CN103006647B - Use of 3-amido-2-pyridone derivative - Google Patents
Use of 3-amido-2-pyridone derivative Download PDFInfo
- Publication number
- CN103006647B CN103006647B CN201310000027.6A CN201310000027A CN103006647B CN 103006647 B CN103006647 B CN 103006647B CN 201310000027 A CN201310000027 A CN 201310000027A CN 103006647 B CN103006647 B CN 103006647B
- Authority
- CN
- China
- Prior art keywords
- acid
- add
- compound
- reaction
- meoc
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- GFFIJCYHQYHUHB-UHFFFAOYSA-N CC(SCC[N+](C)(C)C)=O Chemical compound CC(SCC[N+](C)(C)C)=O GFFIJCYHQYHUHB-UHFFFAOYSA-N 0.000 description 1
- 0 C[N+](C)(C)CC* Chemical compound C[N+](C)(C)CC* 0.000 description 1
- VFUGTBZQGUVGEX-UHFFFAOYSA-O C[N+](C)(C)CCS Chemical compound C[N+](C)(C)CCS VFUGTBZQGUVGEX-UHFFFAOYSA-O 0.000 description 1
- AAZABRCHEPPECE-UHFFFAOYSA-N Cc(cc1)ccc1C(C=CN(c1ccccc1)C1=O)=C1N Chemical compound Cc(cc1)ccc1C(C=CN(c1ccccc1)C1=O)=C1N AAZABRCHEPPECE-UHFFFAOYSA-N 0.000 description 1
- NBUUUJWWOARGNW-UHFFFAOYSA-N Cc(cc1C(O)=O)ccc1N Chemical compound Cc(cc1C(O)=O)ccc1N NBUUUJWWOARGNW-UHFFFAOYSA-N 0.000 description 1
- BQUOLAGKIGZUPV-UHFFFAOYSA-N NC(C(N(C=C1)c2cccc(Br)c2)=O)=C1c1ccccc1 Chemical compound NC(C(N(C=C1)c2cccc(Br)c2)=O)=C1c1ccccc1 BQUOLAGKIGZUPV-UHFFFAOYSA-N 0.000 description 1
- ZVRPTAZJTNILBB-UHFFFAOYSA-N NC(C(N(C=C1)c2ccccc2)=O)=C1c(cc1)ccc1F Chemical compound NC(C(N(C=C1)c2ccccc2)=O)=C1c(cc1)ccc1F ZVRPTAZJTNILBB-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of pharmaceutical chemistry, in particular relates to a medical use of a 3-amido-2-pyridone compound, and a pharmaceutical composition containing such a compound, and especially an application as a cholinesterase inhibitor. Pharmacological experiments show such a compound has good cholinesterase inhibition activity, and has favorable application prospects in the field of treating Alzheimer disease, schizophrenia, chronic brain damage, facial paralysis, hemiplegia and the like.
Description
Technical field
The present invention relates to the purposes of a class 3-Amino-2-pyridone analog derivative for the preparation of medicine, be specifically related to its purposes as cholinesterase inhibitor class medicine.
Background technology
Alzheimer's disease (Alzheimer ' s disease, AD) claim that again senile dementia is a kind of disease taking chronic, carrying out property nerve degeneration as feature occurring in the geratic period, its clinical manifestation is mainly memory, cognition, language, behavior disorder and personality changes etc.Along with the arrival of aging society, its sickness rate grows with each passing day, and has now become the fourth-largest disease that causes old people's death after tumor, heart disease, cerebrovascular.
Have multiple theory about the mechanism of causing a disease of AD, wherein comparatively the cholinergic theory of main flow thinks that AD brain in patients interior neurotransmitter-acetylcholine disappearance causes AD cognitive function of patients to decline, and memory ability is lost.Use cholinesterase inhibitor to improve AD patient's choline levels, by universally recognized class of medications.In human body, there are 2 kinds of enzyme hydrolysis acetylcholine, i.e. acetylcholinesterase (AChE also claims true cholinesterase) and butyrylcholine esterase (BuChE also claims pseudocholinesterase).At present mostly be selectivity AChE inhibitor for clinical cholinesterase inhibitor, but periphery side effect is larger, long-term treatment effect is undesirable.Recently study and show, selectivity BuChE inhibitor can make extracellular acetylcholine concentration increase by 15 times, and does not find choline-like side effect.Therefore, find the double inhibitor of BuChE selective depressant or AChE and BuChE, the treatment that can be AD provides new strategy.Part 3-Amino-2-pyridone analog derivative in this patent is to the selective inhibitory action of BuChE, part 3-Amino-2-pyridone analog derivative has double inhibition effect to AChE and BuChE, the double inhibitor that is expected to become BuChE selective depressant or AChE and BuChE, has a good application prospect.
Summary of the invention
The present invention uses substituted aniline, alkynes aldehyde derivatives, diphenyl methylene glycine ethyl ester to do at NaH to react under the condition of catalyst, prepare after the 3-Amino-2-pyridone analog derivative that N replaces hydrolysis under acid condition again and obtain compound of Formula I, its reaction equation is as follows:
R in compound of Formula I
1for Ph or 3-F-C
6h
4, 3-F-C
6h
4, 3-Cl-C
6h
4, 4-Cl-C
6h
4, 3-Br-C
6h
4, 2,4-2Cl-C
6h
3, 3,4-2Cl-C
6h
3, 3-F-4-Cl-C
6h
3, 4-MeOC
6h
4, 3-MeOC
6h
4, 3-NH
2c
6h
4deng the phenyl ring that contains different substituents; R
2represent Ph or 4-Me-C
6h
4, 4-MeOC
6h
4, 3,4-MeOC
6h
4, 4-Cl-C
6h
4, 3-Cl-C
6h
4, 2-Cl-C
6h
4, 4-F-C
6h
4deng the phenyl ring that contains different substituents and 2-naphthyl, 2-furanyl, Alkyl etc.
According to the present invention, pharmaceutically acceptable salt comprises the acid-addition salts that compound of Formula I and following acid form: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, LOMAR PWA EINECS 246-676-2, citric acid, tartaric acid, lactic acid, acetone acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid.Comprise in addition the acid salt of inorganic base, as: alkalinous metal cation, alkaline earth metal cation, ammonium cation salt contained.
General formula (I) compound is following structural compounds preferably:
3-amino-Isosorbide-5-Nitrae-diphenyl pyridin-2-ones (Ia)
3-amino-1-(3-fluorophenyl)-4-phenylpyridine-2-ketone (Ib)
3-amino-1-(3-chlorphenyl)-4-phenylpyridine-2-ketone (Ic)
3-amino-1-(4-chlorphenyl)-4-phenylpyridine-2-ketone (Id)
3-amino-1-(3-bromophenyl)-4-phenylpyridine-2-ketone (Ie)
3-amino-1-(2,4-Dichlorobenzene base)-4-phenylpyridine-2-ketone (If)
3-amino-1-(3,4-Dichlorobenzene base)-4-phenylpyridine-2-ketone (Ig)
3-amino-1-(the chloro-3-fluorophenyl of 4-)-4-phenylpyridine-2-ketone (Ih)
3z amino-1-(4-methoxyphenyl)-4-phenylpyridine-2-ketone (Ii)
3-amino-1-(3-methoxyphenyl)-4-phenylpyridine-2-ketone (Ij)
3-amino-1-(3-aminophenyl)-4-phenylpyridine-2-ketone (Ik)
3-amino-4-(4-fluorophenyl)-1-phenylpyridine-2-ketone (Il)
3-amino-4-(3-chlorphenyl)-1-phenylpyridine-2-ketone (Im)
3-amino-4-(4-aminomethyl phenyl)-1-phenylpyridine-2-ketone (In)
3-amino-4-(3-aminomethyl phenyl)-1-phenylpyridine-2-ketone (Io)
3-amino-4-(4-methoxyphenyl)-1-phenylpyridine-2-ketone (Ip)
Concrete synthesis step is:
By amine, alkynes aldehyde derivatives mixes, and reacts 30 minutes under condition of no solvent, adds diphenyl methylene glycine ethyl ester, adds anhydrous methylene chloride, after question response thing dissolves completely, adds catalyst sodium hydride, and room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains corresponding 3-Amino-2-pyridone compounds.
This reaction initiation material is easy to get, and mild condition has selected one pot of throwing method to react, and synthetic route is brief, easy to operate, and productive rate reaches more than 85%, and has saved the purge process of intermediate compound, has reduced cost.The 3-Amino-2-pyridone compounds synthetic by this method has good cholinesterase inhibition, has good application prospect in fields such as treatment Alzheimer, schizophrenia, chronic brain injury, facial paralysis, hemiplegias.
Better reaction condition of the present invention is:
(1) catalyst is sodium hydride;
(2) molar ratio of amine, alkynes aldehyde derivatives, diphenyl methylene glycine ethyl ester, sodium hydride is 1.2: 1.2: 1: 0.5;
(2) solvent is anhydrous methylene chloride;
(3) reaction temperature is room temperature.
The compounds of this invention can prepare by above-mentioned or similar above-mentioned preparation method, selects corresponding raw material according to substituent difference is different with substituting group position.
Pharmacology test result shows, compound of Formula I and pharmaceutically acceptable salt thereof all have inhibitory action in various degree to external acetylcholine esterase, therefore, compound of Formula I and pharmaceutically acceptable salt thereof can be used for the treatment of the clinical disease relevant with cholinesterase inhibitor.The described disease relevant with cholinesterase inhibitor can be Alzheimer, schizophrenia, chronic brain injury, facial paralysis, hemiplegia etc.
Part pharmacology test and result below:
[medicine and reagent]
1.AChE(500unit,E.C.3.1.1.7,Type?VI-S,from?Electric?Eel,Sigma-Aldrich)
2.BuChE(500unit,E.C.3.1.1.8,from?equine?serum,Sigma-Aldrich)
Two (2-nitrobenzoic acid) (5,5 '-Dithiobis (2-nitrobenzoic acid), DTNB, J & K Chemical) of 3.5,5 '-bis-sulfur
4. acetyl thio choline (ATC) iodide and Butyryl thiocholine (BTC) iodide (J & K Chemical)
5.DMSO(Sigma-Aldrich)
[experimental principle]
Adopt the outer cholinesterase inhibition of Ellman method test target object, experimental principle is under the buffer solution condition of pH=8, AChE and BuChE can be hydrolyzed to thiocholine by ATC and BTC respectively rapidly, thiocholine can react with DTNB fast thereupon and generate 5-sulfydryl-2-nitrobenzoyl with strong uv absorption, therefore can measure its concentration with ultraviolet spectrophotometry, and then can calculate the maximum inhibition of AChE and BuChE.
[experimental implementation]
(1) preparation buffer solution.13.6g potassium dihydrogen phosphate is dissolved in 1L water, regulates pH=8 ± 0.1 with potassium hydroxide.Be stored in 4 DEG C for subsequent use.
(2) take DTNB 10.8mg for subsequent use in 50mg centrifuge tube, take substrate A TC/BTC 3.5mg for subsequent use in 5ml centrifuge tube.
(3) preparation enzymatic solution.The AChE/BuChE of 500U/ml is dissolved in the gel solution of 1mL 1%, is then diluted with water to 100mL and makes the AChE/BuChE solution that concentration is 5U/mL, be stored in-30 DEG C for subsequent use.
(4) preparation tested material solution.Tested material is dissolved in in DMSO, to make concentration be 10
-2the mother liquor solution of M, then makes respectively the tested material solution of variable concentrations with buffer solution dilution, be stored in-30 DEG C for subsequent use.
When experiment, after being ready to, enzyme (0.25U/ml) is stored in ice chest, then dissolve preprepared DTNB (10.8mg) with 18ml buffer, after dissolving, join immediately in 96 orifice plates, every hole 160 μ l add successively enzyme after adding, every hole 50 μ l, add again the test compounds 10 μ l of respective concentration, incubate at 37 DEG C and bathe 5min.After incubating and bathing and finish, preprepared substrate A CT/BTC (3.5mg) is dissolved in 3.5ml buffer, joins fast successively that in reacting hole, (30 μ l).Under 405nm, test the ultraviolet absorptivity in 0~10min.Blank replaces tested material solution and enzymatic solution with isometric water, and negative control replaces tested material solution to record with isometric water.Measured result GraphPad Prism
tM(GraphPad Software, San Diego, CA, USA) software calculates corresponding IC with non-linear decline analytical model
50value.
[experimental result]
Scheme?1.AChE?and?BuChE?Inhibition?of?Test?Compounds
a,b
aData?is?the?mean?of?at?least?three?determinations.
b?All?values?are?the?mean±SEM.
Pharmacologically active test result shows, the compounds of this invention has good cholinesterase inhibition, part of compounds has selectivity butyrylcholine esterase and suppresses activity and acetylcholinesterase/butyrylcholine esterase dual restraining activities, be expected to become the double inhibitor of Butyrylcholinesterasselective selective inhibitors or acetylcholinesterase/butyrylcholine esterase, wherein R
1, R
2during for larger substituted aryl compound preferably selectivity suppress butyrylcholine esterase, have a good application prospect.For the clinical disease preventing or treatment is relevant with cholinesterase inhibitor, these diseases can be: the fields such as Alzheimer, schizophrenia, chronic brain injury, facial paralysis, hemiplegia.
Detailed description of the invention
The following examples are to further illustrate of the present invention, instead of limit the scope of the invention.
Fusing point shows micro melting point apparatus mensuration by X-4 numeral, and thermometer is not proofreaied and correct; 1HNMR completes (mark in TMS) by BRUKERACF-300 type nuclear magnetic resonance analyser and BRUKERAM-500 type nuclear magnetic resonance analyser; Infrared by FTIR-8400s type fourier-transform infrared spectrophotometric device mensuration.
Embodiment 1 Compound I a's is synthetic
By aniline (0.6mmol); 3-phenyl acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Ia, yield 92%, mp:58-59 DEG C.IR(KBr):v=3449,3049,2957,2924,2850,1699,1646,1580,1520,1498,1373,1072,765,741,698cm
-1.
1H?NMR(300MHz,CDCl
3)δ7.55-7.36(m,10H),6.87(d,J=7.0Hz,1H),6.23(d,J=7.1Hz,1H),4.51(s,2H).
Synthesizing of embodiment 2 compounds ibs
By 3-fluoroaniline (0.6mmol); 3-phenyl acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Ib, yield 81%, mp:64-66 DEG C.IR(KBr):v=3473,3419,3345,3050,2955,2922,2850,1699,1652,1647,1637,1617,1577,1567,1561,1518,1509,1499,1459,1313,746,706.
1H?NMR(500MHz,CDCl
3)δ7.51(d,J=17.8Hz,7H),7.39-7.14(m,2H),6.84(d,J=6.2Hz,1H),6.23(d,J=6.0Hz,1H),4.54(s,2H).
Embodiment 3 Compound I c's is synthetic
By 3-chloroaniline (0.6mmol); 3-phenyl acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Ic, yield 86%, mp:76-77 DEG C.IR(KBr):v=3460,3420,3055,1698,1644,1578,1518,1491,1374,1091,1013,826,742,699cm
-1.
1H?NMR(500MHz,CDCl
3)δ7.55-7.47(m,5H),7.44-7.36(m,4H),6.83(d,J=7.1Hz,1H),6.24(d,J=7.1Hz,1H),4.53(s,2H).
Embodiment 4 Compound I d's is synthetic
By 4-chloroaniline (0.6mmol); 3-phenyl acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Id, yield 97%, mp:148-149 DEG C.IR(KBr):v=3470,3423,3055,1699,1644,1578,1518,1491,1374,1091,1013,826,742,700cm
-1.
1H?NMR(500MHz,CDCl
3)δ7.54-7.46(m,6H),7.42-7.37(m,3H),6.82(d,J=7.1Hz,1H),6.23(d,J=7.1Hz,1H),4.41(s,2H).
Embodiment 5 Compound I e's is synthetic
By 3-bromaniline (0.6mmol); 3-phenyl acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Ie, yield 92%, mp:61-62 DEG C.IR(KBr):v=3441,3316,3060,2967,2921,2849,1699,1654,1593,1579,1570,1562,1519,1475,1375,1242,741,705cm
-1.
1H?NMR(500MHz,CDCl
3)δ7.64(t,J=1.8Hz,1H),7.57-7.47(m,5H),7.43-7.36(m,3H),6.82(d,J=7.1Hz,1H),6.23(d,J=7.1Hz,1H),4.53(s,2H).
Embodiment 6 Compound I f's is synthetic
By 2; 4-dichloroaniline (0.6mmol); 3-phenyl acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely, add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid If, yield 95%, mp:197-198 DEG C.IR(KBr):v=3459,3429,3347,3315,3056,3029,2923,2851,1699,1647,1610,1581,1570,1561,1518,1477,1376,1317,1099,804,766,701.1
H?NMR(500MHz,CDCl
3)δ7.59(d,J=1.1Hz,1H),7.56-7.48(m,4H),7.41-7.34(m,3H),6.65(d,J=7.1Hz,1H),6.25(d,J=7.1Hz,1H),4.51(s,2H).
Embodiment 7 Compound I g's is synthetic
By 3; 4-dichloroaniline (0.6mmol); 3-phenyl acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely, add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Ig, yield 94%, mp:124-125 DEG C.IR(KBr):v=3433,3331,3069,2925,2851,1699,1654,1579,1519,1475,1391,1365,1308,1030,834,754,699.
1H?NMR(500MHz,CDCl
3)δ7.61(d,J=2.2Hz,1H),7.58(d,J=8.5Hz,1H),7.53-7.48(m,4H),7.39(t,J=7.0Hz,1H),7.35(dd,J=8.5,2.4Hz,1H),6.80(d,J=7.1Hz,1H),6.24(d,J=7.2Hz,1H),4.32(s,2H).
Embodiment 8 Compound I h's is synthetic
By chloro-4-3-fluoroaniline (0.6mmol); 3-phenyl acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Ih, yield 82%, mp:146-147 DEG C.IR(KBr):v=3435,3081,2925,1701,1654,1647,1636,1625,1617,1611,1559,1519,1068,755,696.
1H?NMR(500MHz,CDCl
3)δ7.55-7.48(m,5H),7.39(t,J=7.1Hz,1H),7.34(dd,J=9.4,2.3Hz,1H),7.23(d,J=8.4Hz,1H),6.81(d,J=7.2Hz,1H),6.24(d,J=7.2Hz,1H).4.53(s,2H).
Embodiment 9 Compound I i's is synthetic
By 4-aminoanisole (0.6mmol); 3-phenyl acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Ii, yield 95%, mp:177-178 DEG C.IR(KBr):v=3466,3422,3349,3307,3054,2962,2920,2841,1703,1645,1639,1562,1510,1440,1247,1026,830,748,697.
1H?NMR(500MHz,CDCl
3)δ7.55-7.47(m,4H),7.39-7.34(m,3H),7.02-6.99(m,2H),6.84(d,J=7.1Hz,1H),6.20(d,J=7.1Hz,1H),4.52(s,1H),3.86(s,3H).
Embodiment 10 Compound I j's is synthetic
By 3-aminoanisole (0.6mmol); 3-phenyl acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Ij, yield 96%, mp:65-66 DEG C.IR(KBr):v=3293,3064,2839,1698,1683,1653,1578,1560,1491,1457,1324,1034,769,739,702.
1H?NMR(500MHz,CDCl
3)δ7.54(d,J=7.6Hz,2H),7.49(t,J=7.7Hz,2H),7.41-7.36(m,2H),7.04-6.95(m,3H),6.86(d,J=7.1Hz,1H),6.21(d,J=7.1Hz,1H),4.53(s,2H),3.85(s,3H).
Embodiment 11 Compound I k's is synthetic
By 1; 3-o-phenylenediamine (0.6mmol); 3-phenyl acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely, add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Ik, yield 80%, mp:163-164 DEG C.IR(KBr):v=3412,3416,3347,3080,3052,2922,2851,1699,1651,1637,1578,1560,1519,1507,1460,1314,746,706.
1H?NMR(500MHz,CDCl
3)δ7.54(d,J=7.3Hz,2H),7.49(t,J=7.6Hz,2H),7.38(t,J=7.3Hz,1H),7.25-7.22(m,1H),7.18-7.13(m,1H),6.88(t,J=7.0Hz,2H),6.81(d,J=7.1Hz,1H),6.26(d,J=7.1Hz,1H),4.54(s,2H),3.90(s,2H).
Embodiment 12 Compound I l's is synthetic
By aniline (0.6mmol); 3-(4-fluorophenyl)-acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Il, yield 97%, mp:61-62 DEG C.IR(KBr):v=3448,3408,3289,3064,2923,2848,1683,1645,1594,1575,1508,1454,1218,1157,840,752,694.
1H?NMR(500MHz,CDCl
3)δ7.54-7.49(m,4H),7.45-7.41(m,3H),7.20-7.16m,2H),6.86(d,J=7.1Hz,1H),6.18(d,J=7.1Hz,1H),4.39(s,2H).
Embodiment 13 Compound I m's is synthetic
By aniline (0.6mmol); 3-(3-chlorphenyl)-acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Im, yield 95%, mp:55-56 DEG C.IR(KBr):v=3418,3307,3074,2917,2848,1700,1654,1649,1609,1576,1559,1521,1513,1507,1496,1456,1359,1298,1247,779,768.
1H?NMR(500MHz,CDCl
3)δ7.53-7.49(m,3H),7.45-7.41(m,5H),7.37-7.35(m,1H),6.86(d,J=7.1Hz,1H),6.18(d,J=7.1Hz,1H),4.55(s,2H).
Embodiment 14 Compound I n's is synthetic
By aniline (0.6mmol); 3-(4-aminomethyl phenyl)-acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Im, yield 98%, mp:77-78 DEG C.IR(KBr):v=3307,3055,2963,2923,2841,1699,1646,1639,1617,1582,1570,1561,1509,1499,1442,1293,1247,1026,830,748,697.
1H?NMR(500MHz,CDCl
3)δ7.51-7.40(m,7H),7.30(d,J=7.9Hz,2H),6.85(d,J=7.1Hz,1H),6.21(d,J=7.1Hz,1H),4.46(s,2H),2.41(s,3H).
Embodiment 15 Compound I o's is synthetic
By aniline (0.6mmol); 3-(3-aminomethyl phenyl)-acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Io, yield 97%, mp:50-51 DEG C.IR(KBr):v=3448,3074,2917,2848,1685,1654,1648,1637,1576,1522,1496,1260,777,760,696.
1H?NMR(500MHz,CDCl
3)δ7.50(t,J=7.7Hz,2H),7.46-7.40(m,3H),7.39-7.32(m,3H),7.19(d,J=7.3Hz,1H),6.85(d,J=7.1Hz,1H),6.21(d,J=7.1Hz,1H),4.50(s,2H),2.42(s,3H).
Embodiment 16 Compound I p's is synthetic
By aniline (0.6mmol); 3-(4-methoxyphenyl)-acraldehyde (0.6mmol) mixes; under nitrogen protection, under condition of no solvent, react 30 minutes; add diphenyl methylene glycine ethyl ester (0.5mmol); after adding solvent anhydrous methylene chloride question response thing to dissolve completely; add catalyst sodium hydride, room temperature reaction is substantially complete to reaction.Add the 0.5mol/L HCl reaction that is hydrolyzed, after reacting completely, add saturated sodium bicarbonate solution cancellation, ethyl acetate extraction, column chromatography obtains white solid Ip, yield 98%, mp:67-68 DEG C.IR(KBr):v=3453,3051,2956,2918,2849,1699,1647,1610,1579,1513,1465,1253,1173,1026,830,753,694.
1H?NMR(500MHz,CDCl
3)δ7.51-7.46(m,4H),7.45-7.40(m,3H),7.02(d,J=8.5Hz,2H),6.85(d,J=7.1Hz,1H),6.20(d,J=7.1Hz,1H),4.43(s,2H),3.86(s,3H)。
Claims (3)
1. following general formula I compound and its pharmaceutically acceptable salt, and the purposes of the pharmaceutical composition that contains compound of Formula I and its pharmaceutically acceptable salt in the medicine for the preparation of prevention or the treatment disease relevant with cholinesterase inhibitor:
R
1for Ph or 3-F-C
6h
4, 3-Cl-C
6h
4, 4-Cl-C
6h
4, 3-Br-C
6h
4, 2,4-2Cl-C
6h
3, 3,4-2Cl-C
6h
3, 3-F-4-Cl-C
6h
3, 4-MeOC
6h
4, 3-MeOC
6h
4, 3-NH2C
6h
4;
R
2for Ph or 4-Me-C
6h
4, 4-MeOC
6h
4, 4-Cl-C
6h
4, 4-F-C
6h
4.
2. purposes according to claim 1, wherein pharmaceutically acceptable salt is selected from the acid-addition salts of compound of Formula I and following acid formation: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, LOMAR PWA EINECS 246-676-2, citric acid, tartaric acid, lactic acid, acetone acid, acetic acid, maleic acid or benzenesulfonic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.
3. purposes according to claim 1, wherein the disease relevant with cholinesterase inhibitor is Alzheimer, schizophrenia, chronic brain injury, facial paralysis, hemiplegia.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310000027.6A CN103006647B (en) | 2013-01-04 | 2013-01-04 | Use of 3-amido-2-pyridone derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310000027.6A CN103006647B (en) | 2013-01-04 | 2013-01-04 | Use of 3-amido-2-pyridone derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103006647A CN103006647A (en) | 2013-04-03 |
CN103006647B true CN103006647B (en) | 2014-09-10 |
Family
ID=47956113
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310000027.6A Expired - Fee Related CN103006647B (en) | 2013-01-04 | 2013-01-04 | Use of 3-amido-2-pyridone derivative |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103006647B (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101255134A (en) * | 2008-04-08 | 2008-09-03 | 温州医学院 | Aryl pyridine compounds and medicament uses thereof |
CN101440061A (en) * | 2008-04-08 | 2009-05-27 | 温州医学院 | Arylpyridone derivatives with acetylcholine esterase inhibition activity |
-
2013
- 2013-01-04 CN CN201310000027.6A patent/CN103006647B/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101255134A (en) * | 2008-04-08 | 2008-09-03 | 温州医学院 | Aryl pyridine compounds and medicament uses thereof |
CN101440061A (en) * | 2008-04-08 | 2009-05-27 | 温州医学院 | Arylpyridone derivatives with acetylcholine esterase inhibition activity |
Also Published As
Publication number | Publication date |
---|---|
CN103006647A (en) | 2013-04-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2774510T3 (en) | 1,3,4-Oxadiazole sulfamide derivatives as histone deacetylase 6 inhibitors and pharmaceutical composition comprising the same | |
US20210032207A1 (en) | Quinolone compound | |
Lan et al. | Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer’s disease | |
Knez et al. | Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents | |
CZ2004634A3 (en) | Quinoline compound, process for its preparation and pharmaceutical composition in which the compound is comprised | |
Derabli et al. | A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives | |
CA2400368A1 (en) | Catechol diethers as selective pde iv inhibitors | |
CA2763960C (en) | Bicyclic and tricyclic compounds as kat ii inhibitors | |
Hamdani et al. | Synthesis, crystal structures, computational studies and α-amylase inhibition of three novel 1, 3, 4-oxadiazole derivatives | |
Abdullah et al. | Design, synthesis, molecular docking, anti-Proteus mirabilis and urease inhibition of new fluoroquinolone carboxylic acid derivatives | |
Ozadali-Sari et al. | Novel multi-targeted agents for Alzheimer's disease: Synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl) phenyl] benzimidazoles | |
Le-Nhat-Thuy et al. | Synthesis and biological evaluation of novel quinazoline-triazole hybrid compounds with potential use in Alzheimer’s disease | |
BRPI0616452B1 (en) | quinolines and their therapeutic use | |
JPH06500794A (en) | Heterocyclic-cyclic amine derivatives | |
JPH04312584A (en) | Aryl (or heteroaryl) piperazinylalkylazole derivatives, method of manufacturing same and use thereof for medicinal use | |
Bhagat et al. | Novel series of triazole containing coumarin and isatin based hybrid molecules as acetylcholinesterase inhibitors | |
CN105524043B (en) | Lactams histon deacetylase (HDAC) inhibitor | |
Bajda et al. | Novel carbamate derivatives as selective butyrylcholinesterase inhibitors | |
CN111410659A (en) | PDE9 inhibitors and uses thereof | |
Ullah et al. | Synthesis of substituted benzohydrazide derivatives: In vitro urease activities and their molecular docking studies | |
Pashaei et al. | Synthesis and molecular dynamic simulation studies of novel N-(1-benzylpiperidin-4-yl) quinoline-4-carboxamides as potential acetylcholinesterase inhibitors | |
Shatsauskas et al. | Synthesis of benzo [c][1, 7] naphthyridine derivatives | |
CN103006647B (en) | Use of 3-amido-2-pyridone derivative | |
KR101679262B1 (en) | 4-Isopropylchroman-3-ol derivatives | |
Muscia et al. | Synthesis and evaluation of 2-(1H-indol-3-yl)-4-phenylquinolines as inhibitors of cholesterol esterase |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140910 Termination date: 20180104 |