CN102091067B - New application of furocoumarin compound in preparing drug - Google Patents
New application of furocoumarin compound in preparing drug Download PDFInfo
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- CN102091067B CN102091067B CN 200910200179 CN200910200179A CN102091067B CN 102091067 B CN102091067 B CN 102091067B CN 200910200179 CN200910200179 CN 200910200179 CN 200910200179 A CN200910200179 A CN 200910200179A CN 102091067 B CN102091067 B CN 102091067B
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- furocoumarin
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- furocoumarin compound
- helicobacter pylori
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Abstract
The invention relates to new application of a furocoumarin compound in preparing a drug, in particular to application of the furocoumarin compound as an effective component in preparing the drug for treating or preventing diseases caused or mediated by helicobacter pylori.
Description
Technical field
The invention belongs to the medicinal application technical field.Particularly, the present invention relates to furocoumarin compound (furocoumarin derivatives) a kind of new purposes, particularly furocoumarin compound of preparation in the medicine as effective ingredient preparation treatment or prevention caused by helicobacter pylori or the medicine of the disease that mediates in purposes.
Background technology
Helicobacter pylori (Helicobacter pylori, Hp) is the microaerophilic gram negative bacilli of spiral type, is present in people's gastric mucosa.Modern study shows that the generation of the diseases such as active gastritis, peptic ulcer and gastric cancer and treatment are all closely related with helicobacter pylori: the Hp recall rate reaches 95% among active gastritis, the gastric erosion patient, eradicates Hp and can make the gastritis resolution of symptoms; The Hp recall rate reaches respectively 70-100% and 90-100% in gastric ulcer, the duodenal ulcer patients, eradicates Hp, can accelerate ulcer healing, and reduces relapse rate; Gastric lymphoid tissue lymphoma patient Hp recall rate>90%, and the high gastric lymphoid tissue lymphoma sickness rate height of Hp infection rate are eradicated Hp, and gastric lymphoid tissue lymphoma can disappear; Hp can cause gastric cancer, 1994 international cancer research institution (IARC) classify Hp as human I class carcinogen; Hp also can cause intestinal gland metaplasia or atypical hyperplasia, and its patient must eradicate the treatment of Hp.The dependency of the various diseases such as above Helicobacter pylori infection and active gastritis, peptic ulcer and gastric cancer sees document (Hu Fulian, the Zhou Dianyuan chief editor, " Preclinic and clinic of Helicobacter pylori infection " (revised edition), Beijing: China Science Tech Publishing House, 2002) among, be that the professional person knows together.
Statistics shows that the whole world has the population more than 50% to infect helicobacter pylori approximately, and the infection of developing country is particularly serious, reaches 60-80% among the adult.The infection of all adopting at present both at home and abroad the therapy of anti-endocrine medicine and Antibiotic combination medication to treat Hp, but because side effect is large, and patient's toleration is poor, also produces drug resistance, so curative effect and application have been subject to impact.Therefore, seeking the significant anti-Hp infection medicine of effect is the research topic that people pay close attention to.
Furocoumarin compound is that 6,7 or 7,8 of Coumarins are with furyl and the general name of closing the chemical compound that forms.More known furocoumarin compounds such as psoralen (psoralen), 8-methoxypsoralen (8-methoxypsoralen) etc. have good antibacterial action, can significantly suppress the growth of escherichia coli, micrococcus luteus, its pharmacological results is found in following document:
1.Ulate-Rodriguez?J.Inhibition?of?Listera?monocytogenes,Eschericha?coli0157-H7?and?Mierocoeeus?luteus?by?linear?furanocoumarins:In?culture?media[J].J?Food?Prot,1997,60(9),1046-1049.
2.Ulate-Rodriguez?J.Inhibition?of?Listeria?monocytogenes,Eschericha?coli0157-H7?and?Mierocoeeus?luteus?by?linear?furanocoumarins:In?a?model?foodsystem[J].J?Food?Prot,1997,60(9),1050-1053.
Yet up to now, not relevant for furocoumarin compound (as psoralen, 2 '-nitrofuran coumarin, 3 '-methylfuran coumarin and 5-nitro-8-methoxyl group furocoumarin, 4-methylfuran coumarin, thio-furan coumarin etc.) report of anti-Helicobacter pylori infection activity, and their precedents of in anti-Hp infection medicine, using.The inventor is on the basis to the anti-Hp screening active ingredients of a large amount of chemical compounds, find that first furocoumarin compound has good In Vitro Anti helicobacter pylori effect astoundingly, can have treatment or preventive effect to the disease that is caused by helicobacter pylori or mediate thus, and the Hp such as the chronic inflammation cellular infiltration such as gastric antrum and/or the visible lymphocyte of body of stomach gastric mucosa lamina propria, oxyphil cell, plasma cell and/or neutrophil infiltration are infected relevant positive pathological changes have good repair, thereby has potential purposes at pharmaceutical field.
Summary of the invention
An object of the present invention is to provide furocoumarin compound as effective ingredient preparation treatment or prevention caused by helicobacter pylori or the medicine of the disease that mediates in purposes.
Furocoumarin compound of the present invention is preferably that general formula I is the chemical compound of parent nucleus shown in following:
Wherein, X is oxygen or sulfur.
Particularly, furocoumarin compound of the present invention can be for being disclosed in the furocoumarin compound in above-mentioned document and the following document:
1. model chrysanthemum sister-in-law. isolation identification psoralen and isopsorapen [J] from Fructus Psoraleae. Guiyang Medical College journal, 2003,28 (2), 171,174;
2.Bang-Le?Zhang,Fang-Dao?Wang,Jian-Min?Yue.A?new?efficient?method?forthe?total?synthesis?of?linear?furocoumarins.Synlett?2006,4,567-570;
3.Bang-Le?Zhang,Fang-Dao?Wang,Jian-Min?Yue.A?concise?and?efficientsynthesis?of?linear?furocoumarins:psoralen?and?4-methylpsoralen.SyntheticCommunications,2007,37,63-70;
4.Bastian?G,Rene?L,Buisson?J-P,Royer?R,Averbeck?D,Averbeck?S.Syntheseet?etude?photobiologique?furocoumarines?nitrees[J].Eur?J?Med?Chem?ChimTher,1981,16(6):563-568;
5.Ray?J?N,Silooja?S?S,Vaid?V?R.Experiments?on?the?synthesis?of?bergaptenand?its?derivatives.Part?I.Ferocoumarins[J].J?Chem?Soc,1935,813-817;
6.Kim?J?H,Sohn?S?Ho,Yang?K?S,Park?B?Seo.Theoretical?studies?on?thephotochemical?reaction?of?Psoralen?Derivatives.III.Photoadducts?ofmethylpsoralen?and?hydroxypsoralen?with?thymine[J].J?Korean?Chem.Soc,1994,38(6),405-10;
7.Adam?W,Arnold?M?A,Grimm?G?N,Saha-Moeller?C?R,Dall′Acqua?F.Photochem?Photobiol,1998,68(4),511-518;
8.Brokke?M?E,Christensen?B?E.Psoralene?I:Certain?reactions?of?xanthotoxin[J].J?Org?Chem,1958,22(4),589-596;
9.Heindel?N?D,Foster?N,Choudhuri?M.Transfer?hydrogenation?offurocoumarin?derivatives[J].J?Org?Chem,1983,48(21),3817-3819;
10.Abu-Mustafa?E?A,El-Tawil?B?A?H,Fayez?M?B?E.Natural?coumarins:partVIII-Some?reaction?of?imperatorin?and?related?products[J].Indian?J?Chem,1967,5,283-286;
11.Rodighiero?G.Nitroxanthotoxol?and?some?of?its?derivatives[J].Nat.1961,119,201-204;
12.Juettermann?R,Averbeck?D,Averbeck?S,Bastian?G,Royer?R.Photobiological?properties?of?furothiocoumarins?in?saccharomyces?cerevisiae[J].Farmaco?Ed?Sci,1985,40(1),3-13,
The full content of these documents is incorporated this paper by reference into.
The structure of the preferred particular compound of the present invention sees Table 1, and its part physical property and physicochemical data see Table 2.
The structure of the active furocoumarin compound of the anti-Hp of table 1
Part physical property and the physicochemical data of the active furocoumarin compound of the anti-Hp of table 2
Most preferably, furocoumarin compound of the present invention is to be selected from the following chemical compound one or more:
Psoralen 2 '-nitrofuran coumarin, 3 '-the methylfuran coumarin,
5-nitro-8-methoxyl group furocoumarin 4-methylfuran coumarin
4-ethyl furan coumarin thio-furan coumarin
Furocoumarin compound of the present invention can make for the method in commercially available or the above-mentioned open source literature of foundation.For example, psoralen (Zb-1a) can adopt conventional chemical extraction, separation method to prepare in a large number from leguminous plant such as Fructus Psoraleae, also can seemingly utilize the raw material of industry to make through existing methodology of organic synthesis with its derivatives class; Other furocoumarin compound all can utilize the raw material of industry to make through known methodology of organic synthesis.
Of the present inventionly caused or the disease that mediates comprises active gastritis, gastric erosion, duodenal ulcer, gastric lymphoid tissue lymphoma and the gastric cancer that is caused or mediated by helicobacter pylori by helicobacter pylori, but be not limited to these.
Another object of the present invention provide a kind of be used for the treatment of or prevent caused or the pharmaceutical composition of the disease that mediates by helicobacter pylori, its comprise treat effective dose furocoumarin compound as effective ingredient and pharmaceutic adjuvant.Described furocoumarin compound is same as described above.Described pharmacy adjuvant is for well known to a person skilled in the art, such as excipient, filler, binding agent, disintegrating agent, wetting agent, surfactant etc., and its consumption also is that those skilled in the art's routine is selected.
Below extraction and the pharmacological evaluation process of the part of compounds among the present invention will be illustrated with specific embodiment, but to one skilled in the art, various modifications and variation can be made to this within the scope of the invention.
The specific embodiment
Embodiment 1: the extraction of psoralen (Zb-1a) separates
Fructus Psoraleae 2.0Kg, 90% ethanol merceration of 10 times of amounts of adding 5 days extracts merge extractive liquid, 3 times.Get total extractum 592g after removing solvent under reduced pressure.Add suitable quantity of water, add again ethyl acetate extraction 3 times.Extract merges, concentrating under reduced pressure.Add 200 order silica gel mixings, porphyrize behind the normal temperature drying.Silica gel column chromatography carries out gradient elution (30: 1~10: 1) with petroleum ether-acetone, collects the concentrated stream part of psoralen (Zb-1a), obtains crude product.Get psoralen (Zb-1a), yield 0.15% (in raw material) behind the acetone recrystallization.(or referring to document: Fan Judi. isolation identification psoralen and isopsorapen [J] from Fructus Psoraleae. Guiyang Medical College journal, 2003,28 (2), 171,174)
Embodiment 2: furocoumarin compound In Vitro Anti helicobacter pylori pharmacological testing
Furocoumarin compound and positive control metronidazole (metronidazole) are dissolved with a small amount of DMSO respectively, after being diluted to finite concentration with sterilized water, the testing sample of getting doses joins each nutrient agar (COLUMBIAAGAR BASE of OXOID company self-quantitatively, defiber Sanguis caprae seu ovis or the horse blood of adding 10%) in, mix homogeneously, prepare a series of twice dilutions and contain sample culturing base (DMSO of dissolution sample is controlled at ultimate density≤1%), pour into into aseptic flat board.Hp (the reference culture Hp-Sydney strain 1 of inoculation, Hp SS1) (the first Gastroenterology dept. of Affiliated Hospital of Zhongshan Medical Univ.) bacterium liquid select fresh cultured be in logarithmic growth, in the microscopy antibacterial the spherical ratio of class helicobacter pylori seldom, than turbid concentration 〉=10
8CFU/mL.Culture environment: 5%O
2, 10%CO
2, 85%N
2, humidity>90%, 37 ℃ of temperature; Little aerobic cultivation is after 5 days, and blind scraping is transferred to without in the medicine culture medium.37 ℃ of little aerobic cultivations 4-5 days, observation had or not the helicobacter pylori growth, to record the separately minimum bactericidal concentration of sample (MBC) value again.Every sample parallel assay 3 times the results are shown in Table 3.
The effect of the In Vitro Anti helicobacter pylori of table 3 furocoumarin compound (Hp SS1)
Data as seen from table 3, psoralen (Zb-1a), 2 '-nitrofuran coumarin (Zb-2c), 3 '-furocoumarin compound such as methylfuran coumarin (Zb-7), 5-nitro-8-methoxyl group furocoumarin (Zb-12a), 4-methylfuran coumarin (Zb-22a), 4-ethyl furan coumarin (Zb-22c), thio-furan coumarin (Zb-27) has good In Vitro Anti Hp effect astoundingly, and the part of compounds activity is near the positive control metronidazole.
Embodiment 3: anti-helicobacter pylori pharmacological testing in the body of psoralen (Zb-1a) and 4-methylfuran coumarin (Zb-22a)
Getting respectively positive control medicine, psoralen (Zb-1a) and 4-methylfuran coumarin (Zb-22a), to prepare in right amount desired concn for subsequent use.Experimental strain Hp Sydney strain (Sydney Strain, SS1) is containing 10% defiber Sanguis caprae seu ovis and vancomycin (10mg/L, U.S. Lilly company) and amphotericin (5mg/L, U.S. ERSquibb ﹠amp; Sons company) etc. on the antibiotic COLUMBIA culture medium, 37 ℃ of little oxygen were cultivated after 3 days, scraped in the brucella broth, and bacterium is dense to be controlled at 10
9CFU/ml.Laboratory animal adopts C
57The BL/6 mice, body weight 18g~25g is female, 100, raises condition SPF level.Laboratory animal every day fills with by stomach tube and feeds Hp bacterium liquid, mice 0.4ml/ only, continuous 14 times, finish in 14 days, the solvent control group is not correspondingly processed.Begin to calculate in the second day of last inoculation, observed 30 days, random packet again, administration; Each group is administered twice (the upper and lower noon respectively once) according to corresponding dosage (seeing Table 4) every day, totally 14 days.Begin timing from the 14th day next day of administration, administration was observed after 30 days, fasting 24h, adopt the cervical vertebra dislocation method to put to death, cut the abdominal cavity open, stomach is taken out, get fundic gland section and pyloric gland section, cut a part and place 10% formalin solution fixing, send pathology detection.
Anti-Hp test grouping in the body of table 4 furocoumarin chemical compound Zb-1a, Zb-22a
Pathological evaluation is according to following standard:
Positive pathological changes: chronic inflammation cellular infiltration and/or the neutrophil infiltration such as gastric antrum and/or the visible lymphocyte of body of stomach gastric mucosa lamina propria, oxyphil cell, plasma cell.The results are shown in Table 5.
Anti-Hp test mice gastric tissue pathological examination in the body of table 5 furocoumarin compound Zb-1a, Zb-22a
As can be seen from Table 5, furocoumarin compound psoralen (Zb-1a), 4-methylfuran coumarin (Zb-22a) have anti-Hp effect in the good body astoundingly, the Hp such as the chronic inflammation cellular infiltration such as gastric antrum and/or the visible lymphocyte of body of stomach gastric mucosa lamina propria, oxyphil cell, plasma cell and/or neutrophil infiltration are infected the positive pathological changes of being correlated with have good repair.Separately treatment group has obvious therapeutic effect, and tentatively presents dose-effect relationship, and the prompting drug effect increases with dosage and improves.According to the habitual Hp therapeutic scheme in the world, generally adopt triple therapy.In this grouping test, furocoumarin compound drug combination group therapeutic effect is identical with positive controls, illustrates in drug combination, and the furocoumarin under the Isodose can substitute metronidazole fully.This shows that furocoumarin compound has treatment or preventive effect to the disease that is caused by helicobacter pylori or mediate, thereby can be used in the pharmaceutical field.Especially consider that most patient has had widely drug resistance to antibiotic such as metronidazoles, the anti-Hp activity of furocoumarin compound provided by the present invention has more special important meaning.
Furocoumarin compound provided by the invention in vivo, in the in vitro tests, all shown good anti-helicobacter pylori effect, thereby can be caused by helicobacter pylori or the active constituents of medicine of the disease that mediates as new treatment or prevention.
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Title |
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Hirotaka Sekiguchi et al.Suppressive effects of selected food phytochemicals on CD74 expression in NCI-N87 gastric carcinoma cells.《Journal of Clinical Biochemistry and Nutrition》.2008,第43卷(第2期),参见第109页摘要、左栏第1段、第112页图2、第113页表1. * |
尹卫平.具有抗癌活性的一个新的香豆素化合物.《中草药》.1997,第28卷(第1期),参见第3-4页. * |
郭江宁等.补骨脂中活性成分的提取分离与抗癌实验研究.《中药材》.2003,第26卷(第3期),参见第185页摘要. * |
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