CN102091067A - New application of furocoumarin compound in preparing drug - Google Patents
New application of furocoumarin compound in preparing drug Download PDFInfo
- Publication number
- CN102091067A CN102091067A CN2009102001794A CN200910200179A CN102091067A CN 102091067 A CN102091067 A CN 102091067A CN 2009102001794 A CN2009102001794 A CN 2009102001794A CN 200910200179 A CN200910200179 A CN 200910200179A CN 102091067 A CN102091067 A CN 102091067A
- Authority
- CN
- China
- Prior art keywords
- helicobacter pylori
- furocoumarin
- compounds
- furocoumarin compounds
- gastric
- 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.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 compounds (furocoumarin derivatives) a kind of new purposes, particularly furocoumarin compounds of preparation in the medicine as effective ingredient preparation treatment or prevention cause by helicobacter pylori or the medicine of the disease that mediates in purposes.
Background technology
(Helicobacter pylori is the microaerophilic gram negative bacilli of spiral type Hp) to helicobacter pylori, is present in people's gastric mucosa.Modern study shows that the generation of 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 70-100% and 90-100% respectively in gastric ulcer, the duodenal ulcer patients, eradicates Hp, can quicken 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 multiple diseases such as above Helicobacter pylori infection and active gastritis, peptic ulcer and gastric cancer sees document (Hu Fulian, the Zhou Dianyuan chief editor, " basis of Helicobacter pylori infection and clinical " (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 drug combination to treat Hp, but because side effect is big, and patient's toleration is poor, also produces drug resistance, so curative effect and application have been subjected to influence.Therefore, seeking the anti-Hp infection medicine of obvious results is the research topic that people pay close attention to.
The furocoumarin compounds 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 The 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 the furocoumarin compounds (as psoralen, 2 '-nitrofuran coumarin, 3 '-methylfuran coumarin and 5-nitro-8-methoxyl group furocoumarin, 4-methylfuran coumarin, thio-furan coumarin etc.) the active report of anti-Helicobacter pylori infection, 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 the furocoumarin compounds has good external anti-helicobacter pylori effect astoundingly, can have treatment or preventive effect to the disease that causes by helicobacter pylori or mediate thus, and Hp such as 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 the excellent repairing effect, thereby has potential purposes at pharmaceutical field.
Summary of the invention
An object of the present invention is to provide the furocoumarin compounds as effective ingredient preparation treatment or prevention cause by helicobacter pylori or the medicine of the disease that mediates in purposes.
It is the chemical compound of parent nucleus that furocoumarin compounds of the present invention is preferably with general formula I shown in following:
Wherein, X is oxygen or sulfur.
Particularly, furocoumarin compounds of the present invention can be for being disclosed in the furocoumarin compounds in above-mentioned document and the following document:
1. model chrysanthemum sister-in-law. isolation identification psoralen and isopsoralen [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 compounds of the anti-Hp of table 1
The part physical property and the physicochemical data of the active furocoumarin compounds of the anti-Hp of table 2
Most preferably, furocoumarin compounds 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 compounds of the present invention can be for commercially available that get or make according to the method in the above-mentioned open source literature.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 compounds all can utilize the raw material of industry to make through known methodology of organic synthesis.
Of the present inventionly cause 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, but be not limited to these by helicobacter pylori.
Another object of the present invention provide a kind of be used for the treatment of or prevent cause or the pharmaceutical composition of the disease that mediates by helicobacter pylori, its comprise treat effective dose the furocoumarin compounds as effective ingredient and pharmaceutic adjuvant.Described furocoumarin compounds is same as described above.Described pharmacy adjuvant is for well known to a person skilled in the art, for example 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 the extraction and the pharmacological evaluation process of the part of compounds among the present invention will be illustrated, but to one skilled in the art, various modifications and variation can be made to this within the scope of the invention with specific embodiment.
The specific embodiment
Embodiment 1: the extraction separation of psoralen (Zb-1a)
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 ethyl acetate extraction again 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 isopsoralen [J] from Fructus Psoraleae. Guiyang Medical College journal, 2003,28 (2), 171,174)
Embodiment 2: the external anti-helicobacter pylori pharmacological testing of furocoumarin compounds
Furocoumarin compounds 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 quantitative separately nutrient agar (the COLUMBIAAGAR BASE of OXOID company, the 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 sample dissolution is controlled at ultimate density≤1%), pour into into aseptic flat board.Hp (the reference culture Hp-Sydney strain 1 of inoculation, Hp SS1) (first Gastroenterology dept. of Affiliated Hospital of Zhongshan Medical Univ.) bacterium liquid select for use 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 in the no medicine culture medium.37 ℃ of little aerobic cultivations 4-5 days, observation had or not the helicobacter pylori growth, to record the minimum bactericidal concentration of sample (MBC) value separately again.Every sample parallel assay 3 times the results are shown in Table 3.
The effect of the external anti-helicobacter pylori of table 3 furocoumarin compounds (Hp SS1)
Data as seen from table 3, psoralen (Zb-1a), 2 '-nitrofuran coumarin (Zb-2c), 3 '-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 furocoumarin compounds such as (Zb-27) have good external 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 positive control medicine, psoralen (Zb-1a) and 4-methylfuran coumarin (Zb-22a) respectively, to prepare desired concn in right amount standby.(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 in experimental strain Hp Sydney strain; 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 irritates 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 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.Pick up counting 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 portion and pyloric gland portion, 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 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 compounds Zb-1a, Zb-22a
As can be seen from Table 5, furocoumarin compounds psoralen (Zb-1a), 4-methylfuran coumarin (Zb-22a) have anti-Hp effect in the good body astoundingly, Hp such as 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 the excellent repairing effect.Separately the 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 compounds drug combination group therapeutic effect is identical with positive controls, illustrates that in drug combination the furocoumarin under the Isodose can substitute metronidazole fully.This shows that the furocoumarin compounds 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 drug resistance widely to antibiotic such as metronidazoles, the anti-Hp activity of furocoumarin compounds provided by the present invention has more special important meaning.
Furocoumarin compounds 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.
Claims (6)
- The furocoumarin compounds as effective ingredient preparation treatment or prevention cause by helicobacter pylori or the medicine of the disease that mediates in purposes.
- 2. require 1 described purposes according to claim, wherein, described furocoumarin compounds is for being the chemical compound of parent nucleus with general formula I shown in following:
Wherein, X is oxygen or sulfur. - 3. require 2 described purposes according to claim, wherein, described furocoumarin compounds is to be selected from the following chemical compound one or more:
- 4. require 3 described purposes according to claim, wherein, described furocoumarin compounds is to be selected from the following chemical compound one or more:
- 5. according to each the described purposes in the claim requirement 1～4, wherein, describedly cause 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.
- 6. one kind is used for the treatment of or prevents by helicobacter pylori and causes or the pharmaceutical composition of the disease that mediates, its comprise treat effective dose the furocoumarin compounds as effective ingredient and pharmaceutic adjuvant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910200179 CN102091067B (en) | 2009-12-09 | 2009-12-09 | New application of furocoumarin compound in preparing drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910200179 CN102091067B (en) | 2009-12-09 | 2009-12-09 | New application of furocoumarin compound in preparing drug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102091067A true CN102091067A (en) | 2011-06-15 |
| CN102091067B CN102091067B (en) | 2013-04-10 |
Family
ID=44124448
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200910200179 Expired - Fee Related CN102091067B (en) | 2009-12-09 | 2009-12-09 | New application of furocoumarin compound in preparing drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102091067B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016146575A1 (en) | 2015-03-13 | 2016-09-22 | 4Sc Discovery Gmbh | Kv1.3 inhibitors and their medical application |
| WO2016146583A1 (en) | 2015-03-13 | 2016-09-22 | 4Sc Discovery Gmbh | Kv1.3 inhibitors and their medical application |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1446814A (en) * | 2003-03-07 | 2003-10-08 | 上海大学 | Method for preparing psoralen and isopsoralen |
-
2009
- 2009-12-09 CN CN 200910200179 patent/CN102091067B/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016146575A1 (en) | 2015-03-13 | 2016-09-22 | 4Sc Discovery Gmbh | Kv1.3 inhibitors and their medical application |
| WO2016146583A1 (en) | 2015-03-13 | 2016-09-22 | 4Sc Discovery Gmbh | Kv1.3 inhibitors and their medical application |
| CN107548397A (en) * | 2015-03-13 | 2018-01-05 | 4Sc股份公司 | Kv1.3 inhibitor and its medical application |
| CN107548396A (en) * | 2015-03-13 | 2018-01-05 | 4Sc股份公司 | Kv1.3 inhibitor and its medical application |
| CN107548396B (en) * | 2015-03-13 | 2020-04-28 | 4Sc股份公司 | Kv1.3 inhibitors and medical uses thereof |
| CN107548397B (en) * | 2015-03-13 | 2020-12-29 | 4Sc股份公司 | Kv1.3 inhibitors and medical uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102091067B (en) | 2013-04-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI598104B (en) | Use of Antrodia cinnamomea extract to improve side effects of chemotherapy | |
| CN103169737B (en) | Composite of Antrodia camphorata entity and shell-broken ganoderma lucidum spore powder and application thereof in immune adjustment | |
| CN101805246B (en) | Urushiol compound and medicinal composition thereof, preparation method and application thereof | |
| CN102091067B (en) | New application of furocoumarin compound in preparing drug | |
| RU2367458C1 (en) | Medicinal agent, pharmaceutical composition, helicobacter pylori growth inhibitor and method of antihelicobactery therapy | |
| KR20080107794A (en) | Composition comprising the extract of arctium lappa seed for anti-cancer | |
| CN105726631A (en) | Application of officinal magnolia bark extract to prepare medicine for treating cow mastitis | |
| CN103142683B (en) | Be used for the treatment of Chinese medicinal perfusion liquid containing Herba Sophorae alopecuroidis total alkali of bovine mastitis and endometritis and preparation method thereof | |
| CN102731597A (en) | Abelmoschus manihot extract and novel application of chemical components thereof | |
| CN101948473B (en) | New NEO-clerodane diterpenoid compound and application thereof | |
| CN102858359B (en) | Medicinal composition comprising alcohol-soluble and water-insoluble licorice extract, pharmaceutical preparation, pharmaceutical application, therapeutic method, and preparative method thereof | |
| WO2021208080A1 (en) | Use of ovatodiolide against novel coronavirus | |
| CN108785316A (en) | Purposes of the cortex periplocae C21 steroids in preparing IDO inhibitor | |
| CN102028698B (en) | Medicine for treating colon cancer and preparation method thereof | |
| CN101336916A (en) | Use of tea polyphenol | |
| TW202139995A (en) | Use of ovatodiolide against sars-cov-2 | |
| CN105541631B (en) | Raw element A (spiratisanin A) of meadow sweet Ah Ti and preparation method thereof and the application on medicine | |
| CN1748779A (en) | Medicinal composition for treating chronic prostatitis and its preparation method and use | |
| CN109575091A (en) | Dimethyl 1,3,5-trihydroxybenzene derivative and its pharmaceutical composition and its application | |
| CN109470788A (en) | A kind of method of quality control of FUKE QIANJIN PIAN | |
| CN102670811B (en) | External medicament for treating bacterial vaginosis and colpitis mycotica | |
| CN103271983A (en) | Perfusate for treating endometritis and kysthitis of pig as well as preparation method and application thereof | |
| WO2010025621A1 (en) | Extracts of flavonoids-containing traditional chinese medicine, extraction method, pharmaceutical composition and application thereof | |
| TWI430792B (en) | A pharmaceutical composition for treating hepatitis and/or cancer | |
| CN108785317A (en) | Purposes of the cortex periplocae C21 steroids in preparing IDO inhibitor |
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 |
Granted publication date: 20130410 Termination date: 20141209 |
|
| EXPY | Termination of patent right or utility model |