CN101348456B - Benzyl piperidine compound, and preparation and use thereof - Google Patents
Benzyl piperidine compound, and preparation and use thereof Download PDFInfo
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- CN101348456B CN101348456B CN2007100439108A CN200710043910A CN101348456B CN 101348456 B CN101348456 B CN 101348456B CN 2007100439108 A CN2007100439108 A CN 2007100439108A CN 200710043910 A CN200710043910 A CN 200710043910A CN 101348456 B CN101348456 B CN 101348456B
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- 0 C*CNC(C[C@@](C*)O)=O Chemical compound C*CNC(C[C@@](C*)O)=O 0.000 description 7
- SSDFADNKEFUFAE-OIDHKYIRSA-N CCCN(CCC)C(c1cc(C(N[C@@H](Cc2ccccc2)[C@H](C(NCCC2CCN(Cc3ccccc3)CC2)=O)O)=O)cc(N=O)c1)=O Chemical compound CCCN(CCC)C(c1cc(C(N[C@@H](Cc2ccccc2)[C@H](C(NCCC2CCN(Cc3ccccc3)CC2)=O)O)=O)cc(N=O)c1)=O SSDFADNKEFUFAE-OIDHKYIRSA-N 0.000 description 1
- ANLILAZSRUYEOO-HYSPWWBUSA-N C[C@H](c(cc1)ccc1F)NC(c1cc(NC)cc(C(N[C@@H](Cc2ccccc2)C(C(NC2CCN(Cc3ccccc3)CC2)=O)O)=O)c1)O Chemical compound C[C@H](c(cc1)ccc1F)NC(c1cc(NC)cc(C(N[C@@H](Cc2ccccc2)C(C(NC2CCN(Cc3ccccc3)CC2)=O)O)=O)c1)O ANLILAZSRUYEOO-HYSPWWBUSA-N 0.000 description 1
Abstract
The invention discloses a benzyl piperidine compound with the following structural formula and a preparation method and application thereof. The compound has the significant Beta-secretase inhibitory activity as shown by tests on the biological activity, and the compound is also proved to have significant inhibitory effect on acetylcholinesterase. Therefore, the benzyl piperidine compound provided by the invention as an inhibitor having inhibitory effect on both Beta secretase and acetylcholinesterase can be applied to prevention and supportive treatment of Alzheimer's Disease.
Description
Technical field
The present invention relates to benzyl piperidine coumpound and its production and use.
Background technology
Presenile dementia (Alzheimer ' s disease, hereinafter referred AD) is a kind of chronic nerve degenerative diseases that is common in elderly population, and its clinical manifestation is that carrying out the property disturbance of intelligence, hypomnesis, the mental act that increase the weight of are unusual etc.The elderly's health in its serious threat, especially current society aging gradually, and this situation is all the more severe, has caused people's common concern.
Acetylcholinesterase depressant remains the main medicine of clinical treatment AD at present, though can reverse study, memory impairment that the choline function damage causes, the part patient symptom is alleviated, but can not fundamentally change morbid state (Barril, X.et al Mini Rev.Med.Chem.2001,1,255).
Studies show that in recent years, the generation of the amyloid beta in the brain (β-amyloid peptide, hereinafter referred A β) and gathering are considered to cause an important factor of disease generation.A β is the polypeptide of about 4kD of being produced by amyloid precursor protein (amyloid precursor protein, hereinafter referred APP) hydrolysis, and what its terminal 11-15 amino acid was positioned at APP strides the film district.Mainly contain three kinds of Secretasess and participated in hydrolytic process, be called α, β and gamma-secretase APP.The restriction enzyme site of alpha-secretase enzyme is positioned at A β sequence, acts on and produces soluble α-APP fragment and C83 peptide behind the APP, and the C83 peptide can continue to be generated the P3 peptide by the gamma-secretase hydrolysis, does not produce A β.And the restriction enzyme site of beta-secretase is positioned at A β N and holds first amino acid, produces β-APP and C99 peptide after acting on APP, and the C99 peptide produces A β through the gamma-secretase effect again.This shows that beta-secretase is a rate-limiting enzyme very crucial in the A β forming process.And the mouse demonstration that knocks out the beta-secretase gene does not have the generation of A β not have the obstacle of tangible nerve and other physiological function aspect simultaneously fully, therefore beta-secretase is considered to treat the safe and effective novel targets of AD (D.J.Selkoe Science.2002,297,353-356.).
Because AD is a kind of multi-pathogenesis disease (Michael W.Marlatt.et al.Current MedicinalChemistry, 2005,12,1137.), and make the therapeutic strategy at single target spot be subjected to great challenge.Recently, research and development have the single molecule of many target spots effect, and the strategy that is used for the treatment of disease has caused concern (Moussa B.H.Youdim et al.Trends in Pha Sci, 2005,1,27).Use several respond well anticarcinogens of having developed of this strategy success.Based on this, the formation of considering A β is the important step of disease progression, and improve the maincenter choline function is the main clinical treatment method of improving the AD symptom at present, the inventor has designed and synthesized the double inhibitor of a series of acetylcholine esterase inhibitions simultaneously and beta-secretase, in the hope of reaching the purpose that improves treatment AD.
Summary of the invention
An object of the present invention is to provide a class has benzyl piperidine coumpound or its pharmacy acceptable salt of double inhibition effect to beta-secretase and acetylcholinesterase.
Another object of the present invention provides the preparation method of this compounds.
A further object of the present invention provides the purposes of this compounds as beta-secretase and acetylcholinesterase double inhibitor, and promptly it is as the medicinal application of treatment AD.
Benzyl piperidine coumpound of the present invention has following general structure:
Wherein:
R
1For
X is NH, O, CH
2Or vacancy; Y is
CH
2Or vacancy;
R
5Be H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl or C
1-C
6Alkoxyl group;
R
2For
(Z=0-6), H, C
1-C
4Straight or branched alkyl, nitro, amino, cyano group, hydroxyl, methoxyl group, trifluoromethyl, acetamido or halogen;
R
6Be H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl or C
1-C
6Alkoxyl group;
R
7Be H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl or C
1-C
6Alkoxyl group;
R
3Be H, C
1-C
6Straight or branched alkyl, C
3-C
6Cycloalkyl, aromatic nucleus or contain halogen or aromatic nucleus that hydroxyl replaces;
W is CH or N;
U is CHR
8Or vacancy;
R
8Be H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl or C
1-C
6Alkoxyl group;
V is
Or vacancy;
R
4Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, nitro, amino, cyano group, hydroxyl, trifluoromethyl, acetamido or halogen;
m＝0-5，n＝0-5；
And there is chiral centre specifically not indicate in the compound structure, comprises all individual isomer or its mixture.
In the present invention's one embodiment preferred, m=0 in the above-mentioned general structure, U are vacancy, and V is
And further preferred:
R
1For
Or
X is NH; Y is
R
5Be H or C
1-C
6Alkyl;
R
2For
Or nitro;
R
6Be H or C
1-C
6Alkyl;
R
7Be H or C
1-C
6Alkyl;
R
4Be H or C
1-C
4Alkyl;
R
3Be phenyl;
W is CH;
N=0,1 or 2.
This compounds can synthesize by following route 1.
Route 1
Wherein, the Ar in the reaction formula is
R wherein
4Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, nitro, amino, cyano group, hydroxyl, trifluoromethyl, acetamido or halogen.
As shown in Scheme 1, but used raw material 1a reference method (Scott L.Harbeson.et al JMC.1994,37,2918) make.
1a is a condensing agent at 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI), 1-hydroxy benzo triazole (HOBt), N, N-diisopropylethylamine (DIPEA) under the condition of organic bases with amine react 1b, temperature of reaction is between 15-40 ℃, solvent is N, dinethylformamide (DMF).
1b sloughs Boc under the acidic conditions of 4-dioxane and gets 1c at 4NHCl/1.
1c is a condensing agent at EDCI, HOBt, and DIPEA gets 1d with acid-respons under the condition of organic bases, and temperature of reaction is between 15-40 ℃, and solvent is DMF.
The 1d head product can pass through methyl alcohol: the eluent of methylene dichloride=1: 10 carries out silica gel column chromatography separating purification.
1d is dissolved in the diethyl ether solution,, can obtains its hydrochloride to wherein feeding the exsiccant hydrogen chloride gas.
In the another embodiment preferred of the present invention, m=1 in the above-mentioned general structure, U are vacancy, and V is
This compounds can synthesize by following route 2.
Route 2
Wherein, the Ar in the reaction formula is
R wherein
4Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, nitro, amino, cyano group, hydroxyl, trifluoromethyl, acetamido or halogen.
As shown in Scheme 2, but used raw material 2a reference method (Dawei Ma.et al.Tetrahedron:Asymmetry.1996,7,2365) make.
2a is a condensing agent at EDCI, HOBt, DIPEA be under the condition of organic bases with amine react 2b, temperature of reaction is between 15-40 ℃, solvent is DMF.
2b under alkaline condition, slough fluorenylmethyloxycarbonyl (Fmoc) 2c, alkali can be with 20% piperidines DMF solution, temperature of reaction is between 15-40 ℃.
2c is a condensing agent at EDCI, HOBt, and DIPEA gets 2d with corresponding acid-respons under the condition of organic bases, and temperature of reaction is between 15-40 ℃, and solvent is DMF.
Above 2d can pass through methyl alcohol: the eluent of methylene dichloride=1: 10 carries out silica gel column chromatography separating purification.
2d is dissolved in the diethyl ether solution,, can obtains its hydrochloride to wherein feeding the exsiccant hydrogen chloride gas.
In the another embodiment preferred of the present invention, m=1 in the above-mentioned general structure, U are CHCH
3, V is
And further preferred,
X is NH; Y is
R
5Be H or C
1-C
6Alkyl;
R
2For
R
6Be H or C
1-C
6Alkyl;
R
7Be H or C
1-C
6Alkyl;
R
4Be H or C
1-C
4Alkyl;
R
3Be H or C
1-C
6The straight or branched alkyl;
W is CH;
N=0,1 or 2.
This compounds can synthesize by following route 3.
Route 3
Wherein, the Ar in the reaction formula is
R wherein
4Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, nitro, amino, cyano group, hydroxyl, trifluoromethyl, acetamido or halogen.
As shown in Scheme 3, but used raw material 3a reference method (Arun K.Ghosh.et al.J.Am.Chem.Soc.2000,122,3522) make.
3a sloughs Boc and gets 3b under the methylene dichloride acidic solution condition of 30% trifluoroacetic acid, temperature of reaction is between 15-40 ℃.
3b is being solvent with DMF, and EDCI is a condensing agent, with DIPEA is to get 3c with corresponding acid-respons under the condition of alkali, and temperature of reaction is between 15-40 ℃.
3c open loop under the alkaline condition of 1N lithium hydroxide, temperature of reaction are between 15-40 ℃, and product is regulated about pH value to 3 with 10% citric acid solution, with ethyl acetate extraction, and the organic phase washing, anhydrous sodium sulfate drying, decompression removes solvent and gets 3d.
3d is an alkali at imidazoles, and DMF obtains head product with TERT-BUTYL DIMETHYL CHLORO SILANE (TBDMSCl) reaction under the condition of solvent, and temperature of reaction is between 15-40 ℃.The head product that obtains is with methyl alcohol: methylene dichloride=1: 20 is that purification by silica gel column chromatography gets product 3e under the condition of eluent.
3e is a condensing agent at EDCI, HOBt, DIPEA be under the condition of organic bases with amine react 3f, temperature of reaction is between 15-40 ℃, solvent is DMF.
3f is being a solvent with tetrahydrofuran (THF) (THF), under the tetrabutyl fluoride amine condition, sloughs tertiary butyl dimethylsilane (TBDMS) group, and the head product that obtains purification by silica gel column chromatography under the condition that with methyl alcohol: methylene dichloride=1:10 is eluent gets product and gets 3g.
3g is dissolved in the diethyl ether solution,, can obtains its hydrochloride to wherein feeding the exsiccant hydrogen chloride gas.
Again in the embodiment preferred, m=1 in the above-mentioned general structure, U are vacancy in the present invention, when V is vacancy, and further preferred,
R
1For
Or
X is NH; Y is
R
5Be H, C
1-C
6Alkyl or C
3-C
6Cycloalkyl;
R
2For
H or nitro;
R
6Be H or C
1-C
6Alkyl;
R
7Be H or C
1-C
6Alkyl;
R
4Be H or C
1-C
4Alkyl;
R
3Be phenyl;
W is CH;
N=0,1 or 2.
This compounds can synthesize by pass course 4.
Route 4
Wherein, the Ar in the reaction formula is
R wherein
4Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, nitro, amino, cyano group, hydroxyl, trifluoromethyl, acetamido or halogen.
As shown in Scheme 4, the available or reference method (Ping Chen.et al.Tet.Lett.1997,38) of used raw material 4a makes.
4a and amine react 4b, temperature of reaction is between 60-120 ℃, solvent is a Virahol, the gained head product is at methyl alcohol: methylene dichloride=1: 15 gets 4b for carrying out purification by silica gel column chromatography under the condition of eluent.
4b sloughs Boc under the acidic conditions of 4-dioxane and gets 4c at 4N HCl/1, and temperature of reaction is between 15-40 ℃.
4c is a condensing agent at EDCI, HOBt, and DIPEA is under the condition of organic bases and acid-respons, and temperature of reaction is between 15-40 ℃, and solvent is DMF, and the gained head product is at methyl alcohol: methylene dichloride=1: 10 gets 4d for purification by silica gel column chromatography under the condition of eluent.
4d is dissolved in the diethyl ether solution,, can obtains its hydrochloride to wherein feeding the exsiccant hydrogen chloride gas.
Benzyl piperidine coumpound pharmacy acceptable salt of the present invention, for example salt of formation such as benzyl piperidine coumpound and hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartrate, succsinic acid.
Beneficial effect
Proteic acquisition of beta-secretase and beta-secretase activity determination method:
The beta-secretase extracellular region protein is adopted in experiment, and 1-454 amino acid (hereinafter referred BACE1) is secretory protein, and this is proteic gene constructed in pFastBac
TMIn 1 carrier, the C end adds 6 Histidines.By
(Invitrogen) baculovirus expression system obtains target protein.
At first recombinant plasmid transformed is arrived intestinal bacteria DH10Bac
TMIn the competent cell, wherein comprised the baculovirus shuttle vectors, i.e. rod granule, picking contains pFastBac after transposition
TMThe recombinant clone of middle goal gene section is cultivated and extracting reorganization rod granule.With the Sf9 insect cell of reorganization rod granule transfection complete TNM-FH culture medium culturing, cultivate and gather in the crops the substratum that contains first-generation virus after 3-5 days, continue transfection and obtain the s-generation, third generation virus respectively.The substratum that employing contains third generation virus infects Express
The High Five that serum free medium is cultivated
TMInsect cell is expressed target protein, collects the substratum that contains target protein after 72 hours, remains next step purifying.To contain level pad (20mM sodium phosphate (sodium phosphate) pH8.0 of the substratum (25-30mL) of target protein at 1L, 300mM NaCl, 10mM imidazoles (imidazole)) middle dialysed overnight, centrifugal 15 minutes of 12000rpm, repeat once, collect supernatant liquor.With sample on the supernatant liquor to through level pad equilibrated metal ion-chelant chromatography column 1mL HiTrap
TMChelating HP column (GE Healthcare, Life Sciences), after cleaning foreign protein, adopt elution buffer (20mM sodium phosphate pH8.0,300mM NaCl, 250mM imidazole) to obtain target protein be beta-secretase extracellular region (BACE1) to wash-out, the albumen that 12% polyacrylamide gel electrophoresis (SDS-PAGE) isolation identification purifying obtains, purity is about 90%.
DABCYL-Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-EDANS (Synpep is used in experiment, under be called for short BS) as substrate, surveying lives in being reflected in the 384 hole microwell plates carries out, reaction volume is 25 μ l, contain 100mM sodium-acetate (sodium acetate) (pH4.0), 20 μ M BS, 50nMBACE1,2 μ l methyl-sulphoxides (DMSO) or be dissolved in the compound of DMSO.Room temperature reaction is at the multi-functional plate instrument Envision that reads
TM(PerkinElmer) detect fluorescent signal in, excite with absorbing wavelength and be respectively 355nm and 460nm, write down and calculate the increment of enzyme reaction initial stage unit time fluorescent signal, represent the enzyme reaction initial velocity with this, inhibiting rate (inhibition) calculates sees formula 1.
υ in the formula 1
CompoundAnd υ
DMSORepresentative contains the enzyme reaction initial velocity of compound and DMSO respectively.
If compound to be detected inhibiting rate when 20 μ g/mL further dilutes 7-9 concentration again greater than 50%, calculate IC
50, promptly the enzyme initial velocity is suppressed a half compound concentrations.Positive inhibitor is compound OM99-2 (OM99-2 has replaced the compound of leucine-L-Ala peptide bond based on octapeptide [L-glutamic acid-OMR99-1] with the isostere hydroxyalkyl vinyl base of a transition state).
The cholinesterase activity measuring method:
Acetylcholinesterase enzyme source adopts rat layer 5% homogenate (to use 75mmol, pH7.4,4 ℃ of phosphoric acid buffers are made the homogenate medium), add the selective depressant tetra isopropyl pyrophosphoramide (iso-OMPA) of 4mmol butyrylcholine esterase by 10:1 before the experiment, 37 ℃ of insulations 5 minutes.Butyrylcholine esterase enzyme source is a rat blood serum.With colorimetric method for determining acetylcholinesterase (AChE) vigor.The reaction total volume is 4ml, include acetylthiocholine iodide 0.3mmol, 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 60% 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 regression, 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.Gained part of compounds activity is listed as follows:
"-" expression is not surveyed
By the screening on molecular level, the discovery part of compounds shows all has activity preferably to two kinds of enzymes, and especially compound 12,15, for further research may have the cognitive function of improvement, the original new drug of alleviating the AD progression of disease simultaneously provides valuable information.
Specific embodiment:
Example 1:N-[(1S, 2 (R, S))-1-benzyl-2-hydroxyl-3-(1-benzyl piepridine-4-amino) carbonyl propyl group]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (compound 1)
With 30mg2-(R, S)-hydroxyl-3-(S)-(N-tertiary butyloxycarbonyl amino)-4-benzenebutanoic acid is dissolved among the 2mlDMF, adds 20mg EDCI under the ice-water bath condition, 14mg HOBt, 20 μ l DIPEA stir adding 4-aminobenzyl piperidines 20 μ l after ten minutes, react down in room temperature condition and spend the night.Add 20ml water dilution DMF solution, with 20ml ethyl acetate extraction twice, organic phase is used 1N dilute hydrochloric acid in succession, saturated NaHCO3 solution washing, anhydrous Na
2SO
4Drying is filtered, and decompression removes solvent and gets crude product, and crude product passes through methyl alcohol: methylene dichloride=1:15 is further purified for the eluent silica gel column chromatography.The product that obtains reacted two hours in the 1ml4NHCl/ dioxane, and decompression removes solvent, and the crude product that obtains is not purified directly to carry out next step reaction.35mg5-(methyl first sulfo group) amino-3-(1R)-1-(4-fluorobenzene ethyl) aminocarbonyl phenylformic acid is dissolved among the 2ml DMF, under the ice-water bath condition, add 20mg EDCI, 14mg HOBt, 20 μ l DIPEA, stir after ten minutes, it is slowly added in the above-mentioned crude product reaction system, react down in room temperature condition and spend the night.Add water 20ml dilution DMF solution, with 20ml ethyl acetate extraction twice, organic phase is used 1N dilute hydrochloric acid in succession, saturated NaHCO
3Solution is washed, anhydrous Na
2SO
4Drying is filtered, and decompression removes solvent, crude product, with methyl alcohol: methylene dichloride=1:10 be the eluent silica gel column chromatography be further purified unformed spumescence solid 17mg, productive rate 25.5%.
LC-MS：m/z744.8[M+H]
+；
1HNMR(300MHz，CD
3Cl)：δ8.10(s，0.5H)，8.06(s，0.5H)，7.91(s，0.5H)，7.88(s，0.5H)，7.81(s，0.5H)，7.72(s，0.5H)，7.06-7.60(m，12H)，6.85-6.98(m，2H)，5.20(m，1H)，4.52(br，1H)，4.34(m，0.5H)，4.14(m，0.5H)，3.70(m，2H)，3.59(s，1H)，3.61(s，1H)，3.24(s，1.5H)，3.20(s，1.5H)，2.54-3.16(m，8H)，2.07-2.33(m，2H)，1.82(m，2H)，1.55(d，J＝6.7Hz，3H)。
Example 2:N-[(1S, 2 (R, S))-1-benzyl-2-hydroxyl-3-(1-benzyl piepridine-4-methylamino-) carbonyl propyl group]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (compound 2)
Operating process such as example 1 just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-methylamine, and end product is unformed spumescence solid 36mg, productive rate 53.0%.
LC-MS：m/z758.8[M+H]
+；
1H?NMR(300MHz，CD
3Cl)：δ8.27(s，0.5H)，8.26(s，0.5H)，7.95(s，0.5H)，7.89(s，0.5H)，7.88(s，0.5H)，7.76(s，0.5H)，7.03-7.44(m，12H)，6.80-6.98(m，2H)，5.23(m，1H)，4.62(m，1H)，4.35(m，0.5H)，4.12(m，0.5H)，3.52-3.61(m，2H)，2.69-3.29(m，12H)，1.88-2.14(m，2H)，1.24-1.85(m，6H)。
Example 3:N-[(1S, 2 (R, S))-1-benzyl-2-hydroxyl-3-(1-benzyl piepridine-4-ethylamino) carbonyl propyl group]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (compound 3)
Operating process such as example 1 just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, and end product is unformed spumescence solid 26mg, productive rate 37.6%.
LC-MS：m/z772.8[M+H]
+；
1H?NMR(300MHz，CD
3Cl):δ8.40(s，0.5H)，8.20(s，0.5H)，7.97(s，0.5H)，7.95(s，0.5H)，7.88(s，0.5H)，7.81(s，0.5H)，7.12-7.90(m，12H)，6.86-7.12(m，2H)，5.20(m，1H)，4.62(m，1H)，4.30(m，0.5H)，4.14(m，0.5H)，2.72-3.38(m，14H)，1.18-2.44(m，12H)。
Example 4:N-[(1S, 2 (R, S))-1-benzyl-2-hydroxyl-3-(1-benzyl piepridine-4-amino) carbonyl propyl group]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine (compound 4)
Operating process such as example 1, just replace 5-(methyl first sulfo group) amino-3-(1R)-1-(4-fluorobenzene ethyl) aminocarbonyl phenylformic acid with 32mg5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid, get unformed spumescence solid 30mg, productive rate 49.2%.
LC-MS：m/z726.5[M+H]
+；
1H?NMR(300MHz，CD
3Cl):δ8.13(s，0.5H)，8.07(s，0.5H)，7.91(s，0.5H)，7.86(s，0.5H)，7.81(s，0.5H)，7.72(s，0.5H)，7.05-7.39(m，15H)，5.22(m，1H)，4.56(m，1H)，4.36(m，0.5H)，4.12(m，0.5H)，3.72(br，2H)，3.58(s，1H)，3.56(s，1H)，3.21(s，1H)，3.17(s，1H)，2.68-3.13(m，18H)，1.62-2.24(m，4H)，1.58(s，1.5H)，1.55(s，1.5H)。
Example 5:N-[(1S, 2 (R, S))-1-benzyl-2-hydroxyl-3-(1-benzyl piepridine-4-methylamino-) carbonyl propyl group]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine (compound 5)
Operating process such as example 1, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-methylamine, 32mg5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid replaces 5-(methyl first sulfo group) amino-3-(1R)-1-(4-fluorobenzene ethyl) aminocarbonyl phenylformic acid, get unformed spumescence solid 24mg, productive rate 38.5%.
LC-MS：m/z741.0[M+H]
+；
1H?NMR(300MHz，CD3Cl):δ8.34(s，0.5H)，8.24(s，0.5H)，7.78-8.02(m，3H)，7.07-7.46(m，14H)，5.29(m，1H)，4.63(m，1H)，4.36(m，0.5H)，4.11(m，0.5H)，3.47-3.63(m，2H)，2.69-3.29(m，12H)，1.88-2.14(m，2H)，1.24-1.85(m，6H)。
Example 6:N-[(1S, 2 (R, S))-1-benzyl-2-hydroxyl-3-(1-benzyl piepridine-4-ethylamino) carbonyl propyl group]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine (compound 6)
Operating process such as example 1, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, 32mg5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid replaces 35mg5-(methyl first sulfo group) amino-3-(1R)-1-(4-fluorobenzene ethyl) aminocarbonyl phenylformic acid, get unformed spumescence solid 27mg, productive rate 42.6%.
LC-MS：m/z754.6[M+H]
+；
1HNMR(300MHz，CD
3Cl):δ8.04(s，0.5H)，7.97(s，0.5H)，7.94(s，0.5H)，7.85(s，0.5H)，7.83(s，0.5H)，7.70(s，0.5H)，7.64(m，0.5H)，7.46(m，0.5H)7.01-7.39(m，14H)，5.20(m，1H)，4.44(m，1H)，4.36(m，0.5H)，4.09(m，0.5H)，3.66(m，2H)，3.46(s，1H)，3.42(s，1H)，2.70-3.29(m，12H)，2.00-2.13(m，1H)，1.86(m，2H)，0.80-1.43(m，9H)。
Example 7:N-[(1S, 2 (R, S))-1-benzyl-2-hydroxyl-3-(1-benzyl piepridine-4-amino) carbonyl propyl group]-5-nitro-N ', N '-dipropyl isophthaloyl amine (compound 7)
Operating process such as example 1, just 30mg5-nitro-3-(N, N-dipropyl aminocarbonyl) phenylformic acid replaces 35mg5-(methyl first sulfo group) amino-3-(1R)-1-(4-fluorobenzene ethyl) aminocarbonyl phenylformic acid, gets unformed spumescence solid 23mg, productive rate 35.8%.
LC-MS：m/z644.7[M+H]
+；
1HNMR(300MHz，CD
3Cl):δ8.54(m，1H)，8.25(m，1H)，8.03(m，1H)，7.88(m，1H)，7.08-7.39(m，9H)，4.62(m，1H)，?4.20(m，1H)，2.89-3.87(m，13H)，2.31(m，2H)，1.45-1.94(m，6H)，0.66-0.99(m，6H)。
Example 8:N-[(1S, 2 (R, S))-1-benzyl-2-hydroxyl-3-(1-benzyl piepridine-4-methylamino-) carbonyl propyl group]-5-nitro-N ', N '-dipropyl isophthaloyl amine (compound 8)
Operating process such as example 1, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-methylamine, 30mg5-nitro-3-(N, N-dipropyl aminocarbonyl) phenylformic acid replaces 35mg5-(methyl first sulfo group) amino-3-(1R)-1-(4-fluorobenzene ethyl) aminocarbonyl phenylformic acid, get unformed spumescence solid 40mg, productive rate 60.9%.
LC-MS：m/z658.7[M+H]
+；
1H?NMR(300MHz，CD
3Cl)：δ8.58(t，J＝1.7Hz，0.5H)，8.50(t，J＝2.1Hz，0.5H)，8.32(d，J＝9.0Hz，0.5H)，8.20(m，1H)，8.16(m，0.5H)，8.03(m，0.5H)，7.97(d，J＝8.0Hz，0.5H)，7.56(br，0.5H)，7.09-7.46(m，8.5H)，4.61-4.85(m，2H)，4.37(m，0.5H)，4.21(m，0.5H)，3.70-3.92(m，2H)，3.42(t，J＝6.9Hz，2H)，2.77-3.50(m，9H)，2.17(m，2H)，1.43-1.73(m，7H)，0.96(m，3H)，0.74(m，3H)。
Example 9:N-[(1S, 2 (R, S))-1-benzyl-2-hydroxyl-3-(1-benzyl piepridine-4-ethylamino) carbonyl propyl group]-5-nitro-N ', N '-dipropyl isophthaloyl amine (compound 9)
Operating process such as example 1, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, 30mg5-nitro-3-(N, N-dipropyl aminocarbonyl) phenylformic acid replaces 35mg5-(methyl first sulfo group) amino-3-(1R)-1-(4-fluorobenzene ethyl) aminocarbonyl phenylformic acid, get unformed spumescence solid 30mg, productive rate 44.7%.
LC-MS：m/z672.8[M+H]
+；
1HNMR(300MHz，CD
3Cl):δ8.48(s，0.5H)，8.41(s，0.5H)，8.25(s，0.5H)，8.18(m，1H)，8.02(s，0.5H)，7.96(m，1H)，7.10-7.29(m，9H)，5.28(m，1H)，4.57(m，1H)，4.33(m，0.5H)，4.19(m，0.5H)，2.77-3.50(m，13H)，2.16(m，1H)，1.86(q，J＝5.1Hz，2H)，1.11-1.74(m，8H)，0.90-1.03(m，3H)，0.66-0.78(m，3H)。
Example 10:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-amino)-2-hydroxypropyl]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-styroyl] isophthaloyl amine (compound 10)
(2S, 3S)-1,2-epoxy-3-(N-tertiary butyloxycarbonyl amino)-4-phenylpropyl alcohol alkane was dissolved in the 1ml Virahol 26mg, adds 60 μ l4-aminobenzyl piperidines, in 100 ℃ of reactions 24 hours.Behind the concentrated solvent, directly going up silicagel column, is that the eluent separation and purification obtains corresponding product with methyl alcohol: methylene dichloride=1:15.The product that obtains was reacted two hours in 1ml4N HCl/ dioxane, and solvent evaporated gets crude product, and this crude product is not purified directly to carry out next step reaction.20mg5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid is dissolved among the 2ml DMF, adds 20mg EDCI, 14mg under condition of ice bath
HOBt, 20 μ l DIPEA stirred after ten minutes, and it is slowly added in the above-mentioned crude product reaction system, reacted down in room temperature condition and spent the night.Add water 20ml dilution DMF solution, with ethyl acetate 20ml extracting twice, organic phase is washed with 1N dilute hydrochloric acid respectively, saturated NaHCO
3Solution is washed, anhydrous Na
2SO
4Drying is filtered, and decompression removes solvent, crude product, with methyl alcohol: methylene dichloride=1:10 be eluent carry out silica gel column chromatography be further purified unformed spumescence solid 14mg, productive rate 39.3%.
LC-MS：m/z712.6[M+H]
+；
1H?NMR(400MHz，CD
3OD):δ8.00(m，1H)，7.96(m，1H)，7.78(m，1H)，7.30(m，15H)，5.22(q，J＝7.0，14.1Hz，1H，)，4.27(m，1H)，3.79(m，1H)，3.53(s，2H)，3.32(s，3H)，3.22(m，1H)，2.79(m，9H)，2..07(m，2H)，1.91(m，2H)，1.56(d，J＝7.0Hz，3H)，1.48(m，2H).
13C?NMR(100MHz，CDCl
3)：166.396，164.707，143.333，141.912，137.873，137.791，135.773，135.468，129.024，128.473，128.409，128.140，127.607，127.156，127.034，126.410，126.268，123.900，70.073，62.700，55.331，51.888，49.765，48.057，37.669，36.335，35.228，31.352，21.888.[α]
D 20＝-56.5°(c1.1000，CH
2C1
2)。
Example 11:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-methylamino-)-2-hydroxypropyl]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-styroyl] isophthaloyl amine (compound 11)
Operating process such as example 10 just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-methylamine, get unformed spumescence solid 12mg, productive rate 33.1%.
LC-MS：m/z726.6[M+H]
+；
1H?NMR(400MHz，CD
3OD)：δ.8.03(t，J＝1.3Hz，1H)，7.96(t，J＝2.1Hz，1H)，7.78(t，J＝2.0Hz，1H)，7.30(m，15H)，5.48(s，1H)，5.22(q，J＝7.0，14.1Hz，1H)，4.27(m，1H)，3.81(m，1H)，3.52(s，2H)，3.30(s，3H)，3.23(m，1H)，2.83(m，8H)，2.58(m，2H)，2..02(m，2H)，1.75(m，2H)，1.57(d，，J＝7.0Hz，4H)，1.27(m，2H).
13C?NMR(100MHz，CD
3OD)：166.457，164.786，143.416，142.018，137.742，137.650，135.811，135.068，129.289，129.152，128.596，128.519，128.232，127.850，127.276，127.203，126.565，126.374，124.106，69.986，63.036，54.840，54.834，52.894，51.359，49.906，37.796，36.111，35.605，34.244，29.798，22.033.[α]
D 20＝-42.4°(c0.9000，CH
2Cl
2)。
Example 12:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-styroyl] isophthaloyl amine (compound 12)
Operating process such as example 10 just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, get unformed spumescence solid 20mg, productive rate 54.1%.
LC-MS：m/z740.5[M+H]
+；1H?NMR(400MHz，CD
3OD)：δ8.02(m，1H)，7.96(m，1H)，7.78(m，1H)，7.30(m，15H)，5.21(m，1H)，4.25(m，1H)，3.79(m，1H)，3.50(s，2H)，3.32(s，3H)，3.17(m，1H)，2.78(m，10H)，2.01(m，2H)，1.66(m，2H)，1.50(m，5H)，1.28(m，3H).
13C?NMR(100MHz，CDCl
3):166.401，164.802，143.365，141.908，137.914，137.809，135.778，135.218，129.247，129.092，12.541，128.459，128.131，127.698，127.229，127.006，126.492，126.332，124.132，70.114，63.264，55.103，53.486，51.159，49.834，?47.133，37.760，36.030，35.360，34.818，33.470，31.876，21.975；[α]
D 20＝-34.0°(c0.3000，CH
2Cl
2)。
Example 13:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-amino)-2-hydroxypropyl]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (compound 13)
Operating process such as example 10, just replace 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid with 5-(methyl first sulfo group) amino-3-(1R)-1-(4-fluorobenzene ethyl) aminocarbonyl phenylformic acid, get unformed spumescence solid 24mg, productive rate 65.8%.
LC-MS：m/z730.8[M+H]
+；
1H?NMR(400MHz，CD
3OD)：δ8.05(m，1H)，7.96(m，1H)，7.80(m，1H)，7.41(m，2H)，7.25(m，12H)，5.22(q，J＝7.2，13.7Hz，1H，)，4.27(m，1H)，3.81(m，1H)，3.51(s，2H)，3.31(s，3H)，3.23(m，1H)，2.79(m，8H)，2.67(m，1H)，2..09(m，2H)，1.92(m，2H)，1.54(d，J＝7.0Hz，3H)，1.48(m，2H).
13C?NMR(100MHz，CD
3OD)：159.197，158.190，155.002，152.584，134.125，131.625，130.381，128.774，127.817，127.599，121.232，120.836，119.929，119.838，119.706，119.624，119.314，119.005，117.893，116.454，62.873，54.197，47.056，46.587，45.311，43.462，40.834，40.479，28.788，27.905，26.388，22.244，21.993，12.657.[α]
D 20＝(c，CH
2Cl
2)。
Example 14:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-methylamino-)-2-hydroxypropyl]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (compound 14)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-methylamine, replace 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid with 5-(methyl first sulfo group) amino-3-(1R)-1-(4-fluorobenzene ethyl) aminocarbonyl phenylformic acid, get unformed spumescence solid 15mg, productive rate 40.4%.
LC-MS：m/z744.3[M+H]
+；
1HNMR(400MHz，CD
3OD)：δ8.01(m，1H)，7.95(m，1H)，7.78(m，1H)，7.41(m，2H)，7.24(m，12H)，5.22(q，J＝7.0，14.0Hz，?1H)，4.27(m，1H)，3.77(m，1H)，3.49(s，2H)，3.31(s，3H)，3.24(m，1H)，2.87(m，8H)，2..49(m，2H)，1.99(m，2H)，1.71(m，2H)，1.57(m，4H)，1.28(m，2H).[α]
D 20＝-27.8°(c0.4000，CH
2Cl
2)。
Example 15:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (compound 15)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, replace 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid with 5-(methyl first sulfo group) amino-3-(1R)-1-(4-fluorobenzene ethyl) aminocarbonyl phenylformic acid, get unformed spumescence solid 20mg, productive rate 52.8%.
LC-MS：m/z758.6[M+H]
+；
1HNMR(400MHz，CD
3OD)：δ8.05(m，1H)，7.97(m，1H)，7.80(m，1H)，7.42(m，2H)，7.30(m，12H)，5.48(s，1H)，5.22(m，1H)，4.26(m，1H)，3.87(m，1H)，3.52(s，2H)，3.31(s，3H)，3.30(m，1H)，2.92(m，10H)，2.03(m，2H)，1.71(m，2H)，1.57(m，5H)，1.28(m，3H).
13C?NMR(100MHz，CDCl
3)：166.328，164.688，162.962，160.521，141.972，139.239，138.100，137.800，135.659，135.318，129.160，129.024，128.411，128.086，128.040，127.958，127.580，126.924，126.492，124.023，115.315，115.101，70.123，63.278，55.303，53.372，51.209，49.137，47.242，37.706，36.152，35.360，35.223，33.570，31.994，21.939；[α]
D 20＝-53.1°(c0.5500，CH
2Cl
2)。
Example 16:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-5-[(methyl first sulfo group) amino]-N ', N '-dipropyl isophthaloyl amine (compound 16)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, with 5-(methyl first sulfo group) amino-3-(N ', N '-dipropyl) the aminocarbonyl phenylformic acid replaces 5-(methyl first sulfo group) amino-3-(1R)-styroyl aminocarbonyl phenylformic acid, get unformed spumescence solid 14mg, productive rate 38.9%.
LC-MS：m/z720.3[M+H]
+；
1H?NMR(400MHz，CDCl
3):δ7.69(m，1H)，7.56(m，1H)，7.49(m，1H)，7.28(m，10H)，5.30(m，1H)，4.35(m，1H)，3.69(m，1H)，3.47(m，4H)，3.30(s，3H)，3.13(m，2H)，3.01(m，2H)，2.83(m，7H)，2.68(m，2H)，1.93(m，2H)，1.64(m，4H)，1.48(m，3H)，1.28(m，4H)，0.97(s，3H)，0.73(s，3H).[α]
D 22＝-15.6°(c0.4500，CH
2Cl
2)。
Example 17:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-5-[(methyl first sulfo group) amino]-N '-[4-fluorobenzene methyl] isophthaloyl amine (compound 17)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, replace 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid with 5-(methyl first sulfo group) amino-3-(4-fluorobenzene methyl aminocarbonyl) phenylformic acid, get unformed spumescence solid 13mg, productive rate 34.9%.
LC-MS：m/z744.3[M+H]
+；
1H?NMR(400MHz，CDCl
3)：δ8.07(m，1H)，7.92(m，2H)，7.80(m，1H)，7.30(m，1H)，7.26(m，10H)，6.97(m，2H)，4.54(m，2H)，4.35(m，1H)，3.76(m，1H)，3.45(s，2H)，3.28(s，3H)，3.00(m，3H)，2.84(m，6H)，2.63(m，2H)，1.88(m，2H)，1.56(m，2H)，1.43(m，2H)，1.25(m，3H).[α]
D 22＝-47.7°(c0.7500，CH
2Cl
2)。
Example 18:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-5-[(methyl first sulfo group) amino]-N '-isobutyl-isophthaloyl amine (compound 18)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, replace 5-(methyl first sulfo group) amino-3-(1R)-styroyl aminocarbonyl phenylformic acid with 5-(methyl first sulfo group) amino-5-(isobutyl-aminocarbonyl) phenylformic acid, get unformed spumescence solid 16mg, productive rate 46.3%.
LC-MS：m/z692.3[M+H]
+；
1H?NMR(400MHz，CDCl
3)：δ8.17(m，2H)，7.90(m，1H)，7.80(m，1H)，7.30(m，1H)，7.26(m，8H)，4.34(m，1H)，3.90(m，1H)，3.46(s，3H)，3.33(s，3H)，3.21(m，2H)，2.83(m，10H)，1.90(m，3H)，1.54(m，4H)，1.25(m，2H)，0.95(s，3H)，0.93(s，3H).[α]
D 22＝-44.6°(c0.8500，CH
2Cl
2)。
Example 19:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-5-nitro-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (compound 19)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, replace 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid with 5-nitro-3-(R)-1-(4-fluorobenzene ethyl) aminocarbonyl phenylformic acid, get unformed spumescence solid 18mg, productive rate 51.8%.
LC-MS：m/z696.7[M+H]
+；
1H?NMR(400MHz，CDCl
3):δ8.62(s，1H)，8.53(s，1H)，8.47(s，1H)，7.54(m，1H)，7.26(m，11H)，6.95(m，2H)，5.30(m，1H)，4.39(br，1H)，3.90(br，1H)，3.46(s，2H)，2.82(m，8H)，1.89(m，2H)，1.58(d，J＝6.5Hz，6H)，1.47(m，1H)，1.25(m，3H).[α]
D 22＝-40.2°(c0.4500，CH
3OH)。
Example 20:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-5-nitro-N '-[(1R)-and the 1-styroyl] isophthaloyl amine (compound 20)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, replace 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid with 5 nitros-3-(R)-1-styroyl aminocarbonyl phenylformic acid, get unformed spumescence solid 14mg, productive rate 41.4%.
LC-MS：m/z678.3[M+H]
+；
1H?NMR(400MHz，CDCl
3)：δ8.65(m，1H)，8.49(m，1H)，8.43(m，1H)，8.34(d，J＝8.3Hz，1H)，7.30(m，13H)，7.03(d，J＝7.5Hz，1H)，5.29(m，1H)，4.42(m，1H)，3.76(m，1H)，3.46(s，2H)，3.02?(m，1H)，2.82(m，5H)，2.64(m，2H)，1.88(m，2H)，1.59(m，5H)，1.41(m，2H)，1.26(m，3H).[α]
D 22＝-45.6°(c0.5500，CH
3OH)。
Example 21:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-5-nitro-N ', N '-dipropyl isophthaloyl amine (compound 21)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, with 5-nitro-3-(N ', N '-dipropyl aminocarbonyl) phenylformic acid replaces 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid, get unformed spumescence solid 16mg, productive rate 48.7%.
LC-MS：m/z658.6[M+H]
+；
1H?NMR(400MHz，d
6-DMSO):δ8.61(m，1H)，8.29(m，1H)，8.14(m，1H)，7.30(m，10H)，4.38(m，1H)，3.83(m，1H)，3.46(m，1H)，3.42(s，3H)3.20(m，3H)，2.78(m，7H)，1.90(m，2H)，1.22(m，11H)，0.95(m，3H)，0.72(m，3H).[α]
D 22＝-27.1°(c0.3500，CH
2Cl
2)。
Example 22:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-N '-[(1R)-and the 1-styroyl] isophthaloyl amine (compound 22)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, replace 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid with 3-(R)-1-styroyl aminocarbonyl phenylformic acid, get unformed spumescence solid 14mg, productive rate 44.3%.
LC-MS：m/z633.3[M+H]
+；
1H?NMR(400MHz，CDCl
3)：δ8.10(s，1H)，7.86(d，J＝7.8Hz，1H)，7.70(d，J＝10.8Hz，1H)，7.47(d，J＝4.6Hz，1H)，7.30(m，13H)，6.85(d，J＝7.3Hz，1H)，5.30(m，1H)，4.39(m，1H)，3.78(m，1H)，3.46(s，2H)，2.98(d，J＝6.9Hz，2H)，2.81(m，4H)，2.64(m，2H)，1.87(m，2H)，1.58(m，5H)，1.44(m，2H)，1.25(m，3H).[α]
D 22＝-34.0°(c0.7500，CH
2Cl
2)。
Example 23:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-N '-[(1R)-and 1-(4-fluorobenzene ethyl)] isophthaloyl amine (compound 23)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, replace 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid with 3-(R)-1-(4-fluorobenzene ethyl) aminocarbonyl phenylformic acid, get unformed spumescence solid 15mg, productive rate 46.2%.
LC-MS：m/z651.3[M+H]
+；
1H?NMR(400MHz，CDCl
3)：δ8.05(s，1H)，7.80(d，J＝7.7Hz，1H)，7.65(d，J＝7.7Hz，1H)，7.55(d，J＝8.9Hz，2H)，7.24(m，11H)，6.91(m，3H)，5.23(m，1H)，4.31(m，1H)，3.72(m，1H)，3.39(s，2H)，2.89(d，J＝6.9Hz，2H)，2.78(m，4H)，2.58(m，2H)，1.81(m，2H)，1.50(d，J＝7.0Hz，5H)，1.36(m，2H)，1.17(m，3H).[α]
D 22＝-52.9°(c0.8500，CH
2Cl
2)。
Example 24:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-N ', N '-dipropyl isophthaloyl amine (compound 24)
Operating process such as example 10, just replace 4-aminobenzyl piperidines, replace 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid with 3-(N, N-dipropyl aminocarbonyl) phenylformic acid with 1-benzyl piepridine-4-ethamine, get unformed spumescence solid 13mg, productive rate 42.5%.
LC-MS：m/z613.6[M+H]
+；
1H?NMR(400MHz，CD
3OD):δ7.70(m，1H)，7.56(m，1H)，7.49(m，2H)，7.25(m，10H)，4.26(m，1H)，3.84(m，1H)，3.51(s，2H)，3.46(m，2H)，3.27(m，1H)，3.13(m，2H)，2.86(m，7H)，2.02(m，2H)，1.72(m，4H)，1.51(m，4H)，1.28(m，3H)，0.99(t，J＝7.3Hz，3H)，0.69(t，J＝7.3Hz，3H)。
Example 25:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-N '-cyclopentyl isophthaloyl amine (compound 25)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, replace 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid with 3-(N-cyclobutyl aminocarbonyl) phenylformic acid, get unformed spumescence solid 10mg, productive rate 34.4%.
LC-MS：m/z597.7[M+H]
+；
1H?NMR(400MHz，CD
3OD):δ8.08(M，1H)，7.91(m，1H)，7.76(m，1H)，7.48(m，1H)，7.31(m，10H)，5.48(s，1H)，4.28(m，2H)，3.86(m，1H)，3.53(s，2H)，3.26(m，1H)，2.88(m，8H)，2.04(m，4H)，1.60(m，15H).[α]
D 22＝-27.0°(c0.2500，CH
2Cl
2)。
Example 26:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-N '-isobutyl-isophthaloyl amine (compound 26)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, replace 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid with 3-(N-isobutyl-aminocarbonyl) phenylformic acid, get unformed spumescence solid 11mg, productive rate 37.7%.
LC-MS：m/z585.3[M+H]
+；
1HNMR(400MHz，CDCl
3)：δ7.99(m，1H)，7.80(m，1H)，7.66(m，1H)，7.55(m，1H)，7.31(m，1H)，7.22(m，8H)，6.58(m，1H)，4.33(m，1H)，3.67(m，1H)，3.39(s，2H)，3.17(t，J＝6.8Hz，2H)，2.87(m，2H)，2.76(m，4H)，2.53(m，2H)，1.81(m，3H)，1.53(m，2H)，1.33(m，2H)，1.18(s，3H)，0.89(d，J＝6.7Hz，3H).[α]
D 22＝-30.6°(c0.5000，CH
2Cl
2)。
Example 27:N-[(1S, 2R)-1-benzyl-3-(1-benzyl piepridine-4-ethylamino)-2-hydroxypropyl]-N '-3-trifluoromethyl isophthaloyl amine (compound 27)
Operating process such as example 10, just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, replace 5-(methyl first sulfo group) amino-3-(1R)-1-styroyl aminocarbonyl phenylformic acid with 3-(N-3-trifluoromethyl) aminocarbonyl phenylformic acid, get unformed spumescence solid 11mg, productive rate 37.7%.
LC-MS：m/z673.3[M+H]
+；
1H?NMR(400MHz，CD
3OD)：δ8.26(s，1H)，8.21(d，J＝7.9Hz，1H)，8.10(s，1H)，7.91(d，J＝8.5Hz，1H)，7.73(m，2H)，7.40(m，2H)，7.28(m，9H)，7.14(m，1H)，5.48(s，1H)，4.26(m，1H)，3.87(m，1H)，3.50(s，2H)，3.43(m，1H)，2.89(m，7H)，2.35(m，1H)，2.01(m，2H)，1.54(m，6H).[α]
D 22＝(c0.5000，CH
2Cl
2)。
Example 28:N-[(1S, 2S, 4R)-1-isobutyl--2-hydroxyl-4-(1-benzyl piepridine-4-amino) carbonyl amyl group]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (compound 28)
Compound 1.4g (3R; 5S; 1 ' S)-5-[1 '-[(tertbutyloxycarbonyl) amino]-3 '-methyl butyl]-3-methyl dihydrofuran-2 (3H)-ketone adds to and contains in the 4mL trifluoracetic acid 20mL dichloromethane solution reaction 35 minutes; take out solvent; add 10mL water; drip saturated sodium bicarbonate aqueous solution to solution system and be alkalescence; 30mL * 3 ethyl acetate extractions three times; twice of saturated common salt water washing; anhydrous sodium sulfate drying; filter, concentrate to such an extent that 0.59g removes the compound of BOC protecting group, the not purified the next step of directly carrying out.Get the compound 0.233g that the step obtains, be dissolved in the 8mL dry DMF, the ice-water bath cooling, add compound 5-(methyl first sulfo group) amino-3-(1R)-1-(4-fluorophenyl) second aminocarbonyl phenylformic acid 0.496g, HOBt0.179g and DIPEA0.22mL, stir and add EDCI0.254g after 10 minutes, naturally be warming up to room temperature, stirring is spent the night, and adds the 100mL ethyl acetate in reaction system, 1N dilute hydrochloric acid washing three times, water washing one time, saturated sodium bicarbonate washing three times, saturated common salt water washing twice, anhydrous sodium sulfate drying.Filter, concentrate white foam shape solid product 0.656g, productive rate: 24.3%.
1H?NMR(300MHz，CDCl
3)：δ8.12(s，1H)，7.96(s，2H)，7.32(m，2H)，7.01(m，2H)，6.83(br，1H)，6.81(br，1H)，5.21(m，1H)，4.62(m，1H)，4.48(m，1H)，3.38(s，3H)，2.84(s，3H)，2.62(m，1H)，2.40(m，1H)，1.99(m，1H)，1.68(m，1H)，1.53(d，J＝7.0Hz，3H)，1.44(m，1H)，1.25(d，J＝7.2Hz，3H)，0.94(d，J＝6.4Hz，6H)。
Get step compound 0.640g and be dissolved in the 5mL tetrahydrofuran (THF), the ice-water bath cooling drips 1N lithium hydroxide aqueous solution 6mL down, finish, be warming up to room temperature naturally, stirring is spent the night, the TLC plate steams tetrahydrofuran (THF) after showing conversion fully, the cooling of surplus solution ice-water bath, with 25% citric acid acidifying to pH to 3～4, ethyl acetate 10ml extraction three times merges organic phase, washes one time, saturated common salt water washing twice, anhydrous sodium sulfate drying.Filter, concentrate the compound of five-ring open loop, for white foam shape solid 0.66g (less stable, under the room temperature placement can slowly be transformed into go up the step reactant), directly carry out next step reaction without being further purified.
To go up step product 0.66g is dissolved in the 9mL dry DMF; add imidazoles 1.71g; t butyldimethylsilyl chloride 1.892g; behind the room temperature reaction 26 hours; add 6mL methyl alcohol; stirred 1 hour; add the 30mL25% aqueous citric acid solution; ethyl acetate 10ml extracts three times; merge organic layer, pure water and saturated aqueous common salt respectively wash one time, anhydrous sodium sulfate drying; filter, concentrate, methyl alcohol: methylene dichloride=1:20 be eluent carry out silica gel column chromatography separate the protected white foam shape of hydroxyl solid product 0.603g. productive rate: 79.9%.
1H?NMR(300MHz，d
6-DMSO):δ9.01(broad?d，J＝7.6Hz，1H)，8.32(broadd，J＝7.9Hz，1H)，8.26(s，1H)，7.98(s，1H)，7.96(s，1H)，7.42(m，2H)，7.16(m，2H)，5.16(m，1H)，4.08(m，1H)，3.72(m，1H)，3.31(s，3H)，3.02(s，3H)，2.45(m，1H)，1.92(m，1H)，1.58(m，2H)，1.50(d，J＝7.0Hz，3H)，1.40-1.22(m，2H)，1.11(d，J＝7.1Hz，3H)，0.93(d，J＝8.2Hz，3H)，0.86(s，9H)，0.82(d，J＝6.3Hz，3H)，0.16(s，3H)，0.08(s，3H)。
To go up step compound 80mg and be dissolved among the 1mL DMF, the ice-water bath cooling adds 4-aminobenzyl piperidines 0.027mL, DIPEA0.022mL and HOBt18mg, stir after 10 minutes, add EDCI25mg, room temperature reaction spends the night, in reaction system, add the 30mL ethyl acetate, with 1N dilute hydrochloric acid washing three times, water washing one time, saturated sodium bicarbonate solution washing three times, saturated common salt water washing twice, anhydrous sodium sulfate drying.Filter, concentrate and obtain product;
The product that the last step was obtained is dissolved in the 1mL tetrahydrofuran (THF), add 1.0M tetrabutyl ammonium fluoride tetrahydrofuran solution 0.3mL, reacted one day, steam solvent, resistates methyl alcohol: methylene dichloride=1:10 is a developping agent, preparation silica gel thin sheet chromatographic separation gets unformed spumescence solid 56mg, productive rate 56.0%.
LC-MS(m/z):752.7[M+H]
+；
1H?NMR(300MHz，CD
3OD)：δ8.25(s，1H)，8.02(s，2H)，7.45-7.32(m，7H)，7.06(m，2H)，5.22(q，J＝6.9Hz，1H)，4.19(m，1H)，3.80(s，2H)，3.62(m，2H)，3.38(s，3H)，3.29(m，2H)，3.10?(m，2H)，2.96(s，3H)，2.65(m，1H)，2.38(m，2H)，1.72-1.40(m，7H)，1.12(d，J＝7.2Hz，3H)，1.01(d，J＝7.3Hz，3H)，0.99(d，J＝7.3Hz，3H)，0.94(d，J＝6.2Hz，3H)。
Example 29:N-[(1S, 2S, 4R)-1-isobutyl--2-hydroxyl-4-(1-benzyl piepridine-4-methylamino-) carbonyl amyl group]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (compound 29)
Operating process such as example 28 just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-methylamine, get unformed spumescence solid 42mg, productive rate 48.0%.
LC-MS(m/z):766.8[M+H]
+；
1H?NMR(300MHz，CD
3OD)：δ8.31(s，1H)，8.02(s，2H)，7.58-7.35(m，7H)，7.02(m，2H)，5.22(q，J＝7.1Hz，1H)，4.18(m，1H)，4.01(m，2H)，3.60(m，1H)，3.38(s，3H)，3.25(m，4H)，2.99(s，3H)，2.82(m，1H)，2.72-2.63(m，3H)，1.92(m，1H)，1.70-1.48(m，6H)，1.12(d，J＝6.6Hz，3H)，1.02(d，J＝7.2Hz，3H)，0.93(d，J＝6.5Hz，3H)，0.88(d，J＝6.4Hz，3H)。
Example 30:N-[(1S, 2S, 4R)-1-isobutyl--2-hydroxyl-4-(1-benzyl piepridine-4-ethylamino) carbonyl amyl group]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (compound 30)
Operating process such as example 28 just replace 4-aminobenzyl piperidines with 1-benzyl piepridine-4-ethamine, get unformed spumescence solid 47mg, productive rate 52.7%.
LC-MS(m/z):780.7[M+H]
+；
1H?NMR(300MHz，CD
3OD)：δ8.25(s，1H)，8.03(s，1H)，8.01(s，1H)，7.43(m，2H)，7.32(m，5H)，7.02(m，2H)，5.23(q，J＝7.1Hz，1H)，4.21(m，1H)，3.63(s，2H)，3.58(m，1H)，3.36(s，3H)，3.16(m，2H)，2.98(s，3H)，2.92(m，2H)，2.61(m，1H)，2.18(m，2H)，?1.90(m，2H)，1.62(m，4H)，1.58(d，J＝7.0Hz，3H)，1.45-1.23(m，6H)，1.13(d，J＝7.3Hz，3H)，0.95(d，J＝6.6Hz，6H)。
Example 31:N-[(1S, 2S, 4R)-1-isobutyl--2-hydroxyl-4-(1-benzyl piepridine-4-amino) carbonyl amyl group]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (compound 31)
Operating process such as example 28, just 5-(methyl first sulfo group) amino-3-(1R)-1-phenylethyl aminocarbonyl phenylformic acid replaces 5-(methyl first sulfo group) amino-3-(1R)-1-(4-fluorophenyl) ethyl aminocarbonyl phenylformic acid, get unformed spumescence solid 50mg, productive rate 59.6%.
LC-MS(m/z):734.6[M+H]
+；
1H?NMR(300MHz，CD
3OD)：δ8.26(s，1H)，8.03(s，1H)，7.99(s，1H)，7.42-7.21(m，10H)，5.27(q，J＝7.1Hz，1H)，4.20(m，1H)，3.79(s，2H)，3.58(m，2H)，3.38(s，3H)，3.26(m，2H)，3.09(m，2H)，2.98(s，3H)，2.62(m，1H)，2.44(m，2H)，1.90(m，2H)，1.75-1.45(m，5H)，1.13(d，J＝7.1Hz，3H)，1.01(d，J＝7.6Hz，3H)，0.95(d，J＝6.6Hz，3H)，0.94(d，J＝6.5Hz，3H)。
Claims (8)
1. the benzyl piperidine coumpound or its pharmacy acceptable salt that have following general structure:
Wherein:
M=0, U are vacancy, and V is
R
1For
X is NH; Y is
R
5Be H or C
1-C
6Alkyl;
R
2For
Or nitro;
R
6Be H or C
1-C
6Alkyl;
R
7Be H or C
1-C
6Alkyl;
R
4Be H or C
1-C
4Alkyl;
R
3Be phenyl;
W is CH;
N=0,1 or 2.
2. the benzyl piperidine coumpound or its pharmacy acceptable salt that have following general structure:
Wherein:
M=1, U are CHCH
3, V is
R
1For
X is NH; Y is
R
5Be H or C
1-C
6Alkyl;
R
2For
R
6Be H or C
1-C
6Alkyl;
R
7Be H or C
1-C
6Alkyl;
R
4Be H or C
1-C
4Alkyl;
R
3Be H or C
1-C
6The straight or branched alkyl;
W is CH;
N=0,1 or 2.
3. the benzyl piperidine coumpound or its pharmacy acceptable salt that have following general structure:
Wherein:
M=1, U are vacancy, and V is a vacancy;
R
1For
X is NH; Y is
R
5Be H, C
1-C
6Alkyl or C
3-C
6Cycloalkyl;
R
2For
H or nitro;
R
6Be H or C
1-C
6Alkyl;
R
7Be H or C
1-C
6Alkyl;
R
4Be H or C
1-C
4Alkyl;
R
3Be phenyl;
W is CH;
N=0,1 or 2.
4. benzyl piperidine coumpound or its pharmacy acceptable salt is characterized in that, described benzyl piperidine coumpound is one of following compound:
5. the preparation method of benzyl piperidine coumpound as claimed in claim 1 is characterized in that, may further comprise the steps:
1a is a condensing agent at EDCI, HOBt, N, N-diisopropylethylamine DIPEA be under the condition of organic bases with amine react 1b, temperature of reaction is between 15-40 ℃, solvent is N, dinethylformamide DMF;
1b sloughs Boc under the acidic conditions of 4-dioxane and gets 1c at 4N HCl/1;
1c is a condensing agent at EDCI, HOBt, and DIPEA gets 1d with acid-respons under the condition of organic bases, and temperature of reaction is between 15-40 ℃, and solvent is DMF;
The 1d head product passes through methyl alcohol: the eluent of methylene dichloride=1: 10 carries out silica gel column chromatography separating purification;
Wherein, the Ar in the reaction formula is
R wherein
4Definition identical with claim 1; R
1, R
2, R
3, W and n definition identical with claim 1.
6. the preparation method of benzyl piperidine coumpound as claimed in claim 2 is characterized in that, may further comprise the steps:
3a sloughs Boc and gets 3b under the methylene dichloride acidic solution condition of 30% trifluoroacetic acid, temperature of reaction is between 15-40 ℃;
3b is being solvent with DMF, and EDCI is a condensing agent, with DIPEA is to get 3c with corresponding acid-respons under the condition of alkali, and temperature of reaction is between 15-40 ℃;
3c open loop under the alkaline condition of 1N lithium hydroxide, temperature of reaction are between 15-40 ℃, and product is regulated pH value to 3 with 10% citric acid solution, with ethyl acetate extraction, and the organic phase washing, anhydrous sodium sulfate drying, decompression removes solvent and gets 3d;
3d is an alkali at imidazoles, and DMF obtains head product with the TERT-BUTYL DIMETHYL CHLORO SILANE reaction under the condition of solvent, and temperature of reaction is between 15-40 ℃; The head product that obtains is with methyl alcohol: methylene dichloride=1: 20 is that purification by silica gel column chromatography gets product 3e under the condition of eluent;
3e is a condensing agent at EDCI, HOBt, DIPEA be under the condition of organic bases with amine react 3f, temperature of reaction is between 15-40 ℃, solvent is DMF;
3f is being solvent with the tetrahydrofuran (THF), under the tetrabutyl fluoride amine condition, sloughs tertiary butyl dimethylsilane group, and the head product that obtains is with methyl alcohol: methylene dichloride=1: 10 is that purification by silica gel column chromatography gets product and gets 3g under the condition of eluent;
Wherein, the Ar in the reaction formula is
R wherein
4Definition identical with claim 2; R
1, R
2, R
3, W and n definition identical with claim 2.
7. the preparation method of benzyl piperidine coumpound as claimed in claim 3 is characterized in that, may further comprise the steps:
4a and amine react 4b, temperature of reaction is between 60-120 ℃, solvent is a Virahol, the gained head product is at methyl alcohol: methylene dichloride=1: 15 gets 4b for carrying out purification by silica gel column chromatography under the condition of eluent;
4b sloughs Boc under the acidic conditions of 4-dioxane and gets 4c at 4N HCl/1, and temperature of reaction is between 15-40 ℃;
4c is a condensing agent at EDCI, HOBt, and DIPEA is under the condition of organic bases and acid-respons, and temperature of reaction is between 15-40 ℃, and solvent is DMF, and the gained head product is at methyl alcohol: methylene dichloride=1: 10 gets 4d for purification by silica gel column chromatography under the condition of eluent;
Wherein, the Ar in the reaction formula is
R wherein
4Definition identical with claim 3; R
1, R
2, R
3, W and n definition identical with claim 3.
8. as claim 1 or 2 or 3 or 4 described benzyl piperidine coumpounds or the application in preparation treatment presenile dementia disease medicament of its pharmacy acceptable salt as beta-secretase and acetylcholinesterase double inhibitor.
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| Roy K. Hom, et al..Design and Synthesis of Hydroxyethylene-BasedPeptidomimetic Inhibitors of Human β-Secretase.J. Med. Chem.47 1.2003,47(1),158-164. * |
| 肖坤等.β-分泌酶抑制剂的研究进展.中国药物化学杂志16 4.2006,16(4),246-252. |
| 肖坤等.β-分泌酶抑制剂的研究进展.中国药物化学杂志16 4.2006,16(4),246-252. * |
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