CN1417209A - Tetrahydroquinoline ketopiperidine compounds and their prepn and use - Google Patents

Tetrahydroquinoline ketopiperidine compounds and their prepn and use Download PDF

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CN1417209A
CN1417209A CN 01132147 CN01132147A CN1417209A CN 1417209 A CN1417209 A CN 1417209A CN 01132147 CN01132147 CN 01132147 CN 01132147 A CN01132147 A CN 01132147A CN 1417209 A CN1417209 A CN 1417209A
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CN1257901C (en
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蔡茂军
沈竞康
唐希灿
蒋华良
陈凯先
罗小民
郑苏欣
王昕�
严晓明
胡定宇
黄小琴
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Shanghai Institute of Materia Medica of CAS
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Abstract

The present invention discloses tetrahydroquinoline ketopiperidine compounds and their preparation and use. Pharmacological experiment shows that the compounds are acetylcholine inhibitor and can inhibit the activity of acetylcholinesterase, delay the hydrolysis of acetylchoine and thus raise the function of acetylcholine in synapse and reach the aim of treating presenile dementia.

Description

Tetrahydroquinoline ketopiperidine compounds and its production and use
Technical field
The present invention relates to the synthetic and purposes of tetrahydroquinolones piperidine derivatives.
Background technology
Presenile dementia (Alzheimer ' s disease) be that a kind of multi-pathogenesis participates in gradual cerebral functional deterioration disease, its cause of disease does not have conclusive illustrating so far yet.But it is a kind of common geriatric disease, the health that is seriously threatening the elderly, and during aging, this situation is all the more severe, thereby causes people's common concern gradually in especially current society.
At present presenile dementia is carried out drug research and mainly contains the following aspects:
1, acetylcholinesterase depressant (ChEI), it is the activity of acetylcholine esterase inhibition competitively, slows down the hydrolysis of vagusstoff, thereby strengthens the purpose that be used for reach treatment presenile dementia of vagusstoff in cynapse.
2, from the vagusstoff precursor, as considerations such as vagusstoff phosphoric acid ester, purpose is to supply with by the synthesising biological that improves vagusstoff in the body;
3, consider from the vagusstoff releasing agent,, thereby increase the generation of vagusstoff because the vagusstoff releasing agent is used for the presynaptic.
4, consider M1 receptor stimulant, simulation vagusstoff and act on postsynaptic acceptor from receptor stimulant.
5, M2 and M4 receptor stimulant act on the presynaptic, regulate the release of vagusstoff by reverse feedback.
6, nicotine compound also can increase the release of vagusstoff.
At present the treatment to presenile dementia mainly is according to acetylcholinesterase depressant (AChEI), with what the clinical drug of this mechanism of action was used tacrine (Cognex is arranged ), donepezil (Aricept ), ravastigmine (Exelon ) etc., still there are tens kinds of medicines to be in preclinical research or doing clinical study, from present researching and analysing, the structure of these inhibitor has nothing in common with each other, and not tangible structure activity relationship has the patent of part similar structures that US05110815 is arranged with the present invention, WO9307140, EP562832 etc.
Though scientist has made big quantity research and has obtained bigger progress the presenile dementia disease, the appearance of example tacrine and donepezil medicine, but they still have different defectives, tacrine is bigger to hepatotoxicity, and donepezil the biological agent availability is poor in vivo, therefore the presenile dementia disease is required further study and seek out a class novel cpd, the Development of New Generation toxic side effect is low, the medicine that curative effect is high.
Summary of the invention
The present invention seeks to seek a class and have the inhibiting tetrahydroquinolones piperidines of acetylcholinesterase highly selective, it can be used for treating in the presenile dementia disease medicament uses.
Tetrahydroquinoline ketopiperidine compounds has following general structure:
Figure A0113214700061
Wherein:
W-U be for
Figure A0113214700062
Or Group, R on it and R1 are
Figure A0113214700064
, H, low alkyl group, light alkene base, rudimentary alkynes base, aryl etc.;
R 2Be H, C 1-C 4Alkyl etc.;
V-X is C-C, C-O, C-N-Ra, C-S, C=C, C=N etc., and wherein Ra is H, C 1-C 4Alkyl, aryl, benzyl, C1～C4 alkyloyl, benzoyl etc.;
Y is C=O, C=S, S, S=O, SO 2,
Figure A0113214700065
Deng;
R3 is C 1-C 4Alkyl or be (CH 2) q, q=2～3
Z is N-Rb, O, CH 2Deng, wherein Rb is H, C 1-C 4Alkyl, aryl, benzyl;
M=0～8, n=0-8, P=0,1 or 2.
Perhaps V-X is C-N-Ra, and n=0, Y-Z are CH 2, m=0～7
And physiologically acceptable salt.Reaction formula 1 is as follows:
Above-mentioned reaction formula has provided the synthetic method of some key intermediates.But compound III a reference literature method makes (Hachiro Sugimoto et a1, J.Med.Chem.1990,33,1880).Compound I va can be buied or be made with reference to amino acid handbook method by commodity; But compound Va reference method (BergesD.a., Chan G.w., Polanshy T.J., Taggart J.J.and Dunn G.L.J.Heterocyclic.Chem.1978 15:981-992) makes; But compound VI a reference method makes; But compound VI Ia reference (Sugimoto H. Tsuchiya Y.Sugumi H.et al J.Med.Chem.1992,35:4542-4548) method makes;
Shown in reaction formula: compound III a and carboxylic acid or acyl chlorides form acid amides, reduce in inert solvent with tetrahydrochysene lithium aluminium then and obtain amine IIIb.In this reaction, used solvent is tetrahydrofuran (THF) (THF), ether (Et 2O) etc., at room temperature carry out.Compound IV a and compound III a or IIIb form the acyl ammonia of protection under the catalysis of organic bases, in this reaction, the solvent of use has some solvents commonly used such as tetrahydrofuran (THF) (THF), ether (Et 2O), methylene dichloride (CH 2Cl 2), chloroform (CHCl 3), benzene, toluene, N, N-diformamide (DMF), ethanol (EtOH), methyl alcohol (MeOH), n-propyl alcohol (n-PrOH), propyl carbinol (n-BuOH), Virahol (i-PrOH), ethyl acetate (EtOAc) etc.This acyl ammonia is then at Iodotrimethylsilane or at Pd-C/H 2Deprotection obtains intermediate compound IV b under the condition.Acyl chlorides Va and compound III a or IIIb form the sulphonamide of protection under the catalysis of organic bases, use hydrazine (N then 2H 4) hydrolysis gets SULFAMIDE Vb; Compound VI a and thiocarbamide reflux in ethanol or methyl alcohol and obtain isothiourea, hydrolysis obtains mercaptan VI under alkaline condition then, used alkali is generally strong alkali aqueous solution, as the aqueous solution of potassium hydroxide, sodium hydroxide, lithium hydroxide etc., react generally under refluxad, in rare gas element, carry out.The mercaptan of gained obtains thioether with the chloroamides condensation under the effect of alkali, employed here alkali has potassium hydroxide, sodium hydroxide, lithium hydroxide, yellow soda ash, salt of wormwood, triethylamine (TEA), Trimethylamine 99 (TMA), diisopropylethylamine (DIPEA).The thioether of gained reduces in inert solvent with tetrahydrochysene lithium aluminium then and obtains thioether amine VIb.In this reaction, used solvent is tetrahydrofuran (THF) (THF), ether (Et 2O) etc., at room temperature carry out.Acyl chlorides VIIa and diazomethane react in ether or tetrahydrofuran (THF) and form diazo-ketones; obtain chloro ketone VII with the concentrated hydrochloric acid reaction then; this chloro ketone and sodiumazide or cyanogen sodium or potassium cyanide etc. are at methyl alcohol or the alcoholic acid aqueous solution or N; reaction obtains substitution product in N-diformamide (DMF) or the methyl-sulphoxide; be generally under the acid catalysis under the p-methyl benzenesulfonic acid in inert solvent as benzene with ortho-formiate or glycol then; toluene; dimethylbenzene; azeotropic dehydration protection carbonyl uses tetrahydrochysene lithium aluminium at inert solvent such as ether again in the hexanaphthenes etc.; reduction obtains the keto-amine VIIb of thioether amine protection in the tetrahydrofuran (THF).
Reaction formula 2 is as follows:
Figure A0113214700081
Working as V-X in the preparation general formula is C-N-Ra, and n=0, Y-Z are CH 2The time the reaction formula of compound as noted above.Wherein initiator II is available or according to document (Luisa Mosti; Pietro Schenoneand Giulia Menozzi, J.Heterocylic.Chem.1985,22,1053; And David Mulfink etal, J.Med.Chem.1995,38,3645) etc. method make.But IIIa reference literature method makes (Hachiro Sugimoto et al, J.Med.Chem.1990,33,1880).
Shown in reaction formula, Compound I I and excessive slightly compound III are in inert solvent or solvent-freely be condensed into imines down in the presence of dehydrating agent.Reaction is usually at tetrahydrofuran (THF) (THF), ether (Et 2O), methylene dichloride (CH 2Cl 2), chloroform (CHCl 3), benzene, toluene, N, carry out in N-diformamide (DMF) equal solvent, used dehydrating agent has titanium tetrachloride, tetrabutyl titanate and titanium isopropylate etc.Reaction can be carried out between-20～40 ℃, at room temperature reacts usually 24～48 hours.Perhaps Compound I I and excessive compound III are in inert solvent, and azeotropic dehydration obtained imines in 24～48 hours under acid catalysis.Used solvent has benzene,toluene,xylene, hexanaphthene etc.
The imines of gained then with gentle reductive agent under protic solvent, reduce product Ia.The protic solvent that is suitable for has ethanol (EtOH), methyl alcohol (MeOH), n-propyl alcohol (n-PrOH), propyl carbinol (n-BuOH), Virahol (i-PrOH) etc., is generally methyl alcohol and ethanol.Used reductive agent has sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride etc.Reaction is carried out between-40～40 ℃ usually, generally at room temperature carries out.The product of gained can get pure products through purifications such as appropriate means such as column chromatography, recrystallizations.And then make hydrochloride, oxalate, vitriol, acetate etc.
Reaction formula 3 is as follows:
Working as V in the preparation general formula is C, and when X was N-Ra, Y was CO, S, SO, SO 2,
Figure A0113214700101
The time, the compound when Z is C, O, N-Rb is seen above-mentioned reaction formula.
As above shown in the reaction formula, Compound I I and excessive slightly intermediate compound IV b, Vb, Vib, VIIb etc. are in inert solvent or solvent-freely be condensed into imines down in the presence of dehydrating agent.Reaction is usually at tetrahydrofuran (THF) (THF), ether (Et 2O), methylene dichloride (CH 2Cl 2), chloroform (CHCl 3), benzene, toluene, N, carry out in N-diformamide (DMF) equal solvent, used dehydrating agent has titanium tetrachloride, tetrabutyl titanate and titanium isopropylate etc.Reaction can be carried out between-20～40 ℃, at room temperature reacts usually 24～48 hours.Perhaps Compound I I and excessive compound III are in inert solvent, and azeotropic dehydration obtained imines in 24～48 hours under acid catalysis.Used solvent has benzene,toluene,xylene, hexanaphthene etc.
The imines of gained then with gentle reductive agent under protic solvent, reduce product Ib.The protic solvent that is suitable for has ethanol (EtOH), methyl alcohol (MeOH), n-propyl alcohol (n-PrOH), propyl carbinol (n-BuOH), Virahol (i-PrOH) etc., is generally methyl alcohol and ethanol.Used reductive agent has sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride etc.Reaction is carried out between-40～40 ℃ usually, generally at room temperature carries out.
The product Ib of gained and the aldehyde of equivalent, ketone etc. carry out reduction amination and obtain the product Ic that alkyl replaces on the nitrogen.Be reflected at tetrahydrofuran (THF) (THF), ether (Et 2O), methylene dichloride (CH 2Cl 2), chloroform (CHCl 3), benzene, toluene, N; N-diformamide (DMF), 1; carry out in 2-ethylene dichloride (DCE), the dioxane; general aldehyde is with 1; 2-ethylene dichloride (DCE); ketone is made solvent with tetrahydrofuran (THF) (THF), and used reductive agent has sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, cyano group POTASSIUM BOROHYDRIDE, cyano group lithium borohydride, triacetyl sodium borohydride, triacetyl POTASSIUM BOROHYDRIDE, triacetyl lithium borohydride etc.Reaction is generally at room temperature carried out in rare gas element.In inert solvent, react the product Ic that obtains acidylate on the nitrogen with acid anhydrides or acyl chlorides.Used solvent is the same.
Working as Y among the product Ib of gained or the Ic is
Figure A0113214700102
The time, in rare gas element, obtain carbonyl compound Id with acid hydrolysis.When Y is S, use KHSO 5Make oxygenant and carry out oxidation obtain sulfoxide compound Ie in pure water, reaction is generally carried out in rare gas element under 0 ℃, and used alcohol is methyl alcohol, ethanol etc.; As in acetic acid, carrying out oxidation with hydrogen peroxide, then obtain sulphones If, reaction is generally carried out in rare gas element under 0 ℃.
The product of gained can get pure products through purifications such as appropriate means such as column chromatography, recrystallizations.And then make physiologically acceptable salts such as hydrochloride, oxalate, vitriol, acetate.Reaction formula 4 is as follows:
Figure A0113214700111
As X=O or S, Y is CO in the preparation general formula, and Z is N-Rb, O, CH 2The time compound as shown in the figure.Wherein compound III c can (Sugimoto H.Tsuchiya Y.Sugumi H.etal J.Med.Chem.1992 35:4542-4548) obtains by literature method.
As shown in the figure: Compound I I obtains VIII with gentle reductive agent reduction, and used reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride etc., carries out in ethanol or methyl alcohol.The compound VIII of gained obtains the ether acid ester with the reaction of halo acid esters in the presence of alkaline in polar aprotic solvent, used polar aprotic solvent has tetrahydrofuran (THF) (THF), ether (Et 2O), two N, N-diformamide (DMF), dioxane, glycol dimethyl ether (DME), ethylene glycol diethyl ether (DEE) etc., used highly basic has sodium hydride (NaH), potassium hydride KH (KH), potassium tert.-butoxide (t-BuOK), sodium tert-butoxide (t-BuONa), butyllithium (BuLi), diisopropylamine lithium (LDA) etc., carries out under 0 ℃ in rare gas element.Used halo acid esters chloro or bromo carboxylate methyl ester, ethyl ester, butyl ester, the tert-butyl ester, benzyl ester etc.The ether-ether of gained obtains ether acid IX under acid, alkali or reduction.This ether acid and IIIa, IIIb or IIIc react in the presence of dewatering agent in inert solvent and obtain product Ig, and used inert solvent has tetrahydrofuran (THF) (THF), ether (Et 2O), methylene dichloride (CH 2Cl 2), chloroform (CHCl 3), benzene, toluene, N, N-diformamide (DMF), 1,2-ethylene dichloride (DCE), dioxane etc., used dewatering agent have carbodicyclo hexylimide (DCC), sec.-propyl carbodiimide (DIC) etc.Perhaps compound VIII directly and VII condensation in the presence of highly basic obtain compounds X, employed solvent and highly basic are the same.Compounds X obtains final product Ig (when Z is carbon atom) through parlkaline or acidic hydrolysis.
The product of gained can get pure products through purifications such as appropriate means such as column chromatography, recrystallizations.And then make hydrochloride, oxalate, vitriol, acetate etc.
Reaction formula 5 is as follows:
When V-X was C-C or C=C, when Y was C=O, Z was N-Rb, O, CH in the preparation general formula 2The time compound as shown in the figure.
As above shown in the reaction formula: carboxylic carbon negativity compound and Compound I I addition are dewatered under acidic conditions then and are obtained olefin(e) acid ester XIa and XIb, used carboxylic carbon negativity compound has Grignard reagent, zincon, the rare reagent of ladder Wei (Wittig) etc., at inert solvent such as tetrahydrofuran (THF) (THF), ether (Et 2O), under rare gas element, carry out in dioxane, glycol dimethyl ether (DME), ethylene glycol diethyl ether (DEE) etc., temperature of reaction is seen used reagent and is determined between-20～100 ℃.The used acid of dewatering has sulfuric acid, phosphoric acid, hydrochloric acid, oxalic acid, perchloric acid etc., and temperature of reaction is between 0～100 ℃.Resultant olefin(e) acid ester XIa and Xib hydrolysis under acid or alkali; then in inert solvent in the presence of dewatering agent or make acyl chlorides with acylating reagent and obtain double bond containing product Ih and Ii with compound condensations such as IIIa, IIIb, IIIc again; used inert solvent is the same; used dehydrating agent has DCC, DIC etc., and used acylating reagent has thionyl chloride (SOCl 2), oxalyl chloride ((COCl) 2), phosphorus pentachloride (PCl 5), phosphorus oxychloride (POCl 3) etc.Resulting double bond containing product Ih and Ii reduce under catalytic hydrogenation and obtain saturated product Ig, used catalyzer has palladium-carbon (Pd-C), platinum carbon (Pt-C), thunder nickel (Ranny nickel) etc., carries out in ethanol, methyl alcohol, ethyl acetate, tetrahydrofuran (THF) equal solvent.
The product of gained can get pure products through purifications such as appropriate means such as column chromatography, recrystallizations.And then make physiologically acceptable salts such as hydrochloride, oxalate, vitriol, acetate.
Reaction formula 6 is as follows:
Figure A0113214700131
When V-X was C-NH, and Y was C=S or C=O in the preparation general formula, n=0 wherein, and the compound when Z is NH can be obtained by following method.
As above shown in the reaction formula: compound III a is in inert solvent, in the presence of alkali, and dithiocarbonic anhydride (CS 2) obtain different sulphur cyanogen IIId with chloro-formic ester or other acyl chlorides effects again after the reaction, used inert solvent is the same, alkali has mineral alkali such as yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide etc., organic bases such as triethylamine, Trimethylamine 99, diisopropylethylamine etc., used acyl chlorides has methyl-chloroformate, Vinyl chloroformate, chloroformic acid benzyl ester, isobutyl chlorocarbonate, phosphorus oxychloride etc.; Compound I Ia and azanol condensation are reduced under alkaline condition with alumino nickel then and are obtained amine XII in addition, and reduction is carried out in alcohol solution, and used alcohol has ethanol, methyl alcohol etc., and used alkali is sodium hydroxide, potassium hydroxide etc.Resulting compound III d and XII react in alcohol and obtain thiocarbamide Ik, and used alcohol is more above-mentioned lower alcohols, and reaction is generally carried out under refluxing.The thiocarbamide that obtains obtains urea Il with the Sodium Nitrite oxidation under acidic conditions, generally reaction at room temperature obtains product in dilute hydrochloric acid.
The product of gained can get pure products through purifications such as appropriate means such as column chromatography, recrystallizations.And then make physiologically acceptable salts such as hydrochloride, oxalate, vitriol, acetate.
Reaction formula 7 is as follows:
Figure A0113214700141
The preparation general formula in when V-X be C=O, and W-U be for
Figure A0113214700142
, the R on it is
Figure A0113214700143
The time compound can obtain by following method.Wherein compound III f can (Inada Y.et al.Chem.Pharm.Bullet.1986 34:3747-61) obtains for Itoh K., Kori M. by literature method.
As shown in the figure: Compound I I handles with highly basic in inert solvent, obtains compounds X III with excessive compound III f reaction then.Used here inert solvent has tetrahydrofuran (THF) (THF), ether (Et 2O), N, N-diformamide (DMF), N-Methyl pyrrolidone, dioxane etc., temperature of reaction generally 0 ℃ between the room temperature, used highly basic has sodium hydride, potassium hydride KH, sodium hydroxide, potassium hydroxide etc.The compounds X III of gained refluxes under hydrochloric acid and sloughs benzoyl, is dissolved in tetrahydrofuran (THF) (THF), ether (Et then 2O), methylene dichloride (CH 2Cl 2), chloroform (CHCl 3), benzene, toluene, N, N-diformamide (DMF), 1 in the inert solvents such as 2-ethylene dichloride (DCE), dioxane, under the existence of alkali, obtains product with benzyl bromine or the reaction of benzyl chlorine.Here used alkali has mineral alkali such as yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide etc., organic bases such as triethylamine, Trimethylamine 99, diisopropylethylamine etc.
The product of gained can get pure products through purifications such as appropriate means such as column chromatography, recrystallizations.And then make physiologically acceptable salts such as hydrochloride, oxalate, vitriol, acetate.
The cholinesterase activity measuring method:
Acetylcholinesterase (AChE) enzyme source adopts rat layer 5% homogenate (to use 75mmol, pH7.4,4 ℃ of phosphoric acid buffers are made the homogenate medium), by the selective depressant tetra isopropyl pyrophosphoramide (iso-OMPA) that adds 4mmol butyrylcholine esterase (BuChE) at 10: 1,37 ℃ are incubated 5 minutes before the experiment.Butyrylcholine esterase enzyme source is a rat blood serum.With colorimetric method for determining AChE vigor.The reaction total volume is 4ml, include acetylthiocholine iodide 0.3mmol or sulfur iodide for BuCh 0.4mmol, 0.1M pH7.4 sodium phosphate buffer 1ml, compound 0.1-0.5ml, adding water mends to 4ml (comprising the enzyme-added liquid measure in back), add enzyme liquid 0.1 or 0.2ml after 5 minutes in 37 ℃ of insulations, add 1ml3% sodium laurylsulfonate (SDS) termination reaction after being incubated 8 minutes again, add the colour developing of 1ml0.2% two (3-carboxyl-4-nitro) phenyl disulphide (being Ellman ' s reagent) solution at last, produce yellow 5-sulphur-2-nitrophenoxy acid negatively charged ion.Measure optical density(OD) with 752 type spectrophotometers in 440nm, all samples is all surveyed two-tube.As 100%, compound determination pipe optical density(OD) compares with it with the mensuration pipe optical density(OD) that do not add compound, and the percentage of reduction is enzyme inhibition rate.Each compound all is made into 10 -5Mol/L concentration is carried out primary dcreening operation, and enzyme inhibition rate reaches 50% above person and carries out IC 50Mensuration.Select seven to nine its enzyme inhibition rates of concentration determination of compound according to the primary dcreening operation result, and carry out linear recurrence, try to achieve the IC that 50% volumetric molar concentration when suppressing is this compound with the negative logarithm and the enzyme inhibition rate of this compound volumetric molar concentration 50Value.The active the results list of the part of compounds of gained is as follows: Table 1
?Comp. Ra R1 ??(CH 2)· nYZ(CH 2) m ???IC 50(μmol)
?AChE ?BuChE
?1 ?NH ?Me ?CH 2 ?6.68
?2 ?NH ?Me ?CH 2CH 2 ?1.09
?3 ?NH ?Me ?CH 2CH 2CH 2 ?0.75
?4 ?NH ?n-Pr ?CH 2CH 2CH 2 ?0.20
?5 ?NH ?Me ?CH 2CONHCH 2CH 2 ?0.009 ?45
?6 ?NMe ?Me ?CH 2CONHCH 2CH 2 ?0.11 ?99
?7 ?NAc ?Me ?CH 2CONHCH 2CH 2 ?4.4 ?455
?8 ?NH ?n-Pr ?CH 2CONHCH 2CH 2 ?0.022 ?38
?9 ?NH ?Me ?CH 2CONH(CH 2) 3 ?0.12 ?11.5
?10 ?NH ?Me ?CH 2CONH(CH 2) 4 ?0.13 ?11.6
?11 ?NH ?Me ?CH 2CH 2CONHCH 2CH 2 ?0.18
?12 ?NH ?Me ?CH 2CH 2CONHCH 2 ?1.2
?13 ?NH ?Me ?CH 2CH 2CON(CH 3)CH 2 ?1.2
?14 ?NH ?H ?CH 2CH 2CON(CH 3)CH 2CH 2 ?0.27
?15 ?NH ?Me ?CH 2CH 2CON(CH 3)CH 2CH 2 ?0.2
?16 ?NH ?n-Pr ?CH 2CH 2CON(CH 3)CH 2CH 2 ?0.098
?17 ?NH ?Me ?(CH 2) 4CONHCH 2CH 2 ?0.053 ?1.6
?18 ?NH ?Me ?CH 2CH 2SO 2NHCH 2 ?0.477
?19 ?NH ?Me ?CH 2CH 2SO 2N(CH 3)CH 2 ?0.87
?20 ?NH ?Me ?CH 2CH 2SO 2NHCH 2CH 2 ?0.093
?21 ?NH ?H ?CH 2CH 2SO 2N(CH 3)CH 2CH 2 ?0.57
?22 ?NH ?Me ?CH 2CH 2SO 2N(CH 3)CH 2CH 2 ?0.27
?23 ?NH ?n-Pr ?CH 2CH 2SO 2N(CH 3)CH 2CH 2 ?0.24
?24 ?NH ?Me ?CH 2CH 2SCH 2CH 2 ?0.17
As shown in table 1, these compounds all have stronger activity, in addition, a little less than their effects very to BuChE, thereby very high selectivity are arranged.
Specific embodiment
The preparation of embodiment 1 intermediate compound IV b
1-a-1:N-carbobenzoxyglycine 3.0g glycine is dissolved in the 40ml water, add 8g yellow soda ash, the ice-water bath cooling adds the 6ml chloroformic acid benzyl ester, stirred 1 hour, with the ethyl acetate washing, be acidified to pH=1～2, use ethyl acetate extraction then, anhydrous sodium sulfate drying, evaporate to dryness, recrystallization from ethanol obtains 4g crystal N-carbobenzoxyglycine.Productive rate: 48%.Fusing point: 120～121 ℃;
1-a-2:N-carbobenzoxyglycine p-nitrophenyl phenolic ester 2.0gN-carbobenzoxyglycine is dissolved in the 30ml ethyl acetate, add 1.4g p-NP and 2.2gDCC, stirred overnight at room temperature then, add 1ml acetate, stir 20 minutes after-filtration, filtrate is used saturated aqueous sodium carbonate, water, dilute hydrochloric acid, saturated common salt water washing successively, anhydrous magnesium sulfate drying, evaporate to dryness, use ethyl alcohol recrystallization, obtain slightly yellow crystals N-carbobenzoxyglycine p-nitrophenyl phenolic ester of 2.7g white, productive rate: 84%.Fusing point: 130 ℃;
1-a-3:N-carbobenzoxy-(Cbz) glycyl-2-(1-benzyl-4-piperidines) ethamine is got the above-mentioned p-nitrophenyl phenolic ester of 1.7g and is dissolved among the 10mlTHF, add 0.9g1-benzyl-4-(2-amido) ethyl piperidine and 1ml triethylamine, stirred overnight at room temperature, boil off solvent, dissolve with methylene dichloride, the saturated sodium carbonate washing is to colourless, anhydrous sodium sulfate drying, evaporate to dryness, ethyl acetate-sherwood oil recrystallization, obtain 1.7g white crystal N-carbobenzoxy-(Cbz) glycyl-2-(1-benzyl-4-piperidines) ethamine, productive rate: 84%.Fusing point: 97～98 ℃ 1H NMR (CDCl 3, AM=400): δ 7.33～7.37 (m, 5H), 7.28～7.31 (m, 5H), 5.90 (br., 1H), 5.38 (br., 1H), 5.12 (s, 2H), 3.82 (d, 2H, J=5.8), 3.48 (s, 2H), 3.24～3.32 (br.q, 2H, J=7.1), 2.82～2.90 (br.d, 2H, J=11.4), 1.86～1.98 (br.t, 2H, J=10.8);
1-a-4:N-glycyl-2-(1-benzyl-4-piperidines) ethamine is got the above-mentioned acid amides of 1.3g and is dissolved in the 18ml acetonitrile; add 4g sodium iodide and 10ml trimethylchlorosilane; stirred 1 hour, and added the dilute hydrochloric acid of 50ml10%, use the ethyl acetate washed twice; be transferred to alkalescence with salt of wormwood; use dichloromethane extraction immediately, evaporate to dryness carries out column chromatography; use chloroform: methyl alcohol=drip washing in 5: 1 obtains 0.78g white waxy solid N-glycyl-2-(1-benzyl-4-piperidines) ethamine.Productive rate: 90%. 1H?NMR(CDCl 3，AM＝400)：δ7.18～7.32(m，5H)，3.46(s，2H)，3.30(s，2H)，3.26～3.30(t，2H，J＝7.1)2.84～2.90(br.d，1H，J＝11.4)，1.88～1.94(br.t，2H，J＝10.9)，1.64～1.70(br.d，2H，J＝9.2)，1.48～1.52(m，2H)，1.20～1.34(m，3H)。
Can make following compound with method:
1-b:N-glycyl 33-(1-benzyl-4-piperidines) propylamine overall yield: 44%. 1H?NMR(CDCl 3，AM＝400)：δ7.18～7.32(m，5H)，3.46(s，2H)，3.30(s，2H)，3.26～3.30(t，2H，J＝7.1)2.84～2.90(br.d，1H，J＝11.4)，1.88～1.94(br.t，2H，J＝10.9)，1.64～1.70(br.d，2H，J＝9.2)，1.48～1.50(m，2H)，1.20～1.44(m，5H)；
1-c:N-glycyl-4-(1-benzyl-4-piperidines) butylamine overall yield: 72%. 1H?NMR(CDCl 3，AM＝400)：δ7.20-7.40(m，5H)，3.56(s，2H)，3.32(s，2H)，3.24(q，2H，J＝6.7)，2.92(d，2H，J＝11.7)，1.90～2.10(m，4H)，1.62(br.d，2H，J＝10.3)，1.10～1.52(m，9H)；
1-d: β-alanyl (1-benzyl-4-piperidines) ethamine overall yield: 67%. 1H?NMR(CDCl 3，AM＝400)：δ7.16-7.40(m，5H)，6.98(br.，1H)，3.40(s，2H)，3.08～3.22(q，2H，J＝6.8)，2.84～2.98(t，2H，J＝5.9)，2.70～2.84(m，4H)，2.22～2.30(t，2H，J＝5.9)，1.82～1.94(br.t，2H，J＝10.3)，1.16～1.70(m，7H)；
1-e: ε-penta aminoacyl-2-(1-benzyl-4-piperidines) ethamine productive rate: 82%. 1H?NMR(CDCl 3，AM＝400)：δ7.30(m，5H)，6.00(br.，1H)，5.72(br.，1H)，5.42(br.，1H)，3.48(s，2H)，3.20(m，2H)，2.86(br.d，2H，J＝11.4)，2.44(br.，2H)，2.18(t，2H，J＝11.0)，1.92(m，2H)，1.20-1.70(m，11H)；
1-f:N '-methyl-β-alanyl (1-benzyl-4-piperidines) methylamine overall yield: 54%. 1HNMR(CDCl 3，AM＝400)：δ7.24-7.34(m，5H)，3.60(s，2H)，3.12～3.24(q，2H，J＝6.8)，3.02(br.d，2H，J＝11.0)，2.72～2.86(m，4H)，2.70(s，3H)，2.02～2.14(br.t，2H，J＝10.8)，1.60～1.70(br.d，2H，J＝12.8)，1.46～1.58(m，1H)，1.26～1.40(m，2H)；
1-g:N '-methyl-β-alanyl-2-(1-benzyl-4-piperidines) ethamine overall yield: 75%. 1HNMR(CDCl 3，AM＝400)：δ7.20-7.32(m，5H)，3.42(s，2H)，3.08～3.22(q，2H，J＝6.8)，2.84～2.98(t，2H，J＝5.9)，2.72～2.86(m，4H)，2.62(s，3H)，2.22～2.30(t，2H，J＝5.9)，1.82～1.94(br.t，2H，J＝10.3)，1.16～1.70(m，7H)；
1-h: β-alanyl (1-benzyl-4-piperidines) methylamine overall yield: 52%. 1H?NMR(CDCl 3，AM＝400)：δ7.20-7.32(m，5H)，6.86(br.，1H)，3.68(s，2H)，3.08～3.22(q，2H，J＝6.8)，3.02(br.d，2H，J＝11.0)，2.82(m，4H)，2.02～2.14(br.t，2H，J＝11.1)，1.60～1.70(br.d，2H，J＝13.8)，1.46～1.58(m，1H)，1.28～1.40(m，2H)。
The preparation of embodiment 2 intermediate Vb
The 2-a:(2-aminoethyl) sulphonyl acyl group-2-(1-benzyl-4-piperidines) ethamine 5.0g1-benzyl-4-(2-amido ethyl) piperidines is dissolved in the 30ml methylene dichloride; add the 1g triethylamine; cryosel is bathed cooling; slowly add the above-mentioned SULPHURYL CHLORIDE Va of 2.5g, stirred 20 minutes, use the saturated common salt water washing; dry; carry out column chromatography, use ethyl acetate drip washing, obtain the sulphonamide 1 of 3g white solid protection.1.5g above-mentioned sulphonamide is dissolved in the ethanol of 35ml95%, adds the hydrazine hydrate of 0.4g80%, refluxed 5 hours, and cooling, acidifying refluxed 5 minutes again, and cooling is filtered.Filtrate is transferred to pH=8～9 with yellow soda ash, uses dichloromethane extraction then, carries out column chromatography, uses methylene dichloride: methyl alcohol=10: 1～drip washing in 1: 1, obtaining the 0.83g solid is 2-a.Productive rate: 78%.Fusing point: 60～61 ℃ 1H NMR (CDCl 3, AM=400): δ 7.20～7.36 (m, 5H), 3.48 (s, 2H), 3.20 (t, 2H, J=6.8), 3.04～3.14 (m, 4H), 2.82～2.92 (br.d, 2H, J=11.6), 1.90～2.00 (t-d, 2H, J 1=11.6, J 2=2.8), 1.20～1.84 (m, 9H);
2-b:N-methyl-(2-aminoethyl) sulphonyl acyl group-2-(1-benzyl-4-piperidines) ethamine operating process such as 2-a just replaces 1-benzyl-4-(2-amido) ethyl piperidine to obtain overall yield 60% with 1-benzyl-4-(2-methylamino) ethyl piperidine.Fusing point: 58～60 ℃ 1H NMR (CDCl 3, AM=400): δ 7.28～7.31 (m, 5H), 3.48 (s, 2H), 3.20 (m, 4H), 3.04 (t-d, 2H, J 1=6.0, J 2=1.5), 2.84～2.90 (br.d, J=11.8), 2.84 (s, 3H), 1.90～2.00 (2H, t-d, J 1=11.4, J 2=1.8), 1.64～1.74 (m, 2H), 1.48～1.54 (br.q, 2H, J=7.0), 1.24～1.38 (m, 3H);
The 2-c:(2-aminoethyl) sulphonyl acyl group (1-benzyl-4-piperidines) methylamine operating process just replaces 1-benzyl-4-(2-amido) ethyl piperidine to obtain overall yield with 1-benzyl piepridine-4-methylamine: 50% as reaction 1-a.Fusing point: 53～57 ℃ 1H NMR (DMSO-d6, AM=400): δ 7.20-7.34 (m, 5H), 3.40 (s, 2H), 3.04 (t, 2H, J=6.8), 2.86 (t, 2H, J=6.8), 2.76 (m, 4H), 1.88 (bt t, 2H, J=11.6), 1.60 (br.d, 2H, J=12.0), 1.36 (m, 1H), 1.10 (m, 2H);
2-d:N-methyl-(2-aminoethyl) sulphonyl acyl group (1-benzyl-4-piperidines) methylamine operating process just replaces 1-benzyl-4-(2-amido) ethyl piperidine to obtain overall yield with 1-benzyl-4-methylamine methyl piperidine: 57% as reaction 1-a.Fusing point: 63～65 ℃ 1H NMR (CDCl 3, AM=400): δ 7.30 (m, 5H), 3.50 (s, 2H), 3.20 (t, 2H, J=6.0), 3.06 (m, 4H), 2.80-2.96 (m, 5H), 1.94 (br.t, 2H, J=10.6), 1.60-1.76 (m, 3H), 1.18～1.36 (m, 2H).
The preparation of embodiment 3 intermediate VIb
3-a:1-benzyl-4-(2-chloroethyl) piperidine hydrochlorate 6.8g1-benzyl-4-(2-hydroxyethyl) piperidines is dissolved in the 15ml methylene dichloride, and the ice-water bath cooling drips the solution of 4.6ml thionyl chloride in the 10ml methylene dichloride, adds the back and refluxes 4 hours.Solvent evaporated is used the alcohol-ether recrystallization, obtains 6.5g white solid 1-benzyl-4-(2-chloroethyl) piperidine hydrochlorate.Productive rate: 84%. 1H?NMR(D 2O，AM＝400)：δ7.40～7.56(m，5H)，4.31(s，2H)，3.62～3.70(t，2H，J＝7.6)，3.52～3.60(d，2H，J＝12.2)，2.98～3.08(t，2H，J＝12.5)，1.98～2.08(br.d，2H，J＝14.4)，1.80～1.98(m，1H)，1.78～1.80(q，2H，J＝6.5)，1.36～1.50(br.q，2H，J＝12.3)；
Above-mentioned hydrochloride of 3-b: sulfide amide 2.7g and 1.4g thiocarbamide refluxed 6 hours in 15ml ethanol, and cooling adds dilute hydrochloric acid, and with the ethyl acetate washing, with the salt of wormwood alkalization, dichloromethane extraction obtains the 2.9g solid.Be suspended in the 20ml water (removing oxygen), drip dilute hydrochloric acid and dissolve just, add the solution of 6g potassium hydroxide in the 40ml oxygen-free water under the vigorous stirring, refluxed under nitrogen 2 hours, cooling was transferred to PH=8 with dilute hydrochloric acid, dichloromethane extraction, evaporate to dryness obtain 2.2g oily matter.Be dissolved among the 12mlDMF, add 1.1g chlor(o)acetamide and 2g Anhydrous potassium carbonate, nitrogen stirred 2 hours down, pour in the cold water, use dichloromethane extraction, the saturated common salt water washing, carry out column chromatography after the drying, use ethyl acetate: methyl alcohol=drip washing in 10: 1 obtains the 2.2g sulfide amide.Productive rate: 78%.Fusing point: 56～58 ℃ 1H NMR (CDCl 3, AM=400): δ 7.30 (m, 5H), 6.70 (br., 1H), 5.54 (br., 1H), 3.48 (s, 2H), 3.20 (s, 2H), 2.86 (br.d, 1H, J=11.8), 2.58 (t, 2H, J=7.7), 1.92 (bt t, 2H, J=11.6), 1.62 (br.d, 2H, J=12.4), 1.52 (m, 2H), 1.18-1.38 (m, 3H);
3-c:2-aminoethyl-2-(1-benzyl-4-piperidines) above-mentioned sulfide amide of ethyl thioether 1.5g obtains 2-aminoethyl-2-(1-benzyl-4-piperidines) ethyl thioether with tetrahydrochysene lithium aluminium reducing in ether.Productive rate: 82%. 1H?NMR(CDCl 3，AM＝400)：δ7.26～7.32(m，5H)，3.46(s，2H)，2.84～2.90(m，4H)，2.56～2.62(t，2H，J＝6.2)，2.48～2.54(t，2H，J＝7.7)，1.88～2.00(br.d，2H，J＝11.4)，1.20～1.70(m，9H)。
The preparation of embodiment 4 body VIIb
4-a: chloromethyl-2-(1-benzyl-4-piperidines) ethyl ketone 11.0g3-(1-benzoyl piperidyl) propionic acid is dissolved in the 100ml methylene dichloride, adds the 18ml oxalyl chloride, stirring at room 4 hours; evaporate to dryness; with the methylene dichloride dissolving, activated carbon decolorizing filters, evaporate to dryness.Again dissolve evaporate to dryness, handle 3 times.Be dissolved in the 20ml methylene dichloride, the ice-water bath cooling is added drop-wise to the diazomethane diethyl ether solution that is made by the 32g nitrosomethylurea down.Stirring is spent the night, and boils off solvent, is dissolved in the 60ml methylene dichloride, and cryosel is bathed cooling down, adds the 20ml concentrated hydrochloric acid, stirs 10 minutes.Water, 5% sodium bicarbonate aqueous solution, saturated common salt water washing successively.Drying is carried out column chromatography behind the evaporate to dryness, use ethyl acetate: sherwood oil=1: 10～drip washing in 1: 2.Obtain the faint yellow oily thing of 9g chloroamides ketone, placement is solidified.Overall yield: 70%. 1H?NMR(CDCl 3，AM＝400)：δ7.34～7.44(m，5H)，4.69(br.，1H)，4.05(s，2H)，3.72(br.，1H)，2.94(br.，1H)，2.72(br.，1H)，2.60～2.70(t，2H，J＝7.3)，1.50～1.86(m，5H)，1.04～1.32(m，2H)；
4-b: azido-methyl-2-above-mentioned chloroamides ketone of (1-benzyl-4-piperidines) ethyl ketone 2.0g and 0.7g sodiumazide mix with 30ml ethanol, add 5ml water, stir 5 hours at 35～45 ℃.Boil off ethanol (temperature is no more than 50 ℃).Use dichloromethane extraction, drying is carried out column chromatography behind the evaporate to dryness, obtains 1.9g colorless oil nitrine acid amides ketone.Productive rate: 93%. 1H?NMR(CDCl 3，AM＝400)：δ7.34～7.44(m，5H)，4.64～4.78(br.d，1H，J＝10.3)，3.98(s，2H)，3.68～3.80(br.d，1H，J＝10.6)，2.90～3.02(br.，1H)，2.66～2.80(br.，1H)，2.46～2.56(t，2H，J＝7.2)，1.48～1.86(m，5H)，1.04～1.32(m，2H)；
4-c:2-azido-methyl-2-[2-(1-benzyl-4-piperidines)] ethyl-1, the above-mentioned nitrine acid amides of 3-dioxolanes 1.8g ketone is dissolved in the 50ml benzene, add 0.1g p-methyl benzenesulfonic acid and 1.5ml ethylene glycol, reflux dewatering 4 hours, boil off big portion benzene, pour in the cold water, use ethyl acetate extraction, the saturated common salt water washing, drying.Evaporate to dryness carries out column chromatography, obtains 2.0g colorless oil title product 4-c.Productive rate: 96%. 1H?NMR(CDCl 3，AM＝400)：δ7.34～7.44(m，5H)，4.64～4.78(br.d，1H，J＝11.0)，4.00～4.10(m，4H)，3.68～3.80(br.d，1H，J＝11.0)，3.20(s，2H)，2.96(br.，1H)，2.74(br.，1H)，1.70～1.74(t，2H，J＝8.0)，1.04～1.84(m，7H)；
4-d:2-aminomethyl-2-[2-(1-benzyl-4-piperidines)] ethyl-1,3-dioxolanes 2.0g compound 4-c obtains with tetrahydrochysene lithium aluminium reducing in ether.Productive rate: 96%.1H?NMR(CDCl3，AM＝400)：δ7.26～7.32(m，5H)，3.96～4.00(m，4H)，3.46(s，2H)，2.86(br.d，2H，J＝11.7)，2.70(s，2H)，1.86～1.96(br.t，2H，J＝11.4)，1.14～1.66(m，9H)。
Embodiment 5 5-(1-benzyl-4-piperidines) methylamino-5,6,7, the preparation of 8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 1)
300mg5,6,7,8-tetrahydrochysene-5-O-1-methyl-2 (1H)-quinolinone, 400mgl-benzyl piepridine-4-methylamine and 2ml methylene dichloride mix, and nitrogen adds the 1ml titanium isopropylate down.Stirring at room 48 hours.Methylene dichloride is removed in decompression, is dissolved in the 15ml methyl alcohol, and the ice-water bath cooling slowly adds the 100mg sodium borohydride down.Add the back and stirred 1 hour, add the saturated aqueous sodium carbonate of 20ml, filter, use methanol wash, filtrate is used dichloromethane extraction, and anhydrous sodium sulfate drying carries out column chromatography behind the evaporate to dryness, use methylene dichloride: methyl alcohol=drip washing in 20: 1 obtains 400mg solid 211.Fusing point: 131～132 ℃.Productive rate: 68%.1H?NMR(CDCl3，AM＝400)：δ7.20-7.38(m，6H)，6.46(d，1H，J＝9.2)，3.40-3.52(m+s+s，6H)，2.86(br.d，2H，J＝11.2)，2.48-2.66(m，6H)，1.62-2.00(m，6H)，1.48(m，1H)，1.26(m，2H)。
Embodiment 6 5-[2-(1-benzyl-4-piperidines) ethyl] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 2)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with 1-benzyl-4-(2-amido ethyl) piperidines, obtain oily matter.Be dissolved in the ethyl acetate, the ice-water bath cooling feeds exsiccant hydrogenchloride down.Separate out the solid salt hydrochlorate.Fusing point: 147～149 ℃ of overall yields: 51%.1H?MR(CDCl3，AM＝400)：δ7.20～7.46(m，6H)，6.46(d，1H，J＝9.3)，3.52(m，1H)，3.46(s，3H)，3.44(s，2H)，2.82～2.90(br.d，2H，J＝11.6)，2.40～2.72(m，4H)，1.20～2.00(m，13H)。
Embodiment 7 5-[3-(1-benzyl-4-piperidines) propyl group] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 3)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with 1-benzyl-4-(3-amido n-propyl) piperidines, obtain oily matter.Be dissolved in the ethyl acetate, the ice-water bath cooling feeds exsiccant hydrogenchloride down.Separate out the solid salt hydrochlorate.Fusing point: 131～135 ℃ of overall yields: 43%. 1H?NMR(D 2O，AM＝400)：δ7.64(d，1H，J＝9.3)，7.48～7.62(m，5H)，6.60(d，1H，J＝9.3)，4.44(br.，1H)，4.30(s，2H)，3.56(s，3H)，3.50～3.60(s，2H)，2.80～3.10(m，6H)，2.20～2.38(m，1H)，1.88～2.14(m，5H)，1.60～1.80(m，3H)，1.38～1.48(m，4H)。
Embodiment 8 5-[3-(1-benzyl-4-piperidines) propyl group] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 4)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with 1-benzyl-4-(3-amido n-propyl) piperidines, with 5,6,7,8-tetrahydrochysene-5-O-1-n-propyl-2 (1H)-quinolinone replaces 5,6,7,8-tetrahydrochysene-5-O-1-methyl-2 (1H)-quinolinone obtains oily matter.Be dissolved in the ethyl acetate, the ice-water bath cooling feeds exsiccant hydrogenchloride down.Separate out the solid salt hydrochlorate.Fusing point: 121～123 ℃.Overall yield: 40%. 1H?NMR(D2O，AM＝400)：δ7.58(d，1H，J＝9.3)，7.40～7.52(m，5H)，6.58(d，1H，J＝9.2)，4.41(m，1H)，4.30(s，2H)，3.98～4.12(m，2H)，3.50～3.60(br.d，2H，J＝12.3)，2.60～3.34(m，4H)，1.22～2.20(m，17H)，1.00～1.08(t，3H，J＝7.3)。
Embodiment 9 5-[2-(1-benzyl-4-piperidines) ethamine carbonyl methyl] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 5)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 1-a, obtain oily matter.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Boil off solvent, the solid of gained obtains the solid oxalate with methyl alcohol-ether recrystallization.Fusing point: 151～153 ℃ of overall yields: 72%. 1H?NMR(CDCl 3，AM＝400)：δ7.20～7.40(m，6H)，7.08(br.，1H)，6.48(d，1H，J＝9.3)，3.56(m，1H)，3.47(s，3H)，3.46(s，2H)，3.26～3.36(m，4H)，2.82～2.90(br.d，2H，J＝10.9)，2.50～2.70(m，2H)，1.20～2.00(m，13H)。
Embodiment 10 N-methyl-5-[2-(1-benzyl-4-piperidines) ethamine carbonyl methyl] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 6)
200mg compound 5 is dissolved in 10ml1; in the 2-ethylene dichloride; the formalin that adds 50mg37%; nitrogen adds 400mg triacetyl sodium borohydride down, and stirred overnight at room temperature adds water washing; drying is carried out column chromatography; use methylene dichloride: methyl alcohol=drip washing in 10: 1 obtains 79mg oily title product, productive rate: 38%.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Boil off solvent, the solid of gained obtains the solid oxalate with methyl alcohol-ether recrystallization. 1H?NMR(CDCl 3，AM＝400)：δ7.46(d，1H，J＝9.5)，7.30～7.36(m，5H)，6.98(br.t，1H，J＝6.0)，3.72(br.t，1H，J＝8.8)，3.56(s，2H)，3.52(s，3H)，3.28～3.36(m，2H)，2.90～3.10(m，4H)，2.60～2.64(m，2H)，2.26(s，3H)，1.28～2.08(m，13H)。
Embodiment 11 N-ethanoyl-5-[2-(1-benzyl-4-piperidines) ethamine carbonyl methyl] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 7)
200mg compound 5 is dissolved in the methylene dichloride, uses the acetic anhydride acidylate, obtains the 100mg title product, productive rate: 44%.Be dissolved in the methyl alcohol, the ice-water bath cooling adds a seminormal oxalic acid down.Separate out the solid oxalate, methyl alcohol-ether recrystallization.Fusing point: 141～143 ℃ 1H NMR (CDCl 3, AM=400): δ 730～7.38 (m, 5H), 6.98 (d, 1H, J=9.5), 6.74 (br.t, 1H, J=5.7), 6.46 (d, 1H, J=9.5), 4.80 (m, 1H), 3.68 (s, 2H), 3.50 (s, 3H), 3.00～3.30 (m, 7H), 2.60～2.70 (m, 1H), 1.60～2.10 (m, 10H, at 2.04 is s, 3H), 1.20～1.50 (m, 4H).
Embodiment 12 5-[2-(1-benzyl-4-piperidines) ethamine carbonyl methyl] amido-5,6,7,8-tetrahydrochysene-1-n-propyl-2 (1H)-quinolinone (compound 8)
Operating process such as example 5 just replace 1-phenylpiperidines-4-methylamine with compound 1-a, and with 5,6,7,8-tetrahydrochysene-5-O-1-n-propyl-2 (1H)-quinolinone replaces 5,6,7, and 8-tetrahydrochysene-5-O-1-methyl-2 (1H)-quinolinone obtains oily matter.Overall yield: 44%.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Boil off solvent, the solid of gained obtains the solid oxalate with methyl alcohol-ether recrystallization.Fusing point: 143～145 ℃ 1H NMR (CDCl 3, AM=400): δ 7.20～7.40 (m, 6H), 7.08 (br., 1H), 6.48 (d, 1H, J=9.3), 3.92～4.02 (m, 1H), 3.80～3.90 (m, 1H), 3.56 (m, 1H), 3.46 (s, 2H), 3.26～3.36 (m, 4H), 2.82～2.90 (br.d, 2H, J=10.6), 2.68～2.80 (m, 1H), 2.50～2.66 (m, 1H), 1.20～2.00 (m, 15H), 0.98～1.06 (t, 3H, J=7.5).
Embodiment 13 5-[3-(1-benzyl-4-piperidines) propylamine carbonyl methyl] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 9)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 1-b, obtain oily matter.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Boil off solvent, the solid of gained obtains the solid oxalate with methyl alcohol-ether recrystallization.Overall yield: 56%.Fusing point: 166～168 ℃ 1HNMR (CDCl 3, AM=400): δ 7.24～7.32 (m, 6H), 7.14 (br., 1H), 3.54 (br., 1H), 3.48 (br., 5H), 3.32 (s, 2H), 3.20～3.32 (br.q, 2H, J=6.8), 2.80～2.88 (br.d, 2H, J=9.5), 2.62～2.72 (m, 1H), 2.48～2.58 (m, 1H), 1.16～1.94 (m, 15H).
Embodiment 14 5-[4-(1-benzyl-4-piperidines) butylamine carbonyl methyl] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 10)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 1-c, obtain oily matter.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Boil off solvent, the solid of gained obtains the solid oxalate with methyl alcohol-ether recrystallization.Overall yield: 60%.Fusing point: 155～157 ℃ 1HNMR (CDCl 3, AM=400): S 7.26～7.34 (m, 6H), 7.12 (br., 1H), 6.48 (d, 1H, J=9.2), 3.54 (br., 1H), 3.48 (br., 5H), 3.32 (s, 2H), 3.36 (br.q, 2H, J=6.8), 2.80～290 (br.d, 2H, J=10.3), 2.60～2.72 (m, 1H), 2.48～2.58 (m, 1H), 1.20～1.96 (m, 17H).
Embodiment 15 5-{2-[2-(1-benzyl-4-piperidines) ethamine carbonyl] ethyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 11)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 1-d, obtain oily matter.Be dissolved in the ethyl acetate, the ice-water bath cooling feeds exsiccant hydrogenchloride down.Separate out the solid salt hydrochlorate.Fusing point: 149～151 ℃ of overall yields: 65%. 1H?NMR(D 2O，AM＝400)：δ7.70(d，1H，J＝9.3)，7.52(m，5H)，6.68(d，1H，J＝9.3)，4.56(br.，1H)，4.36(s，2H)，3.60(s，3H)，3.26-3.56(m，2H)，3.18～3.22(m，2H)，2.90～3.12(m，3H)，2.74～2.82(m，3H)，2.20～2.34(m，1H)，1.74～2.40(m，6H)，1.40～1.54(m，4H)。
Embodiment 16 5-{2-[(1-benzyl-4-piperidines) methylamine carbonyl] ethyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 12)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 1-h, obtain oily matter.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Boil off solvent, the solid of gained obtains the solid oxalate with methyl alcohol-ether recrystallization.Overall yield: 66%.Fusing point: 166～168 ℃ 1HNMR (D 2O, AM=400): δ 7.68 (d, 1H, J=9.1), 7.54 (m, 5H), 6.66 (d, 1H, J=9.1), 4.58 (br., 1H), 4.36 (s, 2H), 3.60 (s, 3H), 3.26-3.56 (m, 2H), 3.18～3.22 (m, 2H), 2.90～3.12 (m, 3H), 2.74～2.82 (m, 3H), 2.20～2.34 (m, 1H), 1.74～2.40 (m, 6H), 1.40～1.54 (m, 2H).
Embodiment 17 5-{2-[N-methyl-(1-benzyl-4-piperidines) methylamine carbonyl] ethyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 13)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 1-f, obtain oily matter.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Boil off solvent, the solid of gained obtains the solid oxalate with methyl alcohol-ether recrystallization.Overall yield: 70%.Fusing point: 157～159 ℃ 1HNMR (D 2O, AM=400): δ 7.68 (d, 1H, J=9.1), 7.54 (m, 5H), 6.66 (d, 1H, J=9.1), 4.58 (br., 1H), 4.42 (s, 2H), 3.60 (s, 3H), 3.30-3.66 (m, 4H), 2.80～3.16 (m, 6H), 1.70～2.40 (m, 9H), 1.46～1.66 (m, 2H).
Embodiment 18 5-{2-[N-methyl-2-(1-benzyl-4-piperidines) ethamine carbonyl] ethyl } amido-5,6,7,8-tetrahydrochysene-2 (1H)-quinolinone (compound 14)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 1-g, and with 5,6,7,8-tetrahydrochysene-5-O-2 (1H)-quinolinone replaces 5,6,7, and 8-tetrahydrochysene-5-O-1-methyl-2 (1H)-quinolinone obtains white solid.Fusing point: 160～163 ℃, overall yield: 40%. 1H?NMR(CDCl 3，AM＝400)：δ12.40(br.，1H)，7.48(d，1H，J＝9.2)，7.20-7.30(m，5H)，6.38(d，1H，J＝9.2)，3.58(br.，1H)，3.50(s，2H)，3.38(br.t，1H，J＝7.5)，3.28(br.t，1H，J＝7.8)，2.50-3.00(m，11H)，1.20-2.00(m，11H)。
Embodiment 19 5-{2-[N-methyl-2-(1-benzyl-4-piperidines) ethamine carbonyl] ethyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 15)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 1-g, obtain oily matter.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Boil off solvent, the solid of gained obtains the solid oxalate with methyl alcohol-ether recrystallization.Overall yield: 60%.Fusing point: 143～145 ℃ 1HNMR (D 2O, AM=400): δ 7.68 (d, 1H, J=9.1), 7.48～7.62 (m, 5H), 6.68 (d, 1H, J=9.1), 4.54 (br., 1H), 4.38 (s, 2H), 3.60 (s, 3H), 3.30～3.60 (m, 6H), 3.08 (s, 3H), 2.84～3.10 (m, 6H), 2.26～2.34 (m, 1H), 1.90～2.20 (m, 4H), 1.40～1.70 (m, 6H).
Embodiment 20 5-{2-[N-methyl-2-(1-benzyl-4-piperidines) ethamine carbonyl] ethyl } amido-5,6,7,8-tetrahydrochysene-1-n-propyl-2 (1H)-quinolinone (compound 16)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 1-g, and with 5,6,7,8-tetrahydrochysene-5-O-1-n-propyl-2 (1H)-quinolinone replaces 5,6,7, and 8-tetrahydrochysene-5-O-1-methyl-2 (1H)-quinolinone obtains oily matter.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Boil off solvent, the solid of gained obtains the solid oxalate with methyl alcohol-ether recrystallization.Overall yield: 50%.Fusing point: 133～135 ℃ 1H NMR (D 2O, AM=400): δ 7.68 (d, 1H, J=9.1), 7.48～7.62 (m, 5H), 6.68 (d, 1H, J=9.1), 4.54 (br., 1H), 4.36 (s, 2H), 4.40～4.56 (m, 2H), 3.30～3.60 (m, 6H), 3.07 (s, 3H), 2.88～3.10 (m, 6H), 2.24～2.36 (m, 1H), 1.80～2.20 (m, 6H), 1.40～1.80 (m, 6H), 1.00～1.10 (t, 3H, J=7.3).
Embodiment 21 5-{4-[2-(1-benzyl-4-piperidines) ethamine carbonyl] butyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 17)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 1-e, obtain oily matter.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Boil off solvent, the solid of gained obtains the solid oxalate with methyl alcohol-ether recrystallization.Overall yield: 64%.Fusing point: 139～141 ℃ 1HNMR (D 2O, AM=400): δ 7.68 (d, 1H, J=9.1), 7.52～7.62 (m, 5H), 6.68 (d, 1H, J=9.1), 4.48 (br., 1H), 4.36 (s, 2H), 3.62 (s, 3H), 3.57 (s, 3H), 3.12～3.38 (m, 6H), 2.98～3.10 (m, 4H), 2.70～2.82 (m, 2H), 2.22～2.40 (m, 3H), 1.90～2.20 (m, 6H), 1.60～1.84 (m, 6H).
Embodiment 22 5-{2-[(1-benzyl-4-piperidines) methylamine sulfuryl] ethyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 18)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 2-c, obtain the solid oxalate.Overall yield: 63%.Fusing point: 148～150 ℃ 1H NMR (D 2O, AM=400): δ 7.68 (br.d, 1H, J=9.0), 7.54 (m, 5H), 6.64 (br.d, 1H, J=9.0), 4.58 (m, 1H), 4.36 (s, 2H), 3.56-3.76 (m, 9H), and 2.80-3.40 (m, 6H), 1.90-2.46 (m, 7H), 1.46-1.52 (m, 2H).
Embodiment 23 5-{2-[N-methyl-(1-benzyl-4-piperidines) methylamine sulfuryl] ethyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 19)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 2-d, obtain the solid oxalate.Overall yield: 66%.Fusing point: 149～152 ℃ 1H NMR (CDCl 3, AM=400): δ 7.18～7.46 (m, 6H), 6.46 (d, 1H, J=9.3), 3.56 (br., 1H), 3.47 (s, 2H), 3.45 (s, 3H), 3.10～3.22 (m .1H), 2.96～3.10 (m, 5H), 2.84～2.90 (br.d, 2H, J=11.3), 2.83 (s, 3H), 2.60～2.70 (br.d, 1H, J=17.6), 2.46～2.56 (m, .1H), 1.62～2.02 (m .9H), 1.24～1.34 (m .2H).
Embodiment 24 5-{2-[2-(1-benzyl-4-piperidines) ethamine sulfuryl] ethyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 20)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 2-a, are dissolved in the ethyl acetate, and the ice-water bath cooling feeds exsiccant hydrogenchloride down.Separate out the solid salt hydrochlorate.Overall yield: 70%.Fusing point: 157～160 ℃ 1H NMR (D 2O, AM=400): δ 7.64 (d, 1H, J=9.1), 7.46～7.60 (m, 5H), 6.64 (d, 1H, J=9.1), 4.48 (br., 1H), 4.34 (s, 2H), 3.62 (s, 3H), 3.50～3.70 (m, 6H), 3.40 (s, 1H), 3.16～3.30 (m, 2H), 2.80～3.10 (m, 4H), 2.20～2.38 (m, 1H), 1.90～2.20 (m, 5H), 1.60～1.86 (m, 1H), 1.38～1.64 (m, 4H).
Embodiment 25 5-{2-[N-methyl-2-(1-benzyl-4-piperidines) ethamine sulfuryl] ethyl } amido-5,6,7,8-tetrahydrochysene-2 (1H)-quinolinone (compound 21)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 2-b, and with 5,6,7,8-tetrahydrochysene-5-O-2 (1H)-quinolinone replaces 5,6,7, and 8-tetrahydrochysene-5-O-1-methyl-2 (1H)-quinolinone obtains white solid.Overall yield: 33%.Fusing point: 129～131 ℃ 1H NMR (CDCl 3, AM=400): δ 12.24 (br., 1H), 7.50 (d, 1H, J=9.3), 7.30 (m, 5H), 6.40 (d, 1H, J=9.3), 3.56 (br., 1H), 3.50 (s, 2H), 3.20 (t, 2H, J=6.7), 2.84-3.16 (m, 6H), 2.80 (s, 3H), 2.56-2.70 (m, 2H), 1.20-2.00 (m, 13H).
Example 26 5-{2-[N-methyl-2-(1-benzyl-4-piperidines) ethamine sulfuryl] ethyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 22)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 2-b, obtain the solid oxalate.Overall yield: 63%.Fusing point: 143～145 ℃ 1H NMR (D 2O, AM=400): δ 7.64 (d, 1H, J=9.2), 7.46～7.60 (m, 5H), 6.664 (d, 1H, J=9.2), 4.48 (br., 1H), 4.36 (s, 2H), 3.60 (s, 3H), 3.50～3.70 (m, 6H), 3.24～3.40 (m, 2H), 2.80～3.10 (m, 4H), 2.98 (s, 3H), 2.20～2.38 (m, 1H), 1.88～2.14 (m, 5H), 1.60～1.80 (m, 3H), 1.38～1.48 (m, 2H).
Embodiment 27 5-{2-[N-methyl-2-(1-benzyl-4-piperidines) ethamine sulfuryl] ethyl } amido-5,6,7,8-tetrahydrochysene-1-n-propyl-2 (1H)-quinolinone (compound 23)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 2-b, and with 5,6,7,8-tetrahydrochysene-5-O-1-n-propyl-2 (1H)-quinolinone replaces 5,6,7, and 8-tetrahydrochysene-5-O-1-methyl-2 (1H)-quinolinone obtains the solid oxalate.Overall yield: 61%.Fusing point: 150～152 ℃ 1HNMR (D 2O, AM=400): δ 7.68 (br.d, 1H, J=9.1), 7.54 (m, 5H), 6.64 (br.d, 1H, J=9.1), 4.58 (br.s, 1H), 4.38 (s, 2H), 4.00-4.20 (m, 2H), 3.54-3.66 (m, 4H), 3.26-3.46 (m, 2H), 3.00-314 (m, 4H), 2.94 (s, 3H), 2.28 (m, 1H), 1.40-2.20 (m, 12H), 1.00 (br.t, 3H, J=7.0).
Embodiment 28 5-{2-[2-(1-benzyl-4-piperidines) ethylmercapto group] ethyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 24)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with compound 3-c, obtain oily matter.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Boil off solvent, the solid of gained obtains the solid oxalate with methyl alcohol-ether recrystallization.Overall yield: 73%.Fusing point: 182～184 ℃ 1HNMR (CDCl 3, AM=400): δ 7.20～7.44 (m, 6H), 6.46 (d, 1H, J=9.3), 3.56 (br., 1H), 3.48 (br., 5H), 2.76～2.90 (m, 4H), 2.64～2.70 (m .3H), 2.48～2.56 (m, 3H), 1.88～2.00 (m, 3H), 1.76～1.84 (m, 2H), 1.50～1.70 (m, 6H), 1.20～1.40 (m, 2H).
Embodiment 29 5-{2-[2-(1-benzyl-4-piperidines) second sulfoxide group] ethyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 25)
210mg compound 24 is dissolved in the 8ml acetate, the ice-water bath cooling, and the hydrogen peroxide of adding 56mg30% stirred 2 hours, pour in the frozen water, with salt of wormwood alkalization, dichloromethane extraction, carry out column chromatography, use methylene dichloride: methyl alcohol=drip washing in 10: 1 obtains 200mg oily matter quinoline ketoamine sulfoxide.Productive rate: 91%.Be dissolved in the ethyl acetate, the ice-water bath cooling feeds exsiccant hydrogenchloride down.Separate out the solid salt hydrochlorate.Fusing point: 131～135 ℃ 1H NMR (CDCl 3, AM=400): δ 7.18～7.40 (m, 6H), 4.46 (d, 1H, J=9.1), 3.58 (br., 1H), 3.49 (s, 2H), 3.46 (s, 3H), 3.02～3.44 (m, 2H), 2.50～3.00 (m, 8H), 1.66～2.20 (m, 10H), 1.36～1.50 (m, 3H).
Embodiment 30 5-{2-[2-(1-benzyl-4-piperidines) ethyl sulfone] ethyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 26)
200mg compound 24 is dissolved in the 4ml methyl alcohol, and the ice-water bath cooling adds the KHSO of 40mg49% down 5Solution in 4ml water stirred 4 hours, added 15ml water, and with the salt of wormwood alkalization, dichloromethane extraction carries out column chromatography, uses methylene dichloride: methyl alcohol=drip washing in 20: 1 obtains 190mg oily quinoline ketoamine sulfone.Productive rate: 88%.Be dissolved in the ethyl acetate, the ice-water bath cooling feeds exsiccant hydrogenchloride down.Separate out the solid salt hydrochlorate.Fusing point: 167～169 ℃ 1H NMR (CDCl 3, AM=400): δ 7.18～7.38 (m, 6H), 4.46 (d, 1H, J=9.3), 3.56 (br., 1H), 3.48 (s, 2H), 3.45 (s, 3H), 3.02～3.38 (m, 6H), 2.38 (br.d, 2H, J=10.2), 2.62～2.70 (br.d, 1H, J=17.7), 2.48～2.56 (m, 1H), 1.60～2.00 (m, 10H), 1.34～1.46 (m, 3H).
Embodiment 31 5-[(1-benzyl-4-piperidines) formyl radical] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 27)
31-a:4.0g1-benzyl piepridine-4-ethyl formate is dissolved in the 12ml ethanol, adds 1.0g sodium hydroxide and 2ml water, stirring at room 1 hour, be transferred to pH=7 with dilute hydrochloric acid, the pressure reducing and steaming solvent is done the water band with benzene, use 95% alcohol extraction solid then, filter the filtrate evaporate to dryness.Residue is dissolved in the 20ml methylene dichloride, adds 1.6g p-NP and 3.0gDCC, and stirring is spent the night.Add 5ml acetate, stir 1 hour after-filtration, filtrate is washed with saturated sodium carbonate, carries out column chromatography after the drying, uses ethyl acetate: sherwood oil=drip washing in 1: 4 obtains 1.6g solid active ester.Fusing point: 111～112 ℃ of overall yields: 88%. 1H?NMR(CDCl 3，AM＝400)：δ8.26～8.30(d-d，2H，J 1＝7.0，J 2＝2.2)，7.38～7.44(m，5H)，7.26～7.30(d-d，2H，J 1＝7.0，J 2＝2.2)，4.58～4.70(br.，1H)，3.76～3.94(br.，1H)，3.04～3.20(br.，2H)，2.86～2.94(m，1H)，1.60～2.20(m，4H)。
Compound 27:400mg active ester, 180mg5-amido tetrahydroquinolones 158,0.5ml triethylamine and 5mlDMF mixture at room temperature stir and spend the night, carry out column chromatography after the processing, use ethyl acetate: methyl alcohol=drip washing in 5: 1 obtains 300mg white crystal compound 27.Productive rate: 65%.Fusing point: 176～177 ℃ 1H NMR (CDCl 3, AM=400): δ 7.30 (m, 5H), 7.16 (d, 1H, J=9.3), 6.40 (d, 1H, J=9.3), 5.78 (br.d, 1H, J=7.9), 4.96 (br., 1H), 3.50 (s, 2H), 3.46 (s, 3H), 2.90 (br.d, 2H, J=11.2), 2.60 (br.q, 2H, J=18.9), 1.70-2.16 (m, 11H).
Embodiment 32 5-[3-(1-benzyl-4-piperidines) propionyl] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 28)
Operating process such as example 31 just replace 1-benzyl piepridine-4-ethyl formate with the benzyl piepridine ethyl propionate, obtain white crystal.Overall yield: 21%.Fusing point: 164～165 ℃ 1H NMR (CDCl 3, AM=400): δ 7.30 (m, 5H), 7.16 (d, 1H, J=9.3), 6.40 (d, 1H, J=9.3), 6.20 (br.d, 1H, J=8.0), 4.90 (br.d, 1H, J=4.3), 3.50 (s, 2H), 3.44 (s, 3H), 2.86 (br.d, 2H, J=10.6), and 2.46-2.64 (m, 2H), 2.24 (t, 2H, J=7.8), 1.56-2.00 (m, 11H), 1.38 (br., 2H).
Embodiment 33 5-[2-(1-benzyl-4-piperidines) ethamine thioformyl] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 29)
33-a:330mg1-benzyl-4-(2-amido ethyl) piperidines is dissolved in the 5ml methylene dichloride, adds the 150mg triethylamine, the ice-water bath cooling, drip the solution of 125mg dithiocarbonic anhydride in the 2ml methylene dichloride, stirred 4 hours, and dripped the 0.15ml ethyl chloroacetate, stirring is spent the night, pour in the frozen water, with the yellow soda ash alkalization, dichloromethane extraction carries out column chromatography after the drying, use ethyl acetate drip washing, obtain 320mg oily sulphur cyanogen piperidines.Productive rate: 81%;
33-b:320mg above-mentioned sulphur cyanogen piperidines and 260mg5-amido tetrahydroquinolones are dissolved in the 15ml ethanol, and stirring is spent the night.Boil off solvent, residue carries out column chromatography, uses methylene dichloride: methyl alcohol=drip washing in 20: 1, obtaining the 5.2g white crystal is the quinolinone thiocarbamide.Productive rate: 96%.Fusing point: 86～88 ℃ 1HNMR (CDCl 3, AM=400): δ 7.20-7.40 (m, 6H), 6.52 (br., 1H), 6.08 (d, 1H, J=9.1), 5.40 (br.s, 1H), 3.56 (br., 1H), 3.50 (s, 2H), 3.32 (s, 3H), 2.88 (br.d, 2H, J=11.4), 2.50 (m, 2H), 2.30 (m, 2H), 1.30-2.02 (m, 13H).
Embodiment 34 5-[2-(1-benzyl-4-piperidines) ethamine formyl radical] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 30)
310mg above-claimed cpd 29 is dissolved in the dilute hydrochloric acid of 7ml3.5N, slowly adds the 78mg Sodium Nitrite under the room temperature, stirs 1 hour, with the yellow soda ash alkalization, dichloromethane extraction carries out column chromatography, use methylene dichloride: methyl alcohol=drip washing in 10: 1 obtains the 250mg white crystal.Productive rate: 84%.Fusing point: 101～102 ℃ 1H NMR (CDCl 3, AM=400): δ 7.20～7.38 (m, 5H), 6.46 (d, 1H, J=9.8), 6.02 (d, 1H, J=9.8), 4.26 (br., 1H), 3.50 (s, 2H), 3.26～3.34 (t, 2H, J=7.1), 2.92 (s, 3H), 2.36～2.40 (br.d, 1H, J=10.7), 1.26～2.30 (m, 15H).
Embodiment 35 5-{4-(1-benzyl-4-piperidines)-2-[1-(1,3-dioxy cyclopentyl)] butyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 31)
Operating process such as example 5 just replace 1-benzyl piepridine-4-methylamine with 4-d, obtain white solid quinoline ketoamine.Fusing point: 121～122 ℃.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Separate out the solid oxalate, methyl alcohol-ether recrystallization gets solid.Overall yield: 73%. 1HNMR(CDCl 3，AM＝400)：δ7.36(d，1H，J＝9.2)，7.28～7.32(m，5H)，6.46(d，1H，J＝9.2)，3.90～4.00(m，4H)，3.52～3.56(m，1H)，3.46～3.50(br.，5H)，2.86～2.94(br.d，2H，J＝11.4)，2.60～2.78(d-d，2H，J 1＝42.5?J 2＝11.7)，2.48～2.70(m，2H，)，1.20～2.00(m，15H)。
Embodiment 36 N-methyl-5-{4-(1-benzyl-4-piperidines)-2-[1-(1,3-dioxy cyclopentyl)] butyl } amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 32)
200mg compound 31 usefulness formaldehyde reduction aminations obtain N-toluquinoline ketoamine, productive rate: 44%.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Separate out the solid oxalate, methyl alcohol-ether recrystallization gets solid.Fusing point: 146～147 ℃ 1H NMR (CDCl 3, AM=400): δ 7.66 (d, 1H, J=9.5), 7.28～7.32 (m, 5H), 6.46 (d, 1H, J=9.5), 3.90～4.00 (m, 4H), 3.64～3.70 (m, 1H), 3.58 (s, 2H), 3.48 (s 3H), 2.90～3.00 (br.d, 2H, J=10.2), 2.46～2.64 (m, 4H), 2.17 (s, 3H), 1.20～2.08 (m, 15H).
Embodiment 37 5-[3-(1-benzyl-4-piperidines) the third carbonyl methyl] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 33)
200mg compound 31 is dissolved among the 6mlTHF, adds the sulfuric acid of 2.5ml20%, refluxes cooling 6 hours, add 10ml water, with the salt of wormwood alkalization, dichloromethane extraction carries out column chromatography, use methylene dichloride: methyl alcohol=drip washing in 10: 1 obtains the 100mg oily, productive rate: 55%.Be dissolved in the methyl alcohol, the ice-water bath cooling adds the oxalic acid of equivalent down.Separate out the solid oxalate, methyl alcohol-ether recrystallization gets solid.Fusing point: 153～155 ℃ 1H NMR (CDCl 3, AM=400): δ 7.44 (d, 1H, J=9.2), 7.28～7.32 (m, 5H), 6.46 (d, 1H, J=9.2), 3.52～3.56 (m, 3H), 3.50 (s, 2H), 3.48 (s, 3H), 2.86～2.94 (br.d, 2H, J=12.7), 2.64～2.72 (d-t, 1H, J 1=17.6, J 2=4.8), 2.46～2.56 (m, 1H), 2.38～2.44 (t, 2H, J=7.7), 1.20～2.60 (m, 13H).
Embodiment 38 5-[2-(1-benzyl-4-piperidines) ethamine carbonyl methylene radical] amido-5,6,7,8-tetrahydrochysene-1-methyl-2 (1H)-quinolinone (compound 34)
38-a:500mg1-methyl tetrahydroquinolones, 2g activated zinc powder, 100mg iodine are blended among the 20mlTHF, under the nitrogen, add the 0.8ml ethyl bromoacetate, refluxed 2 hours, cooling adds 5ml ethanol, filters, filtrate adds the sulfuric acid of 5ml10%, 60 ℃ were stirred 10 minutes, and the cooling dichloromethane extraction carries out column chromatography behind the dry evaporate to dryness, ethyl acetate: sherwood oil=drip washing in 1: 4 obtains 0.6g white crystal quinoline olefin(e) acid ester.Productive rate: 86%.Fusing point: 213～214 ℃ 1H NMR (CDCl 3, AM=400): δ 7.64 (d, 1H, J=9.8), 6.48 (d, 1H, J=9.8), 6.02 (s, 1H), 4.18 (q, 2H, J=7.1), 3.52 (s, 3H), 3.06～3.12 (m, 2H), 2.74～2.78 (t, 2H, J=6.4), 1.88～1.96 (m, 2H), 1.06～1.10 (t, 3H, J=7.1);
38-b:350mg quinoline olefin(e) acid ester is with after the lithium hydroxide hydrolysis, obtains compound 34 with 128 condensations of 1-benzyl-4-(2-amido) ethyl piperidine after making active ester with p-NP.Overall yield: 20%.Fusing point: 165～167 ℃ 1H NMR (CDCl 3, AM=400): δ 7.58 (d, 1H, J=9.9), 7.30～7.36 (m, 5H), 6.48 (d, 1H, J=9.5), 5.92 (s, 1H), 5.60 (br.t, 1H, J=5.9), 3.54 (s, 3H), 3.48 (s, 2H), 3.32～3.38 (br.q, 2H, J=6.8), 3.10～3.16 (t d, 2H, J 1=9.5, J 2=1.1), 2.88 (m, 2H), 2.76～2.80 (t, 2H, J=9.2), 1.20～2.00 (m, 11H).
Embodiment 39 5, and 6,7,8-tetrahydrochysene-5-O-1-[3-(1-benzyl-4-piperidines) propyl group]-2 (1H)-quinolinones (compound 35)
39-a:1.0g tetrahydroquinolones is suspended among the 60mlDMF; add 270mgNaH; stirred 1 hour; add 1.8g1-benzoyl-4-(3-iodine propyl group) piperidines, stirring is spent the night, and pours in the frozen water; ethyl acetate extraction; carry out column chromatography behind the dry evaporate to dryness, use ethyl acetate: sherwood oil=drip washing in 1: 1 obtains 0.62g oily matter benzoyl piperidines propyl group tetrahydroquinolones.Productive rate: 31%. 1HNMR(CDCl 3，AM＝400)：δ7.96(d，1H，J＝9.5)，7.34～7.44(m，5H)，6.44(d，1H，J＝9.5)，4.69(br.，1H)，4.00(t，2H，J＝7.5)，3.72(br.，1H)，2.86～3.00(m，3H)，2.72(br.，1H)，2.48～2.58(t，2H，J＝6.2)，2.12～2.20(m，2H)，1.06～1.86(m，9H)；
39-b:250mg benzoyl piperidines propyl group tetrahydroquinolones and 8ml concentrated hydrochloric acid, 8ml water and 8ml alcohol reflux 4 hours; cooling; the yellow soda ash alkalization; dichloromethane extraction; carry out column chromatography behind the evaporate to dryness; use chloroform: methyl alcohol=drip washing in 4: 1 obtains 0.14g oily matter piperidines propyl group tetrahydroquinolones.This product is dissolved in the 5ml methylene dichloride, adds 1.3 normal triethylamines and 1.1 normal benzyl bromines, and stirring is spent the night.Carry out column chromatography after the processing, methylene dichloride: methyl alcohol drip washing obtains 130mg compound 35.Overall yield: 54%.Fusing point: 171～173 ℃ 1H NMR (CDCl 3, AM=400): δ 7.98 (d, 1H, J=9.5), 7.28～7.40 (m, 5H), 6.46 (d, 1H, J=9.5), 4.00 (t, 2H, J=7.9), 3.62 (s, 2H), 2.90～3.00 (m, 4H), 2.50～2.56 (m, 2H), 2.14～2.22 (m, 2H), 2.00～2.12 (br.t, 1H, J=11.0), 1.64～1.76 (m, 4H), 1.30～1.46 (m, 5H).

Claims (15)

1, tetrahydroquinoline ketopiperidine compounds has following general structure:
Wherein:
W-U be for Or
Figure A0113214700023
Group, R on it and R1 are , H, low alkyl group, light alkene base, rudimentary alkynes base, aryl;
R 2Be H, C 1-C 4Alkyl;
V-X is C-C, C-O, C-N-Ra, C-S, C=C, C=N etc., and wherein Ra is H, C 1-C 4Alkyl, aryl, benzyl, C1～C4 alkyloyl, benzoyl;
Y is C=O, C=S, S, S=O, SO 2,
Figure A0113214700025
R3 is C 1-C 4Alkyl or be (CH 2) q, q=2～3;
Z is N-Rb, O, CH 2Deng, wherein Rb is H, C 1-C 4Alkyl, aryl, benzyl;
M=0～8, n=0-8, P=0,1 or 2;
Perhaps V-X is C-N-Ra, and n=0, Y-Z are CH 2, m=0～7, wherein the Ra substituting group is identical with above-mentioned Ra substituting group;
And their physiologically acceptable salts.
2, compound according to claim 1 is characterized in that:
When W-U is
Figure A0113214700026
The time, p=0,1,2, its R are H, low alkyl group, light alkene base, rudimentary alkynes base or aryl;
R 2Be H, C 1-C 4Alkyl.
3, compound according to claim 1 is characterized in that:
When W-U is The time, p=0,1,2, its R1 are H, low alkyl group, light alkene base, rudimentary alkynes base or aryl;
R 2Be H, C 1-C 4Alkyl.
4, compound according to claim 2 is characterized in that:
When V-X is C-C, C-O, C-S,
Y is C=O, and Z is N-Rb, O, CH 2, wherein Rb is H, C 1-C 4Alkyl, aryl, benzyl;
M=0～8, n=0-8, P=0,1 or 2;
R 2Be H, C 1-C 4Alkyl.
5, compound according to claim 2 is characterized in that:
When V-X is C-N-Ra,
Y is CO, C=S, SO, SO 2
Ra is H, C 1-C 4Alkyl, aryl, benzyl, C1～C4 alkyloyl, benzoyl;
Z is N-Rb, O, CH 2, wherein Rb is H, C 1-C 4Alkyl, aryl, benzyl;
M=0～8, n=0-8, P=0,1 or 2.
6, compound according to claim 2 is characterized in that:
When V-X is that C-N-Ra, Y are
Figure A0113214700031
The time,
Ra is H, C 1-C 4Alkyl, aryl, benzyl, C1～C4 alkyloyl, benzoyl;
R3 is C 1-C 4Alkyl or be (CH 2) q, q=2～3;
Y is that C=O, Z are N-Rb, O, CH 2Deng, wherein Rb is H, C 1-C 4Alkyl, aryl, benzyl;
M=0～8, n=0-8, P=0,1 or 2.
7, compound according to claim 2 is characterized in that:
V-X is C-N-Ra, and n=0, Y-Z are CH 2, m=0～7;
Ra is H, C 1-C 4Alkyl, aryl, benzyl, C1～C4 alkyloyl, benzoyl.
8, compound according to claim 2 is characterized in that:
When V-X is that C=C, C=N, Y be not when existing;
Z is N-Rb, O, CH 2, wherein Rb is H, C 1-C 4Alkyl, aryl, benzyl;
M=0～8, n=0-8, P=0,1 or 2.
9, compound according to claim 3 is characterized in that:
When V-X is C-C, C-O, C-S,
Y is C=O, and Z is N-Rb, O, CH 2, wherein Rb is H, C 1-C 4Alkyl, aryl, benzyl;
M=0～8, n=0-8, P=0,1 or 2;
R 2Be H, C 1-C 4Alkyl.
10, compound according to claim 3 is characterized in that:
When V-X is C-N-Ra,
Y is CO, C=S, SO, SO 2
Ra is H, C 1-C 4Alkyl, aryl, benzyl, C1～C4 alkyloyl, benzoyl etc.;
Z is N-Rb, O, CH 2, wherein Rb is H, C 1-C 4Alkyl, aryl, benzyl;
M=0～8, n=0-8, P=0,1 or 2.
11, compound according to claim 3 is characterized in that:
When V-X is that C-N-Ra, Y are The time,
Ra is H, C 1-C 4Alkyl, aryl, benzyl, C1～C4 alkyloyl, benzoyl etc.;
R2 and R3 are C 1-C 4Alkyl or be (CH 2) q, q=2～3;
Y is that C=O, Z are N-Rb, O, CH 2, wherein Rb is H, C 1-C 4Alkyl, aryl, benzyl;
M=0～8, n=0-8, P=0,1 or 2.
12, compound according to claim 3 is characterized in that:
When V-X is C=C, C=N,
Y is C=O, and Z is N-Rb, O, CH 2, wherein Rb is H, C 1-C 4Alkyl, aryl, benzyl;
M=0～8, n=0-8, P=0,1 or 2.
13, compound according to claim 2 is characterized in that:
V-X is C-N-Ra, and n=0, Y-Z are CH 2, m=0～7;
Ra is H, C 1-C 4Alkyl, aryl, benzyl, C1～C4 alkyloyl, benzoyl.
14, tetrahydroquinoline ketopiperidine compounds preparation method according to claim 1 is characterized in that:
(1) the amino acid active ester of piperidinamines compound and amido protecting, 2-phthalimide-based ethyl sulfonyl chloride then deprotection make amino amides compound IV b, Vb;
(2) compound VI b, VIIb and preparation thereof;
(3) prepare the tetrahydroquinolones piperidines by the reduction amination method.
15, tetrahydroquinoline ketopiperidine compounds and physiologically acceptable salt thereof are used in treatment presenile dementia disease medicament according to claim 1.
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