CN102526052A - Application of 2-gylcosyl chinoline compound in preparing acetylcholine esterase resisting medicines - Google Patents

Application of 2-gylcosyl chinoline compound in preparing acetylcholine esterase resisting medicines Download PDF

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CN102526052A
CN102526052A CN2012100191936A CN201210019193A CN102526052A CN 102526052 A CN102526052 A CN 102526052A CN 2012100191936 A CN2012100191936 A CN 2012100191936A CN 201210019193 A CN201210019193 A CN 201210019193A CN 102526052 A CN102526052 A CN 102526052A
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chemical compound
glycosyl
quinoline
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application
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CN102526052B (en
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龙玉华
张寒梅
刘真权
周亭
邹致富
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South China Normal University
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Abstract

The invention discloses application of 2-gylcosyl chinoline compound in preparing acetylcholine esterase resisting medicines. The 2-gylcosyl chinoline compound is of a structural formula as shown in formula (I), wherein R1, R2, R3 and R4 independently choose -H, -OCH3 or -Br. A preparation method of the 2-gylcosyl chinoline compound can be produced according to the prior art. The 2-gylcosyl chinoline compound is strong in dissolubility in water, high in biological utilization, strong in restrain activity on acetylcholine esterase and wide in application prospect on preparing acetylcholine esterase resisting medicines. The 2-gylcosyl chinoline compound is simple in preparation path, low in cost, small in environment pollution and suitable for large-scale industrial production.

Description

The application of a kind of 2-glycosyl quinoline chemical compound in the preparation anti-acetylcholinesterasemedicine medicine
Technical field
The invention belongs to medicine and chemical field, be specifically related to the application of a kind of 2-glycosyl quinoline chemical compound in the preparation anti-acetylcholinesterasemedicine medicine.
Background technology
Alzheimer (Alzheimer ' s disease, AD), promptly alzheimer disease or presenile dementia are that a kind of the infringement with cognitive disorder of carrying out property and memory is master's central nervous system degenerative disease.This sick main clinical manifestation is that memory ability goes down, and the decline of persistence cognitive competence and the dyskinesia, can lose independent living ability etc. gradually when serious, and is attended by a series of psychotic symptoms.Prevalence research shows that the U.S. is 4,500,000 at Alzheimer case number in 2000.Every increase of age 5 years old, Alzheimer patient's percent will be risen 2 times.At present, the AD disease has become the healthy disease of second largest threat person in middle and old age except that cardiovascular and cerebrovascular disease.
About this sick pathogeny several kinds of hypothesis are arranged, wherein nineteen eighty-two Bartus and partner propose the disorderly cholinergic hypothesis of memory function and are generally admitted.This hypothesis thinks that it is the main mechanism of AD morbidity that the cholinergic nerve function reduces.Cholinergic nerve is the easiest to be impaired in patient's brain, and along with PD, 90% cholinergic neuron all can be destroyed, and makes acetylcholine (Ach) level reduction in the brain, and the reduction degree is significantly relevant with the reduction of patient's cognitive competence, and continues the whole course of disease.Go down active inseparable with Acetylcholinesterase (AChE) of acetylcholine systemic-function.Therefore prepare and the discovery novel structure, active strong acetylcholinesteraseinhibitors inhibitors, significant.
Quinoline is a kind of active chemical compound of good biological that has, and its derivant is widely used in field of medicaments.Nagarajan etc. are at Carbohydrate Research [J] .2009; 1028-1031 discloses the one-pot synthesis method of 2-glycosyl quinoline chemical compound; But,, particularly be applied to prepare anti-acetylcholinesterasemedicine medicine and do not see that report is arranged for 2-glycosyl quinoline application of compound.
Summary of the invention
The objective of the invention is to overcome the deficiency of prior art, the application of 2-glycosyl quinoline chemical compound in the preparation anti-acetylcholinesterasemedicine medicine is provided.Said 2-glycosyl quinoline chemical compound has significant acetylcholine esterase inhibition activity, aspect the preparation anti-acetylcholinesterasemedicine medicine, has broad application prospects.
Above-mentioned purpose of the present invention is achieved through following technical scheme:
The application of a kind of 2-glycosyl quinoline chemical compound in the preparation anti-acetylcholinesterasemedicine medicine, said 2-glycosyl quinoline chemical compound has suc as formula structural formula shown in (I):
Figure BDA0000132370210000021
Wherein, R 1, R 2, R 3And R 4Independently be selected from-H ,-OCH 3Or-Br.
As a kind of preferred version, said 2-glycosyl quinoline chemical compound is preferably:
R 1, R 2, R 3And R 4Be-formula (I) chemical compound of H;
Or R 2And R 3For-H, R 1And R 4For-OCH 3Formula (I) chemical compound;
Or R 1And R 4For-H, R 2And R 3For-OCH 3Formula (I) chemical compound;
Or R 2And R 4For-Br, R 1And R 3Formula (I) chemical compound for-H.
The method for preparing of said 2-glycosyl quinoline chemical compound comprises the steps:
(1) under the effect of sodium bicarbonate, D-glucose and acetylacetone,2,4-pentanedione generate β-D-acetonyl Fructus Vitis viniferae carbon glycosides;
(2) with o-Aminobenzaldehyde or substituted o-Aminobenzaldehyde and β-D-acetonyl Fructus Vitis viniferae carbon glycosides with dissolve with methanol, in the presence of pyrrolidine, react, obtain said 2-glycosyl quinoline chemical compound.
As a kind of most preferably scheme, in the step (2), the consumption of said pyrrolidine most preferably is the 25mol% with respect to o-Aminobenzaldehyde or substituted o-Aminobenzaldehyde consumption.
As a kind of most preferably scheme, in the step (2), the temperature of said reaction most preferably is 60～120 ℃.
As a kind of preferred version, the said 2-glycosyl quinoline chemical compound that step (2) prepares can carry out purification through crossing post, and crossing the used eluent of post is that volume ratio is an ethyl acetate: isopropyl alcohol: the mixed solution of water=16: 2: 1.
The method for preparing of 2-glycosyl quinoline chemical compound according to the invention also can be with reference to prior art such as Carbohydrate Research [J] .2009, and the method for 1028-1031 is carried out.
Compared with prior art; The present invention has following beneficial effect: 2-glycosyl quinoline chemical compound according to the invention dissolubility in water is strong, and bioavailability is high, and it has strong inhibition active to Acetylcholinesterase; Aspect the preparation anti-acetylcholinesterasemedicine medicine, have broad application prospects; The preparation route of said 2-glycosyl quinoline chemical compound is simple, with low cost, and environmental pollution is little, is fit to carry out large-scale industrial production.
The specific embodiment
Below in conjunction with specific embodiment the present invention is described further, but specific embodiment is not done any qualification to the present invention.
Synthesizing of embodiment 1 intermediate β-D-acetonyl Fructus Vitis viniferae carbon glycosides
The preparation route:
Figure BDA0000132370210000041
Take by weighing D-glucose 1～5g and sodium bicarbonate 0.5～2.5g places round-bottomed flask, add distilled water and also under room temperature, stir 10～30min, add 1～5g acetylacetone,2,4-pentanedione then and in 50～120 ℃ of oil baths, stirs and react 2～10h down.Stopped reaction, cooling are then with the carbon dichloride extraction, and using dilute hydrochloric acid to transfer pH is 7, and decompression removes to anhydrate and adds methanol then, and inorganic salt is separated out because of being insoluble to methanol, and filtration can be removed (also can remove through crossing silicagel column).Again removal of solvent under reduced pressure get final product product.Yield is about 77%, m.p:122～124 ℃.
Embodiment 2, compd A 1 synthetic
The preparation route:
Take by weighing 2-aminobenzaldehyde 0.5mmol and β-acetonyl heteroside 0.5mmol in round-bottomed flask, add methanol, stir under the room temperature and make it dissolving.Add 25mol% pyrrolidine (with respect to the 2-aminobenzaldehyde), under 60～120 ℃ of oil baths, with TLC follow the tracks of reaction to reaction do not change till.Stopped reaction and cooling, decompression removes the solvent in the dereaction, uses ethyl acetate: isopropyl alcohol: water=16: 2: 1 (v/v/v) is crossed post and is got net product.
White solid; M.p:257-258 ℃; IR (KBr, cm -1): 3482 (vs), 3385 (s), 3329 (s), 3104 (m), 2908 (m), 1601 (m), 1563 (w), 1427 (m), 1298 (s), 1127 (m), 1088 (vs), 1033 (s), 838 (m), 763 (m); 1H NMR (DMSO-d 6): δ 8.23 (dd, J=2.8Hz, J=5.2Hz, 1H, Ar-H), 7.94 (t, J=7.2Hz, 2H, Ar-H), 7.72 (s, 1H; Ar-H), 7.55 (d, J=8.0Hz, 2H, Ar-H), 5.20 (s, 1H), 5.00 (s, 1H), 4.91 (s; 1H), 4.33 (s, H), 3.58 (s, 1H), 3.56 (s, 1H), 3.47 (s, 1H), 3.43 (s; 1H), 3.21 (s, 1H), 3.20 (s, 1H), 3.02 (s, 2H), 2.91 (t, J=16.0Hz, 2H); 13C NMR (DMSO-d 6): δ 161.0,147.6, and 136.1,129.7,128.8,128.1,127.0,126.1,123.1,81.0,79.6,78.6,74.5,70.8,61.6,41.7; ESI-MS m/zcalcd for C 16H 19NO 5([M+1] +): 305.13.Found ([M+1] +): 306.44, ([M+23] +): 328.41.Anal.Calcd for C 16H 19NO 5: C, 62.94; H, 6.27; N, 4.59; Found:C, 62.88; H, 6.34; N, 4.49.
Synthesizing of embodiment 3 compd As 2
Method for preparing is with embodiment 2, and difference is with 3, and 6-dimethoxy-2-aminobenzaldehyde replaces the 2-aminobenzaldehyde, obtains compd A 2.
Figure BDA0000132370210000051
White solid; M.p:121-122 ℃; IR (KBr, cm -1): 3522 (s), 3268 (s), 2871 (s), 1619 (s), 1604 (s), 1346 (s), 1263 (vs), 1117 (vs), 1090 (vs), 1043 (s), 908 (m), 723 (m); 1H NMR (DMSO-d 6): δ 8.33 (s, 1H, Ar-H), 7.52 (s, 1H, Ar-H), 7.02 (s, 1H, Ar-H); 6.85 (s, 1H, Ar-H), 5.25 (s, 1H), 4.96 (s, H), 4.88 (s; 1H), 4.30 (s, 1H), 4.15 (s, 1H), 3.89 (s, 3H), 3.88 (s; 3H), 3.17 (s, 2H), 3.09-2.97 (m, 3H), 2.87 (d, J=8.0H, 1H); 13C NMR (DMSO-d 6): δ 164.6,153.9,153.2,144.5,135.0,127.5,124.4,113.1,108.7,85.7,84.5,79.3,75.5,66.4,60.9,60.8.0,46.5; ESI-MS m/z calcd for C 18H 23NO 7([M+1] +): 365.15, Found: ([M+1] +): 366.44, ([M+23] +): 388.32, ([2M+23] +): 752.87; Anal.Calcd for C 18H 23NO 7: C, 59.17; H, 6.34; N, 3.83; Found:C, 59.25; H, 6.43; N, 3.77.
Embodiment 4, compound A-13 synthetic
Method for preparing is with embodiment 2, and difference is with 4, and 5-dimethoxy-2-aminobenzaldehyde replaces the 2-aminobenzaldehyde, obtains compound A-13.
Figure BDA0000132370210000061
White solid; M.p:122-123 ℃; IR (KBr, cm -1): 3400 (m), 2945 (m), 1703 (w), 1625 (m), 1509 (m), 1420 (m), 1256 (s), 1080 (m), 1002 (m), 856 (m); 1H NMR (DMSO-d6): δ 8.01 (d, J=8.0Hz, 1H, Ar-H), 7.31 (d, J=8.0Hz, 1H, Ar-H), 7.28 (s, 1H, Ar-H); 7.25 (s, Ar-H), 5.00 (s, 3H), 4.24 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.55 (s; 2H), 3.47 (d, J=8.0Hz, 4H), 3.35 (d, J=20.0Hz, 5H), 3.17 (t, J=8.0Hz, 3H), 3.08 (d; J=12.0Hz, 2H), 3.47 (t, J=8.0Hz, 4H), 2.99 (t, J=8.0Hz, 3H), 2.80 (t, J=8.0Hz, 2H); 13C NMR (DMSO-d 6): δ 158.1,152.3, and 149.2,144.4,134.5,122.2,120.9,107.7,105.9,80.9,79.7,78.6,74.4,70.8,61.6,56.0,49.0,43.4; ESI-MS m/z calcd for C 18H 23NO 7([M+1] +): 365.15.Found: ([M+1] +): 366.37, (2 [M+23] +): 753.04; Anal.Calcd for C 18H 23NO 7: C, 59.17; H, 6.34; N, 3.83; Found:C, 59.21; H, 6.39; N, 3.79.
Embodiment 5, compd A 4 synthetic
Method for preparing is with embodiment 2, and difference is with 3, and 5-two bromo-2-aminobenzaldehydes replace the 2-aminobenzaldehyde, obtain compd A 4.
Figure BDA0000132370210000071
White solid; M.p:164-165 ℃; IR (KBr, cm -1): 3304 (s), 2874 (m), 1648 (m), 1589 (s), 1542 (w), 1443 (m), 1306 (m), 1186 (m), 1083 (s), 1037 (s), 979 (s), 863 (s), 768 (m); ESI-MS m/z calcd for C 16H 17Br 2NO 5([M+1] +): 460.95; Found ([M+1] +): 462.28, ([M+3] +): 464.27, ([M+5] +): 466.32.
Embodiment 6 2-glycosyl quinoline chemical compounds of the present invention are to the inhibitory action of Acetylcholinesterase
Suppress activity test method:
With the acetylthiocholine is substrate, 5 of chemical labeling, and 5-dithio two (2-nitrobenzoic acid) is a developer, working sample suppresses active to AchE in sample cell.Its reaction equation is:
Acetylthiocholine+H 2O+AchE → CH 3The CO-AchE+ thiocholine
Thiocholine+5, two (2-the nitrobenzoic acid) → 5-sulfur of 5-dithio-2-nitrobenzoic acid
Acetylthiocholine produces thiocholine after by the AChE hydrolysis, can be with 5,5-dithio two (2-nitrobenzoic acid) reaction, the 5-sulfur-2-nitrobenzoic acid of generation can be at 412nm place generation characteristic uv absorption.
Get 7 sample cells, add 30uL 4mg/mL 5 respectively, 5-dithio two (2-nitrobenzoic acid) adds 0 respectively; 5,10,15,20; 30,50uL, the sample solution of 1.0mM, with 0.1M pH 8.0 PBS standardize solution to 950uL; Add the 1.0mg/mL of 10uL respectively, AChE solution, and at 37 ℃ of insulation 15min.Add 40uL2mg/mL acetylthiocholine solution immediately, measure it after shaking up immediately at the A at 412nm place value (A n).Reference is with 0.1M pH 8.0 phosphate buffer solutions.
The relative enzyme activity of application of sample=(A not n/ A Control) * 100
Relative vigor with enzyme is mapped to inhibitor concentration, tries to achieve the IC of all cpds according to suppressing curve 50Value (inhibitor concentration during inhibitory enzyme vigor 50%).To survey the result as shown in table 1:
Table 12-glycosyl quinoline chemical compound anti-acetylcholinesterase inhibitory action
Figure BDA0000132370210000081
aPositive control medicine---tacrine
Can find out that from embodiment 6 2-glycosyl quinoline chemical compound of the present invention has strong inhibition active to Acetylcholinesterase, aspect the preparation anti-acetylcholinesterasemedicine medicine, have broad application prospects.

Claims (9)

1. the application of 2-glycosyl quinoline chemical compound in the preparation anti-acetylcholinesterasemedicine medicine is characterized in that said 2-glycosyl quinoline chemical compound has suc as formula structural formula shown in (I):
Wherein, R 1, R 2, R 3And R 4Independently be selected from-H ,-OCH 3Or-Br.
2. the application of 2-glycosyl quinoline chemical compound in the preparation anti-acetylcholinesterasemedicine medicine according to claim 1 is characterized in that said 2-glycosyl quinoline chemical compound is:
R 1, R 2, R 3And R 4Be-formula (I) chemical compound of H;
Or R 2And R 3For-H, R 1And R 4For-OCH 3Formula (I) chemical compound;
Or R 1And R 4For-H, R 2And R 3For-OCH 3Formula (I) chemical compound;
Or R 2And R 4For-Br, R 1And R 3Formula (I) chemical compound for-H.
3. the application of 2-glycosyl quinoline chemical compound in the preparation anti-acetylcholinesterasemedicine medicine according to claim 1 is characterized in that the method for preparing of said 2-glycosyl quinoline chemical compound comprises the steps:
(1) under the effect of sodium bicarbonate, D-glucose and acetylacetone,2,4-pentanedione generate β-D-acetonyl Fructus Vitis viniferae carbon glycosides;
(2) with o-Aminobenzaldehyde or substituted o-Aminobenzaldehyde and β-D-acetonyl Fructus Vitis viniferae carbon glycosides with dissolve with methanol, in the presence of pyrrolidine, react, obtain said 2-glycosyl quinoline chemical compound.
4. like the application of the said 2-glycosyl quinoline of claim 3 chemical compound in the preparation anti-acetylcholinesterasemedicine medicine, it is characterized in that in the step (2), the consumption of said pyrrolidine is the 25mol% with respect to o-Aminobenzaldehyde or substituted o-Aminobenzaldehyde consumption.
5. like the application of the said 2-glycosyl quinoline of claim 3 chemical compound in the preparation anti-acetylcholinesterasemedicine medicine, it is characterized in that in the step (2), the temperature of said reaction is 60～120 ℃.
6. like the application of the said 2-glycosyl quinoline of claim 3 chemical compound in the preparation anti-acetylcholinesterasemedicine medicine; It is characterized in that; Said 2-glycosyl quinoline chemical compound carries out purification through crossing post, and crossing the used eluent of post is that volume ratio is an ethyl acetate: isopropyl alcohol: the mixed solution of water=16: 2: 1.
7. the said R of claim 2 1, R 2, R 3And R 4Be-formula (I) chemical compound of H.
8. the said R of claim 2 2And R 3For-H, R 1And R 4For-OCH 3Formula (I) chemical compound.
9. the said R of claim 2 1And R 4For-H, R 2And R 3For-OCH 3Formula (I) chemical compound.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9302992B2 (en) 2013-04-02 2016-04-05 Annji Pharmaceutical Co., Ltd. Multifunctional quinoline derivatives as anti-neurodegenerative agents
JP2016515617A (en) * 2013-04-02 2016-05-30 アンジー ファーマスーティカル シーオー．，エルティーディー．Ａｎｎｊｉ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． Multifunctional quinoline derivatives as anti-neurodegenerative agents

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BERNHARD ROSENGARTEN, ET AL: "acetylcholine esterase inhibitor donepezil improves dynamic cerebrovascular regulation in Alzheimer patients", 《J NEUROL》 *
JOSEPH P. TAVERNI, ET AL: "donepezil mediated memory improvement in traumatic brain injury during post acute rehabilitation", 《BRAIN INJURY》 *
PAUL A ADLARD, ET AL: "rapid restoration of cognition in Alzheimer"s transgenic mice with 8-Hydroxy quinoline analogs is associated with decreased interstitial Abeta", 《NEURON》 *
SUBBIAH NAGARAJAN ET AL.: "facile one-pot synthesis of sugar-quinoline derivatives", 《CARBOHYDRATE RESEARCH》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9302992B2 (en) 2013-04-02 2016-04-05 Annji Pharmaceutical Co., Ltd. Multifunctional quinoline derivatives as anti-neurodegenerative agents
JP2016515617A (en) * 2013-04-02 2016-05-30 アンジー ファーマスーティカル シーオー．，エルティーディー．Ａｎｎｊｉ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． Multifunctional quinoline derivatives as anti-neurodegenerative agents
AU2013385618B2 (en) * 2013-04-02 2017-01-05 Annji Pharmaceutical Co., Ltd. Multifunctional quinoline derivatives as anti-neurodegenerative agents

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