CN106187999A

CN106187999A - Substituted piperidines and its production and use

Info

Publication number: CN106187999A
Application number: CN201510221044.1A
Authority: CN
Inventors: 邵黎明; 周璐; 李炜; 谢琼; 沈剑
Original assignee: Fudan University
Current assignee: Fudan University
Priority date: 2015-05-04
Filing date: 2015-05-04
Publication date: 2016-12-07

Abstract

The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field.It is specifically related to a kind of by the substituted piperidines shown in formula I, its stereoisomer and pharmaceutically acceptable salt thereof or its solvate, its preparation method, the medical composition and its use that comprises this compound.The present invention passes through biological activity test the results show, described compound and acetylcholine associated proteins have higher combination activity, and the substituted piperidines of the present invention can be as the little molecule of the part of nAChR for preparing prevention and/or treatment neurodegenerative diseases or dementia or the medicine of depression.

Description

Substituted piperidines and its production and use

Technical field

The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field.It is specifically related to a kind of by the substituted piperidine class shown in formula I Compound, its stereoisomer and pharmaceutically acceptable salt thereof or its solvate, its preparation method, comprise this chemical combination The medical composition and its use of thing.The substituted piperidines of the present invention can be as the little molecule of the part of nAChRs For preparing preventing and treating neurodegenerative diseases or the medicine of depression.

Background technology

Alzheimer's disease (Alzheimer ' s disease, hereinafter referred AD), also known as presenile dementia, it is to be common in always A kind of chronic neurodegenerative disease of year crowd, its clinical manifestation be Progressive symmetric erythrokeratodermia increase the weight of disturbance of intelligence, hypomnesis, Mental act is abnormal.The gradually aging of the health of old people, especially society, this situation in its serious threat All the more severe, cause the common concern of people.Depression is a kind of psychosis being changed to cardinal symptom with emotion morbid state, Whole world patients with depression reaches 3.5 hundred million people.Depression has become the fourth-largest disease in the world, the clinical demand of this illness treatment Huge.Treat first-line drug selective 5-hydroxy tryptamine (5-HT) reuptake inhibitor (selective of depression at present Serotonin reuptake inhibitor, SSRI) and 5-HT/NE dual reuptake inhibitor (5-HT/NE reuptake inhibitor,SNRI).But these medicines all exist, and onset time is slow, some patients is failed to respond to any medical treatment, can not be effectively improved Anhedonia, Patients ' Cognitive ability is improved slowly, is easily caused the problems such as sexual dysfunction.

Acetylcholinesteraseinhibitors inhibitors remains the key agents of clinical treatment AD, practice display, although it is permissible at present Reverse choline function and damage study, the memory impairment caused, make some patients's symptom alleviate, but can not fundamentally change Become morbid state (Barril, X.et al Mini Rev.Med.Chem.2001,1,255).

Research display, brain Cholinergic receptor has two classes: muscarinic type (mAChRs) and nicotine type nicotinic (nAChRs), the former In AD brain, there is no change, and the number of the latter significantly reduces.And the agonist nicotine of nAChRs can improve Cognition and memory.Therefore nAChRs starts to become emphasis of concern.Research shows, nAChRs has regulation god Through first excitatoty function, neuron can be made to be in a kind of suitably physiological status, maintain normally performed activity reaction, especially It it is cognitive process.The little molecule of part of the most existing more nAChRs is the entrance clinical II phase in terms for the treatment of AD, e.g., The ABT-089 of Abbott, the match SSR-180711 of Norfin, Inc, the AZD-1446 of Astrazeneca AB.

As far back as 1972, Janowsky etc. found that the unbalance meeting of choline-epinephrine causes depressed sample effect.Gotti in 2006 Propose to be distributed widely in Basal ganglia, striatum, thalamus, hypothalamus, corpus amygdaloideum, ventral tegmental area, locus coeruleus and the middle seam back of the body The α of core₄β₂The release of monoamines good at managing such as dopamine when (a kind of hypotype of nAChRs) is activated.Clinical data also table Bright, patients with depression drug administration varenicline (α₄β₂Partial agonist) retarded depression symptom can alleviate.And it is strong mice Compel, in swimming test, to take α₄β₂The antidepressant effect of citalopram and reboxetine can be strengthened after agonist.Whereas for β₂ The mice of gene knockout, in forced swim test mobility reduce, even if take tricyclic antidepressant also entirely without Effect.The nAChRs part little molecule BB-243 of Hispanic Univ Madrid Autonoma research, at present in treatment depression Field is in the preclinical study stage.The additionally nAChRs part little molecule CP601927 of Pfizer, hangs mice In tail experiment and forced swim test, performance was good, and entered the clinical II phase in 2010.

Within 2003, Miyazawa has delivered the nAChRs cryotronics micro-image of electric ray on Nature.This allows about grinding The person of studying carefully has individual understanding substantially to the basic structure of nAChRs.But owing to nAChRs is a transmembrane protein, therefore it is pure Change and separate extremely difficult, not yet obtaining complete crystal structure by the end of at present.But in new drug research, about grinding The person of studying carefully is it should be understood that the change of nAChRs domain when different ligands is combined and the similarities and differences, and this wishes the most urgently Understand the crystal structure of nAChRs.

In sum, in view of in prior art AChBP be proved to that there is with nAChRs similar part and be combined Domain and identical pharmacological property, the most general is to use acetylcholine associated proteins (AChBP) indirectly to study The way of nAChRs, present inventor intends seeking the albumen of complete crystal structure and replaces nAChRs, due to AChBP With the ligand binding domain of nAChRs, there is homology, both basic features, construction features, binding site position etc. all Having similarity, the application intends studying nAChRs by acetylcholine associated proteins (AChBP), it is provided that a class has Acetylcholine associated proteins (AChBP) combines the substituted piperidines of activity, is used for preparing prevention and/or treatment Neurodegenerative diseases or dementia or antidepressant agents.

Summary of the invention

The acetylcholine associated proteins (AChBP) that has that it is an object of the present invention to provide formula I combines activity Substituted piperidines, this compounds can be used for preparing preventing and treating neurological as the little molecule of the part of nAChRs Property disease or the medicine of depression.

It is a further object to provide a kind of different by the substituted piperidines that hereafter formula I represents, its solid Structure body and pharmaceutically acceptable salt thereof or its solvate.

A further object of the present invention is to provide a kind of containing the substituted piperidines represented by formula I, its solid Isomer and pharmaceutically acceptable salt thereof or the preparation method of its solvate.

The present invention further an object is that offer is a kind of containing the substituted piperidines represented by formula I, its solid Isomer and pharmaceutically acceptable salt thereof or the pharmaceutical composition of its solvate.

A further object of the present invention be provide represented by formula I substituted piperidines, its stereoisomer and Its pharmaceutically acceptable salt or its solvate and comprise the purposes of pharmaceutical composition of this compound.

Specifically, the invention provides a kind of be represented by the following general formula I substituted piperidines, its stereoisomerism Body and pharmaceutically acceptable salt thereof or its solvate and comprise the pharmaceutical composition of this compound；X、Y、R₁、 R₂, m, n be defined as follows；

Wherein:

Be each independently in nitrogen or carbon, and X, Y one of X, Y be nitrogen another be carbon；

R₁For H, alkyl or aromatic group.Alkyl is the straight or branched alkyl of C1～C10, the cycloalkyl of C3～C6 Or Heterocyclylalkyl；Aromatic group is the benzene series aryl such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyrrole Piperidinyl, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole radicals, miaow The heteroaryls such as oxazolyl, condensed hetero ring base, aromatic group are optionally replaced by following one or more substituent groups: halogen, Trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxygen alkane Base, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R ' ' or -NR ' (C=O) R "；

R₂For aromatic group, aromatic group is the benzene series aryl such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrroles The heteroaryls such as base, imidazole radicals, condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: Halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alkoxyalkyl, ring Alkoxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R " Or-NR ' (C=O) R "；

M is the integer of 1-4；N is the integer of 1-4.

In the present invention one preferred embodiment, when X is carbon, and Y is nitrogen:

M is the integer of 1-4；N is the integer of 1-4.

In the present invention one preferred embodiment, when X is nitrogen, and Y is carbon:

R₁For heteroaryl, heteroaryl is pyridine ring (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine Base, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole radicals, imidazole radicals, condensed hetero ring base etc., on heteroaryl optionally by under Arrange one or more substituent group to replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, Cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl, -NR ' R " ,-(C=O) NR ' R ' ' or-NR ' (C=O) R "；

M is the integer of 1-4；N is the integer of 1-4.

R₁For H, alkyl or benzene series aryl.Alkyl be the straight or branched alkyl of C1～C10, the cycloalkyl of C3～C6 or Heterocyclylalkyl；Benzene series aryl is phenyl, naphthyl (1-naphthyl or 2-naphthyl) etc., on benzene series aryl optionally by under Arrange one or more substituent group to replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, Cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl, -NR ' R " ,-(C=O) NR ' R ' ' or-NR ' (C=O) R "；

R₂For hetero-aromatic ring, hetero-aromatic ring is pyridine ring (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine ring (2-pyrimidine Base, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole ring, imidazole ring, condensed hetero ring etc..Optionally by following on hetero-aromatic ring One or more substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, Cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl, -NR ' R " ,-(C=O) NR ' R " or-NR ' (C=O) R "；

M is the integer of 1-4；N is the integer of 1-4.

R₂For benzene series aryl, benzene series aryl is phenyl, naphthyl (1-naphthyl or 2-naphthyl) etc., optional on benzene series aryl Property ground by following one or more substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, Alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, Phenyl ,-NR ' R " ,-(C=O) NR ' R " or-NR ' (C=O) R "；

M is the integer of 1-4, and n is the integer of 1-4, but is 1 during m, n difference.

In the present invention one preferred embodiment, be each independently in nitrogen or carbon, and X, Y one of X, Y is nitrogen Another is carbon；

R₁For aromatic group, aromatic group is the benzene series aryl such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrroles The heteroaryls such as base, imidazole radicals, condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: Halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alkoxyalkyl, ring Alkoxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R ' ' or It is-NR ' (C=O) R "；

R₂For heteroaryl, heteroaryl is pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine Base, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole radicals, imidazole radicals, condensed hetero ring base etc..On heteroaryl optionally by under Arrange one or more substituent group replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, Cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl, -NR ' R " ,-(C=O) NR ' R " or-NR ' (C=O) R "；

M is the integer of 1-4；N is the integer of 1-4.

R₁For aromatic group, aromatic group is the benzene series aryl such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrroles The heteroaryls such as base, imidazole radicals, condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: Halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkane Base, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

R₂For heteroaryl, heteroaryl is pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine Base, 4-pyrimidine radicals or 5-pyrimidine radicals), condensed hetero ring base etc..Optionally by following one or more replacements on heteroaryl Base replaces: halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxygen Alkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

M is the integer of 1-4；N is the integer of 1-4.

R₁、R₂It is each independently phenyl, naphthyl (1-naphthyl or 2-naphthyl), pyridine radicals (2-pyridine radicals, 3-pyridine radicals Or 4-pyridine radicals), the aryl such as pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), R₁、R₂On can be independently Replaced by following one or more substituent groups: halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkanes oxygen Base, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

M, n are each independently 1 or 2 or 3.

R₁For phenyl, naphthyl (1-naphthyl or 2-naphthyl), pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals) Deng aryl, R₂For pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals Or 5-pyrimidine radicals) etc. heteroaryl.R₁、R₂On can independently by following one or more substituent groups replace: halogen, trifluoro Methyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, Cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

M, n are each independently 1 or 2 or 3.

R₁、R₂It is each independently the benzene series aryl such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), R₁、R₂On can be independent Ground is replaced by following one or more substituent groups: halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkanes Epoxide, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

M, n are each independently 1 or 2 or 3, but are 1 during m, n difference.

In the present invention, unless otherwise mentioned or point out, term " halogen " refers to fluorine, chlorine, bromine or iodine；

Unless otherwise mentioned or point out, term " alkyl " refers both to unit price saturated straight chain or branched hydrocarbon chain.Hydrocarbon chain Typically contain 1-6 carbon, including pentyl, isoamyl alkyl, neopentyl, tertiary pentyl, hexyl, isohesyl.One Plant preferable alkyl type and represent the hydrocarbon chain containing 1-4 carbon, including butyl, isobutyl group, sec-butyl and the tert-butyl group.Separately A kind of preferable alkyl type represents the hydrocarbon chain containing 1-3 carbon, especially methyl, ethyl, propyl group, isopropyl；

Unless otherwise mentioned or point out, term " thiazolinyl " all comprises only the carbochain of one or more double bond, including diene, Triolefin, polyolefin.A kind of preferable thiazolinyl type represents the hydrocarbon chain containing 2-6 carbon, comprises at least one double bond.One Planting best thiazolinyl type is vinyl；1-or 2-acrylic；1-, 2-or 3-cyclobutenyl；1,3-butadienyl； 1-, 2-, 3-, 4-or 5-hexenyl；1,3-hexadienyl or 1,3,5-hexatriene base；

Unless otherwise mentioned or point out, term " alkynyl " all comprises only the carbochain of one or more three keys, including diine, Three alkynes and carbene base.A kind of preferable alkynyl type represents the hydrocarbon chain containing 2-6 carbon, comprises at least one three key. It is acetenyl in the most best alkynyl type；1-or 2-propynyl；1-, 2-or 3-butynyl；1,3-diacetylene Base；1-, 2-, 3-or 4-pentynyl；1,3-pentadiine base；1-, 2-, 3-, 4-or 5-hexin base；1,3-hexadiine base or Oneself three alkynyls of 1,3,5-；

Epoxy alkyl refers both to the alkyl of cyclisation, preferably comprises 3-7 carbon atom, including cyclopropyl, cyclobutyl, ring penta Alkyl, cyclohexyl and suberyl.

Unless otherwise mentioned or point out, term " alkoxyl " refers to O-alkyl, and alkyl is as defined above；

Unless otherwise mentioned or point out, term " epoxy alkyl " refers to O-ring alkyl, and cycloalkyl is as defined above；

Unless otherwise mentioned or point out, term " aromatic group " refers to fragrance carbochain such as phenyl, naphthyl (1-naphthyl or 2- Naphthyl) or fluorenyl；

Unless otherwise mentioned or point out, in described one or more substituent groups, halogen substiuted is 2-chlorine, 3-chlorine, 4-chlorine, 2,3-dichloros, 2,4-dichloros replace；Described trifluoromethyl is substituted by 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl Replace；Described alkyl is substituted by 2-methyl, 3-methyl, and 4-methyl replaces；

Unless otherwise mentioned or point out, substituted piperidines described in formula I, its stereoisomer and pharmaceutically Acceptable salt or its solvate, it is characterised in that described stereoisomer can be chipal compounds levo form, D-isomer, racemic modification, and the mixture of arbitrary proportion；

Unless otherwise mentioned or point out, substituted piperidines described in formula I, its stereoisomer and pharmaceutically Acceptable salt or its solvate, it is characterised in that described salt by described substituted piperidines with inorganic Acid or organic acid form pharmaceutically acceptable acid-addition salts；

Unless otherwise mentioned or point out, substituted piperidines described in formula I, its stereoisomer and pharmaceutically Acceptable salt or its solvate, it is characterised in that described mineral acid be hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, A kind of or any two kinds or above compositions in sulphuric acid, phosphoric acid；Described organic acid be tartaric acid, acetic acid, mandelic acid, Maleic acid, fumaric acid, benzoic acid, succinic acid, lactic acid, citric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid and to toluene A kind of or any two kinds or above compositions in sulfonic acid；

The invention provides substituted piperidines, its stereoisomer and pharmaceutically acceptable salt thereof or its solvation The preparation method of thing, the method following synthetic route of use:

Reactions steps is as follows:

A) with compound A as raw material, under triethylamine effect, compound B is obtained with Boc anhydride reaction；

B) compound B obtains compound C with alkyl halide generation nucleophilic substitution under LDA effect；

C) compound B and malonic acid ring isopropyl ester, triisopropyl borate ester reacting generating compound E；

D) compound E occurs with the aralkyl Grignard reagent of one or more different carbon chain lengths under Hydro-Giene (Water Science). is catalyzed Nucleophilic substitution obtains compound F；

E) compound F is at DMSO-H₂The mixed solution of O is heated to 135 DEG C of reactions and within two days, obtains compound G；

F) compound G is with borine as reducing agent, and the 24-48h that refluxes in THF obtains compound H；

G) compound C obtains compound D through the THF solution reduction of tetrahydrochysene lithium aluminum；

H) compound D and compound H obtains chemical combination with fluoric compound generation nucleophilic substitution under sodium hydride effect Thing J；

I) compound J deprotection base under trifluoroacetic acid effect obtains target compound.

According to substituted piperidines provided by the present invention, its stereoisomer and pharmaceutically acceptable salt thereof or its solvent Compound, one of following compound:

The invention provides acetylcholine associated proteins and combine the piperidines of activity, prepare nAChRs being used for The little molecule of part be further used for prevention, delay or treat neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Application in terms of dementia, depression.

Substituted piperidines of the present invention, has obvious acetylcholine associated proteins and combines activity, for entering one The little molecule of part of the high activity nAChRs that step research is possible, research are likely to be of and improve cognitive function, alleviate simultaneously The original new drug of the progression of disease such as AD and depression provides valuable information.

Detailed description of the invention

Below in conjunction with embodiment, the present invention is further elaborated, and implementation below can only describe this by way of example Bright.It is obvious that those of ordinary skill in the art can carry out various accommodation to the present invention in the scope of the present invention and essence And amendment.It is to be understood that this invention is intended to contain accommodation and the amendment that appended claims includes.

Experiment and sample analysis instrument:

¹HNMR and¹³CNMR all measures in Varian Mercury plus 400 nuclear magnetic resonance analyser.

LS-MS is measured by Agilent 1100Series LC/MSD1946D type mass spectrograph.

Special chemical reagent is purchased from Reagent Company such as sigma, Alfa, Acros, An Naiji.General chemical reagent is purchased from state Solution on Chemical Reagents in Shanghai company of medicine group, is domestic analytical pure.

Primary solvent includes petroleum ether, ethyl acetate, dichloromethane, methanol etc., purchased from traditional Chinese medicines group, is synthesis level.

Column chromatography silica gel uses Haiyang Chemical Plant, Qingdao's chemical pure silica gel, generally 300-400 mesh.

TLC silica gel plate is the HSF-254 thin layer chromatography precoated plate of Yantai Chemical Manufacture.

Uviol lamp is Shanghai Gu Cun electric light instrument plant ZF-1 type ultraviolet analysis instrument for three purposed.

Preparation embodiment

Embodiment 1: compound I-1 3-((4-benzyl piepridine-4-base) methoxyl group) pyridine

Synthetic route:

Reactions steps:

A) raw material A (4-piperidine ethyl formate) (67.5g, 0.43mol) is dissolved in 500ml anhydrous methylene chloride, stirs Mix lower addition triethylamine (72.4ml, 0.52mol), under ice bath, add Boc₂The dichloromethane of O (104.2g, 0.47mmol) Alkane solution, adds rear system and is gradually heating to room temperature reaction overnight.System adds 200ml water after completion of the reaction, organic Phase dilute hydrochloric acid is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, is spin-dried for, and obtains a gluey yellow solid 90g.Product the most directly carries out next step reaction.Yield: 95%

MS(m/z):280[M+Na]⁺

¹H NMR(400MHz,CDCl₃) δ 4.11-4.05 (q, J=7.2Hz, 2H), 4.02-3.88 (m, 2H), 2.84-2.70 (m, 2H), 1.84-1.77 (m, 2H), 1.62-1.51 (m, 2H), 1.39 (s, 9H), 1.19 (t, J=6.8Hz, 3H).

B) during preparing compound C, first carry out the preparation of LDA, by diisopropylamine (3.1ml, 21.7mmol) it is dissolved in the anhydrous THF of 20ml, adds n-BuLi 11ml (2.4N, 26.4mmol) at-78 DEG C, add React 5min after complete at such a temperature and be placed under ice bath reaction 30min.After LDA preparation, again it is cooled to-78 DEG C Under, it being slowly added dropwise the THF solution 10ml of step product B (3.1g, 12.1mmol), after dropping, system is in-30 DEG C Lower reaction 30min.Continue cool to-78 DEG C, be slowly added dropwise benzyl bromide a-bromotoluene (4.1g, 24.2mmol), in this temperature after adding Lower reaction 2h, then system is gradually warmed to room temperature overnight.After having reacted, under ice bath, add 10ml saturated ammonium chloride Solution cancellation is reacted, and 100ml ethyl acetate extracts, and organic facies is washed, and saturated common salt is washed, and anhydrous sodium sulfate is dried. Filter, be spin-dried for, residue silica gel column chromatography (petroleum ether: ethyl acetate=15:1), obtain colorless oil 1.9g.Yield: 45%

MS(m/z):370[M+Na]⁺

¹H NMR(600MHz,CDCl₃)δ7.25-7.19(m,3H),7.05-7.02(m,2H),4.11-4.06(m,2H), 3.95-3.90 (m, 2H), 2.84-2.78 (m, 4H), 2.10-2.06 (m, 2H), 1.46-1.42 (m, 11H), 1.16 (t, J= 7.2Hz,3H).

G) during preparing compound D, upper step product C (482mg, 1.39mmol) is dissolved in 50ml anhydrous In THF, add the THF solution 1.39ml (1N, 1.39mmol) of Lithium Aluminium Hydride under ice bath, after adding at such a temperature Reaction 1h.Add 10ml cancellation, the NaOH solution of 10ml 20% after completion of the reaction under ice bath, add after stirring 1min Entering the extraction of 200ml ethyl acetate, organic facies is washed, and saturated common salt is washed, and anhydrous sodium sulfate is dried.Filter, be spin-dried for One colorless oil, is long placed in referred to as white mucilage binding solid 420mg.It is anti-that product the most directly carries out next step Should.Yield: 95%

MS(m/z):328[M+Na]⁺

¹H NMR(400MHz,CDCl₃)δ7.22-7.16(m,2H),7.15-7.10(m,3H),3.70-3.58(brs,1H), 3.49-3.41(m,2H),3.36-3.28(m,4H),2.67(s,2H),1.44-1.32(m,13H).

H) during preparing compound I, upper step product D (396mg, 1.63mmol) is dissolved in 10ml anhydrous In DMSO, under stirring, add sodium hydride (72mg, 1.79mmol), 3-fluorine pyridine (155 μ l, 1.79mmol), reaction It is warming up at 60 DEG C overnight.After completion of the reaction, frozen water cancellation reaction it is carefully added into.60ml ethyl acetate extracts, organic Washing mutually, saturated sodium-chloride is washed, and anhydrous sodium sulfate is dried, and filters, is spin-dried for, residue silica gel column chromatography (PE:EA=3:1), Obtain colorless oil 280mg.Yield: 45%

MS(m/z):383[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ8.35-8.19(m,2H),7.25-7.14(m,5H),7.05-7.01(m,2H), 3.62(s,2H),3.59-3.51(m,2H),3.46-3.35(m,2H),2.84(s,2H),1.59-1.54(m,4H),1.45-1.43 (m,9H).

I) during preparing compound I-1, upper step product I (100mg, 0.26mmol) is dissolved in 10ml dichloro In the mixed solution of methane: TFA=3:1,1h is reacted in reaction at room temperature.Nitrogen dries up solvent after completion of the reaction, remaining Thing is dissolved in 50ml dichloromethane, and adding 20%NaOH solution 2ml regulation system is strong basicity, the anhydrous sulfur of organic facies Acid sodium is dried.Filtering, be spin-dried for, residue is prepared silica gel plate and is separated (dichloromethane: methanol=15:1), obtains a faint yellow oil Shape thing 72mg.Yield: 99%

MS(m/z):283[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ9.80-9.00(brs,1H),8.33-8.30(brs,1H),8.22-8.19(brs, 1H),7.24-7.14(m,5H),7.02-6.98(m,2H),3.67(s,2H),3.40-3.20(m,4H),2.86(s,2H), 1.94-1.88(m,4H).。

Embodiment 2: compound I-2 3-((4-(2-chlorobenzyl) piperidin-4-yl) methoxyl group) pyridine

Synthetic technology route, with reference to described in embodiment 1, simply replaces benzyl bromide a-bromotoluene, total recovery: 18.1% with 2-bromine chloride.

MS(m/z):317[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ8.23-8.21(m,1H),8.20-8.16(m,1H),7.28-7.17(m,1H), 7.16-7.06(m,5H),3.80(s,2H),3.00-2.90(m,2H),2.84-2.80(m,2H),2.35-2.25(brs,1H), 1.78-1.59(m,4H).。

Embodiment 3: compound I-3 3-((4-(2-(trifluoromethyl) benzyl) piperidin-4-yl) methoxyl group) pyridine

Synthetic technology route, with reference to described in embodiment 1, simply replaces benzyl bromide a-bromotoluene with 2-trifluoromethyl benzyl bromine, total recovery: 18.3%.

MS(m/z):351[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ8.30-8.19(s,2H),7.68-7.62(m,1H),7.48-7.41(m,1H), 7.40-7.35(m,1H),7.35-7.25(m,1H),7.18-7.10(m,1H),3.98-3.92(m,2H),3.38-3.34(m, 2H),3.12-3.09(m,2H),2.01-2.00(m,4H).。

Embodiment 4: compound I-43-((4-(2-methyl-benzyl) piperidin-4-yl) methoxyl group) pyridine

Synthetic technology route, with reference to described in embodiment 1, simply replaces benzyl bromide a-bromotoluene, total recovery: 18.8% with 2-methyl benzyl bromine.

MS(m/z):297[M+H]

¹H NMR(400MHz,CD₃OD)δ8.29-8.28(m,1H),8.19-8.17(m,1H),7.50-7.46(m,1H), 7.43-7.39(m,1H),7.18-7.08(m,4H),3.98(s,2H),3.28-3.14(m,4H),2.97(s,2H),2.32(s, 3H),2.01-1.94(m,2H),1.92-1.82(m,2H).。

Embodiment 5: compound I-5 3-((4-(3-chlorobenzyl) piperidin-4-yl) methoxyl group) pyridine

Synthetic technology route, with reference to described in embodiment 1, wherein, replaces benzyl bromide a-bromotoluene, total recovery: 19.1% with 3-bromine chloride.

Embodiment 6: compound I-6 3-((4-(3-(trifluoromethyl) benzyl) piperidin-4-yl) methoxyl group) pyridine

Synthetic technology route, with reference to described in embodiment 1, wherein replaces benzyl bromide a-bromotoluene with 3-trifluoromethyl benzyl bromine, total recovery: 19.2%.

MS(m/z):351[M+H]

¹H NMR(600MHz,CDCl₃)δ8.35-8.33(m,1H),8.26-8.24(m,1H),7.47-7.43(m,1H), 7.35-7.31(m,2H),7.27-7.22(m,2H),7.20-7.16(m,1H),4.91-4.88(brs,1H),3.68(s,2H), 3.18-3.12(m,2H),3.05-3.00(m,2H),2.96(s,2H),1.78-1.73(m,4H).。

Embodiment 7: compound I-7 3-((4-(3-methyl-benzyl) piperidin-4-yl) methoxyl group) pyridine

Synthetic technology route, with reference to described in embodiment 1, wherein replaces benzyl bromide a-bromotoluene, total recovery: 19.3% with 3-methyl benzyl bromine.

MS(m/z):297[M+H]

¹H NMR(600MHz,CDCl₃)δ8.36-8.35(m,1H),8.24-8.22(m,1H),7.25-7.19(m,2H), 7.12-7.09(m,1H),7.01-6.99(m,1H),6.87-6.85(m,2H),4.46-4.45(brs,1H),3.70(s,2H), 3.16-3.11(m,2H),3.06-3.01(m,2H),2.85(s,2H),2.21(s,3H),1.76-1.72(m,4H).。

Embodiment 8: compound I-8 3-((4-(4-chlorobenzyl) piperidin-4-yl) methoxyl group) pyridine

Synthetic technology route, with reference to described in embodiment 1, wherein replaces benzyl bromide a-bromotoluene, total recovery: 18.3% with 4-bromine chloride.

MS(m/z):317[M+H]

¹H NMR(600MHz,CDCl₃)δ8.78-8.26(m,1H),8.18-8.16(m,1H),7.18-7.15(m,1H), 7.14-7.09(m,3H),6.94-6.91(m,2H),3.58(s,2H),3.54-3.49(m,2H),3.38-3.33(m,2H), 2.79(s,2H),1.54-1.49(m,4H),1.41(s,9H).。

Embodiment 9: compound I-9 3-((4-(4-(trifluoromethyl) benzyl) piperidin-4-yl) methoxyl group) pyridine

Synthetic technology route, with reference to described in embodiment 1, wherein replaces benzyl bromide a-bromotoluene with 4-trifluoromethyl benzyl bromine, total recovery: 18.8%.

MS(m/z):351[M+H]

¹H NMR(400MHz,CD₃OD)δ8.32-8.31(m,1H),8.20-8.18(m,1H),7.56-7.53(m,2H), 7.51-7.47(m,1H),7.43-7.39(m,1H),7.37-7.34(m,2H),3.86(s,2H),3.33-3.28(m,2H), 3.24-3.16(m,2H),3.05(s,2H),1.94-1.80(m,4H).。

Embodiment 10: compound I-10 3-((4-(4-methyl-benzyl) piperidin-4-yl) methoxyl group) pyridine

Synthetic technology route, with reference to described in embodiment 1, simply replaces benzyl bromide a-bromotoluene, total recovery: 19.8% with 4-methyl benzyl bromine.

MS(m/z):297[M+H]

¹H NMR(400MHz,CD₃OD)δ8.32-8.31(m,1H),8.20-8.17(m,1H),7.51-7.47(m,1H), 7.43-7.39(m,1H),7.06-7.00(m,4H),3.83(s,2H),3.42-3.36(m,2H),3.34-3.26(m,2H), 2.91(s,2H),2.26(s,3H),1.96-1.84(m,4H).。

Embodiment 11: compound I-11 3-((4-([1,1'-biphenyl]-4-ylmethyl) piperidin-4-yl) methoxyl group) pyridine

Synthetic technology route, with reference to described in embodiment 1, simply replaces benzyl bromide a-bromotoluene with 4-bromomethylbiphenyl, total recovery: 18.1%.

MS(m/z):359[M+H]

¹H NMR(400MHz,CD₃OD)δ8.33-8.31(m,1H),8.19-8.17(m,1H),7.56-7.53(m,2H), 7.49-7.45(m,3H),7.42-7.36(m,3H),7.32-7.27(m,1H),7.20-7.18(m,2H),3.85(s,2H), 3.40-3.34(m,2H),3.29-3.22(m,2H),2.96(s,2H),1.96-1.84(m,4H).。

Embodiment 12: compound I-12 3-((4-(2,3-dichloro-benzoyl base) piperidin-4-yl) methoxyl group) pyridine

Synthetic technology route is with reference to described in embodiment 1, and simply with 2,3-benzyl dichloride bromine replaces benzyl bromide a-bromotoluene, total recovery: 18.1%.

MS(m/z):351[M+H]

¹H NMR(400MHz,CD₃OD)δ8.20-8.15(m,2H),7.43-7.37(m,3H),7.24-7.15(m,2H), 4.00(s,2H),3.15(s,2H),3.11-3.04(m,2H),3.02-2.95(m,2H),1.88-1.75(m,4H).。

Embodiment 13: compound I-13 3-((4-(3,4-dichloro benzyl) piperidin-4-yl) methoxyl group) pyridine

Synthetic technology route is with reference to described in embodiment 1, and simply with 3,4-benzyl dichloride bromine replaces benzyl bromide a-bromotoluene, total recovery: 18.6%.

MS(m/z):351[M+H]

¹H NMR(400MHz,CD₃OD)δ8.31-8.29(m,1H),8.19-8.17(m,1H),7.42-7.37(m,3H), 7.26-7.25(m,1H),7.07-7.03(m,1H),3.81(s,2H),3.22-3.15(m,2H),3.12-3.04(m,2H), 2.89(s,2H),1.84-1.70(m,4H).。

Embodiment 14: compound I-14 3-((3-(3,4-dichloro benzyl) piperidines-3-base) methoxyl group) pyridine

Synthetic technology route is with reference to described in embodiment 1, and simply with 3,4-benzyl dichloride bromine replaces benzyl bromide a-bromotoluene, nipecotic acid Ethyl ester replaces 4-piperidine ethyl formate；Total recovery: 20.1%；It is carried out chiral column isolated I-14A and I-14B, Their nuclear magnetic spectrogram is completely the same；

MS(m/z):351[M+H]

¹H NMR(400MHz,CDCl₃)δ8.36-8.34(m,1H),8.25-8.22(m,1H),7.28-7.19(m,4H), 6.94-6.90(m,1H),3.82-3.78(m,1H),3.72-3.68(m,1H),2.90-2.82(m,3H),2.78-2.69(m, 3H),2.36-2.22(brs,1H),1.70-1.54(m,3H),1.50-1.42(m,1H).。

Embodiment 15: compound I-15 3-((4-piperidine-4-base) methoxyl group) pyridine

Synthetic technology route, with reference to described in embodiment 1, simply replaces benzyl bromide a-bromotoluene with phenethyl bromide, total recovery: 13.2%.

MS(m/z):297[M+H]

¹H NMR(400MHz,CD₃OD)δ8.32-8.30(m,1H),8.19-8.16(m,1H),7.55-7.51(m,1H), 7.43-7.39(m,1H),7.26-7.18(m,4H),7.16-7.11(m,1H),4.07(s,2H),3.32-3.27(m,4H), 2.66-2.60(m,2H),2.06-1.98(m,2H),1.94-1.86(m,4H).。

Embodiment 16: compound I-18 2-((4-benzyl piepridine-4-base) methoxyl group) pyridine

Synthetic technology route, with reference to described in embodiment 1, simply replaces 3-fluorine pyridine, total recovery: 15.2% with 2-fluorine pyridine.

MS(m/z):283[M+H]

¹H NMR(400MHz,CDCl3)δ8.13-8.09(m,1H),7.63-7.57(m,1H),7.24-7.16(m,3H), 7.12-7.07(m,2H),6.91-6.86(m,1H),6.82-6.80(m,1H),4.09(s,2H),3.34-3.26(m,2H), 3.21-3.14(m,2H),2.86(s,2H),1.94-1.82(m,4H).。

Embodiment 17: compound I-16 3-(2-(4-piperidine-4-base) ethyoxyl) pyridine

Synthetic route:

Reactions steps:

C) by raw material 4-t-butoxycarbonylpiperidin ketone (compound B) (31.2g, 0.16mol), malonic acid ring isopropyl ester (25g, 0.17mmol), triisopropyl borate ester (72.5ml, 0.32mol) be dissolved in 300ml ethyl acetate, add acetic acid under stirring (1.8ml, 0.03mol) and ammonia (1.1ml, 0.03mol), after adding, system is in room temperature reaction overnight.In system by Gradually generate more solid.After completion of the reaction, filtering, filter cake washs by a little ethyl acetate, dries, for white powder Solid 28g.Yield: 55%

MS(m/z):348[M+Na]⁺

¹H NMR (400MHz, d-DMSO) δ 3.49 (t, J=6.4Hz, 4H), 3.07 (t, J=5.4Hz, 4H), 1.71 (s,6H),1.42(s,9H).

D) during synthesis compound F, raw material Hydro-Giene (Water Science). (300mg, 1.58mmol) is suspended in 200ml In anhydrous THF, add phenethyl base magnesium chloride 77ml (1N, 77mmol) at-10 DEG C, add and react at such a temperature 30min.Add in 10 1h of upper step product E (10g, 30.8mmol) point.Add rear system naturally to rise from-10 DEG C Temperature reacts 3h to 0 DEG C.Addition strong aqua ammonia in system after completion of the reaction: saturated ammonium chloride: the mixed solution 100ml of water=1:2:3 Cancellation is reacted, ethyl acetate extraction (60ml*3), and organic facies merges, and saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, Obtain a white solid.Solid washs with a little ether, dries.Obtain 3.8g white powdery solids.Yield: 30%

MS(m/z):454[M+Na]⁺

¹H NMR(400MHz,CDCl₃)δ7.24-7.20(m,2H),7.12-7.06(m,3H),3.70-3.60(m,2H), 3.10-3.04(m,2H),2.85-2.65(m,2H),1.99(s,2H),1.72-1.62(m,2H),1.48(s,6H),1.38(s, 9H), 1.18 (t, J=7.6Hz, 2H).

E) during synthesis compound G, upper step product F (10.3g, 24.0mmol) is dissolved in DMF/H₂O(1/1) 400ml solution in, system be heated to 135 DEG C react 2 days.After completion of the reaction, system adds the NaOH of 1N Solution 100ml, water 500ml.500ml ether extracts, and organic facies 6N hydrochloric acid solution regulates pH ＜ 2, aqueous phase ether Extraction (200ml*2), merges organic facies, and organic facies is washed, and saturated common salt is washed, and anhydrous sodium sulfate is dried.Filter, It is spin-dried for obtaining a white powdery solids 6.4g.Product the most directly carries out next step reaction.Yield: 80%

MS(m/z):370[M+Na]⁺

¹H NMR(400MHz,d-DMSO)δ7.26-7.22(m,2H),7.18-7.10(m,3H),3.41-3.35(m, 2H),3.30-3.20(m,2H),2.58-2.50(m,2H),2.33(s,2H),1.65-1.58(m,2H),1.55-1.48(m, 2H),1.43-1.35(m,11H).

F) during synthesis compound H, upper step product G (500mg, 1.44mmol) is dissolved in 50ml anhydrous In THF, stirring is lower adds borane dimethylsulfide ethereal solution 2.16ml (2N, 4.32mmol), and system refluxes overnight.Reaction After, adding 50ml water, 200ml ethyl acetate extracts, and organic facies saturated common salt is washed, and anhydrous sodium sulfate is dried. Filter, be spin-dried for.Obtain a water white transparency oily thing 450mg.Product the most directly carries out next step reaction. Yield: 99%

MS(m/z):356[M+Na]⁺

¹H NMR(400MHz,CDCl₃)δ7.26-7.20(m,2H),7.16-7.10(m,3H),3.72-3.66(m, 2H),3.42-3.35(m,4H),2.55-2.48(m,2H),1.74-1.66(m,2H),1.61-1.55(m,2H),1.48-1.38 (m,13H).

H) during synthesis compound J, upper step product H (543mg, 1.63mmol) is dissolved in 10ml anhydrous In DMSO, under stirring, add sodium hydride (72mg, 1.79mmol), 3-fluorine pyridine (155 μ l, 1.79mmol), reaction It is warming up at 60 DEG C overnight.After completion of the reaction, frozen water cancellation reaction it is carefully added into.60ml ethyl acetate extracts, organic Washing mutually, saturated sodium-chloride is washed, and anhydrous sodium sulfate is dried, and filters, is spin-dried for, residue silica gel column chromatography (PE:EA=3:1), Obtain colorless oil 300mg.Yield: 45%

MS(m/z):411[M+H]

¹H NMR(400MHz,CDCl₃)δ8.33-8.26(brs,1H),8.22-8.18(m,1H),7.29-7.24(m,2H), 7.19-7.15 (m, 5H), 4.06 (t, J=8Hz, 2H), 3.48-3.41 (m, 4H), 2.61-2.55 (m, 2H), 1.94 (t, J= 6.8Hz, 2H), 1.72-1.66 (m, 2H), 1.53 (t, J=5.2Hz, 4H), 1.45 (s, 9H).

I) during preparing compound I-16, upper step product J (100mg, 0.26mmol) is dissolved in 10ml dichloro In the mixed solution of methane: TFA=3:1,1h is reacted in reaction at room temperature.Nitrogen dries up solvent after completion of the reaction, remaining Thing is dissolved in 50ml dichloromethane, and adding 20%NaOH solution 2ml regulation system is strong basicity, the anhydrous sulfur of organic facies Acid sodium is dried.Filtering, be spin-dried for, residue is prepared silica gel plate and is separated (dichloromethane: methanol=15:1), obtains a faint yellow oil Shape thing 80mg.Yield: 99%

MS(m/z):311[M+H]

¹H NMR(400MHz,CD₃OD)δ8.25-8.24(m,1H),8.16-8.14(m,1H),7.49-7.46(m,1H), 7.42-7.37 (m, 1H), 7.30-7.22 (m, 4H), 7.19-7.13 (m, 1H), 4.21 (t, J=6Hz, 2H), 3.29-3.23 (m, 4H), 2.67-2.62 (m, 2H), 2.07 (t, J=5.6Hz, 2H), 1.87-1.76 (m, 6H)..

Embodiment 18: compound I-17 3-(2-(4-benzyl piepridine-4-base) ethyoxyl) pyridine

Synthetic technology route, with reference to described in embodiment 17, is simply replaced phenethyl magnesium chloride with benzylmagnesium chloride, is always received Rate: 14.2%.

MS(m/z):297[M+H]

¹H NMR(400MHz,CD₃OD)δ8.28-8.26(m,1H),8.17-8.15(m,1H),7.52-7.48(m,1H), 7.43-7.39 (m, 1H), 7.35-7.30 (m, 2H), 7.28-7.22 (m, 3H), 4.26 (t, J=8Hz, 2H), 3.34-3.28 (m, 4H), 2.86 (s, 2H), 1.96 (t, J=6.4Hz, 2H), 1.82-1.77 (m, 4H)..

Embodiment 19 compound I-19 4-((naphthalene-2-base epoxide) methyl)-4-piperidine

Synthetic technology route, with reference to described in embodiment 17, simply replaces 3-fluorine pyridine, total recovery: 12.2% with 2-fluoronaphthalene.

MS(m/z):346[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ8.01-7.94(m,1H),7.82-7.76(m,3H),7.52-7.47(m,1H), 7.41-7.36(m,1H),7.32-7.27(m,2H),7.23-7.16(m,5H),4.02(s,2H),3.40-3.24(m,4H), 2.64-2.58(m,2H),2.11-1.93(m,6H).。

Embodiment 20 compound I-20 4-(2-(naphthalene-2-base epoxide) ethyl)-4-piperidine

Synthetic technology route, with reference to described in embodiment 17, simply replaces 3-fluorine pyridine, total recovery: 12.6% with 2-fluoronaphthalene.

MS(m/z):360[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.80-7.74(m,3H),7.66-7.58(brs,1H),7.50-7.45(m,1H), 7.38-7.30 (m, 3H), 7.25-7.20 (m, 3H), 7.16-7.11 (m, 2H), 4.16 (t, J=6.8Hz, 2H), 3.32-3.24 (m,4H),2.66-2.60(m,2H),2.07-2.02(m,2H),1.94-1.88(m,4H),1.83-1.77(m,2H).。

Embodiment 21 compound I-21 4-(2-(naphthalene-2-base epoxide) ethyl)-4-piperidine

MS(m/z):346[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.79-7.73(m,3H),7.50-7.44(m,1H),7.39-7.28(m,4H), 7.20-7.11 (m, 4H), 4.21 (t, J=6Hz, 2H), 3.43-3.36 (m, 2H), 3.33-3.24 (m, 2H), 2.81 (s, 2H), 1.98-1.82(m,2H).。

The acetylcholine associated proteins of embodiment 22 substituted piperidines combines determination of activity:

This part biological activity test completes in Fudan University's radioisotopic laboratory.

1. experiment material:

1 AChBP albumen: obtained by the method for plasmid transfection expression.

2 [³H] Epibatidine (54.1Cimmol): purchased from Perkin-Elmer Life Scince company

3 nicotine (nicotinic receptor agonists): purchased from An Naiji company

4 Epibatidine (nicotinic receptor agonists): purchased from Sigma Adrich company

5 scintillation reagents: purchased from Perkin-Elmer company

6 DMSO: purchased from Shanghai Sheng Gong biotech firm

7 water: pure water instrument is that ELGA company produces, numbering CLXXUVFM2

8 ultra-filtration centrifuge tubes: purchased from merk company, model 10kd

9 PBS-TRIs buffer: configuration concentration is 1.4mM KH₂PO₄,4.3mM Na₂HPO₄,137mM NaCl,2.7 MM KCl, 20mM Trizma base, 4%DMSO, 0.05%Tween 20, pH 7.4, inorganic salt used etc. is all state The analytical reagent of medicine group.

2. key instrument:

1 scintiloscope: purchased from Perkin-Elmer company model: Tri-Carb 2910TR

2 centrifuges: model: sigma 3k15

3. experimental technique

On this experimental principle be [³H] Epibatidine competitive binding experiment.Specific experiment method is as follows: use PBS-TRIs AChBP albumen is made into the solution of PBS-TRIs by buffer, incite somebody to action equally [³H] to be made into PBS-TRIs molten for Epibatidine Liquid, to each testing tube add 10 μ L protein solutions and 20 μ L [³H] Epibatidine solution.Add after hatching 3 minutes The DMSO solution 2 μ L of the little molecule of variable concentrations part to be measured, blank group adds the buffer of equal volume.Afterwards With buffer polishing to 200 μ L.3 minutes are hatched after mixing.Then solution is transferred in ultra-filtration centrifuge tube, 10000rpm Centrifugal 10min, gets out test fluid during centrifugal and dodges the vial of reading, adds 2mL in each bottle Lipophilic scintillation solution.After centrifugal end, take the 50 μ L solution being centrifuged and be placed in vial, mixing, liquid dodge Bright calculating instrument measures radioactive intensity, the mensuration of radioactivity total amount by add in vial 20 μ L [³H] Epibatidine solution measures, often group experiment two looped pipelines.

Combination rate=(sample cell dpm blank dpm)/(radioactivity total amount dpm) * 100%

Gained compound activity is as shown in table 1:

Table 1: the acetylcholine associated proteins of part of compounds combines activity

By screening on a molecular scale, result display part of compounds shows certain acetylcholine associated proteins knot Conjunction activity, for studying the little molecule of part of possible high activity nAChRs further, studying to be likely to be of and improve cognitive merit Can, the original new drug simultaneously alleviating the progression of disease such as AD and depression provides valuable information.

Claims

1. the substituted piperidines shown in formula I, its stereoisomer and pharmaceutically acceptable salt thereof or it is molten Agent compound,

Wherein: X, Y, R₁、R₂, m, n be defined as follows:

R₁For H, alkyl or aromatic group；Described alkyl is the straight or branched alkyl of C1～C10, the ring of C3～C6 Alkyl or Heterocyclylalkyl；Described aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyridine Base (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole Cough up base, imidazole radicals, the heteroaryl of condensed hetero ring base, optionally by following one or more replacements on described aromatic group Base replaces: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alcoxyl Alkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R ", -(C=O) NR ' R ' ' or-NR ' (C=O) R "；

R₂For aromatic group, described aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyrrole Piperidinyl (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), Pyrrole radicals, imidazole radicals, the heteroaryl of condensed hetero ring base, optionally by following one or more on described aromatic group Substituent group replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, Alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R ", -(C=O) NR ' R " or-NR ' (C=O) R ".

M is the integer of 1-4；N is the integer of 1-4.

Substituted piperidines shown in formula I the most according to claim 1, its stereoisomer and medicine thereof Acceptable salt or its solvate on, it is characterised in that

When X is carbon, and Y is nitrogen:

R₁For H, alkyl or aromatic group.Alkyl is the straight or branched alkyl of C1～C10, the cycloalkyl of C3～C6 Or Heterocyclylalkyl；Aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyrrole Piperidinyl, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole radicals, miaow Oxazolyl, the heteroaryl of condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: halogen, Trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxygen alkane Base, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R ' ' or -NR ' (C=O) R "；

R₂For aromatic group, aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrroles Base, imidazole radicals, the heteroaryl of condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: Halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alkoxyalkyl, ring Alkoxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R " Or-NR ' (C=O) R ".

M is the integer of 1-4；N is the integer of 1-4.

When X is nitrogen, and Y is carbon:

R₁For heteroaryl, heteroaryl is pyridine ring (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine Base, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole radicals, imidazole radicals, condensed hetero ring base, optionally by following on heteroaryl One or more substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, Cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl, -NR ' R " ,-(C=O) NR ' R ' ' or-NR ' (C=O) R "；

R₂For aromatic group, aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrroles Base, imidazole radicals, the heteroaryl of condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: Halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alkoxyalkyl, ring Alkoxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R " Or-NR ' (C=O) R "；

M is the integer of 1-4；N is the integer of 1-4.

When X is nitrogen, and Y is carbon:

R₁For H, alkyl or benzene series aryl, described alkyl is the straight or branched alkyl of C1～C10, the cycloalkanes of C3～C6 Base or Heterocyclylalkyl；Benzene series aryl is phenyl, naphthyl (1-naphthyl or 2-naphthyl), on benzene series aryl optionally by Following one or more substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alcoxyl Base, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, benzene Base ,-NR ' R " ,-(C=O) NR ' R ' ' or-NR ' (C=O) R "；

R₂For hetero-aromatic ring, hetero-aromatic ring is pyridine ring (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine ring (2-pyrimidine Base, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole ring, imidazole ring, condensed hetero ring；On described hetero-aromatic ring optionally by under Arrange one or more substituent group replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, Cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl, -NR ' R " ,-(C=O) NR ' R " or-NR ' (C=O) R "；

M is the integer of 1-4；N is the integer of 1-4.

When X is nitrogen, and Y is carbon:

R₁For H, alkyl or benzene series aryl, described alkyl is the straight or branched alkyl of C1～C10, the cycloalkanes of C3～C6 Base or Heterocyclylalkyl；Benzene series aryl is phenyl, naphthyl (1-naphthyl or 2-naphthyl), alternative on described benzene series aryl Ground is replaced by following one or more substituent groups: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, Alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, Phenyl ,-NR ' R " ,-(C=O) NR ' R ' ' or-NR ' (C=O) R "；

R₂For benzene series aryl, described benzene series aryl is phenyl, naphthyl (1-naphthyl or 2-naphthyl), optional on benzene series aryl Replaced by following one or more substituent groups to selecting property: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, ammonia Base, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, Alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R " or-NR ' (C=O) R "；

R₁For aromatic group, aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrroles Base, imidazole radicals, the heteroaryl of condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: Halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alkoxyalkyl, ring Alkoxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R ' ' or It is-NR ' (C=O) R "；

R₂For heteroaryl, heteroaryl is pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine Base, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole radicals, imidazole radicals, condensed hetero ring base；Optionally by following on heteroaryl One or more substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, Cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl, -NR ' R " ,-(C=O) NR ' R " or-NR ' (C=O) R "；

M is the integer of 1-4；N is the integer of 1-4.

7. according to the substituted piperidines shown in the formula I described in claim 1 or 6, its stereoisomer and Its pharmaceutically acceptable salt or its solvate, it is characterised in that

R₁For aromatic group, aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrroles Base, imidazole radicals, the heteroaryl of condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: Halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkane Base, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

R₂For heteroaryl, heteroaryl is pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine Base, 4-pyrimidine radicals or 5-pyrimidine radicals), condensed hetero ring base；Optionally by following one or more substituent groups on heteroaryl Replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxygen alkane Base, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

M is the integer of 1-4；N is the integer of 1-4.

Substituted piperidines shown in formula I the most according to claim 1 and 2, its stereoisomer and Its pharmaceutically acceptable salt or its solvate, it is characterised in that

When X is carbon, and Y is nitrogen:

R₁、R₂It is each independently phenyl, naphthyl (1-naphthyl or 2-naphthyl), pyridine radicals (2-pyridine radicals, 3-pyridine radicals Or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), R₁、R₂On can be independently by following one Individual or multiple substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkyloxy, alcoxyl Alkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

M, n are each independently 1 or 2 or 3.

9. according to the substituted piperidines shown in the formula I described in claim 1 or 4 or 6 or 7, its solid Isomer and pharmaceutically acceptable salt thereof or its solvate, it is characterised in that

When X is nitrogen, and Y is carbon:

R₁For phenyl, naphthyl (1-naphthyl or 2-naphthyl), pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), R₂For pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine Base)；R₁、R₂On can independently by following one or more substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, Cyano group, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, Alkynyl, phenyl；

M, n are each independently 1 or 2 or 3.

The most according to claim 1 or 5 the substituted piperidines shown in formula I, its stereoisomer and Its pharmaceutically acceptable salt or its solvate, it is characterised in that

When X is nitrogen, and Y is carbon:

R₁、R₂It is each independently phenyl, naphthyl (1-naphthyl or 2-naphthyl), R₁、R₂On can be independently by following one Individual or multiple substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkyloxy, alcoxyl Alkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

M, n are each independently 1 or 2 or 3, but are 1 during m, n difference.

11. according to the substituted piperidines shown in the formula I described in claim 1-10, its stereoisomer and Pharmaceutically acceptable salt or its solvate, it is characterised in that

In described one or more substituent groups, halogen substiuted is 2-chlorine, 3-chlorine, 4-chlorine, 2,3-dichloros, and 2,4-dichloros take Generation；Described trifluoromethyl is substituted by 2-trifluoromethyl, 3-trifluoromethyl, and 4-trifluoromethyl replaces；Described alkyl takes On behalf of 2-methyl, 3-methyl, 4-methyl replaces.

12. substituted piperidines shown in formula I according to claim 1, its stereoisomer and Pharmaceutically acceptable salt or its solvate, it is characterised in that

Described stereoisomer is the mixed of the levo form of chipal compounds, d-isomer, racemic modification, and arbitrary proportion Compound.

Substituted piperidines, its stereoisomer and medicine thereof shown in 13. formula I according to claim 1 Acceptable salt or its solvate on, it is characterised in that

Described salt is formed pharmaceutically acceptable acid by described substituted piperidines with mineral acid or organic acid Addition salts.

Substituted piperidines, its stereoisomer and medicine thereof shown in 14. formula I according to claim 13 Acceptable salt or its solvate on, it is characterised in that

Described mineral acid be the one in hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid or any two kinds or Above compositions；Described organic acid is tartaric acid, acetic acid, mandelic acid, maleic acid, fumaric acid, benzoic acid, succinum One in acid, lactic acid, citric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid and p-methyl benzenesulfonic acid or any two kinds or more than Compositions.

The substituted piperidines shown in formula I, its stereoisomer and medicine thereof described in 15. 1 kinds of claim 1 Acceptable salt or the preparation method of its solvate on, it is characterised in that use following synthetic route:

Instead Answer step as follows:

16. 1 kinds of preventing and treating neurodegenerative diseases or antidepressant agents compositions, it is characterised in that shown in formula I Substituted piperidines, its stereoisomer and pharmaceutically acceptable salt thereof or its solvate are active component.

Arbitrary described substituted piperidines, its stereoisomer and pharmaceutically may be used in 17. claim 1～15 Accept salt or its solvate as nAChRs the little molecule of part preparation prevention and/or treatment nervus retrogression disease Purposes in sick or dementia or antidepressant agents.

18. purposes according to claim 17, it is characterised in that described neurodegenerative diseases is alzheimer ' Silent disease (AD) or Parkinson's disease (PD)；Described dementia is Alzheimer's disease (AD), Lewy body dementia Or vascular dementia (VaD) (DLB).