CN104529865B - Benzylamine derivatives and application thereof in medicines - Google Patents

Abstract

The invention provides novel benzylamine derivatives or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or pro-drugs thereof for treating Alzheimer diseases. The invention also provides a medicine composition containing a compound provided by the invention and a method for treating the Alzheimer diseases by using the compound or the medicine composition of the compound provided by the invention.

Description

Benzylamine analog derivative and its application on medicine

Technical field

The invention belongs to drug world and relate to treat Alzheimer's disease compound, comprise described compound Compositionss and application thereof and using method.Especially, compound of the present invention is can be used as 5-ht₆Receptor antagonist Benzylamine analog derivative.

Background technology

Multiple central nervous system disease such as anxiety, depression etc. all with neurotransmitter serotonin (5-ht) or serotonin Disorder relevant.As main modulability neurotransmitter in brain, the function of neurotransmitter serotonin (5-ht) is by quilt Referred to as 5-ht₁, 5-ht₂, 5-ht₃, 5-ht₄, 5-ht₅, 5-ht₆And 5-ht₇A large amount of receptor families mediations.Based on Gao Shui in brain Flat 5-ht₆Receptor mrna is it has been suggested that 5-ht₆Receptor may play in the pathology of central nervous system disorders and treatment Effect.Specifically it has been determined that 5-ht₆Selective ligands have potential treatment to make to some cns (central nervous system) disease With such as parkinson disease, Huntington Chorea, anxiety neurosis, depression, manic depressive illness, psychosiss, epilepsy, obsession, inclined head Bitterly, Alzheimer's disease (cognition and memory enhancing), sleep disorder, eating disorders such as anorexia and bulimia nerovsa, panic attack, Adhd (attention deficit hyperactivity disorder), attention deficit disorder, Drug abuse such as cocaine, ethanol, nicotine and benzo DiazaDe- recessiveness brain syndrome, schizophrenia and the disease relevant with spinal trauma or head injury that class causes are such as Hydrocephaluss.It is expected that described compound can be additionally used in treating some stomach intestinal disease such as functional intestinal disease.(see, for example, roth, B.l. etc., j.pharmacol.exp.ther., page 268,1403-14120 (1994), sibley, d.r. etc., mol, Pharmacol., 43,320-327 (1993), a.j.sleight etc., neurotransmission, 11,1-5 (1995) and Sleight, a.j. etc., serotonin id research alert, 1997,2 (3), 115-118).

Research find it is known that 5-ht₆Selective antagonist significantly improves glutamic acid and Radix Asparagi ammonia in cortex of frontal lobe The level of acid, and do not improve hormone, dopamine or 5-ht on nor- kidney₆Level.This attention in memory and cognitive process To specific neurochemical selectivity raise strongly suggested that 5-ht₆Effect in cognition for the part (dawson, l.a.；Nguyen, h.q.；Li, p., british journal of pharmacology, 2000,130 (1), 23-26).With Known selectivity 5-ht₆The memory of antagonists in animals and the research that carries out of study have some positive effects (rogers, d.c.；Hatcher, p.d.；Hagan, j.j., society of neuroscience, abstracts, 2000,26,680). 5-ht₆The potential therapeutic use of correlation of part is the ADD for the treatment of child and adult.Because 5-ht₆Antagonist is seen Get up to improve the activity of nigrostriatal dopamine approach, and because adhd relevant with the exception in caudatum (ernst, m；Zametkin, a.j.；Matochik, j.h.；Jons, p.a.；Cohen, r.m., journal of neuroscience, 1998,18 (5), 5901-5907), so, 5-ht₆Antagonist can treat ADD.It has also been determined that 5-ht₆Antagonism Agent is the potentially useful compound for the treatment of obesity.See, for example, bentley etc., br.j.pharmac.1999, supplementary issue 126； Bentley etc., j.psychopharmacol.1997, supplementary issue a64:255；Wooley etc., neuropharmacology 2001, 41:210-129 and wo02098878.

Content of the invention

The present invention relates to the method for new benzylamine analog derivative and treatment Alzheimer's disease.The compounds of this invention or comprise The pharmaceutical composition of described compound is to 5-ht₆There is preferable affinity interaction, particularly Alzheimer's disease is had and preferably control Therapeutic effect.

On the one hand, the present invention relates to a kind of compound, it is the compound shown in formula (i) or compound shown in formula (i) Stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically can connect The salt being subject to or prodrug,

Wherein:

r¹For h, d, f, cl, br, i ,-cn, c_1-6Alkyl, c_1-6Haloalkyl, c_1-6Alkoxyl or c_1-6Halogenated alkoxy；

r²And r⁵It is each independently h, d or c_1-6Alkyl；

Or r²And r⁵It is combined together to form singly-bound ,-ch₂- or-ch₂ch₂-；

r³And r⁴It is each independently d, c_1-6Alkyl, c_1-6Haloalkyl, c_1-6Alkoxyl or c_1-6Halogenated alkoxy, or r³ And r⁴, and form c together with the carbon atom being jointly connected with them_3-8Cycloalkyl；With

r⁶For h, d, c_1-6Alkyl, c_1-6Haloalkyl, c_1-6Alkoxyl or c_1-6Halogenated alkoxy.

In one embodiment, r¹For h, d, f, cl, br, i ,-cn, c_1-4Alkyl, c_1-4Haloalkyl, c_1-4Alkoxyl or c_1-4Halogenated alkoxy；

r²And r⁵It is each independently h, d or c_1-4Alkyl；

Or r²And r⁵It is combined together to form singly-bound or-ch₂-；

r³And r⁴It is each independently d, c_1-4Alkyl, c_1-4Haloalkyl, c_1-4Alkoxyl or c_1-4Halogenated alkoxy, or r³ And r⁴, and form c together with the carbon atom being jointly connected with them_3-6Cycloalkyl；With

r⁶For h, d, c_1-4Alkyl, c_1-4Haloalkyl, c_1-4Alkoxyl or c_1-4Halogenated alkoxy.

In another embodiment, r¹For h, d, methyl, ethyl, n-pro-pyl, isopropyl, methoxyl group, ethyoxyl, positive third oxygen Base or isopropoxy.

In another embodiment, r²And r⁵It is each independently h, d, methyl or ethyl；

Or r²And r⁵It is combined together to form-ch₂-；With

r³And r⁴It is each independently d, methyl, ethyl, n-pro-pyl or isopropyl, or r³And r⁴, and be jointly connected with them Carbon atom form cyclopropyl together.

In another embodiment, r⁶For h, d, methyl, ethyl, n-pro-pyl, isopropyl ,-ch₂f、-chf₂、-cf₃、- ch₂ch₂f、-ch₂chf₂、-ch₂cf₃、-chfch₃、-chfch₂f、-chfchf₂、-chfcf₃、-cf₂ch₃、-cf₂ch₂f、- cf₂chf₂Or-cf₂cf₃.

In another embodiment, compound of the present invention, it has a structure of one of:

Or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, Hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug.

On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises the compound of the present invention, with And pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combinations thereof.

In one embodiment, pharmaceutical composition of the present invention, it comprises additional therapeutic agent further, described additional Therapeutic agent is medicine, the medicine treating nervous disorders or the combinations thereof for the treatment of A Cihaimo disease.Treatment Alzheimer's disease The medicine of medicine nervous disorders or combinations thereof.

In another embodiment, additional therapeutic agent of the present invention is donepezil (donepezil), nalmefene (nalmefene), Risperidone (risperidone), vitamin e (vitamin e), sam-760, avn-211, avn-101, Rp-5063, tozadenant, prx-3140, prx-8066, sb-742457, naluzaton, idalopirdine, tacrine (tacrine), Rivastigmine (rivastigmine), galantamine (galantamine), memantine (memantine), rice he Prick flat (mirtazapine), venlafaxine (venlafaxine), desipramine (desipramine), nortriptyline (nortriptyline), zolpidem (zolpidem), zopiclone (zopiclone), Nicergoline (nicergoline), pyrrole La Xitan (piracetam), selegiline (selegiline), pentoxifylline (pentoxifylline) or their group Close.

On the other hand, the present invention relates to the compounds of this invention or pharmaceutical composition are used for preventing, treat or mitigating in preparation With 5-ht₆Purposes in the medicine of relevant disease.

In one embodiment, the present invention relates to and 5-ht₆Relevant disease is cns disease, disorder of gastrointestinal tract or fat disease.

In another embodiment, the present invention relates to and 5-ht₆Relevant cns disease is adhd, anxiety and psychentonia The disease of correlation, schizophrenia, obsessive idea and behavior disorder, manic depressive illness, nervous disorders, dysmnesia, attention Defect obstacle, parkinson disease, amyotrophic lateral sclerosiss, Alzheimer's disease or Huntington Chorea.

The method that another aspect of the present invention is related to the preparation, separation and purification of the compound shown in formula (i).

Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not Contradiction occurs.Additionally, in any embodiment of either side of the present invention, arbitrary technical characteristic goes for other real Apply this technical characteristic in scheme, as long as they are not in contradiction.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and its The content of his aspect is made more specific complete description below.

Specific embodiment

Definition and general terms

Describe certain embodiments of the present invention in detail now, the example is by the structural formula enclosed and chemical formula explanation.This Invention intention covers all of replacement, modification and equivalent technical solutions, and they are included in as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.In the document being combined, patent and similar material one Or many different from the application or conflicting in the case of (including but not limited to defined term, term application, described Technology, etc.), be defined by the application.

It will further be appreciated that some features of the present invention, it is clearly visible, carry out in multiple independent embodiments Description is but it is also possible to provide in combination in single embodiment.Conversely, the various features of the present invention, for brevity, Single embodiment is described but it is also possible to 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.All patents according to the present invention and public publication are integrally incorporated this by reference Bright.

Unless otherwise indicated it should application is used herein obtains following definition.For purposes of the present invention, chemical element with Periodic table of elements cas version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined Examine " organic chemistry ", thomas sorrell, university science books, sausalito:1999, " march's advanced organic chemistry " by michael b.smith and jerry march, john Description in wiley＆sons, new york:2007, entire contents are incorporated herein by.

There are unless otherwise stated or in context obvious conflict, article " " used herein, " one (kind) " " described " is intended to including " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (being at least one) object.For example, " component " refers to one or more components it is possible to have more than one Component be taken into account in the embodiment of described embodiment using or use.

Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.Tested right As for example also referring to primate (the such as mankind, sex), cattle, sheep, goat, horse, dog, cat, rabbit, rat, little Mus, fish, bird etc..In certain embodiments, described study subject is primate.In other embodiments, described it is subject to Examination to as if people.

Term " patient " used in the present invention refers to people's (including adult and child) or other animals.In some enforcements In scheme, " patient " refers to people.

Term "comprising" is open language, that is, include the content specified by the present invention, but be not precluded from otherwise Content.

Term " stereoisomer " refers to there is identical chemical constitution, but atom or group spatially arrangement mode difference Compound.It is different that stereoisomer includes enantiomer, diastereomer, conformer (rotamer), geometry Structure body (cis/trans) isomer, atropisomer, etc..

Term " chiral " be have with its mirror image can not overlapping property molecule；And " achirality " refer to permissible with its mirror image Overlapping molecule.

Term " enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror image relationship.

Term " racemate " or " racemic mixture " are the optically active two corresponding isomer species of hypodactylia Equimolar mixture.

Term " diastereomer " refers to the solid of two or more chiral centres and its molecule not mirror image each other Isomer.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereo-isomerism Body mixture can be by high resolution analysises operation as electrophoresis and chromatograph, and such as hplc is separating.

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 are existed with optical active forms, and that is, they have makes the flat of linearly polarized light The ability that face rotates.When describing optically active compound, represent molecule with regard to one using prefix d and l or r and s The absolute configuration of individual or mulitiple chiral centers.Prefix d and l or (+) and (-) are to revolve for linearly polarized light caused by appointed compound Turn symbol, wherein (-) or l represent that compound is left-handed.Prefix be (+) or the compound of d be dextrorotation.A kind of specific Stereoisomer is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50 of enantiomer: 50 mixture are referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or three-dimensional special When different in nature, may occur in which this situation.

Any asymmetric atom (for example, carbon etc.) of the open compound of the present invention can be enriched with raceme or enantiomer Presented in, for example (r)-, (s)-or (r, s)-configuration exist.In certain embodiments, each asymmetric atom exists R ()-or (s)-configuration aspect has 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 Excessive.

According to the selection of starting material and method, the compounds of this invention can with one of possible isomer or they Mixture, the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Optically active (r)-or (s)-isomer using chiral synthon or chiral reagent preparation, or can be torn open using routine techniquess 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 substantially pure geometric isomer, enantiomer, diastereomer, for example, by chromatography and/or fractional crystallization Method.

With known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art Familiar method splits into optical antipode, e.g., by carrying out to its diastereoisomeric salt obtaining separating.Racemic product Thing can also be separated by chiral chromatogram, e.g., using the high performance liquid chromatography (hplc) of chiral sorbent.Especially, mapping Isomer can be prepared by asymmetric synthesis, for example, refers to jacques, et al., enantiomers, racemates and resolutions(wiley interscience,new york,1981)；principles of asymmetric synthesis(2^nded.robert e.gawley,jeffrey aube,elsevier,oxford,uk,2012)；eliel, e.l.stereochemistry of carbon compounds(mcgraw-hill,ny,1962)；wilen,s.h.tables of resolving agents andoptical 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).

Term " tautomer " or " tautomeric form " refer to that Tong Guo the mental retardation with different-energy builds (low Energy barrier) mutual inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical equilibrium of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include migrating, by proton, the mutual inversion of phases to carry out, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electronss Lai The mutual inversion of phases carrying out.The instantiation of ketoenol tautomerization is pentane -2,4- diketone and 4- hydroxyl amyl- 3- alkene -2- ketone is mutual The change of tautomeric.Another example tautomeric is phenol-keto tautomerism.One of phenol-keto tautomerism is specifically real 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 are within the scope of the present invention.

Term " optional " or " optionally " refer to the event subsequently describing or situation can but not necessarily occur, and this is retouched State situation about occurring including wherein said event or situation and wherein its absent variable situation.For example, " optional key " refers to This key there may be or can not exist, and this description includes singly-bound, double or triple bonds.

Term " unsaturated " or " undersaturated " expression part contain one or more degrees of unsaturation.

As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, such as General formula compound above, or as special example inside embodiment, subclass, and the class compound that the present invention is comprised. Should be appreciated that " optionally substituted " this term and " substituted or unsubstituted " this term can exchange use.In general, art Language is " substituted " to represent that one or more of given structure hydrogen atom is replaced by concrete substituent group.Unless other aspect tables Bright, an optional substituted radical can be replaced each commutable position in group.When in given structural formula not One or more substituent groups that only position can be selected from concrete group are replaced, then substituent group can identical or differently Replace in each position.Wherein said substituent group can be, but is not limited to, deuterium, hydroxyl, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl Base, azido, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, sulfydryl, The alkyl that nitro, aryloxy group, heteroaryloxy, oxo (=o), carboxyl, haloalkyl, halogenated alkoxy, hydroxyl replace, hydroxyl take The haloalkyl in generation, hydroxyl replace alkoxyl, hydroxyl replace alkyl-c (=o)-, alkyl-c (=o)-, alkyl-s (= O)-, alkyl-s (=o)₂-, hydroxyl replace alkyl-s (=o)-, hydroxyl replace alkyl-s (=o)₂-, Carboxyalkoxy etc. Deng.

In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode that adopted in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can be exchanged, and all should be interpreted broadly, it both may be used To refer in different groups, do not affect it is also possible to represent in phase mutually between expressed concrete option between same-sign In same group, do not affect mutually between expressed concrete option between same-sign.

In each several part of this specification, the substituent group of the open compound of the present invention is open according to radical species or scope.Special Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term “c_1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, c₃Alkyl, c₄Alkyl, c₅Alkyl and c₆Alkyl.

In each several part of the present invention, describe connect substituent.When this structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if this structure needs linking group and for this The Markush group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connecting or arylene group.

Terminology used in the present invention " alkyl " or " alkyl group ", represent contain 1 to 20 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group, wherein, the substituent group institute that described alkyl group can optionally be described by one or more present invention Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1- 12 carbon atoms；In another embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group Containing 1-4 carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.

The example of alkyl 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), isobutyl group (i-bu ,- ch₂ch(ch₃)₂), sec-butyl (s-bu ,-ch (ch₃)ch₂ch₃), the tert-butyl group (t-bu ,-c (ch₃)₃), n-pentyl (- ch₂ch₂ch₂ch₂ch₃), 2- amyl group (- ch (ch₃)ch₂ch₂ch₃), 3- amyl group (- ch (ch₂ch₃)₂), 2- methyl -2- butyl (- c (ch₃)₂ch₂ch₃), 3- methyl -2- butyl (- ch (ch₃)ch(ch₃)₂), 3- methyl isophthalic acid-butyl (- ch₂ch₂ch(ch₃)₂), 2- first Base -1- butyl (- ch₂ch(ch₃)ch₂ch₃), n-hexyl (- ch₂ch₂ch₂ch₂ch₂ch₃), 2- hexyl (- ch (ch₃) ch₂ch₂ch₂ch₃), 3- hexyl (- ch (ch₂ch₃)(ch₂ch₂ch₃)), 2- methyl -2- amyl group (- c (ch₃)₂ch₂ch₂ch₃), 3- first Base -2- amyl group (- ch (ch₃)ch(ch₃)ch₂ch₃), 4- methyl -2- amyl group (- ch (ch₃)ch₂ch(ch₃)₂), 3- methyl -3- penta Base (- c (ch₃)(ch₂ch₃)₂), 2- methyl -3- amyl group (- ch (ch₂ch₃)ch(ch₃)₂), 2,3- dimethyl -2- butyl (- c (ch₃)₂ch(ch₃)₂), 3,3- dimethyl -2- butyl (- ch (ch₃)c(ch₃)₃), n-heptyl, n-octyl, etc..

Term " hetero atom " represents one or more oxygen (o), sulfur (s), nitrogen (n), phosphorus (p) or silicon (si), including nitrogen (n), Sulfur (s) and the form of any oxidation state of phosphorus (p)；Primary, secondary, tertiary amine and the form of quaternary ammonium salt；Or the hydrogen on nitrogen-atoms in heterocycle Substituted form, for example, n (n as in 3,4- dihydro -2h- pyrrole radicals), nh (nh as in pyrrolidinyl) or nr is (as n- Nr in the pyrrolidinyl replacing).

Term " halogen " and " halo " refer to fluorine (f), chlorine (cl), bromine (br) or iodine (i).

Term " haloalkyl " or " halogenated alkoxy " represent alkyl or alkoxy base by one or more halogen atoms Replaced, wherein alkyl and alkoxy base have implication of the present invention, and such example comprises, but is not limited to, two Methyl fluoride, trifluoromethyl, trifluoromethoxy, 2,2- difluoroethoxy, 2,2,2- trifluoro ethoxy, 2,2,3,3- tetrafluoro third oxygen Base, 2,2,3,3,3- five fluorine propoxyl group, etc..Described haloalkyl or halo alkoxy group are optionally by one or more The described substituent group of invention is replaced.

Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.Described alkoxy base is optionally sent out by one or more The substituent group of bright description is replaced.

The example of alkoxy base includes, but is not limited to, methoxyl group (meo ,-och₃), ethyoxyl (eto ,- och₂ch₃), 1- propoxyl group (n-pro, n- propoxyl group ,-och₂ch₂ch₃), 2- propoxyl group (i-pro, i- propoxyl group ,-och (ch₃)₂), 1- butoxy (n-buo, n- butoxy ,-och₂ch₂ch₂ch₃), 2- methyl-l- propoxyl group (i-buo, i- fourth oxygen Base ,-och₂ch(ch₃)₂), 2- butoxy (s-buo, s- butoxy ,-och (ch₃)ch₂ch₃), 2- methyl -2- propoxyl group (t- Buo, t- butoxy ,-oc (ch₃)₃), 1- amoxy (n- amoxy ,-och₂ch₂ch₂ch₂ch₃), 2- amoxy (- och (ch₃) ch₂ch₂ch₃), 3- amoxy (- och (ch₂ch₃)₂), 2- methyl -2- butoxy (- oc (ch₃)₂ch₂ch₃), 3- methyl -2- fourth Epoxide (- och (ch₃)ch(ch₃)₂), 3- methyl-l- butoxy (- och₂ch₂ch(ch₃)₂), 2- methyl-l- butoxy (- och₂ch(ch₃)ch₂ch₃), etc..

Term " cycloalkyl " represents that, containing 3-12 carbon atom, the saturation of unit price or multivalence is monocyclic, bicyclic or three ring bodies System.Bicyclic or three-ring system can include condensed ring, bridged ring and volution.In one embodiment, to comprise 3-10 carbon former for cycloalkyl Son；In another embodiment, cycloalkyl comprises 3-8 carbon atom；In yet another embodiment, cycloalkyl comprises 3-6 carbon Atom.The example of group of naphthene base includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, etc..Described group of naphthene base Optionally replaced by one or more substituent groups described in the invention.

Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising the monocyclic, double of 3-12 annular atom Ring or three-ring system, on its medium ring, one or more atoms are independently replaced by hetero atom, and described hetero atom has as this Bright described implication, ring can be fully saturated or comprise one or more degrees of unsaturation, but an armaticity ring all can not Have.In one embodiment, heterocyclyl groups are that (2-6 carbon atom and be selected from n, the 1-3 of o, p, s miscellaneous for 3-8 yuan of rings monocyclic Atom, is optionally replaced by one or more oxygen atoms in this s or p and obtains as so, so₂, po, po₂Group, when described When ring is three-membered ring, only one of which hetero atom), or bicyclic (the 4-9 carbon atom and selected from n, the 1-3 of o, p, s of 7-12 unit Individual hetero atom, is optionally replaced by one or more oxygen atoms in this s or p and obtains as so, so₂, po, po₂Group).Described Heterocyclyl groups are optionally replaced by one or more substituent groups described in the invention.

Heterocyclic radical can be carbon-based or hetero atom base.- the ch of its medium ring₂- group is optionally by-c (o)-replacement, the sulfur of ring Atom is optionally oxidized to s- oxide, and the nitrogen-atoms of ring are optionally oxidized to n- oxygen compound.The example bag of heterocyclic radical Include, but be not limited to, Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, Tetramethylene sulfide Base, dihydro-thiophene base, 1,3- dioxy cyclopenta, two sulfur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2h- pyranose, 4h- pyrrole Mutter base, tetrahydro thiapyran base, piperidyl, morpholinyl (morpholine -2-base, morpholine-3- base, morpholine-4- base), thio-morpholinyl, piperazine Base (piperazine -1- base, piperazine -2- base, piperazine -3- base), dialkyl group, dithiane base, thiophene alkyl, homopiperazine base, high piperidines Base, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulfur azepineBase, 2- oxa- -5- azepine is double Ring [2.2.1] hept- 5- base, etc..- ch in heterocyclic radical₂- group is included, but not limited to 2- oxygen by the example of-c (=o)-replacement For pyrrolidinyl, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyl, hybar X base, etc..Heterocycle In base, the oxidized example of sulphur atom includes, but not limited to sulfolane base, thio-morpholinyl 1,1- dioxide, etc..Described Heterocyclyl groups optionally replaced by one or more substituent groups described in the invention.

In another embodiment, heterocyclic radical is 4 former molecular heterocyclic radicals, refers to comprise the saturation of 4 annular atoms Or partly undersaturated monocyclic, wherein at least one annular atom is selected from nitrogen, sulfur and oxygen atom.4 former molecular heterocyclic radicals Example includes, but not limited to azelidinyl, oxetanylmethoxy (2- oxetanylmethoxy and 3- oxetanylmethoxy), thia ring fourth Base, etc..4 described former molecular heterocyclyl groups are optionally by one or more substituent group institutes described in the invention Replace.

Term " aryl " represents and contains 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, double Ring and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and it is individual former that each of which member ring systems comprise 3-7 Molecular ring.Aromatic yl group generally, but is necessarily connected with parent molecule by the armaticity ring of aromatic yl group.Term " aryl " can exchange with term " aromatic rings " or " aromatic ring " and use.The example of aromatic yl group can include phenyl, naphthyl and anthracene. Described aromatic yl group is optionally replaced by one or more substituent groups described in the invention.

Term " heteroaryl " represent contain 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom monocyclic, Bicyclic and three-ring system, wherein at least one member ring systems are aromatic, and at least one member ring systems comprise one or more miscellaneous Atom, each of which member ring systems comprise 5-7 former molecular ring.Heteroaryl groups generally, but necessarily pass through heteroaryl The armaticity ring of base group is connected with parent molecule.Term " heteroaryl " can be with term " hetero-aromatic ring ", " heteroaromatic " or " heteroaryl Compounds of group " exchanges and uses.Described heteroaryl groups are optionally replaced by one or more substituent groups described in the invention. In one embodiment, 5-10 former molecular heteroaryl comprises 1,2,3 or 4 and is independently selected from o, the hetero atom of s and n.

The example of heteroaryl groups includes, but is not limited to, 2- furyl, 3- furyl, n- imidazole radicals, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- azoles Base, n- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- Pyrimidine radicals, pyridazinyl (as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (as 5- tetrazole radical), triazole Base (as 2- triazolyl and 5- triazolyl), 2- thienyl, 3- thienyl, pyrazolyl (as 2- pyrazolyl), isothiazolyl, 1,2,3- Di azoly, 1,2,5- di azoly, 1,2,4- di azoly, 1,2,3- triazolyl, 1,2,3- thio biphosphole base, 1,3,4- sulfur For di azoly, 1,2,5- thio biphosphole base, pyrazinyl, cyanuro 1,3,5；Also include following bicyclic, but be not limited to these Bicyclic: benzimidazolyl, benzofuranyl, benzothienyl, indyl (as 2- indyl), purine radicals, quinolyl are (as 2- quinoline Quinoline base, 3- quinolyl, 4- quinolyl), isoquinolyl (as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), imidazo [1,2-a] pyridine radicals, pyrazolo [1,5-a] pyridine radicals, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1, 2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine Base, etc..

As described in the invention, substituent group r is bonded the member ring systems formed on the ring at the center of being connected to (as formula f institute by one Show) represent substituent group r and only limit any on a ring may replace or any rational position is replaced.For example, formula f represents on a ring Any position that may be substituted, as formula f¹-f⁴Shown:

The structure occurring in the present inventionRepresent

Term " prodrug " used in the present invention, 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 affected for precursor structure through enzymatic conversion in blood or tissue.This Bright pro-drug compounds can be ester, and in existing invention, ester can be used as the phenyl ester class that have of prodrug, aliphatic (c_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamatess and amino acid esters.Such as in the present invention one Compound comprises hydroxyl, you can be acylated the compound obtaining prodrug form.Other prodrug form include Phosphate ester, such as these phosphate compounds are to obtain through the di on parent.With regard to complete the begging for of prodrug By may be referred to documents below: higuchi et al., pro-drugs as novel delivery systems, vol.14, a.c.s.symposium series；roche et al.,ed.,bioreversible carriers in drug design,american pharmaceutical association and pergamon press,1987；rautio et al.,prodrugs:design and clinical applications,nature reviews drug discovery, 2008,7,255-270,and hecker et al,prodrugs of phosphates and phosphonates, J.med.chem., 2008,51,2328-2345, every document is incorporated herein by this.

Term " metabolite " used in the present invention refers to that specific compound or its salt passes through metabolism in vivo Obtained product.The metabolite of one compound can be identified by technology known to art, its activity Can adopt as passing through as described in the present invention and experimentally be characterized.Such product can be by administrationization Compound, through peroxidating, reduces, hydrolysis, amidated, and desamido- acts on, esterification, degreasing, and enzymatic lysises etc. method obtains.Phase Ying Di, the present invention includes the metabolite of compound, during including the compound of the present invention and mammal being fully contacted one section Between produced metabolite.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt of compound and the inorganic salt of the present invention.Medicine On, acceptable salt is known to us in 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 Include, but is not limited to, reacting, with amino group, the inorganic acid salt being formed has a hydrochlorate, hydrobromate, phosphate, sulfate, Perchlorate, and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid Salt, or these salt are obtained by described additive method such as ion exchange 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..Alkali metal, alkaline-earth metal, ammonium and n are included by the salt that suitable alkali obtains⁺(c_1-4Alkyl)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 further 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, c_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention is formed Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.

When described solvent is water, it is possible to use term " hydrate ".In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule Can combine with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention divides Son can be combined with the hydrone less than, such as semihydrate.It should be noted that hydrate of the present invention remain with non- The biological effectiveness of the described compound of hydrated form.

When term " blocking group " or " pg " refer to a substituent group and other reacted with functional groups, it is commonly used to hinder Feature disconnected or that protection is special.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or in protection compound amino feature, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (boc, boc), benzyloxycarbonyl group (cbz, cbz) and 9- fluorenes methylene oxygen carbonyl (fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent group of base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes trialkylsilkl, acetyl group, Benzoyl and benzyl." carboxy protective group " refers to the substituent group of carboxyl for blocking or protecting the feature of carboxyl, typically Carboxyl-protecting group include-ch₂ch₂so₂Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) second Epoxide methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro Ethyl, etc..Document: greene et al., protective groups in is referred to for the general description of blocking group organic synthesis,john wiley&sons,new york,1991and kocienski et al., protecting groups,thieme,stuttgart,2005.

The as used in the present invention any disease of term " treatment " or disease, wherein some embodiment middle fingers improve disease Disease or the disease development of its at least one clinical symptoms (slow down or stop or palliate a disease or).In other embodiments In, " treatment " refers to relax or improve at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to (for example stablize perceptible symptom) from body or physiologically (for example stablizes body Parameter) or above-mentioned two aspects regulation diseases or disease.In other embodiments, " treat " and refer to prevent or postpone disease or disease The outbreak of disease, generation or deterioration.

The minimizing that term " preventing " or " prevention " refer to obtain the risk of disease or obstacle (that is: makes at least one clinical condition of disease Shape stops developing in main body, this main body may in the face of or in advance tendency in the face of this disease, but without experience or show The symptom of disease).

Term " adhd " is the abbreviation of attention-deficit hyperactivity disorder, means attention Moving obstacle defect more, be a kind of childhood period very common psychataxia.According to World Health Organization (WHO) " Global Access disease is divided Class handbook " the tenth edition (icd-10, who, 1992) this disease be called " hyperactivity disorder " (hyperkinetic disorder), point It is f90 that class is numbered, and is typically commonly called as " excessively moving youngster " again.

Term " schizophrenia " refers to schizophrenia, schizophrenia-like disorder, schizoaffective disorder and spirit Characteristic of disease mental disorder, wherein term " psychosiss " refer to vain hope, obvious hallucination, amorphous language or unorganized behavior or deadlock Straightization behavior.Referring to diagnostic and statistical manual of mental disorder, fourth edition, American psychiatric association, washington, d.c..

Pharmaceutically useful acid-addition salts can be formed with mineral acid and organic acid, for example 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.

Can by its derivative organic acid obtaining salt include for example acetic acid, 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 i race to the xii race of such as ammonium salt and periodic chart.? In some embodiments, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, ferrum, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salt.

Primary amine, secondary amine and tertiary amine can be included by its derivative organic base obtaining salt, substituted amine includes naturally occurring The amine of replacement, cyclic amine, deacidite etc..Some organic amines include, for example, 2-aminopropane., benzathine benzylpenicillin (benzathine), choline salt (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine And trometamol.

The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes. In general, such salt can by make the free acid form of these compounds and stoichiometry suitable alkali (as na, ca, The hydroxide of mg or k, carbonate, bicarbonate etc.) reaction, or by making free alkali form and the chemistry of these compounds The suitable acid reaction of metered amount is being prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in the case of suitably, need using non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.? Such as " remington ' s pharmaceutical sciences ", the 20th edition, mack publishing company, easton,pa.,(1985)；" pharmaceutical salts handbook: property, selection and application (handbook of pharmaceutical Salts:properties, selection, and use) ", stahl and wermuth (wiley-vch, weinheim, Germany, 2002) list of the suitable salt of other can be found in.

In 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 open compound of the present invention can be with pharmacy Upper acceptable solvent (inclusion water) inherently or passes through design forming solvate；Therefore, it is contemplated that including solvation And unsolvated form.

Any structural formula that the present invention is given be also intended to expression these compounds not by the form of isotope enrichment 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 into Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁷O,¹⁸O,¹⁸F,³¹P,³²P,³⁵S,³⁶Cl and¹²⁵i.

On the other hand, compound of the present invention includes the compound defined in the present invention of isotope enrichment, for example, its In there is radiosiotope, such as³H,¹⁴C and¹⁸Those compounds of f, or wherein there is non radioactive isotope, such as²H and¹³c.The compound of such isotope enrichment can be used for metabolism research and (uses¹⁴C), Reaction kinetics research are (using for example²H or³H), detection or imaging technique, as positron emission tomography (pet) or inclusion medicine or substrate tissue measure of spread SPECT (single photon emission computed tomography) (spect), or can be used in the radiotherapy of patient.¹⁸The compound of f enrichment to pet or It is especially desirable for spect research.Compound shown in the formula (i) of isotope enrichment can be ripe by those skilled in the art Embodiment in the routine techniquess known or the present invention and preparation process are described former using suitable isotope labeling reagent replacement Carry out used unmarked reagent to prepare.

Additionally, higher isotope particularly deuterium is (i.e.,²H or replacement d) can provide some treatment advantages, and these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increases or volume requirements reduce or therapeutic index obtains improving band Come.It should be appreciated that the deuterium in the present invention is seen as the substituent group of formula (i) compound.Can be determined with isotope enrichment factor The concentration of such higher isotope adopted particularly deuterium.Term " isotope enrichment factor " used in the present invention refers to specified same Ratio between the isotope abundance of position element and natural abundance.If the substituent group of the compounds of this invention is designated as deuterium, this change Compound have at least 3500 for each D-atom specified (at each specified D-atom, 52.5% deuterium mixes), at least 4000 (60% deuterium mixes), at least 4500 (67.5% deuterium mixes), at least 5000 (75% deuterium mixes), at least 5500 (82.5% deuterium mix), at least 6000 (90% deuterium mixes), at least 6333.3 (95% deuterium mixes), at least 6466.7 The isotope enrichment of (97% deuterium mixes), at least 6600 (99% deuterium mixes) or at least 6633.3 (99.5% deuterium mixes) The factor.The pharmaceutically useful solvate of the present invention includes the such as d that wherein recrystallisation solvent can be that isotope replaces₂O, acetone-d₆、 dmso-d₆Those solvates.

The description of the compounds of this invention

Benzylamine analog derivative according to the present invention, its pharmaceutically acceptable salt, and its pharmaceutical preparation, there is antagonism 5- ht₆, especially have potential purposes to the treatment of Alzheimer's disease.

The present invention also comprises the compound of the present invention and its application of pharmaceutically acceptable salt, for producing medical product Treatment Alzheimer's disease, described in the invention including those.The compound of the present invention is equally used for producing a kind of pharmaceuticals It is used for mitigating, stops, control or treatment 5-ht₆The disease being mediated, particularly Alzheimer's disease.The present invention comprises medicine group Compound, this pharmaceutical composition includes compound representated by formula formula (i) and at least one pharmaceutically acceptable carrier, adjuvant or Effectively treatment consumption needed for the combination of diluent.

Unless other aspects show, all suitable isotope changes of compound of the present invention, stereoisomer, geometry is different Structure body, tautomer, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug all belong to In the scope of the present invention.

Unless other aspects show, structural formula described in the invention includes all of isomeric forms (as mapping is different Structure, diastereo-isomerism, and geometrical isomerism (or conformational isomerism)): r, s configuration for example containing asymmetric center, (z) of double bond, (e) isomer, and the conformer of (z), (e).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or it is right Reflect isomer, diastereomer, or the mixture of geometric isomer (or conformer) and broadly fall into the scope of the present invention.

Unless other aspects show, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless other aspects show, the structural formula of compound described in the invention includes one or more different former The enriched isotope of son.

The open compound of the present invention can contain asymmetric or chiral centre, therefore can be with different stereoisomer forms Exist.It is contemplated that all stereoisomer forms of compound shown in formula (i), including but not limited to diastereo-isomerism Body, 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 indicate, then this structure All stereoisomers all consider within the present invention, and be included in the invention as the open compound of the present invention.When Spatial chemistry is expressed the real wedge shape line (solid wedge) of particular configuration or when dotted line indicates, then the stereoisomerism of this structure Body clearly and defines with regard to this.

The nitrogen oxides of the compounds of this invention are also contained within the scope of the present invention.Can be by an elevated temperature using normal With oxidant (such as hydrogen peroxide), in the presence of the acid of such as acetic acid, aoxidize corresponding nitrogen-containing basic material, or pass through With acid reaction excessively in suitable solvent, for example, react with peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or React with 3- chloroperoxybenzoic acid in chloroform or dichloromethane, prepare the nitrogen oxides of the compounds of this invention.

On the other hand, the present invention relates to 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 purification method.

Compound shown in formula (i) can exist in a salt form.In one embodiment, described salt refers to pharmaceutically can connect The salt being subject to.Term " pharmaceutically acceptable " refers to that material or compositionss must be with other compositions comprising preparation and/or use it The mammal for the treatment of is chemically and/or compatible in toxicology.In another embodiment, described salt is not necessarily and pharmaceutically may be used The salt accepting, could be for preparation and/or compound shown in purification formula (i) and/or for separating compound shown in this formula (i) Enantiomer intermediate.

If the compound of the present invention is alkaline, conceivable salt can be any suitable by provide on document Method prepares, for example, using mineral acid, example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid etc..Or using organic Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, acetone acid, oxalic acid, glycolic and salicylic acid；Pyrans Saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Aminoacid, such as aspartic acid and paddy Propylhomoserin；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, ethyl sulfonic acid, etc..

If the compound of the present invention is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc. Deng.Suitable salt includes, but is not limited to, the organic salt obtaining from aminoacid, such as glycine and arginine, ammonia, such as primaquine, secondary Ammonia and tertiary ammonia, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, ferrum, copper, zinc, aluminum and lithium obtain Inorganic salt.

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 its pharmaceutically acceptable salt can as not plus The chemical drugss of work give, and the active component being alternatively arranged as pharmaceutical composition provides.Therefore, the present invention also provides a kind of medicine group Compound, the compound including formula (i) or its single stereoisomer, the raceme of isomer or non-racemic mixture or its Pharmaceutically acceptable salt or solvate.In an embodiment of the invention, described pharmaceutical composition comprises further At least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other treatment and/or prevention composition.

That suitable carrier, adjuvant and excipient agent are well known to those skilled in the art and be described in detail in for example ansel h.c.et al.,ansel’s pharmaceutical dosage forms and drug delivery systems(2004)lippincott,williams&wilkins,philadelphia；gennaro a.r.et al., Remington:the science and practice of pharmacy (2000) lippincott, williams＆ wilkins,philadelphia；With rowe r.c., handbook of pharmaceutical excipients (2005) Pharmaceutical press, in chicago.

Comprise the compounds of this invention or the Therapeutic Method of pharmaceutical composition administration, further include that patient is carried out with other resists The administration of Alzheimer disease drug (therapeutic alliance), the wherein medicine of other anti-Alzheimer diseases are donepezil, Na Mei Sweet smell, Risperidone, vitamin e, sam-760, avn-211, avn-101, rp-5063, tozadenant, prx-3140, prx- 8066, sb-742457, naluzaton, idalopirdine, tacrine, Rivastigmine, galantamine, memantine, meter Ta Zha Flat, venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, Nicergoline, piracetam, selegiline, hexanone can Theobromine or their combination.

Term as used herein " therapeutically effective amount " refers to each activearm enough to show significant patient benefit The total amount divided.When being administered alone using single active component, this term only refers to this composition.When combination application, this term No matter then refer to combination, be sequentially or simultaneously administered, all cause the combined amount of the active component of therapeutic effect.Formula formula (i) chemical combination Thing and its pharmaceutically acceptable salt are as described above.In the sense that compatible with preparation other compositions and harmless to its receiver For, carrier, diluent or excipient must be acceptable.According to the another aspect of present disclosure, also provide for making The method of standby pharmaceutical preparation, the method is included formula (i) compound or its pharmaceutically acceptable salt and one or more pharmacy Upper acceptable carrier, diluent or excipient mix.Term " pharmaceutically acceptable " used in the present invention refers to so Compound, raw material, compositionss and/or dosage form, they are in the range of rational medicine judges it is adaptable to and patient tissue contacts And no excessive toxicity, zest, allergy or the other problemses symmetrical with rational interests/Hazard ratio and complication, and Effective for given application.

Generally, the compound of the present invention is treated by any routine method of application of the material for playing similar effectiveness Effective dose is applied.Suitable dosage range is typically daily 1-500mg, preferably daily 1-100mg, most preferably daily 1- 30mg, this depends on many factors, for example the treated seriousness of disease, the age of subject and relative health, institute The approach with the effect of compound, applied and form, apply targeted indication and relevant medical practitioner preference and Experience.The those of ordinary skill treating described disease areas need not excessively test dependence personal knowledge and present disclosure Can determine that the therapeutically effective amount of the compounds of this invention for giving disease.

Generally, the compound of the present invention is applied with pharmaceutical dosage forms, and described pharmaceutical preparation includes those and is suitable to be administered orally (include oral cavity and Sublingual), rectum, nose, locally, lung, vagina or parenteral (include intramuscular, intra-arterial, intrathecal, subcutaneous and vein Interior) pharmaceutical preparation applied or be suitable to suck or be blown into the pharmaceutical preparation of administration form.Preferably method of application is usually oral, Using suitable daily dose scheme, according to disease degree, it can be adjusted.

One or more compound of the present invention can be placed in together with one or more conventional adjuvant, carrier or diluent In pharmaceutical composition and unit dosage form.Pharmaceutical composition and unit dosage form can comprise the conventional ingredient of conventional ratio, With or without other reactive compound or composition, unit dosage form can contain and the plan daily dose scope phase applied The active component of any suitable effective dose claiming.The application form of pharmaceutical composition can be solid such as tablet or filling glue Wafer, semisolid, powder, slow releasing preparation or liquid such as solution, suspensoid, Emulsion, elixir or the filling glue orally using Wafer；Or the suppository form for rectum or vaginal application；Or the sterile injectable solutions form for parenteral use. Therefore, in every containing about 1mg active component or more broadly, the preparation containing about 0.01 to about 100mg active component is suitable Representational unit dosage form.

The compound of the present invention can be configured to various Orally administered dosage forms.Pharmaceutical composition and dosage form can To comprise one or more compound or pharmaceutically acceptable salt thereof of the present invention as active component.Pharmaceutically useful carrier can be solid Or liquid.The preparation of solid form includes: powder agent, tablet, pill, capsule, cachet, suppository and dispersible granule Agent.Solid carrier can be one or more material, and it is also used as diluent, correctivess, solubilizing agent, lubricant, suspension Agent, binding agent, preservative, tablet disintegrant or coating material.In powder, carrier is usually finely ground solid, its with finely ground Active component formed mixture.In tablets, active component generally with there is the carrier of required adhesive power with suitable ratio Example mutually mixes and is pressed into required shapes and sizes.Powder and tablet preferably comprise from about the reactive compound of 1% to about 70%. Suitable carrier includes but is not limited to magnesium carbonate, magnesium stearate, Pulvis Talci, sugar, Lactose, pectin, dextrin, starch, gelatin, Calculus Bovis from Northwest of China Millefolium glue, methylcellulose, sodium carboxymethyl cellulose, low melt wax, cocoa butter etc..Terms " formulation " is intended to including containing encapsulation material Expect as carrier to provide the preparation of the reactive compound of capsule, the active component of with or without carrier in described capsule Surrounded by this carrier in combination.Similarly, cachet and lozenge are also included.Tablet, powder, capsule, pill, sachet Agent and lozenge are all adapted for Orally administered solid form.

Other is suitable to preparation (inclusion Emulsion, syrup, elixir, the aqueous solution that Orally administered form includes liquid form Agent, aqueous suspension) or purport be at once changed into the preparation of the solid form of liquid form preparation before use.Emulsion can be molten Prepare in liquid such as aqueous solution of propylene glycol or emulsifying agent such as lecithin, Arlacel-80 or Arab can be contained Glue.Aqueous solution agent by being dissolved in water active component and can add suitable coloring agent, correctivess, stabilizer and thickening Agent is preparing.Aqueous suspension can be passed through with for example naturally occurring or synthetic glue of stickum, resin, methylcellulose, carboxymethyl Finely ground active component is dispersed in water to prepare by sodium cellulosate and other well known suspending agent.The preparation of liquid form includes Solution, suspensoid and Emulsion, in addition to active component, it can also contain coloring agent, correctivess, stabilizer, buffer agent, people Sweeting agent that make and natural, dispersant, thickening agent, solubilizing agent etc..

The compound of the present invention can be formulated for parenteral administration (for example, by injection such as bolus injection or continuously defeated Note apply) and can be present in a unit ampoule, the syringe of fill in advance, low capacity transfusion in or be present in With the addition of in the multi-dose container of preservative.The suspension that the adoptable form of compositionss has for example in oiliness or aqueous vehicle Agent, solution or Emulsion, such as the solution in Aqueous Solutions of Polyethylene Glycol.Oiliness or non-aqueous carrier, diluent, solvent or The example of excipient includes propylene glycol, Polyethylene Glycol, vegetable oil (such as olive oil) and injection organic ester (such as Oleic acid second Ester), and formulating substances such as preservative, wetting agent, emulsifying agent or suspending agent, stabilizer and/or dispersant can be contained.Or, Active component can be powder type, its preparation method be by sterile solid carry out aseptic subpackaged or by by solution lyophilizing so that Before use with suitable excipient is for example aseptic, pyrogen-free water is built.

The compound of the present invention can be formulated for ointment, ointment or lotion form or with transdermal patch form office Portion is applied to epidermis.Ointment and ointment can be for example with the addition of aqueouss or the oil of suitable thickening agent and/or gellant Property substrate is prepared.One or more emulsifying agent, surely can be prepared and generally also contain to lotion with aqueouss or oleaginous base Determine agent, dispersant, suspending agent, thickening agent or coloring agent.It is suitable to the preparation of local application in mouth to include comprising to be in taste masking base Matter, the lozenge of the active component being usually in sucrose and arabic gum or tragakanta；Comprise to be in inert base such as gelatin and The lozenge of the active component in glycerol or sucrose and arabic gum；And the active component comprising to be in suitable liquid carrier Collutory.

The compound of the present invention can be formulated for applying with suppository form.Can be first by low melt wax such as fatty acid glycerine Ester admixture or cocoa butter fusing, and dispersion that active component for example is passed through to stir.Then by the homogeneous mixture of melting Pour in the mould of suitable size so as to cooling down and solidifying.

The compound of the present invention can be formulated for vaginal application.Also contain carrier known in this field in addition to the active ingredient (s Vaginal suppository, tampon, breast green grass or young crops agent, gel, paste, foam or spray are suitable.

The compound of the present invention can be formulated for nasal administration.Solution or suspensoid can be passed through conventional method, example As directly applied to nasal cavity with dropper, suction pipe or aerosol apparatus.Preparation can be single dose or multiple dose form.For dropper or suction The multiple dose form of pipe, this can be by applying suitable, predetermined solution by patient or suspensoid is realized.For Aerosol apparatus, this can for example be realized by metering atomising atomizing pump.

The compound of the present invention can be formulated for aerosol and apply, and be particularly applied to respiratory tract and include intranasal and apply With.Compound generally has a little granularity, the granularity of such as 5 microns or more decimal magnitude.Described granularity can pass through this area Known method, for example obtained by micronization.Active component is with containing suitable propellant such as chlorofluorocarbon (cfc) such as dichloro The pressurized package of difluoromethane, Arcton 11 or dichlorotetra-fluoroethane or carbon dioxide or other suitable gas provides.Gas Mist agent also can suitably contain surfactant such as lecithin.Drug dose can be controlled by metering valve.Or, active component can With with dry powdered form, for example in suitable powder base such as Lactose, starch, starch derivatives such as hydroxypropyl methyl cellulose and The mixture of powders form of the compound in Polyvinylpyrrolidone provides.Dust carrier will form gel in nasal cavity.Powder Compositionss can for example be existed with gelatine capsule agent or cartridge case or blister package form in a unit can pass through inhaler By wherein applying powder.

When needing, preparation can be prepared with being suitable to the enteric coating of slow release or controlled release administration active component.For example, originally The compound of invention can be formulated into transdermal or subcutaneous drug delivery device.When must slow release compounds when and work as patient for treatment When the compliance of scheme is most important, these delivery systems are favourable.Compound in transdermal delivery system is often attached to On skin-adhesive solid support.Compound of interest can also be with penetration enhancer, such as laurocapram (1- dodecane Base azacyclo- hept- 2- ketone) it is applied in combination.By performing the operation or injecting, Sustained release delivery systems can be subcutaneously inserted hypodermic layer.Subcutaneous Compound is encapsulated in lipid soluble membrane, such as silicone rubber or Biodegradable polymeric such as polylactic acid implant.

Pharmaceutical preparation is preferably unit dosage form.In this form, preparation is subdivided into containing Sq active component Unit dose.Unit dosage form can be the preparation of packaging kit, the preparation containing discrete magnitude in packaging, for example complete bag The tablet of dress, capsule and powder in the vial or ampulla agent.In addition, unit dosage form can be capsule, tablet, flat Wafer or lozenge itself, or it can be any one of these forms of suitable number in packaging kit form.

Other suitable pharmaceutical carriers and their preparation are in remington:the science and practice of Pharmacy 1995martin, e.w edit, mack publishing company, the 19th edition, easton, It is described in pennsylvania.

The compounds of this invention and the purposes of pharmaceutical composition

The compound that the present invention provides and pharmaceutical composition can be used for preparation and be used for preventing, treat or mitigating and 5-ht₆Have The medicine of the disease closed.

The feature of the pharmaceutical composition of the present invention includes the compound shown in formula (i) or the compound listed by the present invention, And pharmaceutically acceptable carrier, adjuvant or excipient.In the compositionss of the present invention, the amount of compound can be visited effectively Geodetic antagonism 5-ht₆To treat obesity, gastroenteropathy, cns disease, wherein said cns disease is adhd, anxiety, with Psychentonia related disease, schizophrenia, obsessive idea and behavior disorder, manic depressive illness, nervous disorders, memory barrier Hinder, attention deficit disorder, parkinson disease, amyotrophic lateral sclerosiss, Alzheimer's disease and Huntington Chorea, etc..

" effective dose " or " effective dose " of the compound of the present invention or pharmaceutically acceptable compositionss refer to process or Mitigate the effective dose that one or more present invention are previously mentioned the severity of disease.The method according to the invention, compound and combination Thing can be the order of severity that any dosage and any route of administration process to be efficiently used for or palliate a disease.Necessary standard Situation according to patient is changed by true amount, this depend on race, the age, the generic condition of patient, the order of severity of infection, Special factor, administering mode, etc..Compound or compositionss can be with one or more other therapeutic agents administering drug combinations, such as The present invention is discussed.

The compound of the present invention and pharmaceutical composition, in addition to beneficial to human treatment, apply also for veterinary treatment and dote on Mammal in the animal of thing, the animal of introduced variety and farm.The example of other animal includes horse, Canis familiaris L. and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.

The general synthetic method of the compounds of this invention

For describing the present invention, it is listed below embodiment.But it is to be understood that the invention is not restricted to these embodiments, simply The method of the present invention is put into practice in offer.

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 this The content of invention.

Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds of many present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, according to the present invention, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art Completed by method of modifying, such as suitable protection disturbs group, by using reagent known to other except described in the invention , or modification reaction condition being made some routines.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the present invention.

The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as aldrich chemical company, inc., arco chemical company and alfa chemical Company, not through being further purified, unless other aspects show during use.General reagent is from western Gansu Province, Shantou chemical industry Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, dragon chemistry examination is risen in Qingdao Agent 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 Stream is dried to obtain.Ethyl acetate, petroleum ether, n, n- dimethyl acetylamide and n, n- dimethylformamide is through anhydrous sodium sulfate thing First it is dried and use.

Hereinafter reaction is usually to cover a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb all suitable rubber closures beyond the Great Wall, 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 cdc1₃、dmso-d₆、cd₃Od or acetone-d₆For solvent (report in units of ppm), with tms (0ppm) or chloroform (7.25ppm) As reference standard.When multiplet occurs, by using following abbreviation: s (singlet, unimodal), and d (doublet, double Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant, is represented with hertz (hz).

By outfit g1312a binary pump and a g1316a tcc, (column temperature is maintained at 30 to Algorithm (ms) data DEG C) agilent 6320 serial lc-ms spectrogrph measuring, g1329a automatic sampler and g1315b dad detector It is applied to analyze, esi source is applied to lc-ms spectrogrph.

Algorithm (ms) data is by being equipped with g1311a quaternary pump and g1316a tcc (column temperature is maintained at 30 DEG C) Agilent 6120 serial lc-ms spectrogrph measuring, g1329a automatic sampler and g1315d dad detector should For analyzing, esi source is applied to lc-ms spectrogrph.

Both the above spectrogrph is provided with agilent zorbax sb-c18 post, and specification is 2.1 × 30mm, 5 μm.Note It is to be determined by sample concentration that beam amasss；Flow velocity is 0.6ml/min；The peak value of hplc is by 210nm and 254nm Uv-vis wavelength is recording reading.Mobile phase be 0.1% formic acid acetonitrile solution (phase a) and 0.1% formic acid ultrapure water-soluble Liquid (phase b).Condition of gradient elution is as shown in table 1:

Table 1

Time (min)	a(ch3Cn, 0.1%hcooh)	b(h2O, 0.1%hcooh)
			0-3	5-100	95-0
3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

Compound purification to be evaluated by agilent 1100 series of high efficiency liquid chromatograph (hplc), and wherein uv detects At 210nm and 254nm, zorbax sb-c18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, and flow velocity is 0.6ml/min, (0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.

The use of brief word below runs through the present invention:

Following synthetic schemes describes the step preparing the open compound of the present invention.Unless otherwise indicated, each m, n, k, r¹, r²And r³There is definition as described in the present invention.

Synthetic method 1

The compounds of this invention can be prepared by the general synthetic method that synthetic schemes 1 describes, and concrete steps can be joined Examine embodiment.Compound 1 is reacted with Bis(tert-butoxycarbonyl)oxide in the presence of alkali, obtains compound 2；Then compound 2 is in alkali In the presence of react with halogenated alkane and obtain compound 3.Compound 3 deprotection base obtains compound 4；Compound 4 is in reduction Compound 5 is obtained in the presence of agent；Compound 5 is reacted with the benzaldehyde replacing and obtains target compound 6 after reduction amination.

Synthetic method 2

The compounds of this invention can be prepared by the general synthetic method that synthetic schemes 1 describes, and concrete steps can be joined Examine embodiment.Compound 1 is reacted with Bis(tert-butoxycarbonyl)oxide in the presence of alkali, obtains compound 2；Then compound 2 is in alkali In the presence of react with halogenated alkane and obtain compound 3.Compound 3 deprotection base obtains compound 4；Compound 4 is in reduction Compound 5 is obtained in the presence of agent；Compound 5 and formaldehyde react and obtain compound 7.Compound 7 is reacted with the benzaldehyde replacing Target compound 8 is obtained after reduction amination.

With reference to embodiments compound, pharmaceutical composition and its application that the present invention provides is further described.

Embodiment

Embodiment 1 2- (1h- indol-3-yl) -2- methyl-n- (3- (2,2,2- trifluoro ethoxy) benzyl) propane -1- amine Synthesis

Step 1) 3- (cyano methyl) -1h- indole -1- t-butyl formate synthesis

At 25 DEG C, 2- (1h- indol-3-yl) acetonitrile (10.0g, 64.1mmol) and dmap (500mg, 4.1mmol) are added Enter in dichloromethane (50ml), be then slowly added into boc₂o(21.0g,96.2mmol).Continue reaction 8 hours, then with satisfying Wash (40ml) with sodium chloride solution, organic faciess anhydrous sodium sulfate drying after point liquid.Filter, filtrate decompression is spin-dried for, column chromatography It is faint yellow solid (7.2g, 44.0%) that purification (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound.

ms(esi,pos.ion)m/z:257.2[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.16 (d, j=6.6hz, 1h), 7.62 (s, 1h), 7.50 (d, j= 7.8hz, 1h), 7.38-7.34 (m, 1h), 7.30-7.26 (m, 1h), 3.75 (d, j=1.2hz, 2h), 1.66 (s, 9h).

Step 2) 3- (2- dicyanopropane -2- base) -1h- indole -1- t-butyl formate synthesis

By 3- (cyano methyl) -1h- indole -1- t-butyl formate (7.2g, 28.0mmol) and sodium hydride at 0 DEG C (2.5g, 63.0mmol) is added in anhydrous dmf (30ml), is then slowly added dropwise into iodomethane (8.8ml, 125.0mmol).Instead After answering ten minutes, it is warming up to 25^oC, reaction is overnight.Add water (100ml) to be quenched, add dichloromethane (100ml) extraction, organic Mutually wash (50mlx 3) again with saturated nacl aqueous solution, organic faciess anhydrous sodium sulfate drying after point liquid.Filter, filtrate decompression Be spin-dried for, column chromatography purification (petrol ether/ethyl acetate (v/v)=50/1) obtain title compound be white solid (2.2g, 28%).

ms(esi,pos.ion)m/z:285.3[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.16 (d, j=6.0hz, 1h), 7.80 (d, j=7.8hz, 1h), 7.51 (s, 1h), 7.35 (t, j=8.4hz, 1h), 7.29 (t, j=7.8hz, 1h), 1.83 (s, 6h), 1.67 (s, 9h).

Step 3) 2- (1h- indol-3-yl) -2- methyl propionitrile synthesis

3- (2- dicyanopropane -2- base) -1h- indole -1- t-butyl formate (5.43g, 19.1mmol) is added to dioxy In the mixed solvent of six rings (20ml) and water (20ml), react 14 hours at 110 DEG C of oil bath；Stopped reaction, adds 50ml dichloro Methane, is washed (50ml) with saturated nacl aqueous solution, organic faciess anhydrous sodium sulfate drying after point liquid.Filter, filtrate decompression is revolved Dry, column chromatography purification (petrol ether/ethyl acetate (v/v)=10:1) obtain title compound be pale yellow oil (3.35g, 95.2%).

ms(esi,pos.ion)m/z:185.1[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.24 (s, 1h), 7.84 (d, j=8.4hz, 1h), 7.37 (d, j= 7.8hz, 1h), 7.25-7.21 (m, 1h), 7.19-7.16 (m, 1h), 7.08 (d, j=3.0hz, 1h), 1.84 (s, 6h).

Step 4) 2- (1h- indol-3-yl) -2- methylpropane -1- amine synthesis

At 25 DEG C, 2- (1h- indol-3-yl) -2- methyl propionitrile (1.8g, 9.8mmol) is dissolved in oxolane (4ml) In, add methanol (10ml) and Raney's nickel (200mg), react 72 hours under 2.2mpa hydrogen.Stopped reaction, filters, filtrate Decompression is spin-dried for, and it is pale yellow oil that column chromatography purification (methylene chloride/methanol (v/v)=20/1) obtains title compound (1.58g, 86%).

ms(esi,pos.ion)m/z:189.2[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.45 (s, 1h), 7.76 (d, j=8.4hz, 1h), 7.33 (d, j= 8.4hz, 1h), 7.18-7.14 (m, 1h), 7.09-7.05 (m, 1h), 6.93 (d, j=2.4hz, 1h), 2.99 (s, 2h), 1.40 (s,6h).

Step 5) 2- (1h- indol-3-yl) -2- methyl-n- (3- (2,2,2- trifluoro ethoxy) benzyl) propane -1- amine Synthesis

By 2- (1h- indol-3-yl) -2- methylpropane -1- amine (300mg, 1.59mmol), 3- (2,2,2- trifluoroethoxies Base) benzaldehyde (488mg, 2.39mmol) and mgso₄(384mg, 3.19mmol) is added in etoh (10ml), under 60 DEG C of oil baths Reaction 6h, stopped reaction, filters, collects filtrate.At 25 DEG C, add nabh toward in filtrate₄(90mg, 2.38mmol), reaction Overnight, decompression is spin-dried for, and it is yellow oil that column chromatography purification (petrol ether/ethyl acetate (v/v)=2/1) obtains title compound (191mg, 31.9%).

ms(esi,pos.ion)m/z:377.1[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.05 (s, 1h), 7.66 (d, j=7.8hz, 1h), 7.34 (d, j= 8.4hz, 1h), 7.16 (t, j=7.8hz, 2h), 7.03 (t, j=7.8hz, 1h), 6.97 (d, j=2.4hz, 1h), 6.82 (d, J=7.8hz, 1h), 6.76 (dd, j=8.4,2.4hz, 1h), 6.67 (s, 1h), 4.14 (q, j=8.4hz, 2h), 3.68 (s, 2h),2.89(s,2h),1.45(s,6h)；

¹³c nmr(150mhz,cdcl₃) δ (ppm): 157.7,143.1,137.4,129.6,125.9,123.7 (q, j= 278.1hz), 122.9,122.2,121.9,121.8,121.1,119.2,113.8,111.6,65.8 (q, j=35.5hz), 59.7,54.1,36.2,27.6.

Embodiment 2 2- (1h- indol-3-yl) -2- methyl-n- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) propane -1- The synthesis of amine

This step title compound prepares with reference to the method described by embodiment 1 step 5, will 2- (1h- indole- 3- yl) -2- methylpropane -1- amine (300mg, 1.59mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (564mg, 2.39mmol), mgso₄(384mg, 3.19mmol) and nabh₄(90mg, 2.38mmol) reaction preparation in etoh (10ml), slightly Through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oily that concentrate drying obtains title compound to product Thing (332mg, 51.0%).

ms(esi,pos.ion)m/z:409.0[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.04 (s, 1h), 7.68 (d, j=8.4hz, 1h), 7.34 (d, j= 8.4hz, 1h), 7.16 (td, j=7.2,3.6hz, 2h), 7.05-7.01 (m, 1h), 6.97 (d, j=2.4hz, 1h), 6.82 (d, j=7.2hz, 1h), 6.73 (dd, j=8.4,2.4hz, 1h), 6.68 (s, 1h), 6.04 (tt, j=52.8,4.8hz, 1h), 4.17 (t, j=12.0hz, 2h), 3.68 (s, 2h), 2.90 (s, 2h), 1.46 (s, 6h)；

¹³c nmr(150mhz,cdcl₃)δ(ppm):157.6,143.2,137.4,129.6,125.9,122.9,122.2, (tt, j=250.1,34.0hz), 121.9,121.8,121.1,119.2,114.8 113.8,113.4,111.6,109.2 (tt, ), j=250.1,34.0hz 65.4 (t, j=29.7hz), 59.8,54.1,36.3,27.6.

Embodiment 3 2- (5- methoxyl group -1h- indol-3-yl) -2- methyl-n- (3- (2,2,2- trifluoro ethoxy) benzyl) The synthesis of propane -1- amine

Step 1) 2- (5- methoxyl group -1h- indol-3-yl) -2- methylpropane -1- amine synthesis

This step title compound prepares with reference to the method described by embodiment 1 step 4, will 2- (5- methoxyl group- 1h- indol-3-yl) -2- methyl propionitrile (750mg, 3.5mmol), Raney's nickel (100mg) is in oxolane (5ml) and methanol (10ml) reaction preparation, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1) in, concentrate drying is marked Topic compound is pale yellow oil (391mg, 51%).

ms(esi,pos.ion)m/z:219.1[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.36 (s, 1h), 7.21 (d, j=9.0hz, 1h), 7.20 (d, j= 1.8hz, 1h), 6.91 (d, j=2.4hz, 1h), 6.84 (dd, j=9.0,2.4hz, 1h), 3.84 (s, 3h), 2.98 (s, 2h), 1.38(s,6h).

Step 2) 2- (5- methoxyl group -1h- indol-3-yl) -2- methyl-n- (3- (2,2,2- trifluoro ethoxy) benzyl) third The synthesis of alkane -1- amine

This step title compound prepares with reference to the method described by embodiment 1 step 5, will 2- (5- methoxyl group- 1h- indol-3-yl) -2- methylpropane -1- amine (250mg, 1.15mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (304mg, 1.49mmol), mgso₄(277mg, 2.3mmol) and nabh₄(65mg, 1.72mmol) reaction in etoh (10ml) Preparation, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is Huang that concentrate drying obtains title compound Color grease (170mg, 36.5%).

ms(esi,pos.ion)m/z:407.2[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 7.36 (s, 1h), 7.28 (t, j=7.8hz, 1h), 7.16 (d, j= 2.4hz, 1h), 7.09 (d, j=9.0hz, 1h), 6.98 (d, j=7.8hz, 1h), 6.91 (s, 1h), 6.88 (dd, j=7.8, 2.4hz, 1h), 6.78 (dd, j=8.4,2.4hz, 1h), 4.28 (q, j=7.8hz, 2h), 3.86 (s, 3h), 2.92-2.86 (m,2h),1.84(s,2h),1.49(s,3h),1.44(s,3h).

Embodiment 4 2- (5- methoxyl group -1h- indol-3-yl) -2- methyl-n- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl Base) propane -1- amine synthesis

This step title compound prepares with reference to the method described by embodiment 1 step 5, will 2- (5- methoxyl group- 1h- indol-3-yl) -2- methylpropane -1- amine (250mg, 1.15mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (352mg, 1.49mmol), mgso₄(276mg, 2.29mmol) and nabh₄(43mg, 1.13mmol) reaction in etoh (10ml) Preparation, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is Huang that concentrate drying obtains title compound Color grease (271mg, 54.0%).

ms(esi,pos.ion)m/z:439.2[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 7.34 (s, 1h), 7.29 (t, j=7.8hz, 1h), 7.17 (d, j= 2.4hz, 1h), 7.09 (d, j=9.0hz, 1h), 6.98 (d, j=7.8hz, 1h), 6.90 (s, 1h), 6.86 (dd, j=8.4, 2.4hz, 1h), 6.78 (dd, j=9.0,2.4hz, 1h), 6.02 (tt, j=52.8,4.8hz, 1h), 4.29 (t, j= 12.0hz,2h),3.86(s,3h),2.93-2.86(m,2h),1.85(s,2h),1.49(s,3h),1.45(s,3h).

Embodiment 5 1- (1- (1h- indol-3-yl) cyclopropyl)-n- (3- (2,2,2- trifluoro ethoxy) benzyl) methylamine Synthesis

Step 1) 3- (1- anocy clopropyl) -1h- indole -1- t-butyl formate synthesis

This step title compound prepares with reference to the method described by embodiment 1 step 2, will 3- (cyano group first Base) -1h- indole -1- t-butyl formate (5.0g, 19.5mmol), sodium hydride (1.72g, 42.9mmol) and glycol dibromide (2.0ml, 23.4mmol) reaction preparation, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/ in dmso (45ml) V)=100/1), concentrate drying obtains title compound is weak yellow liquid (1.43g, 26.0%).

ms(esi,pos.ion)m/z:283.1[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.12 (d, j=6.0hz, 1h), 7.79 (d, j=7.8hz, 1h), 7.47(s,1h),7.38-7.34(m,1h),7.32-7.29(m,1h),1.67-1.64(m,2h),1.66(s,9h),1.36(q, J=4.8hz, 2h).

Step 2) 1- (1h- indol-3-yl) cyclopropylniitrile synthesis

This step title compound prepares with reference to the method described by embodiment 1 step 3, will 3- (1- cyano group ring Propyl group) -1h- indole -1- t-butyl formate (1.4g, 4.9mmol) reaction preparation in water (15ml) and dioxane (3ml), Crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=50/1), it is faint yellow that concentrate drying obtains title compound Liquid (735mg, 82%).

ms(esi,pos.ion)m/z:183.1[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.12 (d, j=6.0hz, 1h), 7.78 (d, j=7.8hz, 1h), 7.48(s,1h),7.38-7.34(m,1h),7.32-7.30(m,1h),1.67-1.63(m,2h),1.38-1.35(m,2h).

Step 3) (1- (1h- indol-3-yl) cyclopropyl) methylamine synthesis

This step title compound prepares with reference to the method described by embodiment 1 step 4, will 1- (1h- indole- 3- yl) cyclopropylniitrile (700mg, 3.8mmol), Raney's nickel (100mg) reaction system in oxolane (5ml) and methanol (10ml) Standby, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is yellowish that concentrate drying obtains title compound Color grease (483mg, 68%).

ms(esi,pos.ion)m/z:187.1[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.11 (s, 1h), 7.67 (d, j=7.8hz, 1h), 7.42 (s, 1h), 7.32-7.28(m,1h),7.24-7.20(m,1h),2.80(s,2h),0.81-0.74(m,4h).

Step 4) 1- (1- (1h- indol-3-yl) cyclopropyl)-n- (3- (2,2,2- trifluoro ethoxy) benzyl) methylamine conjunction Become

This step title compound prepares with reference to the method described by embodiment 1 step 5, will (1- (1h- indole- 3- yl) cyclopropyl) methylamine (182mg, 0.98mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (260mg, 1.27mmol), mgso₄(235mg, 1.95mmol) and nabh₄(55mg, 1.45mmol) reaction preparation, crude on silica gel in etoh (10ml) Column chromatography (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (233mg, 63.4%).

ms(esi,pos.ion)m/z:375.3[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.12 (s, 1h), 7.73 (d, j=7.8hz, 1h), 7.33 (d, j= 8.4hz, 1h), 7.18 (t, j=7.2hz, 1h), 7.15 (t, j=7.8hz, 1h), 7.10 (t, j=7.2hz, 1h), 7.08 (d, J=2.4hz, 1h), 6.83 (d, j=7.8hz, 1h), 6.75 (dd, j=7.8,2.4hz, 1h), 6.72 (s, 1h), 4.13 (q, j =7.8hz, 2h), 3.74 (s, 2h), 2.80 (s, 2h), 0.85-0.76 (m, 4h)；

¹³c nmr(100mhz,cdcl₃)δ(ppm):157.7,142.5,136.7,129.7,127.7,125.0,123.8, (122.4,122.3,120.9 q, j=278.0hz), 119.7,119.6,118.7,114.0,113.9,111.5,65.9 (q, j =35.7hz), 57.4,53.2,29.9,11.4.

Embodiment 6 1- (1- (1h- indol-3-yl) cyclopropyl)-n- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) methylamine Synthesis

This step title compound prepares with reference to the method described by embodiment 1 step 5, will (1- (1h- indole- 3- yl) cyclopropyl) methylamine (186mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (346mg, 1.47mmol), mgso₄(235mg, 1.95mmol) and nabh₄(55mg, 1.45mmol) reaction preparation, crude on silica gel in etoh (10ml) Column chromatography (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtain title compound be yellow oil (218mg, 53.7%).

ms(esi,pos.ion)m/z:407.0[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.09 (s, 1h), 7.74 (d, j=7.8hz, 1h), 7.34 (d, j= 8.4hz, 1h), 7.20-7.17 (m, 1h), 7.17-7.13 (m, 1h), 7.12-7.09 (m, 1h), 7.08 (d, j=2.4hz, 1h), 6.83 (d, j=7.8hz, 1h), 6.72 (d, j=6.0hz, 2h), 6.01 (tt, j=52.8,4.8hz, 1h), 4.16 (t, J=11.4hz, 2h), 3.73 (s, 2h), 2.80 (s, 2h), 0.85-0.75 (m, 4h)；

¹³c nmr(150mhz,cdcl₃)δ(ppm):157.6,142.6,136.7,129.7,127.6,123.8,122.4, (tt, j=250.1,26.7hz), 122.2,119.8,119.6,118.7,114.8 113.9,113.5,111.5,109.2 (tt, ), j=248.4,34.0hz 65.4 (t, j=30.2hz), 57.5,53.3,17.9,11.4.

Embodiment 7 1- (1- (5- methoxyl group -1h- indol-3-yl) cyclopropyl)-n- (3- (2,2,2- trifluoro ethoxy) benzyl Base) methylamine synthesis

Step 1) 3- (1- anocy clopropyl) -5- methoxyl group -1h- indole -1- t-butyl formate synthesis

This step title compound prepares with reference to the method described by embodiment 1 step 2, will 3- (cyano group first Base) -5- methoxyl group -1h- indole -1- t-butyl formate (5.0g, 17.5mmol), sodium hydride (1.75g, 43.8mmol) and 1,2- Bromofume (2.28ml, 26.2mmol) reaction preparation, crude on silica gel column chromatography (petroleum ether/second in dmso (45ml) Acetoacetic ester (v/v)=100/1), it is weak yellow liquid (1.66g, 30.4%) that concentrate drying obtains title compound.

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).

Step 2) 1- (5- methoxyl group -1h- indol-3-yl) cyclopropylniitrile synthesis

This step title compound prepares with reference to the method described by embodiment 1 step 3, will 3- (1- cyano group ring Propyl group) -5- methoxyl group -1h- indole -1- carboxylic acid tert-butyl ester (1.5g, 4.8mmol) is in water (15ml) and dioxane (3ml) Reaction preparation, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=50/1), concentrate drying obtains title compound Thing is weak yellow liquid (685mg, 67%).

ms(esi,pos.ion)m/z:213.1[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 7.98 (s, 1h), 7.44 (s, 1h), 7.20 (d, j=2.4hz, 1h), 6.95 (dd, j=8.8,2.4hz, 1h), 3.89 (s, 3h), 1.67-1.64 (m, 2h), 1.32 (q, j=4.8hz, 2h).

Step 3) (1- (5- methoxyl group -1h- indol-3-yl) cyclopropyl) methylamine synthesis

This step title compound prepares with reference to the method described by embodiment 1 step 4, will 1- (5- methoxyl group- 1h- indol-3-yl) cyclopropylniitrile (670mg, 3.1mmol), Raney's nickel (100mg) is in oxolane (5ml) and methanol (10ml) Reaction preparation, crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), concentrate drying obtains title compound For pale yellow oil (424mg, 63%).

ms(esi,pos.ion)m/z:217.1[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), 0.80-0.73 (m, 4h).

Step 4) 1- (1- (5- methoxyl group -1h- indol-3-yl) cyclopropyl)-n- (3- (2,2,2- trifluoro ethoxy) benzyl Base) methylamine synthesis

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) methylamine (206mg, 0.95mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (252mg, 1.23mmol), mgso₄(228mg, 1.89mmol) and nabh₄(54mg, 1.43mmol) reaction preparation in etoh (10ml), slightly Through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oily that concentrate drying obtains title compound to product Thing (197mg, 51.2%).

ms(esi,pos.ion)m/z:405.3[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 8.02 (s, 1h), 7.22 (d, j=9.0hz, 1h), 7.17-7.11 (m, 2h), 7.06 (d, j=2.4hz, 1h), 6.86-6.80 (m, 2h), 6.76-6.71 (m, 2h), 4.15 (q, j=8.4hz, 2h), 3.82 (s, 3h), 3.74 (s, 2h), 2.78 (s, 2h), 0.83 (t, j=6.0hz, 2h), 0.76 (t, j=6.0hz, 2h)；

¹³c nmr(150mhz,cdcl₃)δ(ppm):157.7,154.2,142.2,139.5,131.8,129.7,128.1, (q, j=278.2hz), 124.8,122.3 118.1,114.0,113.9,112.4,112.2,101.7,65.7 (q, j= 36.0hz),57.1,56.2,53.1,29.9,11.3.

Embodiment 8 1- (1- (5- methoxyl group -1h- indol-3-yl) cyclopropyl)-n- (3- (2,2,3,3- tetrafluoro propoxyl group) Benzyl) methylamine synthesis

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) methylamine (216mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (336mg, 1.43mmol), mgso₄(228mg, 1.89mmol) and nabh₄(54mg, 1.43mmol) reaction in etoh (10ml) Preparation, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is Huang that concentrate drying obtains title compound Color grease (206mg, 47.2%).

ms(esi,pos.ion)m/z:437.2[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 7.98 (s, 1h), 7.22 (d, j=9.0hz, 1h), 7.17-7.12 (m, 2h), 7.06 (d, j=1.8hz, 1h), 6.88-6.80 (m, 2h), 6.72 (d, j=7.8hz, 2h), 6.02 (tt, j=52.8, 4.8hz, 1h), 4.18 (t, j=12.0hz, 2h), 3.83 (s, 3h), 3.73 (s, 2h), 2.78 (s, 2h), 0.84 (t, j= 6.0hz, 2h), 0.76 (t, j=6.0hz, 2h).

Embodiment 9 4,4- dimethyl -2- (3- (2,2,2- trifluoro ethoxy) benzyl) -2,3,4,9- tetrahydrochysene -1h- pyridine The synthesis of [3,4-b] indole

Step 1) 4,4- dimethyl -2,3,4,9- tetrahydrochysene -1h- pyridine [3,4-b] indole synthesis

By 2- (1h- indol-3-yl) -2- methylpropane -1- amine (1.2g, 5.3mmol), ch₃cooh(0.4ml, 5.3mmol)、ch₃Coona (548mg, 5.3mmol), hcho (0.247ml, 7.4mmol) are added in water (10ml), are warming up to 110 DEG C, stirring reaction 12h.Add dichloromethane (50ml), then washed (40ml) with saturated nacl aqueous solution, have after point liquid Machine phase anhydrous sodium sulfate drying.Filter, filtrate decompression is spin-dried for, column chromatography purification (methylene chloride/methanol (v/v)=10/1) It is yellow-brown solid (784mg, 73.0%) to title compound.

ms(esi,pos.ion)m/z:201.2[m+h]⁺；

¹h nmr(400mhz,dmso-d₆) δ (ppm): 10.60 (s, 1h), 7.52 (d, j=7.6hz, 1h), 7.25 (d, j =8.0hz, 1h), 6.96 (t, j=7.2hz, 1h), 6.90 (d, j=6.8hz, 1h), 3.80 (s, 2h), 2.67 (s, 2h), 1.30(s,6h).

Step 2) 4,4- dimethyl -2- (3- (2,2,2- trifluoro ethoxy) benzyl) -2,3,4,9- tetrahydrochysene -1h- pyridine [3, 4-b] indole synthesis

This step title compound prepares with reference to the method described by embodiment 1 step 5, will 4,4- dimethyl- 2,3,4,9- tetrahydrochysenes -1h- pyridine [3,4-b] indole (250mg, 1.25mmol), 3- (2,2,2- trifluoro ethoxy) benzaldehyde (504mg, 2.5mmol), mgso₄(228mg, 1.89mmol) and nabh₃Cn (158mg, 2.5mmol) is anti-in etoh (10ml) Should prepare, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), concentrate drying obtains title compound and is Yellow oil (132mg, 27.2%).

ms(esi,pos.ion)m/z:389.2[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 7.63 (d, j=7.8hz, 1h), 7.59 (s, 1h), 7.27 (t, j= 9.0hz, 2h), 7.10 (d, j=8.4hz, 1h), 7.07 (d, j=7.8hz, 1h), 7.06-7.04 (m, 1h), 6.85 (dd, j= 8.4,2.4hz, 1h), 4.33 (q, j=8.4hz, 2h), 3.71 (s, 2h), 3.56 (s, 2h), 2.48 (s, 2h), 1.41 (s, 6h)；

¹³c nmr(100mhz,cdcl₃)δ(ppm):157.9,141.4,136.6,131.1,129.8,126.1,123.6 (q, j=276.4hz), 123.1,122.2,121.2,119.9,119.4,117.5,115.1,114.1,111.1,66 .4, 66.1 (q, j=35.4hz), 62.6,51.5,33.5,27.6.

Embodiment 10 4,4- dimethyl -2- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) -2,3,4,9- tetrahydrochysene -1h- pyrrole The synthesis of pyridine [3,4-b] indole

This step title compound prepares with reference to the method described by embodiment 1 step 5, will 4,4- dimethyl- 2,3,4,9- tetrahydrochysenes -1h- pyridine [3,4-b] indole (200mg, 1.0mmol), 3- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (708mg, 3.0mmol), mgso₄(180mg, 1.5mmol) and nabh₃Cn (158mg, 2.5mmol) reaction in etoh (10ml) Preparation, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is Huang that concentrate drying obtains title compound Color grease (218mg, 52%).

ms(esi,pos.ion)m/z:421.2[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 7.64 (d, j=7.2hz, 1h), 7.57 (s, 1h), 7.30-7.25 (m, 2h), 7.10 (d, j=3.0hz, 1h), 7.08 (m, 1h), 7.06 (s, 1h), 6.06 (tt, j=52.8,4.8hz, 1h), 4.33 (t, j=12.0hz, 2h), 3.71 (s, 2h), 3.56 (s, 2h), 2.49 (s, 2h), 1.43 (s, 6h)；

¹³c nmr(150mhz,cdcl₃)δ(ppm):157.8,141.4,136.5,131.1,129.8,126.1,123.0, (tt, j=248.6,26.7hz), 121.2,119.8,119.4,117.5,115.0,114.8 113.8,111.2,109.3 (tt, ), j=248.3,33.9hz 66.3,65.5 (t, j=29.7hz), 62.5,51.5,33.5,27.6.

Embodiment 11 6- methoxyl group -4,4- dimethyl -2- (3- (2,2,2- trifluoro ethoxy) benzyl) -2,3,4,9- four The synthesis of hydrogen -1h- pyridine [3,4-b] indole

Step 1) 6- methoxyl group -4,4- dimethyl -2,3,4,9- tetrahydrochysene -1h- pyridine [3,4-b] indole synthesis

This step title compound prepares with reference to the method described by embodiment 9 step 1, will 2- (5- methoxyl group- 1h- indol-3-yl) -2- methylpropane -1- amine (1.25g, 4.93mmol), ch₃cooh(0.3ml,5.0mmol)、ch₃coona (410mg, 5.0mmol), hcho (0.17ml, 5.0mmol) are added to reaction preparation, crude on silica gel column chromatography in water (10ml) (methylene chloride/methanol (v/v)=10/1), it is pale yellow oil (1.01g, 88.0%) that concentrate drying obtains title compound.

ms(esi,pos.ion)m/z:231.1[m+h]⁺；

¹h nmr(400mhz,dmso-d₆) δ (ppm): 10.41 (s, 1h), 7.13 (d, j=8.8hz, 1h), 6.97 (d, j= 2.0hz, 1h), 6.62 (dd, j=8.8,2.0hz, 1h), 3.76 (s, 2h), 3.74 (s, 3h), 2.65 (s, 2h), 1.29 (s, 6h).

Step 2) 6- methoxyl group -4,4- dimethyl -2- (3- (2,2,2- trifluoro ethoxy) benzyl) -2,3,4,9- tetrahydrochysene - The synthesis of 1h- pyridine [3,4-b] indole

This step title compound prepares with reference to the method described by embodiment 1 step 5, will 6- methoxyl group -4, 4- dimethyl -2,3,4,9- tetrahydrochysenes -1h- pyridine [3,4-b] indole (300mg, 1.3mmol), 3- (2,2,2- trifluoro ethoxy) Benzaldehyde (532mg, 2.6mmol) and nabh₃Cn (158mg, 2.5mmol) reaction preparation, crude product warp in etoh (10ml) Silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is yellow oil that concentrate drying obtains title compound (288mg, 52.8%).

ms(esi,pos.ion)m/z:419.1[m+h]⁺；

¹h nmr(600mhz,cdcl₃) δ (ppm): 7.46 (s, 1h), 7.26 (t, j=7.8hz, 1h), 7.15 (d, j= 9.0hz, 1h), 7.10-7.06 (m, 2h), 7.05 (s, 1h), 6.85 (dd, j=7.8,2.4hz, 1h), 6.76 (dd, j=9.0, 2.4hz, 1h), 4.32 (q, j=8.4hz, 2h), 3.84 (s, 3h), 3.69 (s, 2h), 3.54 (s, 2h), 2.47 (s, 2h), 1.40(s,6h)；

¹³c nmr(100mhz,cdcl₃)δ(ppm):157.9,153.9,141.4,132.2,131.8,129.8,126.6, (123.6 d, j=276.4hz), 123.1,117.3,115.1,114.1,111.6,110.4,103.1,66.4,66.1 (q, j= 35.4hz),62.5,56.3,51.6,33.4,27.4.

Embodiment 12 6- methoxyl group -4,4- dimethyl -2- (3- (2,2,3,3- tetrafluoro propoxyl group) benzyl) -2,3,4,9- The synthesis of tetrahydrochysene -1h- pyridine [3,4-b] indole

This step title compound prepares with reference to the method described by embodiment 1 step 5, will 6- methoxyl group -4, 4- dimethyl -2,3,4,9- tetrahydrochysenes -1h- pyridine [3,4-b] indole (300mg, 1.3mmol), 3- (2,2,3,3- tetrafluoro the third oxygen Base) benzaldehyde (615mg, 2.6mmol), mgso₄(180mg, 1.5mmol) and nabh₃Cn (164mg, 2.6mmol) is in etoh (10ml) reaction preparation, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) in, concentrate drying is marked Topic compound is yellow oil (332mg, 56.6%).

ms(esi,pos.ion)m/z:451.1[m+h]⁺；

1h nmr(600mhz,cdcl₃) δ (ppm): 7.46 (s, 1h), 7.26 (t, j=7.8hz, 1h), 7.15 (d, j= 8.4hz, 1h), 7.09 (d, j=2.4hz, 1h), 7.07 (d, j=7.8hz, 1h), 7.04 (s, 1h), 6.82 (dd, j=8.4, 2.4hz, 1h), 6.76 (dd, j=9.0,2.4hz, 1h), 6.04 (tt, j=52.8,4.8hz, 1h), 4.32 (t, j= 12.0hz,2h),3.84(s,3h),3.70(s,2h),3.54(s,2h),2.47(s,2h),1.40(s,6h)；

¹³c nmr(100mhz,cdcl₃)δ(ppm):157.8,153.9,141.4,132.2,131.8,129.8,126.6, (123.0,117.3,115.0,114.8 tt, j=248.0,26.6hz), 113.8,111.6,110.4,109.3 (t, j= ), 248.4,34.1hz 103.1,66.4,65.6,65.3 (t, j=29.9hz), 56.3,51.6,33.4,27.4.

Biologic test

The present invention carries out biologic test using following methods to the compound shown in formula (i):

A. evaluate people source 5-ht to expression on cho cell for the compound with radio ligand binding assay₆The parent of receptor And power

Expression someone source 5-ht that 32 μ g are prepared₆The cho epicyte protein of receptor, 2nm radioactive marker [3h] Lsd, the compound of different test concentrations and assay buffer mix homogeneously, 37 DEG C of incubation 120min；Assay buffer composition is: 50mm tris-hcl (ph 7.4), 10mm mgcl₂, 0.5mm edta, 10 μm of pargylines and 20mg/l protease inhibitor.

100 μm of 5-ht are added to remove nonspecific binding site.After incubation, above-mentioned mixed liquor is used under vacuum Glass filter filters, and filter is first presoaked with 0.3%pei before filtration.50mm tris-hcl is used to rinse several times after filtration again. After filter be dried after, with scintillation mixed solution on scintiloscope counting radioactivity.Standard reference compounds are 5-ht, real every time All test several concentration in testing and obtain its Competitive assays curve, carry out nonlinear regression analyses through hill equation curve, obtain ic₅₀ Value, then calculate through chengprusoff equation, obtain ki value.

According to the method described above compound provided in an embodiment of the present invention is carried out with radio ligand binding assay and evaluates chemical combination Thing people source 5-ht on cho cell to expression₆The affinity of receptor measures, and referring to table 2, table 2 is the embodiment of the present invention to result The affinity measurement result providing.

The affinity measurement result of table 2 compound provided in an embodiment of the present invention

Embodiment	ki(nm)	Embodiment	ki(nm)
				Embodiment 1	b	Embodiment 7	c
Embodiment 2	b	Embodiment 8	a

Embodiment	ki(nm)	Embodiment	ki(nm)
				Embodiment 3	c	Embodiment 9	c
Embodiment 4	b	Embodiment 10	c
				Embodiment 5	c	Embodiment 11	c
Embodiment 6	b	Embodiment 12	c

Note: a<10nm, 10≤b≤100nm, c>100nm.

As shown in Table 2, compound of the present invention is thin in cho to expressing in radio ligand binding assay evaluation compound People source 5-ht on born of the same parents₆Higher activity is generally shown in the affinity test of receptor.

In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or the feature describing with reference to this embodiment or example It is contained at least one embodiment or the example of the present invention.In this manual, need not to the schematic representation of above-mentioned term Identical embodiment or example must be directed to.And, the specific features of description, structure, material or feature can be arbitrary Combine in an appropriate manner in individual or multiple embodiment or example.Additionally, in the case of not conflicting, the technology of this area The feature of the different embodiments described in this specification or example and different embodiment or example can be combined by personnel And combination.

Although embodiments of the invention have been shown and described above it is to be understood that above-described embodiment is example Property it is impossible to be interpreted as limitation of the present invention, those of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changes, replacing and modification.

Claims (9)

1. there is the compound of following structure:

2. a kind of pharmaceutical composition, it comprises compound and pharmaceutically acceptable adjuvant described in claim 1.

3. pharmaceutical composition according to claim 2, wherein, described adjuvant is pharmaceutically acceptable carrier.

4. pharmaceutical composition according to claim 2, wherein, described adjuvant is pharmaceutically acceptable excipient.

5. pharmaceutical composition according to claim 4, wherein, described excipient is pharmaceutically acceptable diluent, Vehicle or combinations thereof.

6. pharmaceutical composition according to claim 2, it comprises additional therapeutic agent further, and described additional therapeutic agent is use Medicine in treatment nervous disorders.

7. pharmaceutical composition according to claim 6, wherein, the medicine of described treatment nervous disorders is treatment A Zihai The medicine of silent disease.

8. the compound described in a kind of usage right requirement 1 or the pharmaceutical composition described in claim 2-7 any one are in system It is ready for use on prevention, treatment or mitigate and 5-ht₆Purposes in the medicine of relevant disease.

9. purposes according to claim 8, wherein said and 5-ht₆Relevant disease be cns disease, disorder of gastrointestinal tract or Obesity.