CN101774922B - 2,3-dyhydroxyl parabens compound as well as preparation and application thereof - Google Patents
2,3-dyhydroxyl parabens compound as well as preparation and application thereof Download PDFInfo
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- CN101774922B CN101774922B CN 201010103098 CN201010103098A CN101774922B CN 101774922 B CN101774922 B CN 101774922B CN 201010103098 CN201010103098 CN 201010103098 CN 201010103098 A CN201010103098 A CN 201010103098A CN 101774922 B CN101774922 B CN 101774922B
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Abstract
The invention provides a method for separating, extracting and preparing 2,3-dyhydroxyl parabens natural compound from traditional Chinese medicine gentian. The preparation method comprises the following steps of: pulverizing the traditional Chinese medicine gentian, extracting with carbinol, and carrying out suction filteration and concentration to obtain a methanol extract crude product, extracting and separating with 80 percent methanol water solution and normal hexane to obtain normal hexane layer crude sample; and separating the crude sample through a silica gel opening column and separating through an ODS opening column, and purifying by using a reverse HPLC to obtain a target compound. The naturally-separated 2,3-dyhydroxyl parabens compound used as a micromolecule compound represents obvious NGF mimics activity in an in-vitro screening model PC 12 cells for senile dementia, and can be applied to preparing medicaments for preventing neurodegenerative diseases of senile dementia and the like. A structure formula of the compound is shown as the following formula.
Description
Technical field
The invention belongs to the preparation method and the application of compound, relate to a kind of 2, the preparation method of 3-dyhydroxyl parabens natural compounds, and the application of this compounds in nerve degenerative diseases such as prevention and treatment senile dementia.
Background technology
Senile dementia is broadly divided into the three major types type: the dementia of Alzheimer's disease (Alzheimer ' s disease, be called for short AD), vascular dementia and other types.Along with increasing of the aged, the morbidity of senile dementia obviously raises, and has become the 4th major cause that causes the grownup dead, is only second to heart trouble, cancer, apoplexy.China senile dementia patient estimates to surpass 5,000,000, accounts for 1/4 of the total case load in the world; And along with the quickening of China's aging population process, this numeral will be more huge, bring great influence for social stability and development.According to statistics, the sickness rate over-65s of Chinese senile dementia is to be to be 30% more than 10%, 80 years old more than 5%, 70 years old, to more than 85 years old then up to 40%.After 20 years, middle-aged people of today will step into the elderly's ranks, and dementia patient's quantity will sharply increase, and the elderly's health also will be related to the stable and development of entire society.The medicine of therefore, researching and developing nerve degenerative diseases such as effective prophylactic treatment senile dementia has become the medical problem that the whole world presses for solution.
In senile dementia three macrotaxonomies, AD is that sickness rate is the highest, also is most important a kind of dementia form disease.AD is a kind of nerve degenerative diseases, is main clinical disease with memory and Cognitive function damage, can cause can't take care of oneself when serious.The definite pathomechanism of AD it be unclear that, and at present main academic viewpoint has following several kinds: 1. beta-amyloyd polypeptide (A β) toxicity and deposition; 2. cholinergic lacks theory; 3. nerve retrograde affection (Neurodegeneration); 4. other multiple factor is like transgenation theory, oxidative stress theory.
A β deposition and toxicity are one of principal elements of Alzheimer's disease morbidity.The unusual adjusting of the app gene in the neurone causes the gathering of toxicity A β in neurocyte, causes the cascade reaction of pathological change, and then causes the degeneration of neurocyte.The focus of research concentrates on the generation that reduces A β both at home and abroad, thereby the configuration that suppresses A beta peptide aggregation, change A β reduces its neurotoxicity, has had several drugs to get into clinical trial at present.
The drug kinds of present stage treatment AD is a lot of; Mainly contain cholinergic agent; E.C. 3.1.1.7 (Acetylcholinesterase wherein; AChE) suppressor factor, the medicine of main listing has tacrine (tacrine), tartrate rivastigmine (rivastigmine), selagine (huperzine A), E2020 (donepezil) etc.; β, gamma secretase Depressant; The brain metabolism regulators is like vincamine, nimodipine, cinnarizine; Influence the medicine of Radical Metabolism, combine vitamin E etc. like vitamins C.But these medicines can only delay the progress of the AD course of disease; And reduce gradually with the PD curative effect of medication, spinoff is arranged, old friends turn to sight the research and development of new anti senile dementia drug; Seek medicine and method, become the focus and the difficult point of current research to the AD cause of disease.
Research shows that neurotrophic factor all has significant effects to the neurodevelopment and the neural lysis of growing up.In the neurodegeneration animal model, find that (nerve growthfactor NGF) can stop or reduce neuronic regression to NGFF.NGF is human first neurotrophic factor of finding, also is most important neurotrophic factor; It is the biologically active polypeptides that there is the important regulating and controlling effect aspects such as a kind of growth to neurocyte, growth, differentiation and function maintenance; Treatment to sacred diseases such as neuratorphy, neurodegeneration, traumatic repair has unusual effect.Discover that NGF to a certain degree can stop the AD progress, it promotes that nerve growth and neuroprotective are the long term studies focuses.Yet it is a polypeptide of being made up of more than 100 amino acid; Reasons such as big and polarity is strong owing to molecular weight; Can not pass through hemato encephalic barrier (Blood Brain Barrier); And be difficult to many factors such as mass preparation, limited to its practical clinical, NGF does not directly also find better treat-ment the dispensing except that operation in the brain.Therefore, seek and to have similar NGF active (NGF mimics) and maybe can strengthen its activity (NGFenhancer) and can just become the research focus naturally through the low molecular compound of hemato encephalic barrier.Because PC12 cell (Pheochromocytoma cells, the clone obtains from the rat adrenal pheochromocytoma) has the general feature of neurocyte and the characteristics that can go down to posterity, cell can stop division under the effect of NGF, grows projection, changes into neuron cell.Therefore, the function PC12 cell at cellular and molecular level research NGF is a good model.At present, NGF mimics has been arranged in the phase iii clinical trial stage.
Herbal medicine is the basic substance of Chinese materia medica, is the cornucopia of natural radioactivity organic cpds.There is traditional Chinese medical science civilization in several thousand in China, and vast territory and abundant resources, and the famous-region drug of a lot of preciousnesses are arranged, because utilizing of Chinese material medicine resource is more convenient, so also just very important to its new composition and new active research.Research shows that Chinese medicine has significant curative effect to senile dementia, and wherein foremost is vegeto-alkali one selagine (huperzine A) that from Herba Lycopodii serrati, extracts, and it is the original new drug with independent intellectual property right of Chinese Academy of Sciences institute of materia medica exploitation; It is not only a kind of E.C. 3.1.1.7 (AChE) Depressant of efficient highly selective, and can also reduce the nerve cell death that L-glutamic acid brings out; Has the response to oxidative stress that significant protection neurocyte antagonism beta-amyloyd polypeptide (A β) produces; Can be to inductive nerve cell apoptosis effects such as resistive to hydrogen peroxide, inhibitors of protein kinase C; It is one of optimal drug of the senile dementia of whole world treatment at present.
Rough gentian, another name: Radix Gentianae, courage grass.Spring, Qiu Erji excavate, cleaning, drying.Nature and flavor, hardship, cold.Return liver, gallbladder channel.Introduce in 2005 editions pharmacopeia, the function of rough gentian cures mainly: heat-clearing and damp-drying drug, purging the liver of pathogenic fire courage fire.Be used for jaundice due to damp-heat, swelling of vulva pruritus vulvae, band down, persistent erection, eczema itch, hot eyes, deafness, hypochondriac pain, bitter taste, convulsion with spasms.Kind had remarkable similar NGFF active 2 surplus separation and purification obtained ten from the extract of the dry root and rhizome of hard rough gentian Gentianarigescens Franch. under the guiding of PC12 cell bio-activity identification systems; 3-dyhydroxyl parabens new compound, called after gentisides.Up to now, about 2, the 3-dyhydroxyl parabens compound has only the aliphatic chain of chemosynthesis to contain the bibliographical information that carbon number is lower than 11 or 16 carbon; European patent (EP 1 930 002 A1) has been described the application of benzoate compounds formula aspect treatment and prophylaxis of viral infections; Chinese patent (CN 1411339A) and the described benzoic acid derivative of USP are mainly used in antibacterial, as foodstuff additive etc.
Frosst) (Aspirin; Have another name called Xaxa), with 2 of natural acquisition, the 3-dyhydroxyl parabens compound has similar parent nucleus; It is classical small molecules NSAIDs (NSAIDs); Clinical application is lasting always for over 100 years more than a hundred years, has stronger analgesic, analgesia, anti-inflammatory, anti rheumatism action.Aspirin has unique effects to anticoagulant, can stop thrombosis, prevents and treats Stroke, coronary heart disease etc. with it, all can receive certain effect.In recent years, along with the research that deepens continuously to the NSAIDs pharmacological action, its novel clinical use is also constantly excavated.Epidemiological study shows that the old man who often takes Frosst) suffers from the dangerous of AD and cognitive disorder and obviously reduces, and prompting NSAIDs has the potential using value of treatment AD.Research thinks that this possible mechanism is: Frosst) can be prevented and treated the inflammatory process of AD and can directly regulate the metabolism of A β.
Aspirin is at the active testing of in-vitro screening model PC 12 cell systems; Find that it does not have tangible similar NGF active, it is natural 2 that separation and purification obtains from the Chinese medicine rough gentian, though the parent nucleus of 3-dyhydroxyl parabens compound is similar with the structure of Aspirin; But can cause a high proportion of PC12 cell generation nervous process elongation phenomenon; Show naturally 2, it is active that 3-resorcylic acid ester has good similar NGF, has the value of exploitation anti-senile dementia prophylactic treatment medicine.In addition, rough gentian has wide material sources, the advantages such as facility of drawing materials, obtain easily a large amount of 2, the 3-dyhydroxyl parabens compound.With 2, the 3-dyhydroxyl parabens compound is as active guide's thing, and the new drug of nerve degenerative diseases such as research and development prevention and treatment senile dementia is significant.
Summary of the invention
The purpose of this invention is to provide a kind ofly 2, the 3-dyhydroxyl parabens compound has formula (I) general structure:
It is described 2 that another object of the present invention provides, and the preparation method of 3-dyhydroxyl parabens compound realizes through following steps:
1) pulverizing and lixiviate:
After the Chinese medicine rough gentian was pulverized, with lixiviate under methyl alcohol (technical grade) room temperature 4～5 days (concussion once in a while), suction filtration concentrated, and gets methyl alcohol extractive substance study, separates with n-hexane extraction with 80% methanol aqueous solution again, obtains normal hexane layer study;
2) separation and purifying:
(200-300 order, solvent systems are normal hexane: ETHYLE ACETATE) through twice silica gel opening column separation earlier with normal hexane layer study; The sample that contains target compound separates through octadecyl silane chromatographic column (ODS) opening column further that (solvent systems is a methyl alcohol: water, methyl alcohol: chloroform); Use reverse hplc purifying twice at last again, moving phase is methanol aqueous solution for the first time, and moving phase is aqueous ethanolic solution for the second time, finally obtains the purpose compound.
A further object of the present invention provides 2, the application of 3-dyhydroxyl parabens compound formula (I) in the medicine of nerve degenerative diseases such as preparation prevention senile dementia.It mainly is the application in preparation treatment Alzheimer's disease nerve degenerative diseases medicines such as (AD).
The present invention further also provides a kind of pharmaceutical composition that prevents nerve degenerative diseases such as senile dementia, and this pharmaceutical composition contains 2 shown in (I) of physiology significant quantity, 3-dyhydroxyl parabens compound and pharmaceutically acceptable carrier or thinner.
Pharmaceutically acceptable carrier described here is meant the pharmaceutical carrier that pharmaceutical field is conventional, and for example thinner, vehicle wait in this way, weighting agent such as starch, sucrose, Microcrystalline Cellulose etc.; Tackiness agent such as starch slurry, TSK-Gel G 2000HXL, gelatin, polyoxyethylene glycol etc.; Wetting agent such as Magnesium Stearate, micropowder silica gel, polyethylene glycols etc.; Absorption enhancer gathers sorb fat, Yelkin TTS etc., and tensio-active agent poloxamer, lipid acid sorb be smooth, gather sorb fat or the like, can also in compsn, add other assistant agent such as flavouring agent, sweeting agent etc. in addition.
Of the present invention 2,3-dyhydroxyl parabens natural compounds can be with the unit dosage form administration, and route of administration can be enteron aisle and non-enteron aisle, comprises oral, muscle, subcutaneous and nasal cavity.
Compound administration approach of the present invention can be intravenously administrable.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection and acupoint injection therapy.
The various formulations of pharmaceutical composition of the present invention can for example make activeconstituents mix with one or more carriers according to the conventional working method preparation of pharmaceutical field, are made into required formulation then.
Form of administration can be solid preparation, capsule or liquid preparation, comprises tablet, capsule, dispersible tablet, oral liquid, infusion solutions, little pin, freeze-dried powder, ointment, liniment or suppository.
Of the present invention 2,3-dyhydroxyl parabens natural compounds has the activity of significant similar NGFF, can in nerve degenerative diseases such as prevention senile dementia, obtain to use.Of the present invention 2, the separation and purification from the Chinese medicine rough gentian of 3-dyhydroxyl parabens compound obtains, and is that a type of finding in the natural product has the compound of new chemical structure (compound I-C is the compound of known structure, but does not have the report of natural origin.)。As micromolecular compound, natural isolating 2, the 3-dyhydroxyl parabens compound shows significant NGF mimics in the in-vitro screening model PC of senile dementia 12 cells active., optimize structure as guide's thing with this compounds,, will have important practical significance for the new drug development of prevention and nerve degenerative diseases such as treatment senile dementia etc. carries out basic research.
2; The preparation process of 3-dyhydroxyl parabens compound is to obtain through serial flow processs such as organic solvent lixiviate, solvent distribution, the separation of opening chromatographic column, performance liquid chromatography (HPLC) purifying, the preparation method has simply, fast, the compound purity advantages of higher that obtains.
Description of drawings
Figure 12, the HPLC preparation of 3-dyhydroxyl parabens natural compounds.
Fig. 2 adds natural compounds I-A and I-B, the variation that the nervous process differentiation rate of PC 12 cells increases with dosage after 48 hours.
Fig. 3 adds natural compounds I-A and I-B, the Photomicrograph of PC 12 cellular neural projections after 48 hours.
Fig. 4 adds natural compounds I-C～L, the nervous process differentiation rate of PC 12 cells after 48 hours.
Embodiment
Below embodiment and accompanying drawing through such some particular compound being prepared instance again foregoing of the present invention is done further to specify; But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Separation and Extraction 2 from the Chinese medicine rough gentian, the preparation method of 3-dyhydroxyl parabens natural compounds formula (I), and concrete steps are:
1) pulverizing and lixiviate:
After 1980g Chinese medicine rough gentian is pulverized, with lixiviate under 10L methyl alcohol (technical grade) room temperature 5 days (concussion once in a while).Suction filtration obtains methyl alcohol extractive substance study 353.6g after concentrating, and it is divided into two parts extracts, and replaces extracting and separating twice with 80% methanol aqueous solution (1500m1) and normal hexane (500ml).Obtain normal hexane layer study 14.6g altogether.
2) separation and purifying:
(200-300 order, following solvent systems are separated into normal hexane for the first time: ETHYLE ACETATE=100: 0,90: 10,85: 15,80: 20,70: 30,50: 50 all by volume through twice silica gel opening column separation earlier with normal hexane layer study; Be separated into for the second time normal hexane: ETHYLE ACETATE=90: 10,85: 15); The sample that then, will contain target compound separates with the ODS opening column further that (solvent systems is methyl alcohol by volume: water=80: 20,85: 15,90: 10,100: 0, methyl alcohol: chloroform=1: 1); At last; The sample (203.4mg) that contains target compound is used the reverse hplc purifying again; Chromatographic condition: permaphase ODS-HG-5 (
10/250mm); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is methyl alcohol: water=98: 2; Obtain the compound behind the HPLC purifying for the first time, referring to Fig. 1.The RT of compound I-A～L is followed successively by: 47.1min, 55.8min, 20.0min, 21.5min, 25.1min, 26.9min, 36.8min, 40.0min, 43.3min, 51.0min, 55.8min, 71.7min.
The chromatographic condition of secondary HPLC purifying is: flow velocity 3ml/min, detect wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 90min, obtains compound I-A (14.8mg, RT is 43.0min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 90-100% aqueous ethanolic solution in the 90min, obtains compound I-B (24.2mg, RT is 31.9min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 80-95% aqueous ethanolic solution in the 60min, obtains compound I-C (1.4mg, RT is 37.0min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 60min, obtains compound I-D (4.8mg, RT is 26.1min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 60min, obtains compound I-E (1.6mg, RT is 29.2min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 120min, obtains compound I-F (2.3mg, RT is 37.3min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 60min, obtains compound I-G (2.9mg, RT is 32.2min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 90min, obtains compound I-H (2.2mg, RT is 43.0min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 90min, obtains compound I-I (3.2mg, RT is 44.7min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 90min, obtains compound I-J (1.0mg, RT is 47.0min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 90-100% aqueous ethanolic solution in the 60min, obtains compound I-K (0.2mg, RT is 36.1min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 90-100% aqueous ethanolic solution in the 60min, obtains compound I-L (0.2mg, RT is 39.6min).
Embodiment 2
To the physicochemical characteristics of embodiment 1 gained compound I-A～L and the qualitative evaluation of chemical structure:
The structure of compound I-A and I-B through MS, HR MS,
1H NMR,
13C NMR, DEPT, H-HCOSY, HMBC, HSQC and HOHAHA confirm.
The structure of compound I-C～L through MS, HR MS,
1H NMR tests, and confirms after comparing with the structure of compound I-A and I-B.
The physico-chemical property of compound I-A: white solid, molecular formula are C
29H
50O
4HR FT-ICR MS:m/z 485.3610 [M+Na]
+, theoretical value C
29H
50O
4Na:485.3601.Ir spectra (KBr) value: 3469,2920,1671,1469,1311 and 1155cm
-1UV spectrum (solvent is an acetonitrile): maximum absorption wavelength 318nm; Hydrogen spectrum and carbon spectrum data are seen table-1.
The physico-chemical property of compound I-B: white solid, molecular formula are C
30H
52O
4Specific rotation light value: [α]
D 22+ 2.4 ° (c 2.04, CHCl
3); Ir spectra (KBr) value: 3476,2920,1674,1468,1309,1153cm
-1UV spectrum (solvent is an acetonitrile): maximum absorption wavelength 318nm; HR FT-ICR MS m/z:499.3775 [M+Na]
+, theoretical value C
30H
52O
4Na:499.3758.Hydrogen spectrum and carbon spectrum data are seen table-1.
Table-1. hydrogen spectrum and the carbon of natural compounds I-A and I-B are composed data (CDCl
3)
aIn the 500MHz, bracket is coupling constant (J in Hz);
b125MHz.；
cChemical displacement value is: 27.4,29.2,29.5,29.6,29.7,30.0;
dChemical displacement value is: 27.1,29.2,29.5,29.6,29.7, and 30.1.
Confirm (hydrolysis reaction of compound I-B) to compound I-B aliphatic chain steric configuration
With compound I-B (8mg), anhydrous K
2CO
3(20mg), 10ml methyl alcohol places the 25ml round-bottomed flask, stirring at room 27 hours.(developping agent: chloroform) follow the tracks of reaction, after reaction stops, steaming methyl alcohol, thick product is used the 10ml water dissolution, 10ml n-hexane extraction three times with thin-layer chromatography.Merge the normal hexane layer, concentrate, silica gel column chromatography (developping agent: chloroform), get compound I-B-2 (4.2mg, yield: 74%).The steric configuration of compound I-B aliphatic chain is further confirmed in the affirmation of the steric configuration of the hydrolysate I-B-2 of compound I-B.Reaction formula is following:
The physico-chemical property of compound I-B-2: white solid, [α]
D 25+ 3.7 ° (c 1.40, CHCl
3),
1HNMR (500MHz, CDCl
3) δ: 3.64 (t, 2H, J=6.5Hz, H-1 '), 1.57 (m, 2H, H-2 '), 1.25～1.35 (m, 35H, H-3 '～21 '), 1.06～1.14 (m, 2H, H-19 ', 21 '), 0.85 (t, 3H, J=7.5Hz, H-22 '), 0.84 (d, 3H, J=6Hz, H-23 ').
Compound I-C:
White solid, molecular formula are C
23H
38O
4 1H NMR (500MHz, CDCl
3) δ: 11.00 (s, 1H, 2-OH), 7.37 (dd, 1H, J=1.5,8.0Hz, H-6), 7.10 (dd, 1H; J=1.0,8.0Hz, H-4), 6.80 (t, 1H, J=8.0Hz, H-5), 5.63 (s, 1H; 3-OH), 4.34 (t, 2H, J=6.5Hz, H-1 '), 1.77 (m, 2H, H-2 '), 1.43 (m; 2H, H-3 '), 1.25～1.35 (m, 24H, H-4 '～15 '), 0.88 (t, 3H, J=7.0Hz, H-16 '); MS (m/z): 377.39 [M-H]
-.
Compound I-D:
White solid, molecular formula are C
24H
40O
4HR FT-ICR MS:m/z 391.2844, theoretical value C
24H
39O
4[M-H]: 391.2854.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.0，7.5Hz，H-6)，7.10(dd，1H，J＝1.5，8.0Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.64(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.78(m，2H，H-2’)，1.44(m，2H，H-3’)，1.10～1.38(m，22H，H-4’～15’)，1.08(m，1H，H-15’)，0.86(t，3H，J＝7.0Hz，H-16’)，0.84(d，3H，J＝6.0Hz，H-17’).
Compound I-E:
White solid, molecular formula are C
25H
42O
4HR FT-ICR MS:m/z 405.2999, theoretical value C
25H
41O
4[M-H]: 405.3010.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.0，8.0Hz，H-6)，7.10(dd，1H，J＝1.0，7.5Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.63(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.51(m，1H，H-16’)，1.45(m，2H，H-3’)，1.23～1.36(m，22H，H-4’～14’)，1.14(m，2H，H-15’)，0.86(d，6H，J＝6.5Hz，H-17’，18’).
Compound I-F:
White solid, molecular formula are C
25H
42O
4HR FT-ICR MS:m/z 405.2999, theoretical value C
25H
41O
4[M-H]: 405.3010.
1H?NMR(500MHz，CDCl
3)δ：11.01(s，1H，2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，H-6)，7.10(dd，1H，J＝1.5，8.0Hz，H-4)，6.80(t，1H，J＝7.5Hz，H-5)，5.64(s，1H，3-OH)，4.34(t，2H，J＝6.0Hz，H-1’)，1.77(m，2H，H-2’)，1.42(m，2H，H-3’)，1.25～1.34(m，28H，H-4’～17’)，0.88(t，3H，J＝7.0Hz，H-18’).
Compound I-G:
White solid, chemical formula are C
26H
44O
4HR FT-ICR MS:m/z 419.3154, theoretical value C
26H
43O
4[M-H]: 419.3167.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.0，8.0Hz，H-6)，7.10(dd，1H，J＝1.0，8.0Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.63(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.43(m，2H，H-3’)，1.10～1.38(m，26H，H-4’～17’)，1.08(m，1H，H-17’)，0.86(m，3H，J＝6.5Hz，H-18’)，0.84(d，3H，J＝6.5Hz，H-19’).
Compound I-H:
White solid, molecular formula are C
27H
46O
4HR FT-ICR MS:m/z 433.3310, theoretical value C
27H
45O
4[M-H]: 433.3323.
1H?NMR(500MHz，CDCl
3)δ：11.01(s，1H，2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，H-6)，7.10(dd，1H，J＝1.5，8.0Hz，H-4)，6.80(t，1H，J＝7.5Hz，H-5)，5.64(s，1H，3-OH)，4.31(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.43(m，2H，H-3’)，1.10～1.38(m，28H，H-4’～18’)，1.08(m，1H，H-18’)，0.85(m，3H，J＝6.5Hz，H-19’)，0.84(d，3H，J＝6.0Hz，H-20’).
Compound I-I:
White solid, molecular formula are C
28H
48O
4HR FT-ICR MS:m/z 447.3463, theoretical value C
28H
47O
4[M-H]: 447.3480.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.0，8.0Hz，H-6)，7.10(dd，1H，J＝1.0，8.0Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.63(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.43(m，2H，H-3’)，1.10～1.38(m，30H，H-4’～19’)，1.08(m，1H，H-19’)，0.85(m，3H，J＝7.5Hz，H-20’)，0.84(d，3H，J＝6.5Hz，H-21’).
Compound I-J:
White solid, chemical formula are C
28H
48O
4HR FT-ICR MS:m/z 447.3464, theoretical value C
28H
47O
4[M-H]: 447.3480.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，H-6)，7.10(dd，1H，J＝1.5，8.0Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.63(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.42(m，2H，H-3’)，1.25～1.34(m，34H，H-4’～20’)，0.88(t，3H，J＝6.5Hz，H-21’).
Compound I-K:
White solid, molecular formula are C
29H
50O
4HR FT-ICR MS:m/z 461.3627, theoretical value C
29H
49O
4[M-H]: 461.3636.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，H-6)，7.10(dd，1H，J＝1.5，8.0Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.63(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.45(m，2H，H-3’)，1.25～1.34(m，36H，H-4’～21’)，0.88(t，3H，J＝7.0Hz，H-22’).
Compound I-L:
White solid, molecular formula are C
31H
54O
4HR FT-ICR MS:m/z 489.3931, theoretical value C
31H
53O
4[M-H]: 489.3949.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，H-6)，7.10(dd，1H，J＝1.5，8.0Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.63(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.43(m，2H，H-3’)，1.25～1.34(m，40H，H-4’～23’)，0.88(t，3H，J＝6.5Hz，H-24’).
2 of rough gentian source, the biological activity of 3-resorcylic acid alkane ester.
In the neurodegeneration animal model, discover that NGF can stop or reduce neuronic regression, to a certain degree can stop the AD progress, have the nerve growth of promotion and neuroprotective.Because the PC12 cell has the general feature of neurocyte, the PC12 cell can stop division under the effect of NGF, grows projection, changes into neuron cell.Therefore, can cause the PC12 cell transformation to become the compound of neuron cell to have the using value of nerve degenerative diseases such as prevention and treatment senile dementia.
Experimental technique:
1) cultivation of PC 12 cells: connect 20 * 10
4Individual PC 12 cells contain 10ml DMEM substratum (wherein containing 10% horse serum, 5% foetal calf serum) in the petridish of 100mm, change a subculture two days later, after three days subcultures.Earlier cell is washed twice, add 10ml PBS again in petridish with PBS, at 37 ℃, 5%CO
2Incubator in cultivated 10 minutes, purge is transferred to the disposable centrifuge tube of 15ml, counts on the blood counting chamber of centrifugal back.The every hole of 24 porocyte culture plates adds the DMEM substratum that 1ml contains serum earlier, and after the cell counting, every hole connects 2 * 10
4Individual cell, CO
2Incubator is cultivated application of sample after 24 hours.
2) active testing: with the negative contrast of DMSO, the positive contrast of NGF 40ng, the DMSO solution that the natural compounds I-A and the I-B of main content is configured to different concns.The DMEM solution (not containing serum) that contains 1%DMSO and sample with 1ml is put into 37 ℃, 5%CO after the former substratum in every hole of 24 porocyte plates is replaced
2Incubator in cultivate.Inverted microscope is every down at a distance from 24 hours, continuous 6 days observation of cell metamorphosis; The nervous process differentiation rate of record cell (nervous process is longer than the ratio of total cell number under cell number and the visual field of one times of cell space diameter); About 100 cells under each visual field; Picked at random 3 places, and statistics mapping analysis.
3) experimental result:
1. under the concentration of 1-30 μ M, 48 as a child latter two compound all to demonstrate good NGF-mimics active.By Fig. 2, Fig. 3 is visible, and the DMSO with 1% is as negative control, and compound I-A and I-B are under the condition of optimal concentration 10 μ M, and the nervous process rate of inducing PC 12 cells to produce can surpass positive control NGF inductive projection rate; This experimental result also shows simultaneously, and compound I-A and I-B relatively can know that the terminal group difference of the long aliphatic chain of compound does not influence the biological activity of this type of material, and concentration can cause cytotoxicity above optimal concentration.Fig. 2 adds natural compounds I-A and I-B, the variation that the nervous process differentiation rate of PC 12 cells increases with dosage after 48 hours, the negative contrast of C:1%DMSO among the figure; The positive contrast of NGF (40ng/ml), the concentration unit M of I-A and I-B.Fig. 3 adds natural compounds I-A and I-B, the Photomicrograph of PC 12 cellular neural projections after 48 hours, figure a, the negative contrast of 1%DMSO; Figure b, the positive contrast of NGF 40ng/ml; Figure c, compound I-A (10M); Figure d, compound I-B (1M).
2. natural compounds I-C～L is under the concentration of 1-30 μ M, and 48 all to demonstrate significant NGF mimics after as a child active.Referring to Fig. 4; DMSO with 1% is as negative control; Compound I-C～L is under the optimal concentration condition, and the nervous process rate of inducing PC 12 cells to produce can be compared with positive control NGF inductive nervous process rate, and the too high meeting of compound concentration causes cytotoxicity.Fig. 4 adds natural compounds I-C～L, the nervous process differentiation rate of PC 12 cells after 48 hours, the wherein negative contrast of C:1%DMSO; The positive contrast of NGF (40ng/ml), the concentration unit of I-C～L: M.
Claims (6)
1. one kind 2, the 3-dyhydroxyl parabens compound has following general structure (I):
2. claim 1 is described 2, and the preparation method of 3-dyhydroxyl parabens compound realizes through following steps:
(1) pulverizing and lixiviate:
After the Chinese medicine rough gentian was pulverized, with lixiviate under the industrial grade benzenemethanol room temperature 4～5 days, suction filtration concentrated, and got methyl alcohol extractive substance study, separated with n-hexane extraction with 80% methanol aqueous solution again, obtained normal hexane layer study;
(2) separation and purifying:
Normal hexane layer study separated through silica gel opening column earlier, and solvent systems is a normal hexane: ETHYLE ACETATE, and the sample that contains the purpose compound further separates through the octadecyl silane chromatographic column; Solvent systems is a methyl alcohol: water; Methyl alcohol: chloroform, use reverse hplc purifying twice at last again, moving phase is methanol aqueous solution for the first time; Moving phase is aqueous ethanolic solution for the second time, finally obtains the purpose compound.
3. according to claim 12, the application of 3-dyhydroxyl parabens compound in the medicine of preparation prevention senile dementia.
4. application according to claim 3 is characterized in that, the application in preparation treatment Alzheimer disease drug.
5. according to claim 3 or 4 described application, it is characterized in that the route of administration of said medicine is enteron aisle and non-enteron aisle.
6. according to claim 3 or 4 described application, it is characterized in that the formulation of said medicine is solid preparation or liquid preparation.
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| CN101068784A (en) * | 2004-11-10 | 2007-11-07 | 塔加西普特公司 | Hydroxybenzoate salts of metanicotine compounds |
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| CN1829437A (en) * | 2003-08-05 | 2006-09-06 | 拜尔作物科学有限公司 | Use of hydroxyaromatics as safeners |
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