,pos.ion)m/z:438.5(M+1)；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.51(s,1H),9.16(s,1H),8.13(s,1H),7.64(d, J=8.4Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.46-7.37 (m, 2H), 7.08 (d, J=2.4Hz, 1H), 7.02 (dd, J=9.0,2.4Hz, 1H), 3.48 (t, J=4.8Hz, 4H), 3.42-3.40 (m, 2H), 3.20 (brs, 4H), 3.05 (d, J= 7.2Hz, 2H), 2.97 (d, J=7.2Hz, 2H), 2.80 (t, J=7.2Hz, 2H), 2.09-2.03 (m, 2H).
Embodiment 3 7-(4-(4-(5-fluoro-1H-indol-3-yl) butyl) piperazine-1-base)-4,5-dihydro-[1,2,4] three Azoles also [4,3-a] quinoline
Step 1) synthesis of 6-oxo ethyl hexanoate
6-caprolactone (15.00g, 0.13mol) is dissolved in ethanol (125mL), and drips concentrated sulphuric acid wherein (1.10mL).Reactant liquor is heated to 80 DEG C, after stirring 24 hours, is cooled to room temperature, and concentrating under reduced pressure.Gained residue frozen water (150mL) dilution, and extract by ethyl acetate (150mL × 3).The organic facies anhydrous sodium sulfate merged is dried, and filters, and subtracts Pressure is concentrated to give 6 hydroxycaproic acid ethyl ester (10.30g).
PCC (16.20g, 75.50mmol) is dissolved in dichloromethane (140mL), is cooled to 0 DEG C, drips 6-wherein Dichloromethane (20mL) solution of hydroxy ethyl caproate (10.30g, 64.30mmol).Reactant liquor is warming up to room temperature, stirs reaction 2 After hour, adding ethyl acetate (100mL), sucking filtration, filtrate concentrates.Residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purification obtains title compound is white solid (9.28g, 45.0%).
LC-MS(ESI,pos.ion)m/z:159.3(M+1).
Step 2) synthesis of 4-(5-fluoro-1H-indol-3-yl) ethyl n-butyrate.
Add by 6-oxo ethyl hexanoate (1.00g, 6.30mmol) with to fluorophenyl hydrazine hydrochloride (1.11g, 6.80mmol) In ethanol (125mL), reactant liquor is warming up to 80 DEG C, after stirring is reacted 20 hours, is cooled to room temperature, and concentrating under reduced pressure.By residual Stay liquid frozen water (100mL) to dilute, and extract by ethyl acetate (150mL × 3).The organic facies merged anhydrous sodium sulfate is done Dry, filter, and concentrating under reduced pressure.Gained residue obtains through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification Title compound is white solid (0.94g, 59.5%).
LC-MS(ESI,pos.ion)m/z:250.2(M+1).
Step 3) synthesis of 4-(5-fluoro-1H-indol-3-yl) butane-1-alcohol
At 0 DEG C, to the oxolane (20mL) of 4-(5-fluoro-1H-indol-3-yl) ethyl n-butyrate. (0.32g, 1.30mmol) Solution is dividedly in some parts Lithium Aluminium Hydride (0.19g, 5.10mmol).After reactant liquor stirs 1 hour at room temperature, it is warming up to 80 DEG C, Continue stirring reaction 20 hours.After reaction terminates, reactant mixture is cooled to 0 DEG C, and is sequentially added into saturated aqueous sodium sulfate Liquid (1mL) and ethyl acetate (150mL), filter, by filtrate reduced in volume.Gained residue is through silica gel column chromatography (petroleum ether/second Acetoacetic ester (v/v)=2/1) to obtain title compound be white solid (0.20g, 75.2%) to purification.
LC-MS(ESI,pos.ion)m/z:208.2(M+1).
Step 4) synthesis of 4-(5-fluoro-1H-indol-3-yl) butyl 4-toluene sulfonic acide ester
The method that this step title compound describes according to embodiment 2 step 2 prepares, will 4-(5-fluoro-1H-Yin Diindyl-3-base) butane-1-alcohol (0.39g, 1.90mmol), triethylamine (0.31mL, 2.30mmol) and paratoluensulfonyl chloride (0.43g, 2.30mmol) reaction in dichloromethane (20mL) prepares crude product, and crude product is through silica gel column chromatography (petroleum ether/second Acetoacetic ester (v/v)=4/1) to obtain title compound be white solid (0.45g, 66.2%) to purification.
LC-MS(ESI,pos.ion)m/z:362.2(M+1).
Step 5) 7-(4-(4-(5-fluoro-1H-indol-3-yl) butyl) piperazine-1-base)-4,5-dihydro-[1,2,4] triazole And the synthesis of [4,3-a] quinoline
By 4-(4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate (300mg, 0.84mmol) join in the ethyl acetate solution (4M, 3mL) of hydrogen chloride, and be stirred at room temperature reaction 1 hour after, decompression rotation Dry.The solid of gained is dissolved in acetonitrile (15mL), and is sequentially added into 4-(5-fluoro-1H-indol-3-yl) butyl 4-methylbenzene Sulphonic acid ester (336mg, 0.93mmol), potassium carbonate (175mg, 1.27mmol) and potassium iodide (14mg, 0.08mmol).Then will be anti- Answering liquid to rise high-temperature, back flow reaction, after 20 hours, is cooled to room temperature, and concentrating under reduced pressure.Residue is through silica gel column chromatography (oil Ether/ethyl acetate (v/v)=1/1) to obtain title compound be white solid (220mg, 58.7%) to purification.
MS(ESI,pos.ion)m/z:445.2(M+1)；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.40(s,1H),9.10(s,1H),8.13(s,1H),7.56(d, J=8.8Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.44 (dd, J=8.4,1.2Hz, 1H), 7.37 (d, J=1.2Hz, 1H), 7.01 (d, J=2.4Hz, 1H), 6.95 (dd, J=9.0,2.4Hz, 1H), 3.23 (brs, 4H), 3.05 (t, J= 7.2Hz, 2H), 2.98 (t, J=7.2Hz, 2H), 2.77 (t, J=7.2Hz, 2H), 2.45 (t, J=4.8Hz, 4H), 2.38 (t, J=7.2Hz, 2H), 1.78-1.73 (m, 2H), 1.63-1.55 (m, 2H).
Embodiment 4 7-(4-(3-(5-fluoro-1H-indol-3-yl) propyl group) piperazine-1-base)-4,5-dihydro-[1,2,4] three Azoles also [4,3-a] quinoline
Step 1) synthesis of 3-(5-fluoro-1H-indol-3-yl) propane-1-alcohol
The method that this step title compound describes according to embodiment 2 step 1 prepares, will 4-fluorophenyl hydrazine hydrochloride (3.37g, 20.80mmol), dilute sulfuric acid (4%, 50mL) and 3,4-dihydro-2H-pyrans (1.90mL, 20.80mmol) are at N, N- Reaction prepares crude product in dimethylformamide (10mL), crude product through silica gel column chromatography (petrol ether/ethyl acetate (v/v)= 2/1) purification obtains title compound is white solid (3.53g, 87.8%).
LC-MS(ESI,pos.ion)m/z:194.2(M+1).
Step 2) synthesis of 3-(5-fluoro-1H-indol-3-yl) propyl group 4-toluene sulfonic acide ester
The method that this step title compound describes according to embodiment 2 step 2 prepares, will 3-(5-fluoro-1H-Yin Diindyl-3-base) propane-1-alcohol (0.97g, 5.00mmol), triethylamine (0.84mL, 6.00mmol) and paratoluensulfonyl chloride (1.15g, 6.00mmol) prepares crude product in dichloromethane (20mL), and crude product is through silica gel column chromatography (petroleum ether/acetic acid Ethyl ester (v/v)=4/1) to obtain title compound be white solid (1.28g, 73.6%) to purification.
LC-MS(ESI,pos.ion)m/z:348.1(M+1).
Step 3) 7-(4-(3-(5-fluoro-1H-indol-3-yl) propyl group) piperazine-1-base)-4,5-dihydro-[1,2,4] triazole And the synthesis of [4,3-a] quinoline
By 4-(4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate (300mg, 0.84mmol) join in the ethyl acetate solution (4M, 3mL) of hydrogen chloride, and be stirred at room temperature reaction 1 hour after, decompression rotation Dry.The solid of gained is dissolved in acetonitrile (15mL), and is sequentially added into 3-(5-fluoro-1H-indol-3-yl) propyl group 4-methylbenzene Sulphonic acid ester (323mg, 0.93mmol), potassium carbonate (175mg, 1.27mmol) and potassium iodide (14mg, 0.08mmol).Then will be anti- Answering liquid to rise high-temperature, back flow reaction, after 20 hours, is cooled to room temperature, and concentrating under reduced pressure.Residue is through silica gel column chromatography (oil Ether/ethyl acetate (v/v)=1/1) to obtain title compound be light yellow solid (210mg, 57.8%) to purification.
MS(ESI,pos.ion)m/z:431.2(M+1)；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.54(s,1H),9.15(s,1H),8.18(s,1H),7.70(d, J=8.4Hz, 1H), 7.63 (d, J=8.4Hz, 1H), 7.50-7.45 (m, 2H), 7.10-7.03 (m, 2H), 3.45 (t, J= 4.8Hz, 4H), 3.41-3.39 (m, 2H), 3.10 (t, J=4.8Hz, 4H), 3.06 (d, J=7.2Hz, 2H), 2.99 (d, J= 7.2Hz, 2H), 2.83 (t, J=7.2Hz, 2H), 2.10-2.05 (m, 2H).
Embodiment 5 3-(4-(4-(1-methyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine- 1-yl) butyl)-1H-indole-5-formonitrile HCN
Step 1) synthesis of 7-bromo-1-methyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline
This step title compound prepares according to the method described by embodiment 1 step 8, will 6-bromo-3,4-bis- The reaction in the tert-butyl alcohol (15mL) of hydrogen quinoline-2 (1H)-thioketone (1.00g, 4.13mmol) and acethydrazide (0.40g, 5.37mmol) Preparing crude product, it is shallow that crude product obtains title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=30/1) purification Red solid (0.89g, 81.7%).
LC-MS(ESI,pos.ion)m/z:264.2(M+1)；
1H NMR(400MHz,DMSO-d6)δ(ppm):7.72(s,1H),7.62-7.57(m,2H),2.98(brs,4H), 2.65(s,3H).
Step 2) 4-(1-methyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-formic acid uncle The synthesis of butyl ester
This step title compound prepares according to the method described by embodiment 1 step 9, will 7-bromo-1-methyl- 4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline (0.89g, 3.37mmol), piperazine-1-t-butyl formate (0.69g, 3.71mmol)、Pd2(dba)3(0.31g, 0.34mmol), X-phos (0.32g, 0.67mmol) and sodium tert-butoxide (0.65g, 6.74mmol) reaction prepares crude product in the toluene (10mL), crude product through silica gel column chromatography (methylene chloride/methanol (v/v)= 50/1) purification obtains title compound is light red solid (1.11g, 89.5%).
LC-MS(ESI,pos.ion)m/z:370.2(M+1)；
1H NMR(400MHz,CDCl3-d6) δ (ppm): 7.38 (d, J=8.8Hz, 1H), 6.90 (d, J=2.4Hz, 1H), 6.87 (dd, J=8.8,2.8Hz, 1H), 3.60 (t, J=5.2Hz, 4H), 3.18 (t, J=5.2Hz, 4H), 3.12-3.09 (m, 2H),2.98-2.94(m,2H),2.73(s,3H),1.49(s,9H).
Step 3) 3-(4-(4-(1-methyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1- Base) butyl) synthesis of-1H-indole-5-formonitrile HCN
By 4-(1-methyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate (300mg, 0.81mmol) joins in the ethyl acetate solution (4M, 3mL) of hydrogen chloride, and be stirred at room temperature reaction 1 hour after, Decompression is spin-dried for.The solid of gained is dissolved in acetonitrile (15mL), and is sequentially added into 4-(5-cyano-1 H-indol-3-base) butyl 4-toluene sulfonic acide ester (329mg, 0.89mmol), potassium carbonate (168mg, 1.22mmol) and potassium iodide (14mg, 0.08mmol). Then reactant liquor rises high-temperature, and back flow reaction, after 20 hours, is cooled to room temperature, and concentrating under reduced pressure.Residue is through silica gel column layer It is white solid (210mg, 55.6%) that analysis (petrol ether/ethyl acetate (v/v)=1/1) purification obtains title compound.
MS(ESI,pos.ion)m/z:466.3(M+1)；
1H NMR(600MHz,DMSO-d6) δ (ppm): 11.36 (s, 1H), 8.12 (s, 1H), 7.55 (d, J=8.4Hz, 1H), 7.49 (d, J=8.4Hz, 1H), 7.40 (dd, J=8.4,1.2Hz, 1H), 7.35 (s, 1H), 7.00 (d, J=2.4Hz, 1H), 6.90 (dd, J=9.0,2.4Hz, 1H), 3.43 (t, J=4.8Hz, 4H), 2.98 (t, J=7.2Hz, 2H), 2.96- 2.93 (m, 2H), 2.74 (t, J=7.2Hz, 2H), 2.65 (s, 3H), 2.52 (t, J=4.8Hz, 4H), 2.38 (t, J= 7.2Hz,2H),1.70-1.66(m,2H),1.53-1.46(m,2H).
Embodiment 6 3-(3-(4-(1-methyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine- 1-yl) propyl group)-1H-indole-5-formonitrile HCN
By 4-(1-methyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate (300mg, 0.81mmol) joins in the ethyl acetate solution (4M, 3mL) of hydrogen chloride, and be stirred at room temperature reaction 1 hour after, Decompression is spin-dried for.The solid of gained is dissolved in acetonitrile (15mL), and is sequentially added into 3-(5-cyano-1 H-indol-3-base) propyl group 4-toluene sulfonic acide ester (317mg, 0.89mmol), potassium carbonate (168mg, 1.22mmol) and potassium iodide (14mg, 0.08mmol). Then reactant liquor rises high-temperature, and back flow reaction, after 20 hours, is cooled to room temperature, and concentrating under reduced pressure.Residue is through silica gel column layer It is white solid (205mg, 55.9%) that analysis (petrol ether/ethyl acetate (v/v)=1/1) purification obtains title compound.
MS(ESI,pos.ion)m/z:452.2(M+1)；
1H NMR(600MHz,DMSO-d6) δ (ppm): 11.40 (s, 1H), 8.11 (s, 1H), 7.50 (d, J=8.4Hz, 1H), 7.48 (d, J=9.0Hz, 1H), 7.41 (dd, J=8.4,0.6Hz, 1H), 7.36 (s, 1H), 7.05 (d, J=2.4Hz, 1H), 6.91 (dd, J=9.0,2.4Hz, 1H), 3.20 (brs, 4H), 2.96-2.94 (m, 2H), 2.91-2.89 (m, 2H), 2.76 (t, J=7.2Hz, 2H), 2.63 (s, 3H), 2.52-2.51 (m, 4H), 2.39 (brs, 2H), 1.86-1.84 (m, 2H).
Embodiment 7 7-(4-(4-(5-fluoro-1H-indol-3-yl) butyl) piperazine-1-base)-1-methyl-4,5-dihydro- [1,2,4] triazol [4,3-a] quinoline
By 4-(1-methyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate (300mg, 0.81mmol) joins in the ethyl acetate solution (4M, 3mL) of hydrogen chloride, and be stirred at room temperature reaction 1 hour after, Decompression is spin-dried for.The solid of gained is dissolved in acetonitrile (15mL), and is sequentially added into 4-(5-fluoro-1H-indol-3-yl) butyl 4- Toluene sulfonic acide ester (323mg, 0.89mmol), potassium carbonate (168mg, 1.22mmol) and potassium iodide (14mg, 0.08mmol).So After reactant liquor is risen high-temperature, back flow reaction, after 20 hours, is cooled to room temperature, and concentrating under reduced pressure.Residue is through silica gel column chromatography It is white solid (190mg, 51.1%) that (petrol ether/ethyl acetate (v/v)=1/1) purification obtains title compound.
MS(ESI,pos.ion)m/z:459.3(M+1)；
1H NMR(600MHz,DMSO-d6) δ (ppm): 11.41 (s, 1H), 8.16 (s, 1H), 7.59 (d, J=8.4Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.42 (dd, J=8.4,1.2Hz, 1H), 7.39 (s, 1H), 7.05 (d, J=2.4Hz, 1H), 6.96 (dd, J=8.8,2.4Hz, 1H), 3.39 (t, J=4.8Hz, 4H), 2.96 (t, J=7.2Hz, 2H), 2.92 (t, J =7.2Hz, 2H), 2.74 (t, J=7.2Hz, 2H), 2.65 (s, 3H), 2.62 (brs, 4H), 2.38 (t, J=7.2Hz, 2H), 1.68-1.64(m,2H),1.53-1.45(m,2H).
Embodiment 8 7-(4-(3-(5-fluoro-1H-indol-3-yl) propyl group) piperazine-1-base)-1-methyl-4,5-dihydro- [1,2,4] triazol [4,3-a] quinoline
By 4-(1-methyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate (300mg, 0.81mmol) joins in the ethyl acetate solution (4M, 3mL) of hydrogen chloride, and be stirred at room temperature reaction 1 hour after, Decompression is spin-dried for.The solid of gained is dissolved in acetonitrile (15mL), and is sequentially added into 3-(5-fluoro-1H-indol-3-yl) propyl group 4- Toluene sulfonic acide ester (310mg, 0.89mmol), potassium carbonate (168mg, 1.22mmol) and potassium iodide (14mg, 0.08mmol).So After reactant liquor is risen high-temperature, back flow reaction, after 20 hours, is cooled to room temperature, and concentrating under reduced pressure.Residue is through silica gel column chromatography It is white solid (230mg, 63.7%) that (petrol ether/ethyl acetate (v/v)=1/1) purification obtains title compound.
MS(ESI,pos.ion)m/z:445.2(M+1)；
1H NMR(600MHz,DMSO-d6) δ (ppm): 11.42 (s, 1H), 8.14 (s, 1H), 7.51 (d, J=8.4Hz, 1H), 7.49 (d, J=8.4Hz, 1H), 7.40 (dd, J=8.4,1.2Hz, 1H), 7.37 (s, 1H), 7.05 (d, J=2.4Hz, 1H), 6.92 (dd, J=8.8,2.4Hz, 1H), 3.30 (brs, 4H), 2.97-2.94 (t, J=7.2Hz, 2H), 2.92-2.90 (m, 2H), 2.76 (t, J=7.2Hz, 2H), 2.63 (s, 3H), 2.55 (t, J=4.8Hz, 4H), 2.41-2.38 (m, 2H), 1.87-1.84(m,2H).
Embodiment 9 3-(4-(4-(1-ethyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine- 1-yl) butyl)-1H-indole-5-formonitrile HCN
Step 1) synthesis of 7-bromo-1-ethyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline
This step title compound prepares according to the method described by embodiment 1 step 8, will 6-bromo-3,4-bis- Hydrogen quinoline-2 (1H)-thioketone (2.30g, 9.50mmol) and propionyl hydrazine (1.09g, 12.35mmol) are anti-in the tert-butyl alcohol (20mL) Should prepare crude product, crude product obtains title compound through silica gel column chromatography (methylene chloride/methanol (v/v)=30/1) purification is Light yellow solid (1.77g, 67.0%).
MS(ESI,pos.ion)m/z:278.3(M+1)；
1H NMR(400MHz,DMSO-d6) δ (ppm): 7.66 (s, 1H), 7.53 (s, 2H), 3.00 (q, J=7.2Hz, 2H), 2.93 (brs, 4H), 1.26 (t, J=7.2Hz, 3H).
Step 2) 4-(1-ethyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-formic acid uncle The synthesis of butyl ester
This step title compound prepares according to the method described by embodiment 1 step 9, by bromo-for 7-1-ethyl-4, 5-dihydro-[1,2,4] triazol [4,3-a] quinoline (1.77g, 6.36mmol), piperazine-1-t-butyl formate (1.30g, 7.00mmol)、Pd2(dba)3(0.58g, 0.63mmol), X-phos (0.60g, 1.26mmol) and sodium tert-butoxide (1.22g, 12.73mmol) in toluene (30mL), reaction prepares crude product, and crude product is through silica gel column chromatography (methylene chloride/methanol (v/v) =50/1) purification obtains title compound is faint yellow solid (1.42g, 58.2%).
MS(ESI,pos.ion)m/z:384.5(M+1)；
1H NMR(400MHz,CDCl3) δ (ppm): 7.34 (d, J=8.8Hz, 1H), 6.87 (s, 1H), 6.84 (dd, J= 8.8,2.4Hz, 1H), 3.57 (t, J=4.8Hz, 4H), 3.14 (t, J=4.8Hz, 4H), 3.09-3.02 (m, 4H), 2.92 (q, J=7.2Hz, 2H), 1.47 (s, 9H), 1.45 (t, J=7.2Hz, 2H).
Step 3) 3-(4-(4-(1-ethyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1- Base) butyl) synthesis of-1H-indole-5-formonitrile HCN
By 4-(1-ethyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate (300mg, 0.78mmol) joins in the ethyl acetate solution (4M, 3mL) of hydrogen chloride, and be stirred at room temperature reaction 1 hour after, Decompression is spin-dried for.The solid of gained is dissolved in acetonitrile (15mL), and is sequentially added into 4-(5-cyano-1 H-indol-3-base) butyl 4-toluene sulfonic acide ester (317mg, 0.86mmol), potassium carbonate (162mg, 1.17mmol) and potassium iodide (14mg, 0.08mmol). Then reactant liquor rises high-temperature, and back flow reaction, after 20 hours, is cooled to room temperature, and concentrating under reduced pressure.Residue is through silica gel column layer It is faint yellow solid (180mg, 48.0%) that analysis (petrol ether/ethyl acetate (v/v)=1/1) purification obtains title compound.
MS(ESI,pos.ion)m/z:480.3(M+1)；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.52(s,1H),8.13(s,1H),7.55-7.52(m,2H), 7.44-7.41 (m, 2H), 7.14 (s, 1H), 7.02 (dd, J=9.0,1.8Hz, 1H), 3.48 (t, J=4.8Hz, 2H), 3.41 (t, J=4.8Hz, 2H), 3.22 (q, J=7.2Hz, 2H), 3.17-3.09 (m, 4H), 3.06-3.02 (m, 4H), 2.95 (t, J =6.6Hz, 2H), 2.80 (t, J=7.8Hz, 2H), 2.08 (brs, 4H), 1.32 (t, J=7.2Hz, 3H).
Embodiment 10 3-(3-(4-(1-ethyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine- 1-yl) propyl group)-1H-indole-5-formonitrile HCN
By 4-(1-ethyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate (300mg, 0.78mmol) joins in the ethyl acetate solution (4M, 3mL) of hydrogen chloride, and be stirred at room temperature reaction 1 hour after, Decompression is spin-dried for.The solid of gained is dissolved in acetonitrile (15mL), and is sequentially added into 3-(5-cyano-1 H-indol-3-base) propyl group 4-toluene sulfonic acide ester (305mg, 0.86mmol), potassium carbonate (162mg, 1.17mmol) and potassium iodide (14mg, 0.08mmol). Then reactant liquor rises high-temperature, and back flow reaction, after 20 hours, is cooled to room temperature, and concentrating under reduced pressure.Residue is through silica gel column layer It is faint yellow solid (195mg, 53.6%) that analysis (petrol ether/ethyl acetate (v/v)=1/1) purification obtains title compound.
MS(ESI,pos.ion)m/z:466.3(M+1)；
1H NMR(600MHz,DMSO-d6) δ (ppm): 11.54 (s, 1H), 8.13 (s, 1H), 7.55 (d, J=9.6Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.43-7.42 (m, 2H), 7.15 (s, 1H), 7.02 (d, J=9.0Hz, 1H), 3.49 (t, J=4.8Hz, 2H), 3.42 (t, J=4.8Hz, 2H), 3.22 (q, J=7.2Hz, 2H), 3.17-3.11 (m, 4H), 3.05 (brs, 4H), 2.97-2.95 (m, 2H), 2.80 (t, J=7.2Hz, 2H), 2.12-2.06 (m, 2H), 1.33 (t, J=7.2Hz, 3H).
Embodiment 11 1-ethyl-7-(4-(4-(5-fluoro-1H-indol-3-yl) butyl) piperazine-1-base)-4,5-dihydro- [1,2,4] triazol [4,3-a] quinoline
By 4-(1-ethyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate (300mg, 0.78mmol) joins in the ethyl acetate solution (4M, 3mL) of hydrogen chloride, and be stirred at room temperature reaction 1 hour after, Decompression is spin-dried for.The solid of gained is dissolved in acetonitrile (15mL), and is sequentially added into 4-(5-fluoro-1H-indol-3-yl) butyl 4- Toluene sulfonic acide ester (311mg, 0.86mmol), potassium carbonate (162mg, 1.17mmol) and potassium iodide (14mg, 0.08mmol).So After reactant liquor is risen high-temperature, back flow reaction, after 20 hours, is cooled to room temperature, and concentrating under reduced pressure.Residue is through silica gel column chromatography It is faint yellow solid (205mg, 55.4%) that (petrol ether/ethyl acetate (v/v)=1/1) purification obtains title compound.
MS(ESI,pos.ion)m/z:473.3(M+1)；
1H NMR(600MHz,DMSO-d6) δ (ppm): 11.50 (s, 1H), 8.15 (s, 1H), 7.53 (d, J=8.8Hz, 2H), 7.42 (d, J=8.8Hz, 2H), 7.13 (s, 1H), 7.03 (dd, J=8.8,1.2Hz, 1H), 3.44 (t, J=4.8Hz, 4H), 3.23 (q, J=7.2Hz, 2H), 3.17-3.10 (m, 4H), 3.04 (brs, 4H), 2.94 (t, J=7.2Hz, 2H), 2.81 (t, J=7.2Hz, 2H), 2.08 (brs, 4H), 1.31 (t, J=7.2Hz, 3H).
Embodiment 12 1-ethyl-7-(4-(3-(5-fluoro-1H-indol-3-yl) propyl group) piperazine-1-base)-4,5-dihydro- [1,2,4] triazol [4,3-a] quinoline
By 4-(1-ethyl-4,5-dihydro-[1,2,4] triazol [4,3-a] quinoline-7-base) piperazine-1-t-butyl formate (300mg, 0.78mmol) joins in the ethyl acetate solution (4M, 3mL) of hydrogen chloride, and be stirred at room temperature reaction 1 hour after, Decompression is spin-dried for.The solid of gained is dissolved in acetonitrile (15mL), and is sequentially added into 3-(5-fluoro-1H-indol-3-yl) propyl group 4- Toluene sulfonic acide ester (300mg, 0.86mmol), potassium carbonate (162mg, 1.17mmol) and potassium iodide (14mg, 0.08mmol).So After reactant liquor is risen high-temperature, back flow reaction, after 20 hours, is cooled to room temperature, and concentrating under reduced pressure.Residue is through silica gel column chromatography It is faint yellow solid (210mg, 58.5%) that (petrol ether/ethyl acetate (v/v)=1/1) purification obtains title compound.
MS(ESI,pos.ion)m/z:459.3(M+1)；
1H NMR(600MHz,DMSO-d6) δ (ppm): 11.50 (s, 1H), 8.11 (s, 1H), 7.56 (d, J=8.8Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.42 (dd, J=8.8,2.4Hz, 2H), 7.15 (s, 1H), 7.02 (d, J=8.8Hz, 1H), 3.46 (brs, 4H), 3.22 (q, J=7.2Hz, 2H), 3.17-3.13 (m, 4H), 3.05 (brs, 4H), 2.96 (d, J= 7.2Hz, 2H), 2.80 (t, J=7.2Hz, 2H), 2.08-2.02 (m, 2H), 1.31 (t, J=7.2Hz, 3H).
Biologic test
Embodiment A: evaluate the affinity of the humanization 5-HT transporter that Chinese hamster ovary celI is transfected by compound
Experimental technique
Under the conditions of 22 DEG C, to cell membrane homogenate albumen (12 μ g), 2nM [3H] imipramine and buffer (50mM Tris-HCl (pH 7.4), 120mMNaCl, 5mM KCl and 0.1%BSA) in the mixed system that formed, add or be added without surveying Examination compound, hatches 60 minutes altogether.
And in the mixed system of above-mentioned condition, add 10 μMs of imipramine, be used for recording non-specific binding value.
Sample after hatching passes through pre-dipped under vacuum with 96 like cell catchers (Unifilter, Packard) Glass fiber filter (GF/B, the Packard) fast filtering of 0.3%PEI, and use ice-cold 50mM Tris-HCl and 150mM Nacl rinses several times repeatedly.It is dried filter membrane, in scintillation counter (Topcount, Packard), uses scintillation solution (Microscint 0, Packard) calculates the radioactivity of residual.Experimental result is with special relative to matched group radioligand Property combine suppression percentage ratio represent.
Standard reference compound is imipramine, obtains competitive curve by the experiment test of series concentration, thus calculates Go out IC50.Experimental result is shown in Table 1.
The affinity of the humanization 5-HT transporter that Chinese hamster ovary celI is transfected by table 1 the compounds of this invention
Embodiment number IC50(nM) Embodiment number IC50(nM)
Embodiment 1 1.2 Embodiment 6 0.6
Embodiment 2 0.7 Embodiment 7 6.5
Embodiment 3 7.3 Embodiment 8 4.3
Embodiment 4 5.2 Embodiment 9 1.1
Embodiment 5 1.0 Embodiment 10 0.57
Experimental result shows, the compounds of this invention has stronger affinity to people source 5-HT transporter (SERT).
Embodiment B:h5-HT 1A Binding affinity is tested
Experimental technique
Under the conditions of 22 DEG C, to people's HEK-293 cell membrane homogenate (36 μ g albumen), 0.3nM [3H]8-OH-DPAT And buffer (50mM Tris-HCl (pH 7.4), 10mM MgSO (Perkin-Elmer)4,0.5mM EDTA,2μg/ml Aprotinine), in the mixed system formed, add or be added without testing compound, hatching 60 minutes altogether.
Standard reference compound is 8-OH-DPAT, in the mixed system of above-mentioned condition, adds 10 μMs of 8-OH-DPAT, For recording non-specific binding value.Data by the 8-OH-DPAT of different experiments test series concentration, it is thus achieved that competitive bent Line.
Sample after hatching passes through pre-dipped under vacuum with 96 like cell catchers (Unifilter, Packard) Glass fiber filter (GF/B, the Packard) fast filtering of 0.3%PEI, and use ice-cold 50mM Tris-HCl repeatedly to rush Wash several times.Be dried filter membrane, in scintillation counter (Topcount, Packard), with scintillation solution (Microscint 0, Packard) radioactivity of residual is calculated.Experimental result is with the suppression hundred specific binding relative to matched group radioligand Proportion by subtraction represents.
Data analysis
[3H] 8-OH-DPAT (0.3nM) and 5-HT in people's HEK-293 cell1AThe flicker by film of the binding tests of receptor Proximity test method completes.Test-compound needs in the case of concentration is more than 6log, at least test three times, and data are through Hill side Journey curve carries out nonlinear regression analysis, obtains IC50Value, then calculate through ChengPrusoff equation, obtain Ki value.
Experimental result shows, the compounds of this invention is to 5-HT1AReceptor has stronger binding affinity.
In the description of this specification, reference term " embodiment ", " embodiment ", " some embodiments ", " show Example ", the description of " concrete example " or " some examples " etc. mean to combine that this embodiment, embodiment or example describe is concrete special Levy, structure, material or feature are contained at least one embodiment, embodiment or the example of the present invention.In this specification In, the schematic representation of above-mentioned term is necessarily directed to identical embodiment, embodiment or example.And, describe Specific features, structure, material or feature can with in one or more embodiments in office, embodiment or example with suitably Mode combines.Additionally, in the case of the most conflicting, those skilled in the art can be by the difference described in this specification The feature of embodiment, embodiment or example and different embodiment, embodiment or example is combined and combines.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is example Property, it is impossible to being interpreted as limitation of the present invention, those of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, revises, replaces and modification.

Claims (10)

1. a compound, it is the stereoisomer of compound, tautomerism shown in the compound shown in formula (I) or formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein:
Q is CH or N；
Each R1And RyIndependently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、C1-C4Alkyl, C1-C4Haloalkyl, C1-C4Alcoxyl Base or C1-C4Halogenated alkoxy, wherein, described C1-C4Alkyl, C1-C4Haloalkyl, C1-C4Alkoxyl and C1-C4Haloalkoxy Base is individually optionally by one or more RxReplaced；
R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-SH ,-C (=O) NH2,-COOH ,-C (=O) CH3、C1-C4Alkane Base, C2-C4Thiazolinyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxyl, C1-C4Halogenated alkoxy, C3-C6Cycloalkyl, 5-6 The heterocyclic radical of individual annular atoms composition, phenyl or the heteroaryl of 5-6 annular atoms composition, wherein, described-C (=O) CH3、C1-C4Alkane Base, C2-C4Thiazolinyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxyl, C1-C4Halogenated alkoxy, C3-C6Cycloalkyl, 5-6 The heteroaryl of the heterocyclic radical of individual annular atoms composition, phenyl and 5-6 annular atoms composition is individually optionally by one or more RxInstitute Replace；
Each R3Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Halogen Substituted alkyl, C1-C6Alkoxyl, C1-C6Halogenated alkoxy, C3-C8Cycloalkyl, the heterocyclic radical of 3-10 annular atoms composition, C6-C10Virtue Base or the heteroaryl of 5-10 annular atoms composition, wherein, described C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Alkyl halide Base, C1-C6Alkoxyl, C1-C6Halogenated alkoxy, C3-C8Cycloalkyl, the heterocyclic radical of 3-10 annular atoms composition, C6-C10Aryl and The heteroaryl of 5-10 annular atoms composition is individually optionally by one or more RxReplaced；
Each RxIndependently be D, F, Cl, Br, I ,-NO2、-CN、-N3、-NH2,-OH ,-SH, oxo (=O), C1-C4Alkyl, C2-C4 Thiazolinyl, C2-C4Alkynyl, C1-C4Haloalkyl, C1-C4Alkoxyl, C1-C4Halogenated alkoxy, C1-C4Alkylamino, C1-C4Alkylthio group, NH2-(C1-C4Alkylidene)-, HO-(C1-C4Alkylidene)-, HS-(C1-C4Alkylidene)-, (C1-C4Alkoxyl)-(C1-C4Alkylene Base)-, (C1-C4Alkylamino)-(C1-C4Alkylidene)-, (C1-C4Alkylthio group)-(C1-C4Alkylidene)-, C3-C6Cycloalkyl, (C3-C6 Cycloalkyl)-(C1-C4Alkylidene)-, the heterocyclic radical of 3-7 annular atoms composition, (heterocyclic radical that 3-7 annular atoms forms)-(C1- C4Alkylidene)-, phenyl, phenyl-(C1-C4Alkylidene)-, the heteroaryl of 5-6 annular atoms composition or (5-6 annular atoms forms Heteroaryl)-(C1-C4Alkylidene)-；
M is 0,1,2 or 3；
N is 0,1,2,3 or 4；With
R is 0,1,2,3,4 or 5.
Compound the most according to claim 1, wherein, each R1And RyIndependently be H, D, F, Cl, Br, I ,-CN ,-NO2、- NH2, methyl, ethyl, n-pro-pyl, isopropyl, methoxyl group, ethyoxyl, n-pro-pyl epoxide, isopropyl epoxide ,-CF3Or-OCF3。
Compound the most according to claim 1, wherein, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、-OH、-SH、- C (=O) NH2,-COOH ,-C (=O) CH3, methyl, ethyl, n-pro-pyl, isopropyl, methoxyl group, ethyoxyl, n-pro-pyl epoxide, different Propyl group epoxide ,-CF3、-CH2CF3、-OCF3、-OCH2CF3Or-OCH2CF2CHF2。
Compound the most according to claim 1, wherein, each R3Independently be H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2、 Methyl, ethyl, n-pro-pyl, isopropyl, methoxyl group, ethyoxyl, n-pro-pyl epoxide, isopropyl epoxide ,-CF3、-CH2CF3、- OCF3、-OCH2CF3、-OCH2CF2CHF2Or phenyl.
5., according to the compound described in claim 1-4 any one, it is to have the compound of one of following structure or have One of the following stereoisomer of compound of structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug:
6. a pharmaceutical composition, comprises the compound described in claim 1-5 any one；With
Described pharmaceutical composition comprises pharmaceutically acceptable excipient, carrier, adjuvant the most further or theirs is any Combination.
Pharmaceutical composition the most according to claim 6, it comprises treatment central nervous system dysfunction further Medicine, the medicine of described treatment central nervous system dysfunction is amitriptyline, desipramine, mirtazapine, amfebutamone, auspicious Bo Xiting, fluoxetine, trazodone, Sertraline, duloxetine, fluvoxamine, midalcipran, left-handed midalcipran, nor-literary composition draw Method is pungent, vilazodone, venlafaxine, dapoxetine, nefazodone, femoxetine, Clomipramine, citalopram, Ai Sixi phthalein Pulan, paroxetine, lithium carbonate, buspirone, olanzapine, Quetiapine, risperidone, Ziprasidone, Aripiprazole, piperazine sieve Grand, clozapine, modafinil, mecamylamine, cabergoline, diamantane (obsolete), imipramine, pramipexole, thyroxine, right U.S. husky Sweet smell, quinidine, naltrexone, samidorphan, buprenorphine, melatonin, alprazolam, pipamperone, dimension are for smooth, sharp Sleep peaceful, perphenazine or their combination in any.
8. the compound described in claim 1-5 any one or the pharmaceutical composition described in claim 6-7 any one exist Preparing the purposes in medicine, wherein, described medicine is used for preventing, treating or alleviate central nervous system dysfunction.
Purposes the most according to claim 8, wherein, described central nervous system dysfunction refers to depression, anxiety Stress after disease, mania, schizophrenia, bipolar disorders, sleep disorder, obsessive idea and behavior disorder, panic disorder, wound Obstacle, the dyskinesia, sexual dysfunction, musculoskeletal pain obstacle, cognitive disorder, dysmnesia, parkinson, Huntingdon Family name's disease, phobia, substance abuse or addiction, drug addiction withdrawal symptom or premenstrualtension syndrome.
10. the compound described in claim 1-5 any one or the pharmaceutical composition described in claim 6-7 any one exist Preparing the purposes in medicine, wherein, described medicine is used for suppressing serotonin reuptake transporter.
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Publication number Priority date Publication date Assignee Title
CN114195695A (en) * 2021-12-14 2022-03-18 上海应用技术大学 Preparation method of 3- (4-hydroxybutyl) -1H-indole compound

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CN104725363A (en) * 2013-12-20 2015-06-24 广东东阳光药业有限公司 Substituted piperazine compound as well as application method and application thereof

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CN104725363A (en) * 2013-12-20 2015-06-24 广东东阳光药业有限公司 Substituted piperazine compound as well as application method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114195695A (en) * 2021-12-14 2022-03-18 上海应用技术大学 Preparation method of 3- (4-hydroxybutyl) -1H-indole compound
CN114195695B (en) * 2021-12-14 2023-02-10 上海应用技术大学 Preparation method of 3- (4-hydroxybutyl) -1H-indole compound

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