CN104496985B - Indole derivatives and the application on medicine thereof - Google Patents

Indole derivatives and the application on medicine thereof Download PDF

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CN104496985B
CN104496985B CN201410742495.5A CN201410742495A CN104496985B CN 104496985 B CN104496985 B CN 104496985B CN 201410742495 A CN201410742495 A CN 201410742495A CN 104496985 B CN104496985 B CN 104496985B
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CN104496985A (en
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张英俊
金传飞
高金恒
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Guangzhou iwahito Medical Technology Co Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • C07D471/10—Spiro-condensed systems

Abstract

The present invention provides a series of indole derivatives or its stereoisomer, tautomer, nitrogen oxides, metabolite, pharmaceutically acceptable salt or prodrug, and it can be used as exciting melatonin receptors agonist.The invention also discloses the pharmaceutical composition containing such compound, and use the compounds of this invention or its medicine composite for curing mammal, the particularly purposes of mankind's central nervous system dysfunction.

Description

Indole derivatives and the application on medicine thereof
Technical field
The invention belongs to drug world, be specifically related to a class and can be used for treating the new chemical combination of central nervous system dysfunction Thing, the method preparing them, the pharmaceutical composition comprising described compound and described compound and pharmaceutical composition thereof are being controlled Treat the application in central nervous system dysfunction.More specifically, the melatonin receptors that can serve as of the present invention is exciting The Benzazole compounds of agent.
Background technology
At present, Drug therapy is one of main method for the treatment of of insomnia patients, and the sedative hypnotic applied clinically has: bar ratio Appropriate class medicine, benzene phenodiazineClass medicine, non-benzene phenodiazineClass medicine, antidepressant class medicine, melatonin and Chinese medicine etc..Barbiturates Medicine is the derivant of barbiturates (malonyl urea), by optionally suppressing thalamus ascending reticular activing system, thus hinders Disconnected excited to corticocerebral conduction.This type of drug main phenobarbital to be had, amobarbital and quinalbarbitone etc..Such medicine Thing toxic and side effects is relatively big, the most serious liver, and nephrotoxicity can be produced after long-time use toleration and dependency, accumulates poisoning, now Clinic is the most less for tranquilizing soporific.Benzene phenodiazineClass medicine has calmness, flesh pine, anxiety and anticonvulsant action, and clinic is often With medicine: mainly have midazolam (midazolam), triazolam (triazolam), alprazolam (alprazolam), Ai Si Azoles logical sequence (estazolam), diazepam (diazepam), flurazepam (flurazepam), clonazepam (clonazepam) etc..This Though a little medicines can extend total sleep time, shorten Sleep latency, reduce S sleep and quickly with dynamic (rapid eye Movement, REM) sleep, the most really improves sleep quality.Its untoward reaction and complication are more apparent, and prolonged application can be drawn Play Drug tolerance, dependency and withdrawal symptom.(Krystal AD.The changing perspective on chronic Insomnia management.J Clin Psychiatry, 2004,65Suppl 8:20-25).Non-benzene phenodiazineClass, criticizes The medicine of quasi-listing has zolpidem (zolpidem), Zaleplon (zalepbn) and zopiclone (zopielone), this type of medicine Thing does not affect ortho sleep structure, does not the most produce rebound insomnia and withdrawal symptom.Common untoward reaction has ataxia, head Bitterly, drowsiness, memory difficulty, (Rotht, Soubranec, Titeuxl, et al., the Efficacy and such as abalienation Safety of zolpidem-MR:a double-blind.placehe-controll study in adults with Primary insomniam.Sleep Med, 2006,7 (5): 397-406).Antidepressant drug does not has special hypnosis and makees With, but it is by treatment is depressed and anxiety is to improve insomnia, and what clinic was conventional has paroxetine (paroxetine), sertraline Woods (sertraline), mirtazapine (mirtazapine), trazodone (trazodone) and amitriptyline etc., individuals patients makes During with SSRIs (novel antidepressant), sleep nothing is improved, even deteriorate (Uhlenhutheh, EH, Balter MB, et al., Trends in recommendations for the pharmacotherapy of anxiety disorders by an Intemationa expert panel, 1992-1997.Eur Neuropsyehopharmacol, 1999.9Suppl 6: 393-398).Therefore, exploitation efficiently, high selectivity, the study hotspot that the little sedative hypnotic drug of side effect becomes.
The good effect of melatonin class medicine, side effect is little, has good application prospect.2005 in U.S.'s Initial Public Offering Melatonin receptors agonist Ramelteon (ramelteon), for treatment of insomnia patients, can shorten Sleep latency, improve sleep Efficiency and sleep maintain, and compared with conventional medicament, this medicine does not damage cognitive activities next day, without withdrawal symptoms；But this medicine has Slight side effect, as having a headache, tired, drowsiness grade (Arendt J, Van Someren E J, Appleton R, et a1., Clinical update:melatonin and sleep disorders.Clin Med, 2008,8 (4): 381-383).
The invention provides some noval chemical compounds with melatonin receptors agonist activity, possess preferable clinical practice Prospect.Compared with existing similar compound, the compound of the present invention has more preferable drug effect, and medicine is special for character and/or toxicity Property.
Summary of the invention
The invention provides a class and there is the compound of melatonin receptors agonist activity, may be used for the preparation treatment mankind Central nervous system dysfunction, such as sleep disorder, stress, seasonal affective disorder, insomnia that the time difference causes and tired Labor and the medicine of insomnia.Present invention provides the method preparing these compounds, use these compounds for treating sucklings to move The method of the above-mentioned disease of thing, the especially mankind and comprise the pharmaceutical composition of these compounds.
On the one hand, the present invention relates to a kind of compound, it is the solid of structure shown in the structure shown in formula (I) or formula (I) Isomer, tautomer, nitrogen oxides, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein:
R1For C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Alkoxyl, C3-C7Cycloalkyl, C2-C9Heterocyclic radical or C2-C6Alkyl；
R2And R3It is each independently hydrogen, C1-C6Alkyl, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkane Epoxide ,-(C1-C6Alkyl)-C (=O) ORc,-(C1-C6Alkyl)-NRaRb, 3-12 former molecular heterocyclic radical, hydroxyl replaces C1-C6Alkyl ,-NRa-(C1-C6Alkyl)-(C6-C10Aryl) ,-(C1-C6Alkyl)-(C6-C10Aryl) ,-(C1-C6Alkyl)- (5-12 former molecular heteroaryl) or 5-12 former molecular heteroaryl；
Or R2And R35-7 former molecular heterocycle is formed together with the atom being connected with them；
R5And R4It is each independently D, F, Cl, Br, I, CN, OH, NO2,-NRaRb,-C (=O) Rc, C1-C4Alkyl, C2-C6 Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl, C1-C6Alkoxyl ,-C (=O)-(C1-C6Alkyl) ,-C (=O) NRaRb,-(C1-C6 Alkyl)-C (=O) ORc,-(C1-C6Alkyl)-NRaRb, 3-12 former molecular heterocyclic radical, the substituted C of hydroxyl1-C6Alkyl ,- NRa-(C1-C6Alkyl)-(C6-C10Aryl) ,-(C1-C6Alkyl)-(C6-C10Aryl) ,-(C1-C6Alkyl)-(5-12 atom group The heteroaryl become) or 5-12 former molecular heteroaryl；
Or R5And R4Cyclopropyl or 3-12 former molecular heterocyclic radical is formed together with the atom being connected with them；
Each RaAnd RbIt is separately H, C1-C6Alkyl ,-(C1-C6Alkyl)-(C6-C10Aryl) ,-C (=O)-RcOr- SO2-(C1-C6Alkyl)；With
Each RcIndependently be as H, C1-C6Alkyl, C6-C10Aryl or C3-C8Cycloalkyl；
Condition is that the compound shown in formula (I) is not
In some embodiments, R1For ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group or the tert-butyl group.
In some embodiments, R2And R3It is each independently H, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl Base, the tert-butyl group, methoxy or ethoxy；
Or R2And R36 former molecular heterocycles are formed together with the atom being connected with them.
In some embodiments, R5And R4It is each independently D, F, Cl, Br, I, CN, OH, NO2, methyl, ethyl, n-pro-pyl, Isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxy or ethoxy；
Or R4And R5Cyclopropyl is formed together with the atom being connected with them.
On the other hand, the present invention provides a kind of compound, its structure one of being as follows or the solid of shown structure Isomer, tautomer, nitrogen oxides, metabolite, pharmaceutically acceptable salt or prodrug,
On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises compound disclosed by the invention.
In one embodiment, pharmaceutical composition of the present invention comprises pharmaceutically acceptable carrier, figuration further Agent, diluent, adjuvant, vehicle or combinations thereof.
In certain embodiments, pharmaceutical composition of the present invention further comprises other treatment nervus centralis The medicine of system dysfunction, the medicine of other described treatment central nervous system dysfunction is sedative hypnotic drug, Antipsychotic drug, antiepileptic, antidepressant drug, antihistamine drug, anti-parkinson class medicine, GABA receptor stimulating agent And/or GABA reuptake inhibitor class medicine, as the medicine of iron ion channel blocker, as oxidase inhibitor Medicine, as adenosine A1/A2The medicine of receptor stimulating agent and as the medicine of melatonin receptors agonist or their any group Close.
In other embodiment, pharmaceutical composition of the present invention, wherein said other treatment maincenter god It is midazolam through the medicine of system dysfunction, triazolam (triazolam), alprazolam (alprazolam), Chinese mugwort department azoles Logical sequence (estazolam), diazepam (diazepam), flurazepam (flurazepam), nitrazepam (nitrazepam), clonazepam (clonazepam), temazepam (temazepam), flunitrazepam (flunitrazepam), oxazepam (oxazepam), Zolpidem (zolpidem), Zaleplon (zaleplon), zopiclone (zopielone), (+)-Zopiclone (eszopiclone), general grand (indiplon) tiagabine (tiagabine) in English ground, gaboxadol (gaboxadol), chlorine miboplatin Bright (clomipramine), doxepin (doxepin), paroxetine (paroxetine), Sertraline (sertraline), rice nitrogen Flat (mirtazapine), chloral hydrate (chloral hydrate), haloperidol (haloperidol), chlorpromazine (chlorpromazine), carbamazepine (carbamazepine), promethazine (promethazine), lorazepam (lorazepam), hydroxyzine (hydroxyzine), aspirin (aspirin), diphenhydramine (diphenhydramine), flutter You are quick (chlorphenamine), brotizolam (lendormin), Ramelteon (ramelteon), Te Simeiertong (tasimelteon), agomelatine (agomelatine), mianserin (mianserine), amitriptyline (amitriptyline), desipramine (desipramine), mirtazapine (mirtazapine), fluoxetine (fluoxetine), Trazodone (trazodone), duloxetine (duloxetine), fluvoxamine (fluvoxamine), vilazodone (vilazodone), dapoxetine (dapoxetine), method Mack Xi Ting (femoxetine), Clomipramine (clomipramine), citalopram (citalopram), escitalopram (escitalopram), paroxetine (paroxetine), Quetiapine (quetiapine), clozapine (clozapine), imipramine (imipramine), nabilone (nabilone), doxepin (doxepin), gabapentin (gabapentin), pramipexole (pramipexole), takes off black sharp Element (circadin), chlordiazepoxide (chlordiazepoxide), perphenazine (perphenazine), suvorexant, Xuezang Guben 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, described Medicine is used for preventing, and treats or alleviates mammal, including the central nervous system dysfunction of the mankind: refer to sleep disorder, and should Swash reaction, depression, anxiety neurosis, seasonal affective disorder, insomnia that the time difference causes and fatigue, schizophrenia, faint from fear, in terror Outbreak, melancholia, insomnia, psychotic disorder, epilepsy, parkinson disease, senile dementia, with normal or pathological seaility Relevant various obstacles, migraine, the loss of memory or Alzheimer.
On the other hand, the present invention relates to compound disclosed by the invention or the compositions purposes in preparing medicine, described Medicine is for selectivity excitement melatonin receptors in biological sample.
On the other hand, the present invention relates to the preparation of the compound that formula (I) is comprised, separate and the method for purification.
Biological results shows, the compound that the present invention provides can be as preferable melatonin receptors agonist.
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.
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, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, 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.
It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise Content.
" stereoisomer " refers to have identical chemical constitution, but the change that atom or group spatially arrangement mode is different Compound.Stereoisomer includes enantiomer, diastereomer, conformer (rotamer), geometric isomer (cis/trans) isomer, atropisomer, etc..
" chirality " is that have can not the molecule of overlapping character with its mirror image；And " achirality " refer to can be overlapping with its mirror image Molecule.
" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror image relationship.
" diastereomer " refers to two or more chiral centres and the stereoisomerism of its molecule mirror image the most each other Body.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereomer mixes Compound can be separated by high resolution analysis operation such as electrophoresis and chromatograph, such as HPLC.
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 plane of linearly polarized light rotate Ability.When describing optically active compound, prefix D and L or R and S is used to represent that molecule is about one or more hands The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix for (+) or the compound of d be dextrorotation.A kind of concrete stereoisomerism Body is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50:50 mixture of enantiomer Be referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or stereospecificity time, 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 Aubé,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.Valence tautomerism body (valence tautomer) includes being come by the restructuring of some bonding electronss The mutual inversion of phases carried out.The instantiation of ketoenol tautomerization be pentane-2,4-diketone and 4-hydroxyl amyl-3-alkene-2-ketone mutual The change of tautomeric.Another example tautomeric is phenol-keto tautomerism.One concrete reality of phenol-keto tautomerism Example is pyridine-4-alcohol and the change of pyridine-4 (1H)-one tautomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms is within the scope of the present invention.
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.With RaAs a example by, structural formula "-N (Ra)C (=O) NRaRb" and structural formula "-(C1-C6Alkyl)-NRaRb" R between the twoaConcrete option the most unaffected, with Time, at same chemical formula "-N (Ra) C (=O) NRaRbIn ", multiple RaConcrete option the most unaffected.
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.
Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight chain or Side chain univalent hydrocarbyl group, unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkane Base group contains 1-12 carbon atom；In another embodiment, alkyl group contains 1-6 carbon atom；Another embodiment party In case, alkyl group contains 1-4 carbon atom；The most in one embodiment, alkyl group contains 1-3 carbon atom.Alkyl base The example of group comprises, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (n-Pr ,-CH2CH2CH3), Isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), 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 " tans ", or the location of " E " and " Z ".In one embodiment, Alkenyl group comprises 2-8 carbon atom；In another embodiment, alkenyl group comprises 2-6 carbon atom；Another embodiment party In case, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group includes, 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 2-8 carbon atom；In another embodiment, alkynyl Group comprises 2-6 carbon atom；In yet another embodiment, alkynyl group comprises 2-4 carbon atom.The example bag of alkynyl group Include, but be not limited to, acetenyl (-C ≡ CH), propargyl (-CH2C ≡ CH), 1-propinyl (-C ≡ C-CH3) etc..
Term " H " represents single hydrogen atom.Such atomic group can be connected with other groups, such as with oxygen atom phase Even, oh group is formed.
The term " undersaturated " used in the present invention represents in group containing one or more degrees of unsaturation.
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 " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " the substituted alkyl of hydroxyl " represents that alkyl group is replaced by one or more oh groups, wherein alkyl base Group has implication of the present invention.Such example comprises, but is not limited to methylol, ethoxy, 1,2-dihydroxy ethyl Deng.
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, and thiazolinyl or alkoxy base are by one Individual or multiple halogen atoms are replaced, and such example comprises, but is not limited to, trifluoromethyl, trifluoromethoxy 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.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), etc..
Term " p former molecular ", wherein p is integer, typically describes the number of ring member nitrogen atoms in molecule, described In molecule, the number of ring member nitrogen atoms is p.Such as, piperidyl is 6 former molecular heterocyclic radicals, and 1,2,3,6-tetrahydrochysene piperidine ring is 6 former molecular heterocycles, and 1,2,3,4-naphthane is 10 former molecular groups of naphthene base.
Term " cycloalkyl " represents containing 3-12 carbon atom, unit price or the saturated monocycle of multivalence, dicyclo or three ring bodies System.In one embodiment, cycloalkyl comprises 3-12 carbon atom；In another embodiment, to comprise 3-8 carbon former for cycloalkyl Son；In yet another embodiment, cycloalkyl comprises 3-6 carbon atom.The example of cycloalkyl includes, but not limited to cyclopropyl, ring Butyl, cyclopenta etc..
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising the saturated of 3-12 annular atoms or portion Dividing undersaturated monocycle, dicyclo or three rings, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.Some of them embodiment In, heterocycle is 5-7 atom composition；In other embodiment, heterocycle is made up of 6 atoms.Unless otherwise indicated, heterocycle Base can be carbon back or nitrilo, and-CH2-group can be optionally by-C (=O)-replacement.The sulphur atom of ring can optionally by It is oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of heterocyclic radical includes, but does not limits In: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolin Base, pyrazolinyl, pyrazolidinyl, tetrahydro thiapyran base, piperidyl, 1,2,3,6-tetrahydrochysene piperidyl, morpholinyl, thio-morpholinyl, Piperazinyl, 2-oxa--5-azabicyclo [2.2.1] hept-5-base.-CH in heterocyclic radical2-group is by-C (=O)-substituted example Include, but not limited to 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3,5-dioxy piperazine piperidinyls and Hybar X base.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to sulfolane base, 1,1-dioxo Quinoline base.
Term " aryl " expression monocycle containing 6-12 annular atoms, dicyclo and the carbocyclic ring system of three rings, wherein, at least one Individual member ring systems is aromatic, and each of which member ring systems comprises 3-7 former molecular ring, and has one or more attachment point It is connected with the remainder of molecule.The example of aromatic yl group can include phenyl, naphthyl and anthracene.
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 member ring systems is aromatic, and at least one member ring systems comprises one or more miscellaneous Atom, each of which member ring systems comprises 5-7 former molecular ring, and has one or more attachment point and molecule remainder It is connected.Term " heteroaryl " can be with term " hetero-aromatic ring ", and " heteroaromatic " or " heteroaromatics " exchange uses.Heteroaryl bag Containing 1,2,3 or 4 hetero atom being independently selected from O, S and N.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-isoxazole Base, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrole radicals, 2-pyrrole radicals, 3-pyrrole radicals, 2-pyridine radicals, 3-pyridine radicals, 4- Pyridine radicals etc..
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: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.
" 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., Described in J.Pharmaceutical Sciences, 66:1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed Including, but is not limited to, reacting, with amino group, the inorganic acid salt formed has a hydrochlorate, hydrobromate, phosphate, sulfate, Perchlorate, and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid Salt, or obtain these salt by additive method such as ion exchange described on books document.Other are pharmaceutically acceptable Salt include adipate, alginate, Ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boric acid Salt, butyrate, Camphora hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, ethyl sulfonic acid Salt, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproic acid Salt, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, Malonate, mesylate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, mistake Sulfate, 3-phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, Undecylate, valerate, etc..The salt obtained by suitable alkali includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4 Salt.The present invention is also intended to contemplate the quaternary ammonium salt that the compound of the group of any comprised N is formed.Water solublity or oil-soluble or Dispersion product can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmacy Upper acceptable salt farther includes the amine cation that suitable, nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halogenation Thing, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
Present invention compound of coming into the open can contain asymmetric or chiral centre, therefore can deposit by different stereoisomer forms ?.It is contemplated that all stereoisomer forms of compound shown in formula (I), include but not limited to diastereomer, Enantiomer, atropisomer and geometry (or conformation) isomer, and their mixture such as racemic mixture, become The ingredient 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 (solid wedge) of particular configuration or time dotted line indicates, then the stereoisomerism of this structure Body clearly and defines with regard to this.
Compound shown in formula (I) can exist with different tautomeric forms, and all these tautomer, As is described in the claims, it is included within the scope of the present 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.
Pharmaceutically useful acid-addition salts can be formed with mineral acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochlorate, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, Fructus Mali pumilae Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly-half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.
Such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. can be included by its derivative mineral acid obtaining salt.
Such as acetic acid can be included by its derivative organic acid obtaining salt, propanoic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..
Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.
Can be included by its derivative inorganic base obtaining salt, the metal of the I race of such as ammonium salt and periodic chart to XII race.? In some embodiment, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, ferrum, silver, zinc and copper；Particularly suitable salt includes ammonium, potassium, Sodium, calcium and magnesium salt.
Can be included that primary amine, secondary amine and tertiary amine, substituted amine include naturally occurring by its derivative organic base obtaining salt Substituted amine, cyclic amine, deacidite etc..Some organic amine includes, such as, 2-aminopropane., benzathine benzylpenicillin (benzathine), choline salt (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine And trometamol.
It addition, compound disclosed by the invention, including their salt, it is also possible to their hydrate forms or comprise it The form of solvent (such as ethanol, DMSO, etc.) obtains, for their crystallization.The present invention comes into the open compound can be with pharmacy Upper acceptable solvent (including water) inherently or passes through design forming solvate；Therefore, it is contemplated that include solvation And unsolvated form.
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 relates to the preparation of compound shown in formula (I), separate and the method for purification.
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, semi-solid, gel or spray Type.
The compounds of this invention and pharmaceutical composition, preparation and administration
When can be used for treatment, formula (I) compound of therapeutically effective amount and pharmaceutically acceptable salt thereof can be as not adding The chemical drugs of work gives, and the active component being alternatively arranged as pharmaceutical composition provides.Therefore, present disclosure also provides for medicine group Compound, this pharmaceutical composition include formula (I) compound of therapeutically effective amount or its pharmaceutically acceptable salt and one or more Pharmaceutically acceptable carrier, diluent or excipient.
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.
Drug pharmaceutical compositions disclosed by the invention can prepare and be packaged as (bulk) in bulk form, wherein can extract safety The compound shown in formula (I) of effective dose, then gives patient with powder or syrup form.Or, medicine disclosed by the invention Compositions can be prepared and be packaged as unit dosage forms, and the most discrete the most each unit contains formula (I) institute of safe and effective amount The compound shown.When preparing with unit dosage forms, pharmaceutical composition disclosed by the invention generally can contain, such as, and 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.Such as, optional can help to produce equal one dosage type low temperature Some pharmaceutically acceptable excipient.Optional some pharmaceutically acceptable figuration that can help to produce stabilizer type Agent.Optional contribute to time patient is administered carrying or transport the present invention come into the open compound from health organ or part to Another organ of health or some pharmaceutically acceptable excipient of part.Optional some medicine strengthening patient compliance Acceptable excipient on.
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 provide alternative function, this depends on existing in preparation and has those other in how many these excipient and preparation 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)。
At Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy,Lippincott Williams & Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker, New York discloses the various carriers for configuring pharmaceutically acceptable compositions, and is used for what it was prepared Known technology, the respective content of these documents is incorporated by reference into the present invention.Except any such as because producing any less desirable life Thing effect, or so that other composition any in harmful way and pharmaceutically acceptable compositions occurs to interact and the present invention Outside any commonly employed carrier that compound of coming into the open is incompatible, pay close attention to its application and belong to the scope of the present invention.
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)。
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 the powder that redissolves；(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.Enteric coatel tablets are to dissolve or the material bag of disintegrate in intestinal with being resistant to gastric acid effect The compressed tablet of clothing, thus prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to fatty acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Coated tablet is the compacting that sugar-coat surrounds Sheet, it can be beneficial to cover taste beastly or abnormal smells from the patient and can prevent tablet from aoxidizing.Thin membrane coated tablet is for using water solublity The compressed tablet that the thin layer of material or thin film cover.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses the general characteristic identical with sweet tablet.Multiple Tabletting is the compressed tablet through preparing more than a press cycles, including multilayer tablet, and pressed coated or dry coated tablet.
Tabules can be crystallized or granular active component one that is single or that describe with the present invention by powder Or prepared by variety carrier or excipient composition, described carrier and excipient include binding agent, disintegrating agent, controlled release polymer, profit Lubrication prescription, diluent and/or coloring agent.Fumet and sweeting agent are particularly useful when forming chewable tablet and lozenge.
The pharmaceutical composition that the present invention provides can provide with soft capsule or hard capsule, and it can be by gelatin, and methyl is fine Dimension element, prepared by starch or calcium alginate.Described hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section Fill in another section, enclose active component the most completely.SEC (SEC) is soft, spherical shell, such as gelatin shell, It is by adding glycerol, sorbitol or the plasticizing of similar polyhydric alcohol.Soft gelatin shell can comprise preservative and carry out prophylaxis of microbial life Long.Suitably preservative be as described in the present invention those, including methyl hydroxybenzoate and nipalgin and refer to, and sorbic acid.This The liquid that invention provides, semi-solid and solid dosage forms can be encapsulated in capsule.Suitably liquid and semisolid dosage form is included in Solution in Allyl carbonate, vegetable oil or triglyceride and suspensoid.The capsule comprising such solution can be as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.Described capsule can also be adopted Use coating as is known to persons skilled in the art, thus improve or maintain the dissolution of active component.
The pharmaceutical composition that the present invention provides can provide with liquid and semisolid dosage form, including Emulsion, solution, suspendible Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in another kind of liquid in pellet form, It can be oil-in-water type or water-in-oil type.Emulsion can include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and Preservative.Suspensoid can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used The acetal accepted, two (low alkyl group) acetal of such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With there is one or many The water-soluble solvent of individual hydroxyl, such as propylene glycol and ethanol.Elixir is transparent, the water-alcohol solution of sweet taste.Syrup is dense The aqueous solution of sugar such as sucrose, and also preservative can be comprised.For liquid dosage form, such as, the solution in Polyethylene Glycol Can be with enough pharmaceutically acceptable liquid-carrier such as water dilutions, to be accurately, conveniently administered.
Other useful liquid and semisolid dosage form include, but are not limited to comprise the active component and two grades that the present invention provides Change list-or those dosage forms of poly-alkylene glycol, described list-or poly-alkylene glycol include: 1,2-dimethoxymethane, diethylene glycol Dimethyl ether, triethylene glycol dimethyl ether., tetraethylene glycol dimethyl ether, Polyethylene Glycol-350-dimethyl ether, Polyethylene Glycol-550-dimethyl ether, poly-second Glycol-750-dimethyl ether, wherein the approximation mean molecule quantity of 350,550,750 finger Polyethylene Glycol.These preparations can be further Including one or more antioxidant, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propylgallate, vitamin E, hydrogen Quinone, Hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfites, burnt Sodium sulfite, thio-2 acid and ester thereof and dithiocarbamate.
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, in wax or the like.
The combination of oral medication that the present invention provides can also be with liposome, and micelle, the form of microsphere or nanometer system carries 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.Such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl Radix Asparagi acyl Amine phenol or the substituted oxide polylysine of palmitoyl residues.Additionally, compound disclosed in this invention can with in reality The class Biodegradable polymeric controlling to use in release of existing medicine combines, such as, polylactic acid, poly-epsilon-caprolactone, poly- Hydroxybutyric acid, poe, polyacetals, poly-dihydropyran, polybutylcyanoacrylate and the crosslinking of hydrogel or amphiphilic block are altogether Polymers.
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, and infusion or implantation parenteral, for local or complete Body is administered.The parenteral used such as the present invention includes intravenous, intra-arterial, intraperitoneal, in sheath, in ventricle, in urethra, and 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, mixed 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).
Be intended for the pharmaceutical composition of parenteral can include one or more pharmaceutically acceptable carriers and Excipient, includes, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or anti-micro-life The preservative of thing growth, stabilizer, dissolution enhancers, isotonic agent, buffer agent, antioxidant, local anesthetic, suspending agent and dispersion Agent, wetting agent or emulsifying agent, chelating agent, sequestering agent or chelating agen, antifreezing agent, cryoprotective agent, thickening agent, pH adjusting agent And noble gas.
Suitably include, but are not limited to containing transporter: water, saline, normal saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers injection, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers injection.Non-transporter includes, but not limited to the fixed oil of plant origin, Oleum Ricini, Semen Maydis oil, Semen Gossypii The middle chain of oil, olive oil, Oleum Arachidis hypogaeae semen, Oleum menthae, safflower oil, Oleum sesami, Oleum Glycines, hydrogenated vegetable oil, hydrogenated soybean oil and Oleum Cocois Triglyceride, and palm seed oil.Water miscibility carrier includes, but not limited to ethanol, 1,3 butylene glycol, the poly-second of liquid two Alcohol (such as Liquid Macrogol and PEG400), propylene glycol, glycerol, METHYLPYRROLIDONE, N, N-dimethylacetamide Amine and dimethyl sulfoxide.
Suitably antimicrobial or preservative includes, but not limited to phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, Methyl parahydroxybenzoate and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl hydroxybenzoate and Propylparaben and sorbic acid.Suitably isotonic agent includes, but not limited to sodium chloride, glycerol and glucose.Suitably buffer agent Include, but not limited to phosphate and citrate.Suitably antioxidant is as the present invention describes, including sulfurous acid Hydrogen salt and sodium metabisulfite.Suitably local anesthetic includes, but are not limited to procaine hydrochloride.Suitably suspending agent and point Powder is as the present invention describes, including sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitably emulsifying agent includes those that the present invention describes, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene moves back Tax sorbitol monooleate 80 and triethanolamine oleate ester.Suitably sequestering agent or chelating agen includes, but are not limited to EDTA. Suitably pH adjusting agent includes, but are not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitably chelating agent includes, but does not limits In cyclodextrin, including alpha-cyclodextrin, beta-schardinger dextrin-, HP-β-CD, Sulfobutylether-beta-schardinger dextrin-and sulfobutyl group Ether 7-beta-schardinger dextrin-(CyDex,Lenexa,KS)。
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.
In one embodiment, pharmaceutical composition provides with instant sterile solution.In another embodiment, medicine Compositions provides with aseptic dried soluble product, and including freeze-dried powder and hypodermic tablet, it uses carrier before use Reconstruct.In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In yet another embodiment, medicine The aseptic dry insolubility product that compositions reconstructs with carrier before being formulated into use.The most in one embodiment, Pharmaceutical composition is formulated into the aseptic Emulsion of instant.
Pharmaceutical composition disclosed in this invention can be configured to immediately or Modified release dosage forms, including postpone-, slow release-, Pulse-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition can be configured to suspensoid, solid, semi-solid or thixotropic liquid, and the reservoir being used as to implant is administered. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior substrate, its be insoluble to body fluid but The outside polymeric membrane allowing the active component in pharmaceutical composition to diffuse through is surrounded.
The internal matrix being suitable for includes polymethyl methacrylate, and poly-butyl methacrylate is plasticising or unplasticizied Polrvinyl chloride, the nylon of plasticising, the polyethylene terephthalate of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly-diformazan silica Alkane, silicone carbonate copolymer, the hydrogel of the ester of hydrophilic polymer such as acrylic acid and methacrylic acid, collagen, crosslinking The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and coach.
The outside polymeric membrane being suitable for includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Thing, ethylene/vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polychlorostyrene second The copolymer of alkene, ethlyene dichloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer is poly-to benzene two Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.
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).
It is suitable for the pharmaceutical composition of topical and can be formulated into ointment, ointment, suspensoid, lotion, powder, Solution, paste, gel, spray, aerosol or oil preparation.Such as, ointment, ointment and gel can be with water or oil Substrate, and the thickening agent and/or gel and/or the solvent that are suitable for configure.Such substrate can include, water, and/or oil example Such as liquid-liquid paraffin and vegetable oil (such as Oleum Arachidis hypogaeae semen or Oleum Ricini), or solvent such as Polyethylene Glycol.Make according to medium property Thickening agent and gel include soft paraffin, aluminium stearate, cetearyl alcohol, Polyethylene Glycol, lanoline, Cera Flava, poly-carboxylic second Alkene and cellulose derivative, and/or glyceryl monostearate and/or nonionic emulsifier.
Lotion can be prepared with water or oil matrix, and generally also contains one or more emulsifying agents, stabilizer, dispersion Agent, suspending agent or thickening agent.
Externally-applied powder can be in the powder substrate such as Pulvis Talci being arbitrarily suitable for, molding in the presence of lactose or starch.Drop Can be formulated with the water or non-aqueous matrix comprising one or more dispersants, solubilizing agent, suspending agent or preservative.
Topical formulations can be by applying one or many to be administered every day in affected part；The impermeable plastic wound dressing covering skin is preferential Used.The administration that adhesiveness store system can realize continuously or extend.
The compounds of this invention and the purposes of compositions
The present invention provides use compound disclosed in this invention and medicine composite for curing, prevention, or it is dynamic to alleviate suckling Thing, including the medicine of the central nervous system dysfunction of the mankind, it is also possible to be used for the medicine of exciting melatonin receptors for preparation Product.
Specifically, in the compositions of the present invention, the amount of compound can the most optionally excitement take off black Element receptor, the compound of the present invention can be as treatment mankind central nervous system (CNS) dysfunction such as sleep disorder, should Swash reaction, seasonal affective disorder, insomnia that the time difference causes and fatigue, insomnia, depression, anxiety neurosis, psychotic The medicine of obstacle, epilepsy, parkinson disease, senile dementia, to normal or that pathological seaility is relevant various obstacles, migraine, note Recall forfeiture or Alzheimer.
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 to be prevented, and treats or alleviates mammal, including the central nervous system dysfunction disease of the mankind.Institute The central nervous system dysfunction disease of the mankind stated, farther includes but is not limited to, sleep disorder, stress, Depression, anxiety neurosis, seasonal affective disorder, insomnia that the time difference causes and fatigue, schizophrenia, faint from fear, panic attack, melancholy Strongly fragrant disease, insomnia, psychotic disorder, epilepsy, parkinson disease, senile dementia, to normal or pathological seaility is relevant Various obstacles, migraine, the loss of memory or Alzheimer 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 thing, the animal of introduced variety and the animal on 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.
Therapeutic alliance
The compounds of this invention can be administered as single active agent, or can be administered with other therapeutic agent, Including there is same or similar therapeutic activity and being defined as other compound safe and efficient for this type of administering drug combinations.
On the one hand, the present invention provides treatment, the method preventing or improving disease or disease, including giving safe and effective amount Comprise the present invention to come into the open the combination medicine of compound and one or more therapeutically active agents.In one embodiment, combination medicine Comprise the medicine of one or more other treatment central nervous system dysfunction.
In another embodiment, the medicine of other treatment central nervous system dysfunction includes but not limited to: calm Hypnotic drug, antipsychotic drug, antiepileptic, antidepressant drug, antihistamine drug, anti-parkinson class medicine, GABA Receptor stimulating agent and/or GABA reuptake inhibitor class medicine, as the medicine of iron ion channel blocker, aoxidize as monoamine The medicine of enzyme inhibitor, as adenosine A1/A2The medicine of receptor stimulating agent and the medicine as melatonin receptors agonist.
In another embodiment, the medicine of the treatment central nervous system dysfunction of described other is midazolam (midazolam), triazolam (triazolam), alprazolam (alprazolam), estazolam (estazolam), diazepam (diazepam), flurazepam (flurazepam), nitrazepam (nitrazepam), clonazepam (clonazepam), for Ma Xi Dissolve (temazepam), flunitrazepam (flunitrazepam), oxazepam (oxazepam), zolpidem (zolpidem), prick Coming general grand (zaleplon), zopiclone (zopielone), (+)-Zopiclone (eszopiclone), English ground is general grand (indiplon) tiagabine (tiagabine), gaboxadol (gaboxadol), clomipramine (clomipramine), doxepin (doxepin) paroxetine (paroxetine), Sertraline (sertraline), mirtazapine (mirtazapine), chloral hydrate (chloralhydrate), haloperidol (haloperidol), chlorpromazine (chlorpromazine), carbamazepine (carbamazepine), promethazine (promethazine), lorazepam (lorazepam), hydroxyzine (hydroxyzine), Ah A department woods (aspirin), diphenhydramine (diphenhydramine), chlorphenamine (chlorphenamine), brotizolam (lendormin), Ramelteon (ramelteon), Te Simeiertong (tasimelteon), agomelatine (agomelatine), mianserin (mianserine), amitriptyline (amitriptyline), desipramine (desipramine), mirtazapine (mirtazapine), fluoxetine (fluoxetine), trazodone (trazodone), Du Luoxi Spit of fland (duloxetine), fluvoxamine (fluvoxamine), vilazodone (vilazodone), dapoxetine (dapoxetine), method Mack Xi Ting (femoxetine), Clomipramine (clomipramine), citalopram (citalopram), escitalopram (escitalopram), paroxetine (paroxetine), Quetiapine (quetiapine), clozapine (clozapine), imipramine (imipramine), nabilone (nabilone), doxepin (doxepin), gabapentin (gabapentin), pramipexole (pramipexole), melatonin (circadin), profit is slept Rather (chlordiazepoxide), perphenazine (perphenazine), suvorexant, Xuezang Guben or they appoint Meaning combination.
On the other hand, the present invention provides the product including the compounds of this invention and at least one other therapeutic agent, can prepare Become in the treatment simultaneously, the combination separately or sequentially used.In one embodiment, treatment is for relevant to melatonin receptors Disease or the treatment of symptom.The product that combining preparation provides includes being present in same pharmaceutical composition and comprises disclosed hereinization Compound and the compositions of other therapeutic agents, or the compound disclosed herein that exists in different forms and other therapeutic agents, such as, Medicine box.
Compound disclosed herein can be used as single-activity component or as such as adjuvant, jointly execute with other medicines With.Described other medicines include, sedative hypnotic drug, antipsychotic drug, antiepileptic, antidepressant drug, antihistaminic Thing, anti-parkinson class medicine, GABA receptor stimulating agent and/or GABA reuptake inhibitor class medicine, as iron ion passage The medicine of blocker, as the medicine of oxidase inhibitor, as adenosine A1/A2The medicine of receptor stimulating agent and conduct The medicine of melatonin receptors agonist.
Above-described associating can be prepared as pharmaceutical composition easily and use, therefore, including defined above group Close the pharmaceutical composition with pharmaceutically acceptable excipient or carrier and represent another aspect of the present invention.
These united each compounds can be with alone or in combination pharmaceutical dosage forms order of administration or be administered simultaneously. In one embodiment, each compound component is to be administered simultaneously with the pharmaceutical dosage forms of combination.Being suitable for of known treatment agent Dosage is prone to be understood by the person skilled in the art.
Therefore, on the other hand, the present invention provides a kind of pharmaceutical composition, comprises compound disclosed by the invention and controls with other Treat the associating of activating agent.
Above-described, can come into the open the compound that compound is applied in combination with the present invention, can be by people in the art Member, prepares according to the method described in above-mentioned document and is administered.
Therapeutic Method
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.Formulations for systemic administration includes oral administration, gastrointestinal External administration, transdermal administration and rectally.Typical parenteral refers to by injection or administered by infusion, including intravenous, Intramuscular and subcutaneous injection or administered by infusion.Topical includes being applied to skin and ophthalmic, ear, intravaginal, sucks and intranasal It is administered.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 it is oral administration.In another embodiment, the present invention comes into the open compound or comprise the present invention and come into the open the drug regimen of compound Thing can be inhalation.In a further embodiment, the present invention comes into the open compound or comprise present invention compound of coming into the open and can be Intranasal administration.
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 time or four times.In one embodiment, it is administered once a day.In yet another embodiment, every day It is administered twice.Can be administered until reaching the therapeutic effect wanted or maintaining the therapeutic effect wanted indefinitely.The present invention is public Become civilized compound or comprise the come into the open appropriate dosage regimen of pharmaceutical composition of compound of the present invention and depend on medicine generation of this compound Kinetic property, such as, dilute, and distribution and half-life, these can be by determination of technical staff.The compound additionally, the present invention comes into the open Or comprise the present invention and come into the open the appropriate dosage regimen of pharmaceutical composition of compound, including implementing persistent period of the program, take Certainly in treated disease, the order of severity of disease being treated, the age of patient under consideration and health, patient under consideration's Medical history, the simultaneously character of therapy, it is desirable to the factor in the range of technical staff's knowledge and experience such as therapeutic effect.Such Technical staff be also to be understood that for the individual patient reaction to dosage regimen, or passage individual patient needs to become over time During 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 same medicine group Solvate form is administered.
For the individuality of about 50-70kg, the open pharmaceutical composition of the present invention and combination can be containing about 1-1000mg, Or about 1-500mg, or about 1-250mg, or about 1-150mg, or about 0.5-100mg, or the unit dose of about 1-50mg active component Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination be depending on individuality species, body weight, the age and Individual instances, treated disease (disorder) or disease (disease) or its order of severity.Possesses the doctor of conventional technical ability Teacher, clinicist or veterinary can easily determine prevention, treat or suppress disease (disorder) or disease (disease) development The effective dose of each active component needed for during.
Dose Characteristics cited above use favourable mammal (such as mice, rat, Canis familiaris L., monkey) or its from Body organ, confirms in the external and in vivo test of tissue and specimen.Present invention compound of coming into the open with solution, such as aqueous solution form Using in vitro, it is also possible to such as suspension or aqueous solution form enteral in vivo, parenteral, especially intravenous uses.
In one embodiment, the come into the open treatment effective dose of compound of the present invention is about 0.1mg to about 2 every day, 000mg.Its pharmaceutical composition should provide about 0.1mg to about 2,000mg this compound of dosage.In a particular In, the pharmaceutical dosage unit forms of preparation is provided that about 1mg to about 2,000mg, and about 10mg to about 1,000mg, about 20mg is to about The combination of each main component in 500mg, or the main active of about 25mg to about 250mg or every dosage unit form.One In particular, the pharmaceutical dosage unit forms of preparation is provided that about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg main active.
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.Comprising and prepare phosphate, amide, ester, monothioester, these variants of carbonate and carbaminate are to people in the art It is well-known from the point of view of Yuan.
The general synthetic method of the compounds of this invention
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.
Those skilled in the art will realize 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 Ling Kai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, the most not through being further purified, unless other aspects show during use.General reagent is from Shantou Chemical plant, western Gansu Province, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao is risen Dragon chemical reagent company limited, and Haiyang Chemical Plant, Qingdao is commercially available.
Anhydrous tetrahydro furan is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride and chloroform are to return through calcium hydride Fluidized drying obtains.Ethyl acetate, N,N-dimethylacetamide and petroleum ether are 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.NMR (Nuclear Magnetic Resonance) spectrum with CDC13Or DMSO-d6For solvent (report in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard. 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, quartet), 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-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Phase: 5%-95% is (containing 0.1% in flowing The CH of formic acid3CN) at (H containing 0.1% formic acid2O) ratio in), use electron spray ionisation (ESI), under 210nm/254nm, Detect with UV.
Use Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (the pillar type of pure compound Number: NOVASEP 50/80mm DAC), detect at 210nm/254nm UV.
The use of brief word below runs through the present invention:
AcONa sodium acetate
MeI,CH3I potassium iodide
BrCH2CH2Br glycol dibromide
CHCl3Chloroform
CDC13Deuterochloroform
DMSO dimethyl sulfoxide
DMSO-d6Deuterated dimethyl sulfoxide
DMAP DMAP
(Boc)2O Boc anhydride, Bis(tert-butoxycarbonyl)oxide
HCHO formaldehyde
H2O water
ML, m milliliter
RT room temperature
Rt retention time
Following synthetic schemes describes the preparation present invention and comes into the open the step of compound:
Synthetic method 1
Compound (7) can be prepared by following process:
Initiation material 2-(5-methoxyl group-1H-indol-3-yl) acetonitrile (1) is under DMAP is catalyzed, with Boc Anhydride reaction obtains intermediate (2).Compound (2) generates intermediate with iodomethane or glycol dibromide under sodium hydride effect (3).Compound (3) is at N2Borane reduction is utilized to obtain intermediate (4) under protection.Compound (4) is at water and 1,4-dioxane Middle heating takes off Boc protection group and generates compound (5), and compound (5) and formaldehyde cyclization under sodium acetate effect are intermediate (6), compound (6) again from different acyl chlorides (R1C (=O) Cl) or carboxylic acid (R1C (=O) OH) reaction obtain target compound (7)。
Wherein, R1There is implication as described in the present invention；It is expressed as
Synthetic method 2
Compound (8) can be prepared by following process:
Intermediate (5) and different acyl chlorides (R1C (=O) Cl) reaction obtain target compound (8).Wherein, R1Have such as this Implication described in invention；It is expressed as
The following examples can the present invention will be further described, but, these embodiments should not be used as this The restriction of bright scope.
Embodiment
Embodiment 1:1-(6-methoxyl group-4,4-dimethyl-3,4-dihydro-1H-pyrido [3,4-b] indole-2 (9H)- Base) synthesis of propyl group-1-ketone
Step 1) synthesis of the tert-butyl group-3-(cyano methyl)-5-methoxyl group-1H-indole-1-carboxylate
By 2-(5-methoxyl group-1H-indol-3-yl) acetonitrile (5.59g, 30.0mmol), DMAP (0.37g, 3.0mmol), anhydrous methylene chloride (30mL) be added sequentially in 250mL eggplant-shape bottle, be slowly added dropwise anhydrous methylene chloride under stirring (50mL) Bis(tert-butoxycarbonyl)oxide (8.51g, 39.0mmol) diluted, drips and finishes, and continues reaction 4 hours under room temperature.Stopped reaction, Adding water stratification, aqueous phase dichloromethane (3 × 50mL) extracts, and merges organic facies, successively with tap water (3 × 50mL), saturated food Saline (30mL) wash, carry out after organic facies evaporated under reduced pressure silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)= 10/1) title compound (yellow solid, 8.15g, 94.9%) is obtained.
MS(ESI,pos.ion)m/z:287.0[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.04 (d, J=8.5Hz, 1H), 7.60 (s, 1H), 6.98 (dd, J= 9.0,2.5Hz, 1H), 6.94 (d, J=2.4Hz, 1H), 3.87 (s, 3H), 3.73 (d, J=1.1Hz, 2H), 1.66 (s, 9H)；
13C NMR(101MHz,CDCl3)δ(ppm):156.2(s),149.2(s),130.3(s),129.3(s),124.8 (s),117.0(s),116.4(s),113.9(s),109.2(s),101.0(s),84.1(s),55.8(s),28.2(s),14.3 (s).
Step 2) synthesis of the tert-butyl group-3-(2-dicyanopropane-2-base)-5-methoxyl group-1H-indole-1-carboxylate
Sodium hydride (1.27g, 31.75mmol) is joined in 100mL eggplant-shape bottle, with DMF (15mL) Dissolve, under the conditions of-5 DEG C, be slowly added dropwise the tert-butyl group-3-(cyano methyl)-5-methoxyl group-1H-indole-1-carboxylate (3.64g, 12.71mmol), iodomethane (3.95mL, 63.4mmol) and the mixed liquor of DMF (25mL) three, drip and finish, Transfer them to room temperature reaction 4 hours.Stopped reaction, is slowly added dropwise saturated aqueous ammonium chloride (5mL) in reactant liquor, continues Stirring 20 minutes, add ethyl acetate layering, aqueous phase ethyl acetate (3 × 30mL) extracts, and merges organic facies, successively with from the beginning Water (3 × 50mL), saturated aqueous common salt (50mL) wash, and carry out silica gel column chromatography separating purification (oil after organic facies evaporated under reduced pressure Ether/ethyl acetate (v/v)=50/1) obtain title compound (yellow liquid, 3.7g, 92.6%).
MS(ESI,pos.ion)m/z:315.2[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.05 (d, J=8.4Hz, 1H), 7.48 (s, 1H), 7.25 (d, J= 2.4Hz, 1H), 6.98 (dd, J=9.1,2.5Hz, 1H), 3.89 (s, 3H), 1.83 (s, 6H), 1.67 (s, 9H)；
13C NMR(151MHz,CDCl3)δ(ppm):155.8(s),149.5(s),128.1(s),123.6(s),122.5 (s),120.9(s),116.4(s),113.5(s),102.9(s),84.1(s),55.8(s),30.9(s),28.2(s),27.4 (s).
Step 3) conjunction of the tert-butyl group-3-(1-amino-2-methyl propane-2-base)-5-methoxyl group-1H-indole-1-carboxylate Become
By the tert-butyl group-3-(2-dicyanopropane-2-base)-5-methoxyl group-1H-indole-1-carboxylate (0.66g, 2.1mmol) Join in 100mL eggplant-shape bottle, with anhydrous tetrahydro furan (15mL) dissolve, slowly drip borine-tetrahydrofuran solution (6.3mL, 6.3mmol), drip and finish, under nitrogen protection, be gradually heating to back flow reaction 12 hours.Stopped reaction, is cooled to room temperature, slowly adds Entering sodium hydrate aqueous solution, add dichloromethane layering, aqueous phase dichloromethane (3 × 30mL) extracts, and merges organic facies, depends on Secondary tap water (3 × 50mL), saturated aqueous common salt (50mL) wash, and carry out silica gel column chromatography and separate pure after organic facies evaporated under reduced pressure Change (methylene chloride/methanol (v/v)=100/1) and obtain title compound (yellow liquid, 296mg, 44.2%).
MS(ESI,pos.ion)m/z:319.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.07 (s, 1H), 7.36 (s, 1H), 7.17 (d, J=2.3Hz, 1H), 6.94 (dd, J=9.0,2.4Hz, 1H), 3.88 (s, 3H), 3.02 (s, 2H), 1.68 (s, 9H), 1.40 (s, 6H).
Step 4) synthesis of 2-(5-methoxyl group-1H-indol-3-yl)-2-methylpropane-1-amine
By the tert-butyl group-3-(1-amino-2-methyl propane-2-base)-5-methoxyl group-1H-indole-1-carboxylate (271mg, 0.85mmol), tap water (15mL) and Isosorbide-5-Nitrae-dioxane (5mL) be added sequentially in 100mL eggplant-shape bottle, be gradually heating to back Stream reaction 12 hours.Stopped reaction, is cooled to room temperature, adds ethyl acetate layering, and aqueous phase ethyl acetate (3 × 30mL) extracts Take, merge organic facies, successively with tap water (3 × 50mL), saturated aqueous common salt (30mL) washing, carry out after organic facies evaporated under reduced pressure Silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=10/1) obtain title compound (weak yellow liquid, 107mg, 57.8%).
MS(ESI,pos.ion)m/z:219.1[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.14 (s, 1H), 7.24 (s, 1H), 7.19 (d, J=2.1Hz, 1H), 6.94 (s, 1H), 6.85 (dd, J=8.8,2.3Hz, 1H), 3.86 (s, 3H), 2.99 (s, 2H), 1.40 (s, 6H).
Step 5) synthesis of 6-methoxyl group-4,4-dimethyl-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole
By 2-(5-methoxyl group-1H-indol-3-yl)-2-methylpropane-1-amine (138mg, 0.63mmol), tap water (25mL), sodium acetate (78mg, 0.95mmol) and 37% formalin (0.05mL, 0.95mmol) are added sequentially to 100mL In eggplant-shape bottle, under nitrogen protection, it is warming up to back flow reaction 10 hours.Stopped reaction, is cooled to room temperature, slowly adds in reactant liquor Entering sodium hydrate aqueous solution, stir 20 minutes, add dichloromethane layering, aqueous phase dichloromethane (3 × 30mL) extracts, and closes And organic facies, successively with tap water (3 × 50mL), saturated aqueous common salt (30mL) washing, after organic facies evaporated under reduced pressure, carry out silica gel Column chromatographic isolation and purification (methylene chloride/methanol (v/v)=30/1) obtains title compound (yellow solid, 83mg, 57%).
MS(ESI,pos.ion)m/z:231.1[M+H]+.
1H NMR(600MHz,CDCl3) δ (ppm): 7.70 (s, 1H), 7.19 (d, J=8.7Hz, 1H), 7.11 (d, J= 2.2Hz, 1H), 6.79 (dd, J=8.7,2.3Hz, 1H), 3.94 (s, 2H), 3.87 (s, 3H), 2.84 (s, 2H), 2.05 (s, 1H),1.39(s,6H).
Step 6) 1-(6-methoxyl group-4,4-dimethyl-3,4-dihydro-1H-pyrido [3,4-b] indole-2 (9H)-yl) The synthesis of propyl group-1-ketone
By 6-methoxyl group-4,4-dimethyl-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole (127mg, 0.55mmol), anhydrous methylene chloride (10mL) and triethylamine (0.31mL, 2.2mmol) be added sequentially in 100mL eggplant-shape bottle ,- Under the conditions of 5 DEG C, it is slowly added into the propionyl chloride (0.06mL, 0.66mmol) that anhydrous methylene chloride (5mL) dilutes, drips and finish, 10 minutes After, transfer them to room temperature reaction 3 hours.Stopped reaction, adds water stratification, and aqueous phase dichloromethane (3 × 30mL) extracts, and merges Organic facies, successively with tap water (3 × 50mL), saturated aqueous common salt (30mL) washing, carries out silicagel column after organic facies evaporated under reduced pressure Chromatography purification (petrol ether/ethyl acetate (v/v)=5/1) obtain title compound (faint yellow solid, 127mg, 80.6%).
MS(ESI,pos.ion)m/z:287.0[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.73 (s, 1H), 7.21 (t, J=11.9Hz, 1H), 7.10 (d, J= 13.3Hz, 1H), 6.80 (dd, J=8.5,1.7Hz, 1H), 4.81 (s, 2H), 3.86 (s, 3H), 3.47 (s, 2H), 2.52 (q, J =7.4Hz, 2H), 1.43 (s, 6H), 1.25 (t, J=7.3Hz, 3H).
13C NMR(151MHz,CDCl3)δ(ppm):173.4(s),153.6(s),131.9(s),130.2(s),125.9 (s),115.9(s),111.8(s),110.4(s),102.7(s),57.1(s),56.1(s),40.8(s),33.8(s),26.4 (s),26.3(s),9.6(s).
Embodiment 2:1-(6-methoxyl group-4,4-dimethyl-3,4-dihydro-1H-pyrido [3,4-b] indole-2 (9H)- Base) synthesis of butyl-1-ketone
Step 1) 1-(6-methoxyl group-4,4-dimethyl-3,4-dihydro-1H-pyrido [3,4-b] indole-2 (9H)-yl) The synthesis of butyl-1-ketone
By 6-methoxyl group-4,4-dimethyl-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole (127mg, 0.55mmol), anhydrous N,N-dimethylformamide (15mL), N, N-diisopropyl ethyl amine (0.39mL, 2.2mmol) and 2- (7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (323mg, 0.82mmol) are added sequentially to In 100mL eggplant-shape bottle, under the conditions of-10 DEG C, slowly drip the n-butyric acie that anhydrous DMF (5mL) dissolves (0.06mL, 0.66mmol), drips and finishes, and after continuing reaction 20 minutes, transfers them to room temperature reaction 10 hours.Stopped reaction, adds Water stratification, aqueous phase dichloromethane (3 × 30mL) extracts, and merges organic facies, successively with tap water (3 × 50mL), saturated common salt Water (30mL) washs, and carries out silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=5/ after organic facies evaporated under reduced pressure 1) title compound (faint yellow solid, 123mg, 74.4%) is obtained.
MS(ESI,pos.ion)m/z:301.3[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.40 (s, 1H), 7.21 (t, J=7.6Hz, 1H), 7.09 (d, J= 1.6Hz, 1H), 6.80 (dd, J=8.6,1.9Hz, 1H), 4.79 (s, 2H), 3.86 (s, 3H), 3.48 (s, 2H), 2.46 (t, J =7.5Hz, 2H), 1.78～1.76 (m, 2H), 1.44 (s, 6H), 1.02 (t, J=7.4Hz, 3H).
13C NMR(151MHz,CDCl3)δ(ppm):172.6(s),153.7(s),131.8(s),130.1(s),125.9 (s),116.1(s),111.7(s),110.4(s),102.7(s),57.2(s),56.1(s),40.6(s),35.1(s),33.8 (s),26.3(s),18.7(s),14.1(s).
The synthesis of embodiment 3:N-((1-(5-methoxyl group-1H-indol-3-yl) cyclopropyl) methyl) propionic acid amide.
Step 1) synthesis of the tert-butyl group-3-(1-anocy clopropyl)-5-methoxyl group-1H-indole-1-carboxylate
This step title compound prepares with reference to the method described by embodiment 1 step 2, will the tert-butyl group-3-(cyanogen Ylmethyl)-5-methoxyl group-1H-indole-1-carboxylate (5g, 17.46mmol), glycol dibromide (2.28mL, 26.9mmol), 60% sodium hydride (1.75g, 43.8mmol) reaction preparation, thick product warp in anhydrous dimethyl sulphoxide (45mL) Silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=100/1) obtain title compound (weak yellow liquid, 1.66g, 30.4%).
MS(ESI,pos.ion)m/z:313.3[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.98 (s, 1H), 7.43 (s, 1H), 7.20 (d, J=2.4Hz, 1H), 6.96 (dd, J=9.0,2.4Hz, 1H), 3.89 (s, 3H), 1.67～1.65 (m, 2H), 1.64 (s, 9H), 1.33 (q, J= 4.8Hz,2H).
13C NMR(151MHz,CDCl3)δ(ppm):156.5,149.5,130.4,130.0,125.2,122.4,116.5, 116.3,114.3,101.9,84.4,56.0,28.4,15.5,5.8.
Step 2) synthesis of the tert-butyl group-3-(1-(aminomethyl) cyclopropyl)-5-methoxyl group-1H-indole-1-carboxylate
This step title compound prepares with reference to the method described by embodiment 1 step 3, will the tert-butyl group-3-(1- Anocy clopropyl)-5-methoxyl group-1H-indole-1-carboxylate (2.7g, 8.6mmol), borine-tetrahydrofuran solution (1M, 25.8mL, 25.8mmol) reaction preparation in anhydrous tetrahydro furan (40mL), thick product is through silica gel column chromatography separating purification (two Chloromethanes/methanol (v/v)=200/1) obtain title compound (pink solid, 1.11g, 41%).
MS(ESI,pos.ion)m/z:317.1[M+H]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.98 (s, 1H), 7.39 (s, 1H), 7.10 (d, J=2.4Hz, 1H), 6.90 (dd, J=9.0,2.4Hz, 1H), 3.85 (s, 3H), 2.14 (s, 2H), 1.63 (s, 9H), 0.80～0.73 (m, 4H).
13C NMR(151MHz,CDCl3)δ(ppm):156.0,149.8,131.5,130.8,126.0,122.6,116.3, 112.9,103.0,83.6,56.0,50.4,31.1,28.4,10.6.
Step 3) synthesis of (1-(5-methoxyl group-1H-indol-3-yl) cyclopropyl) methyl amine
This step title compound prepares with reference to the method described by embodiment 1 step 4, will the tert-butyl group-3-(1- (aminomethyl) cyclopropyl)-5-methoxyl group-1H-indole-1-carboxylate (2.2g, 7.0mmol) is at tap water (10mL) and 1,4-bis- Reaction preparation in oxygen six ring (5mL), thick product obtains through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100/1) To title compound (faint yellow solid, 0.91g, 61%).
MS(ESI,pos.ion)m/z:217.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.01 (s, 1H), 7.22 (s, 1H), 7.17 (d, J=2.4Hz, 1H), 7.03 (d, J=2.4Hz, 1H), 6.85 (dd, J=8.8,2.4Hz, 1H), 3.86 (s, 3H), 2.77 (s, 2H), 0.81～0.71 (m,4H).
Step 4) synthesis of N-((1-(5-methoxyl group-1H-indol-3-yl) cyclopropyl) methyl) propionic acid amide.
This step title compound prepares with reference to the method described by embodiment 1 step 6, will (1-(5-methoxy Base-1H-indol-3-yl) cyclopropyl) methyl amine (0.119g, 0.55mmol), triethylamine (0.31mL, 2.2mmol), propionyl chloride (0.06mL, 0.66mmol) be reaction preparation in anhydrous methylene chloride (15mL), and thick product is through silica gel column chromatography separating purification (stone Oil ether/acetone (v/v)=20/7) obtain title compound (weak yellow liquid, 0.117g, 78%).
MS(ESI,pos.ion)m/z:273.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.47 (s, 1H), 7.26 (d, J=8.8Hz, 1H), 7.19 (d, J= 2.0Hz, 1H), 6.91 (d, J=2.4Hz, 1H), 6.88 (dd, J=8.8,2.4Hz, 1H), 5.22 (s, 1H), 3.84 (s, 3H), 3.32 (s, 2H), 2.12 (q, J=7.6Hz, 2H), 1.05 (t, J=7.6Hz, 3H), 0.75～0.64 (m, 4H).
13C NMR(101MHz,CDCl3)δ(ppm):174.2(s),153.7(s),131.2(s),129.5(s),125.1 (s),117.4(s),112.3(s),110.9(s),102.7(s),58.9(s),56.1(s),29.2(s),21.9(s),10.3 (s),9.7(s).
The synthesis of embodiment 4:N-((1-(5-methoxyl group-1H-indol-3-yl) cyclopropyl) methyl) butyramide
Step 1) synthesis of N-((1-(5-methoxyl group-1H-indol-3-yl) cyclopropyl) methyl) butyramide
This step title compound prepares with reference to the method described by embodiment 1 step 6, will (1-(5-methoxy Base-1H-indol-3-yl) cyclopropyl) methyl amine (119mg, 0.55mmol), triethylamine (0.31mL, 2.2mmol), butyl chloride (0.07mL, 0.66mmol) be reaction preparation in anhydrous methylene chloride (15mL), and thick product is through silica gel column chromatography separating purification (stone Oil ether/acetone (v/v)=20/7) obtain title compound (weak yellow liquid, 132mg, 83.8%).
MS(ESI,pos.ion)m/z:287.3[M+H]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.49 (s, 1H), 7.26 (d, J=8.8Hz, 1H), 7.20 (d, J= 2.0Hz, 1H), 6.91 (d, J=2.4Hz, 1H), 6.87 (dd, J=8.8,2.4Hz, 1H), 5.23 (s, 1H), 3.86 (s, 3H), 3.35 (s, 2H), 2.11 (t, J=7.6Hz, 2H), 1.54～1.46 (m, 2H), 0.88 (t, J=7.8Hz, 3H), 0.78～ 0.63(m,4H).
13C NMR(101MHz,CDCl3)δ(ppm):172.9(s),153.8(s),131.1(s),129.6(s),125.0 (s),117.7(s),112.2(s),110.7(s),101.9(s),59.0(s),56.2(s),38.1(s),21.6(s),20.3 (s),12.8(s),9.9(s).
Embodiment 5:1-(6'-methoxyl group spiral shell [cyclopropyl-1,4'-pyrido [3,4-b] indole]-2'(1'H, 3'H, 9' H)-yl) synthesis of propane-1-ketone
Step 1) 6'-methoxyl group-1', the conjunction of 2', 3', 9'-tetrahydrochysene spiral shell [cyclopropyl-1,4'-pyrido [3,4-b] indole] Become
This step title compound prepares with reference to the method described by embodiment 1 step 5, will (1-(5-methoxy Base-1H-indol-3-yl) cyclopropyl) methyl amine (0.91g, 4.21mmol), sodium acetate (0.52g, 6.32mmol) is in 37% first Reaction preparation in aldehyde aqueous solution (0.33mL, 6.32mmol) and tap water (50mL), thick product is through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) obtains title compound (yellow solid, 481mg, 50%).
MS(ESI,pos.ion)m/z:229.1[M+H]+；
1H NMR(400MHz,d6-DMSO) δ (ppm): 10.52 (s, 1H), 7.14 (d, J=8.4Hz, 1H), 6.61 (dd, J =8.8,2.4Hz, 1H), 6.58 (s, 1H), 3.87 (s, 2H), 3.69 (s, 3H), 2.73 (s, 2H), 1.25 (t, J=6.0Hz, 2H), 0.65 (t, J=5.6Hz, 2H).
Step 2) 1-(6'-methoxyl group spiral shell [cyclopropyl-1,4'-pyrido [3,4-b] indole]-2'(1'H, 3'H, 9'H)- Base) synthesis of propane-1-ketone
This step title compound prepares with reference to the method described by embodiment 1 step 6, will 6'-methoxyl group- 1', 2', 3', 9'-tetrahydrochysene spiral shell [cyclopropyl-1,4'-pyrido [3,4-b] indole] (126mg, 0.55mmol), triethylamine (0.31mL, 2.2mmol), propionyl chloride (0.06mL, 0.66mmol) be reaction preparation, thick product in anhydrous methylene chloride (15mL) Through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=5/1) obtain title compound (faint yellow solid, 143mg, 91.4%).
MS(ESI,pos.ion)m/z:285.2[M+H]+；
1H NMR(400MHz,d6-DMSO) δ (ppm): 11.23 (s, 1H), 7.12 (d, J=8.6Hz, 1H), 6.70 (dd, J =8.8,2.4Hz, 1H), 6.59 (s, 1H), 4.51 (s, 2H), 3.84 (s, 3H), 3.42 (s, 2H), 2.48 (q, J=7.4Hz, 2H), 1.23 (t, J=7.4Hz, 3H), 0.83～0.69 (m, 4H)
13C NMR(101MHz,d6-DMSO)δ(ppm):173.1(s),154.3(s),131.8(s),130.2(s), 129.3(s),119.4(s),111.8(s),110.7(s),102.9(s),69.2(s),56.4(s),43.8(s),28.8(s), 19.3(s),10.4(s),9.6(s).
Embodiment 6:1-(6'-methoxyl group spiral shell [cyclopropyl-1,4'-pyrido [3,4-b] indole]-2'(1'H, 3'H, 9' H)-yl) synthesis of butane-1-ketone
Step 1) 1-(6'-methoxyl group spiral shell [cyclopropyl-1,4'-pyrido [3,4-b] indole]-2'(1'H, 3'H, 9'H)- Base) synthesis of butane-1-ketone
This step title compound prepares with reference to the method described by embodiment 1 step 6, will 6'-methoxyl group- 1', 2', 3', 9'-tetrahydrochysene spiral shell [cyclopropyl-1,4'-pyrido [3,4-b] indole] (126mg, 0.55mmol), triethylamine (0.31mL, 2.2mmol), butyl chloride (0.07mL, 0.66mmol) be reaction preparation, thick product in anhydrous methylene chloride (15mL) Through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=5/1) obtain title compound (faint yellow solid, 132mg, 80.5%).
MS(ESI,pos.ion)m/z:299.3[M+H]+；
1H NMR(400MHz,d6-DMSO) δ (ppm): 11.17 (s, 1H), 7.11 (d, J=8.8Hz, 1H), 6.75 (dd, J =8.8,2.4Hz, 1H), 6.58 (s, 1H), 4.50 (s, 2H), 3.82 (s, 3H), 3.41 (s, 2H), 2.35 (t, J=7.6Hz, 2H), 1.66～1.49 (m, 2H), 0.86 (t, J=7.8Hz, 3H), 0.84～0.68 (m, 4H).
13C NMR(101MHz,d6-DMSO)δ(ppm):172.9(s),154.4(s),131.7(s),130.3(s), 129.2(s),119.4(s),111.8(s),110.9(s),101.9(s),69.3(s),56.4(s),43.6(s),36.2(s), 20.8(s),19.3(s),13.4(s),9.8(s).
The synthesis of embodiment 7:N-(2-(5-methoxyl group-1H-indol-3-yl)-2-methyl-propyl) butyramide
Step 1) synthesis of N-(2-(5-methoxyl group-1H-indol-3-yl)-2-methyl-propyl) butyramide
This step title compound prepares with reference to the method described by embodiment 1 step 6, will 2-(5-methoxyl group- 1H-indol-3-yl)-2-methylpropane-1-amine (120mg, 0.55mmol), triethylamine (0.31mL, 2.2mmol), butyl chloride (0.07mL, 0.66mmol) be reaction preparation in anhydrous methylene chloride (15mL), and thick product is through silica gel column chromatography separating purification (stone Oil ether/acetone (v/v)=20/7) obtain title compound (weak yellow liquid, 138mg, 87.2%).
MS(ESI,pos.ion)m/z:289.3[M+H]+；
1H NMR(400MHz,CDCl3) δ 8.54 (s, 1H), 7.28 (d, J=8.8Hz, 1H), 7.21 (d, J=2.0Hz, 1H), 6.98 (d, J=2.8Hz, 1H), 6.87 (dd, J=8.8,2.4Hz, 1H), 5.25 (s, 1H), 3.85 (s, 3H), 3.65 (d, J=6.0Hz, 2H), 2.02 (t, J=7.4Hz, 2H), 1.64～1.48 (m, 2H), 1.42 (s, 6H), 0.86 (t, J= 7.8Hz,3H).
13C NMR(101MHz,CDCl3)δ(ppm):173.6(s),153.9(s),131.2(s),129.3(s),125.1 (s),117.4(s),112.1(s),110.9(s),102.4(s),58.9(s),56.1(s),40.2(s),39.3(s),29.1 (s),19.8(s),12.8(s)
Biologic test
The LC/MS/MS system analyzed includes Agilent 1200 series vacuum degassing furnace, binary syringe pump, and orifice plate is certainly Dynamic sampler, post calorstat, tri-grades of level Four bar mass spectrographs of Agilent G6430 in charged spray ionization (ESI) source.Quantitative analysis Carry out under MRM pattern, MRM conversion parameter as in Table A:
Analyze and use Agilent XDB-C18,2.1x 30mm, 3.5 μMs of posts, inject 5 μ L sample.Analysis condition: flowing phase It is aqueous formic acid (A) and the formic acid methanol solution (B) of 0.1% of 0.1%.Flow velocity is 0.4mL/min.Eluent gradient such as table Shown in B:
Additionally, also have Agilent 6330 series LC/MS/MS spectrogrph for analyze, note equipped with G1312A binary Penetrate pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrogrph uses ESI radioactive source.Use titer Each analyte is carried out suitable cation models treated and MRM conversion carries out optimal analysis.Use during analyzing Capcell MP-C18 post, specification is: 100x4.6mm I.D., 5 μMs (Phenomenex, Torrance, California, USA).Flowing is 5mM ammonium acetate mutually, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70: 30, v/v)；Flow velocity is 0.6mL/min；Column temperature is maintained at room temperature；Inject 20 μ L sample.
Embodiment A melatonin MT 1 Receptor binding affinity is tested
Test method
Use radioligand associated methods, evaluate the affine of compound humanization MT1 receptor that Chinese hamster ovary celI is transfected Power.Under the conditions of 22 DEG C, to cell membrane homogenate albumen (64 μ g), 0.01nM [125I] iodomelatonin and buffer (50mM Tris-HCl (pH 7.4), 5mM MgCl2And 1%BSA) in the mixed system that formed, add or be added without testization Compound, hatches 60 minutes altogether.Standard reference compound is melatonin, in the mixed system of above-mentioned condition, adds 1 μM Melatonin, is used for recording non-specific binding value.
Sample after hatching passes through pre-dipped under vacuum with 96 like cell catchers (Unifilter, Packard) The glass fiber filter (GF/B, Packard) of 0.3%PEI, and use ice-cold 50mM Tris-HCl repeatedly to rinse several times.Dry Dry filter membrane, in scintillation counter (Topcount, Packard), calculates residual with scintillation solution (Microscint 0, Packard) The radioactivity stayed.Experimental result represents with the suppression percentage ratio specific binding relative to matched group radioligand.
Standard reference compound is melatonin, by the experimental data of the melatonin of series concentration, it is thus achieved that competition Linearity curve.
Data analysis
Use radioligand associated methods, evaluate the humanization MT that Chinese hamster ovary celI is transfected by compound1Receptor affine Power.Test-compound at least tests three times, and data pass through competition curve nonlinear regression analysis through Hill equation curve fitting process Measure IC50Value and Hill coefficient, then calculated by ChengPrusoff equation, calculate Ki value.
The humanization MT that Chinese hamster ovary celI is transfected by the compound that table 1 embodiment of the present invention provides1The binding affinity of receptor is real Test result
Embodiment number Ki(nM) Embodiment number Ki(nM)
Embodiment 1 3.3 Embodiment 2 4.5
Embodiment 3 0.45 Embodiment 4 0.62
Embodiment 5 12 Embodiment 6 15
Embodiment 7 0.12
Experimental result shows, the compounds of this invention is to MT1Receptor demonstrates stronger binding affinity.

Claims (9)

1. a compound, it is the stereoisomer of structure shown in the structure shown in formula (I) or formula (I), tautomer or Pharmaceutically acceptable salt,
Wherein:
R1For C2-C6Alkyl；
R2And R36 former molecular azepine monocycles are formed together with the atom being connected with them；
R5And R4It is each independently C1-C4Alkyl；
Or R5And R4Cyclopropyl is formed together with the atom being connected with them.
Compound the most according to claim 1, wherein, R1For ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group or uncle Butyl.
Compound the most according to claim 1, wherein, R5And R4It is each independently methyl, ethyl, n-pro-pyl, isopropyl Base, normal-butyl, isobutyl group or the tert-butyl group；
Or R4And R5Cyclopropyl is formed together with the atom being connected with them.
4. a compound, its structure one of being as follows or the stereoisomer of shown structure, tautomer or medicine Acceptable salt on,
5. a pharmaceutical composition, it comprises the compound described in claim 1-4 any one, and pharmaceutically acceptable load Body, excipient, diluent, vehicle or combinations thereof.
Pharmaceutical composition the most according to claim 5, it comprises other treatment central nervous system function further The medicine of obstacle, the medicine of other described treatment central nervous system dysfunction is sedative hypnotic drug, psychosis Medicine, antiepileptic, antidepressant drug, antihistamine drug, anti-parkinson class medicine, GABA receptor stimulating agent and/or GABA reuptake inhibitor class medicine, as the medicine of iron ion channel blocker, as the medicine of oxidase inhibitor, As adenosine A1/A2The medicine of receptor stimulating agent and as the medicine of melatonin receptors agonist or their combination in any.
Pharmaceutical composition the most according to claim 6, the medicine of other described treatment central nervous system dysfunction Thing be midazolam, triazolam, alprazolam, estazolam, diazepam, flurazepam, nitrazepam, clonazepam, temazepam, Flunitrazepam, oxazepam, zolpidem, Zaleplon, zopiclone, (+)-Zopiclone, English ground general grand, tiagabine, Jia Bosha Piece, clomipramine, doxepin, paroxetine, Sertraline, mirtazapine, chloral hydrate, haloperidol, chlorpromazine, carbamazepine, Promethazine, lorazepam, hydroxyzine, aspirin, diphenhydramine, chlorphenamine, brotizolam, Ramelteon, Te Simeiertong, Ah Ge Meilating, mianserin, amitriptyline, desipramine, mirtazapine, fluoxetine, trazodone, duloxetine, fluvoxamine, dimension Draw oxazolone, dapoxetine, method Mack Xi Ting, Clomipramine, citalopram, escitalopram, paroxetine, Quetiapine, chlorine Nitrogen is flat, imipramine, nabilone, doxepin, gabapentin, pramipexole, melatonin, chlordiazepoxide, perphenazine, suvorexant Or their combination in any.
8. compound described in claim 1-4 any one or the pharmaceutical composition described in claim 5-7 any one are in system Purposes in standby medicine, described medicine is used for preventing, treating or alleviate mammal, including the central nervous system function of the mankind Obstacle: sleep disorder, stress, depression, anxiety neurosis, seasonal affective disorder, schizophrenia, faint from fear, panic attack, Melancholia, psychotic disorder, epilepsy, parkinson disease, senile dementia, to normal or that pathological seaility is relevant various barriers Hinder, migraine, the loss of memory or Alzheimer.
9. the compound described in claim 1-4 any one or the pharmaceutical composition described in claim 5-7 any one exist Preparing the purposes in medicine, described medicine is for selectivity excitement melatonin receptors in biological sample.
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Title
《Mapping the Melatonin Receptor. 7. Subtype Selective Ligands Based on β-Substituted N-Acyl-5-methoxytryptamines and β-Substituted N-Acyl-5-methoxy-1-methyltryptamines》;Andrew Tsotinis et al.;《 J. Med. Chem.》;20061231;第49卷(第12期);第3509-3519页 *

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Inventor after: Zhang Yingjun

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