CN104974125A - Phaeoporlactone as well as preparation method, medicine composition and application thereof - Google Patents
Phaeoporlactone as well as preparation method, medicine composition and application thereof Download PDFInfo
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- CN104974125A CN104974125A CN201410132369.8A CN201410132369A CN104974125A CN 104974125 A CN104974125 A CN 104974125A CN 201410132369 A CN201410132369 A CN 201410132369A CN 104974125 A CN104974125 A CN 104974125A
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- phaeoporlactone
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- C07—ORGANIC CHEMISTRY
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
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Abstract
The invention discloses phaeoporlactone which is a new compound extracted from phaeoporus obliquus which is a fuscoporia fungus, and further discloses a preparation method of the compound, a medicine composition containing the compound and application of the medicine composition in prevention and/or treatment of tumors or protein tyrosine kinase (PTKs) related diseases. Phaeoporlactone has inhibitory activity and particularly has an inhibitory effect on growth of human hepatoma carcinoma cell Bel-7402 and therefore can be used for preventing, relieving and/or treating diseases related to abnormal rise of PTKs activity (such as tumors), percutaneous transluminal coronary intervention (PCI) restenosis, atherosclerosis, hypertension, multiple sclerosis, diabetic retinopathy, endometriosis, skin diseases (such as psoriasis), asthma and the like(The formula I is shown in the specification).
Description
Technical field
The invention belongs to field of medicaments, relate to particularly one from brown pore fungi belong to the brown pore fungi lactone (Phaeoporlactone) of new compound that fungi tiltedly extracts raw brown pore fungi, its preparation method, comprise this compound pharmaceutical composition and preventing and/or treating tumour and the active abnormal application raised in relative disease of PTKs.
Background technology
The brown pore fungi of oblique life [Phaeoporus obliquus (Pers.:Fr.) J.Schrotet. or Inonotusobliquus (Pers.:Fr.) Pilat or Polyporus obliquus Pers.:Fr.], be agaric guiding principle, rust leather pore fungi order, Hymenochaetaceae, brown pore fungi belong to fungi, former name Phaeopoms obliquus.The brown pore fungi of oblique life have anti-diabetic, anticancer, prevent and treat acquired immune deficiency syndrome (AIDS), improve immunity etc. effect.
Tyrosine phosphorylation plays an important role in many cell regulation process, is mainly reflected in the activation of T cell and B cell, reaction to external irritant, mitotic division, blood vessel hyperplasia, neurotransmitter conduction, the growth control of cell cycle, transcriptional regulatory, glucose uptake, tumour occur and the process such as cytodifferentiation, formation and apoptosis.Tyrosine protein kinase (Protein tyrosinekinases, PTKs) dysfunction may cause numerous disease.Current PTKs activity has become one of mark that measure of cell proliferation cancerates.In view of the vital role of PTKs in tumor cells etiology, people attempt utilizing PTKs inhibitors to inhibitor tumor Growth of Cells and some proliferative diseases, as diseases such as tetter and asthma such as PCI postoperative restenosis, atherosclerosis, hypertension, multiple sclerosis, diabetic retinopathy, endometriosis, psoriasiss.
From broadly antitumour drug can be divided into two generation medicine.First on behalf of traditional cellulotoxic chemotherapeutics, as platinum class and anti-metabolism anticarcinogen; Second on behalf of molecular targeted therapy, and this class medicine typically refers to specifically to the medicine that one or more tumor correlated albumen regulates and controls.Operation, chemotherapy, radiotherapy are the Main Means for the treatment of tumour now, but respectively have drawback, and mainly toxic side effect is larger.Current antitumor drug research and development facing challenges, one is that multiple antitumor drug can not meet clinical demand far away, is badly in need of the more new drug of exploitation; Two is that toxic side effect is large, poor selectivity, and result for the treatment of is undesirable; Three is that anti-tumor drugs targeting also exists resistance problems, and the sex expression of curative effect more obvious Drug-resistant is more outstanding; Four is that the impact of prolonged application anti-tumor drugs targeting on body can not be ignored.Therefore efficient, low toxicity, highly selective the anti-cancer agent that the exploitation third generation is novel is still an important research topic, has important innovative significance.
Summary of the invention
The technical problem that the present invention solves is, on the one hand provides the brown pore fungi lactone (Phaeoporlactone) of a kind of new compound, its structure as shown in the formula (I):
Another aspect provides the method preparing the brown pore fungi lactone (Phaeoporlactone) of compound.
Another aspect of the present invention relates to a kind of pharmaceutical composition, and it comprises compound brown pore fungi lactone (Phaeoporlactone) and pharmaceutically acceptable carrier.
Another aspect of the invention relates to the application that the brown pore fungi lactone (Phaeoporlactone) of compound prevents and/or treats protein tyrosine kinase (PTKs) relative disease, protein tyrosine kinase (PTKs) relative disease including but not limited to tumour, the application in the disease medicaments such as tetter and asthma such as PCI postoperative restenosis, atherosclerosis, hypertension, multiple sclerosis, diabetic retinopathy, endometriosis, psoriasis.Particularly preparing the application prevented and/or treated in the medicine of liver cancer.
For solving technical problem of the present invention, the present invention adopts following technical scheme:
The preparation method of the brown pore fungi lactone (Phaeoporlactone) of a kind of new compound, is characterized in that comprising the following steps:
(1) get the brown pore fungi medicinal material of a certain amount of oblique life, the extraction using alcohol with 95% three times, obtains medicinal extract;
(2) ethanol extract in step (1) is suspended in water, first uses chloroform extraction, be then extracted with ethyl acetate, finally use n-butanol extraction, final rough segmentation becomes four parts such as chloroform, ethyl acetate, propyl carbinol, water;
(3) by ethyl acetate extraction part concentrating under reduced pressure, and be separated through silica gel column chromatography, chloroform-acetone and chloroform-methanol system is used to carry out gradient elution, every 500ml is first-class part, detection, collection obtain brown pore fungi lactone (Phaeoporlactone) crude product, then obtain compound brown pore fungi lactone (Phaeoporlactone) sterling through preparation HPLC purifying.
Wherein in step (3), the separation condition of preparation HPLC is methanol-water-formic acid (30:70:1, V:V:V), and flow velocity 8ml/min, 227nm wavelength detecting, gets 500 μ L sample introductions, at t
r=20min obtains brown pore fungi lactone (Phaeoporlactone) sterling.
Through qualification, the structure of the brown pore fungi lactone (Phaeoporlactone) of the new compound obtained as shown in the formula (I)
Found by pharmacologically active experiment, formula I of the present invention has and arrestin Tyrosylprotein kinase PTKs effect.Can be applicable to prepare and prevent and/or treat the active abnormal medicine raising relative disease of PTKs.Described PTKs relative disease comprises but does not now schedule the diseases such as tetter and asthma such as tumour, PCI postoperative restenosis, atherosclerosis, hypertension, multiple sclerosis, diabetic retinopathy, endometriosis, psoriasis.According to antitumor relevant pharmacological evaluation, new compound brown pore fungi lactone (Phaeoporlactone) has good antitumor pharmacological action, especially suppresses the growth of human liver cancer cell.
Advantageous Effects:
A) brown pore fungi lactone (Phaeoporlactone) is the monomeric compound of extracting and developing in fungi tiltedly raw brown pore fungi, has the simple advantage of preparation technology.
B) its starting material can be cultivated, have good applicating and exploitation prospect.
C) protein tyrosine kinase (PTKs) relative disease is including but not limited to tumour, the application in the disease medicaments such as tetter and asthma such as PCI postoperative restenosis, atherosclerosis, hypertension, multiple sclerosis, diabetic retinopathy, endometriosis, psoriasis.Particularly preparing the application prevented and/or treated in the medicine of liver cancer.
The invention still further relates to a kind of containing formula (I) compound of medicine effective dose and the pharmaceutical composition of pharmaceutically acceptable carrier.
According to embodiment of the present invention, formula (I) compound also comprises its pharmacy acceptable salt, hydrate, ester and prodrug.
The invention still further relates to and contain as formula (I) compound of active ingredient and the pharmaceutical composition of customary pharmaceutical excipients or assistant agent.Usual formula (I) compound accounts for 0.1 ~ 95% of pharmaceutical composition gross weight.Be 0.1 to 100mg at the general content of unit dosage form Chinese style (I) compound.
Pharmaceutical composition of the present invention can be prepared according to method well known in the art.During for this object, if needed, formula of the present invention (I) compound and one or more solids or liquid pharmaceutical excipients and/or assistant agent can be combined, make the suitable administration form or dosage form that can be used as people's medicine or veterinary drug use.
Formula of the present invention (I) compound or the pharmaceutical composition containing it can administrations in a unit, route of administration can be enteron aisle or non-bowel, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, eye, lung, skin, vagina, peritonaeum, rectum etc., preferred oral administration.
Formula of the present invention (I) compound or the route of administration containing its pharmaceutical composition can be drug administration by injection.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, abdominal injection and acupoint injection therapy etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising oil-in-water-type, water-in-oil-type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
Formula of the present invention (I) compound can be made ordinary preparation, also can be sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
In order to unit dosage forms for administration is made tablet, various vehicle well known in the art can be widely used, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyethylene adjoin pyrrolidone, gather second two propyl alcohol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyethylene adjoin pyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
In order to administration unit is made pill, various carrier well known in the art can be widely used.Example about carrier is, such as thinner and absorption agent, as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire 44/14, kaolin, talcum powder etc.; Tackiness agent, as gum arabic, yellow Bodhisattva's glue, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent, as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.
In order to administration unit is made suppository, various carrier well known in the art can be widely used.Example about carrier is, the ester, gelatin, semi-synthetic glyceryl ester etc. of such as polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols.
In order to administration unit is made capsule, formula (I) compound is mixed with above-mentioned various carriers, and the mixture obtained thus is placed in hard gelatine capsule or soft capsule.Also formula (I) compound of the present invention for effective constituent can be made microcapsule, be suspended in aqueous medium and form suspensoid, also can load in hard capsule or make injection application.
Such as, formula (I) compound is made injection preparation, as solution, suspensoid solution, emulsion, lyophilized injectable powder, this preparation can be moisture or non-water, can containing acceptable carrier, thinner, tackiness agent, lubricant, sanitas, tensio-active agent or dispersion agent in a kind of and/or multiple pharmacodynamics.As thinner can be selected from water, ethanol, polyoxyethylene glycol, l, the isooctadecanol of ammediol, ethoxylation, polyoxygenated isooctadecanol, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, in order to prepare isotonic injection liquid, appropriate sodium-chlor, glucose or glycerine can be added in injection preparation, in addition, conventional solubility promoter, buffer reagent, pH adjusting agent etc. can also be added.These auxiliary materials are that this area is commonly used.
In addition, as needs, also tinting material, sanitas, spices, correctives, sweeting agent or other material can be added in pharmaceutical preparation.
For reaching medication object, strengthen result for the treatment of, formula of the present invention (I) compound or pharmaceutical composition can with any known medication administrations.
The dosage of pharmaceutical composition of the present invention depends on many factors, such as to prevent or the character of disease therapy and severity, the sex of patient or animal, age, body weight, personality and individual reaction, route of administration, administration number of times, therapeutic purpose, therefore therapeutic dose of the present invention can have large-scale change.In general, the using dosage of Chinese materia medica composition of the present invention well known to a person skilled in the art.Can according to actual drug quantity contained in preparation last in pharmaceutical composition of the present invention, in addition suitable adjustment, to reach the requirement of its treatment significant quantity, completes prevention of the present invention or therapeutic purpose.The Suitable dosage ranges of the every day of formula (I) compound: the consumption of formula of the present invention (I) compound is 0.001 ~ 100mg/kg body weight, above-mentioned dosage can single dose form or be divided into several, such as two, three or four dosage forms for administration, this depends on the clinical experience of administration doctor and comprises the dosage regimen using other treatment means.The required total dose of each treatment can be divided into repeatedly or by dose administration.Formula of the present invention (I) compound or pharmaceutical composition can be taken separately, or merge with other treatment medicine or symptomatic drugs and use and adjust dosage.
Embodiment
The following examples and pharmacologically active experiment be used for further illustrating the present invention, but this and do not mean that any limitation of the invention.
One, the preparation of brown pore fungi lactone (Phaeoporlactone)
The method of embodiment 1 brown pore fungi lactone (Phaeoporlactone) of extraction and isolation from oblique raw brown pore fungi:
Oblique life brown pore fungi medicinal material 22kg, extraction using alcohol with 95% three times, obtain medicinal extract 710g, get 700g ethanol extract and be suspended in water, first use chloroform extraction, then be extracted with ethyl acetate, finally use n-butanol extraction, rough segmentation becomes four parts such as chloroform (424g), ethyl acetate (51g), propyl carbinol (152g), water (67g).Get ethyl acetate extraction part 50g, through silica gel column chromatography separating for several times, chloroform-acetone and chloroform-methanol system gradient elution, every 500ml is a fraction, obtains brown pore fungi lactone (Phaeoporlactone) crude product in the 18th part, again through preparation HPLC purifying (30% methanol-water, flow velocity 8ml/min, 227nm wavelength detecting), get 500 μ L sample introductions, obtaining compound brown pore fungi lactone (Phaeoporlactone) sterling 52mg at tR=20min, is tawny powder.
Compound brown pore fungi lactone (Phaeoporlactone) physico-chemical property and spectral data as follows:
Fusing point: 132-133 DEG C;
(-) ESIMS:m/z179 [M-H]
-, 359 [2M-H]
-; Molecular formula: C
9h
8o
4;
cm
-1：3349，3245，1730，1646，1616，1596，1522，1477，1347，1300，1264，1217，1182，1165，1089，1060，998，955，877，818，677，578；
UV：λ
max206，227，267，307nm；
1H-NMR（500MHz，C
5D
5N）：δ8.11（1H，s，H-8），7.00（1H，s，H-5），4.36（1H，t，J=6.0Hz，H-3），2.77（1H，t，J=6.0Hz，H-4）；
13C-NMR（125MHz，C
5D
5N）：δ165.2（C-1），67.4（C-2），27.3（C-4），114.4（C-5），146.5（C-6），153.2（C-7），116.9（C-8），133.4（C-9），16.7（C-10）。
Two, pharmacologically active experiment
The brown pore fungi lactone (Phaeoporlactone) of experimental example 1 is tested at protein tyrosine kinase inhibitor screening model
Adopt Enzyme-linked Immunosorbent Assay method, separation and extraction Tyrosylprotein kinase from rat cerebral tissue, with poly-Glu-Tyr (PGT) as substrate, wraps by microwell plate.The tyrosine residues of PGT can by PTKs phosphorylation, then by the phosphospecific monoclonal antibody of HRP mark as probe, with the tyrosine residues specific binding of phosphorylation, by colour developing, measures its absorbancy, to react the activity of PTKs.
1) extraction of PTK in rat cerebral tissue;
2) enzyme plate bag quilt;
3) ptk inhibitor screening: first compound and PTK crude extract are added enzyme plate, hatch for 37 DEG C; Add the ATP of kinase buffer liquid dilution, hatch for 37 DEG C; Remove reaction solution in plate, washing; Add antibody complex, hatch for 37 DEG C; Remove antibody complex in plate, washing; Add the reaction of TMB nitrite ion room temperature lucifuge; Add stop buffer, survey OD value in 450nm.
Inhibiting rate %=(normal-OD sample of OD)/(OD is normal, and-OD is blank) * 100%
The brown pore fungi lactone of table 1 is in protein tyrosine kinase inhibitor screening model experimental result
In the experiment of protein tyrosine kinase inhibitor screening model, the compounds of this invention has good restraining effect when 10 μ g/ml dosage to protein tyrosine kinase.Inhibiting rate reaches 73.59%, its IC
50value is 4.989 μ g/ml.
Experimental example 2 brown pore fungi lactone (Phaeoporlactone) is to external Bel-7402 people's tumor cells of hepatocellular carcinoma Cell suppression test
Tetrazole [MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide] is a kind of dyestuff that can accept hydrogen atom.The MTT of yellow can be changed into insoluble hepatic formazon by desaturase relevant to NADP in viable cell plastosome in cell, and dead cell is then without this function.After dissolving formazon with DMSO, under certain wavelength, measuring optical density value by microplate reader, quantitatively can measure the survival rate of cell, growth of tumour cell inhibiting rate can be obtained by calculating.
Select the attached tumor cells of logarithmic phase, with the RPMI1640 nutrient solution containing 10% foetal calf serum after trysinization, be seeded in 96 well culture plates, 4000, every hole cell, 37 DEG C, 5%CO
2cultivate 24h.Experimental group adds sample and the positive control drug 5-Fu of different concns, and control group then changes the nutrient solution containing equal-volume solvent, 37 DEG C, 5%CO
2cultivate 3d.Abandoning supernatant, every hole adds the serum-free medium of the freshly prepared 0.5mg/ml MTT of 100 μ l, and 37 DEG C are continued to cultivate 4h.Carefully abandon supernatant, and add 100 μ l DMSO dissolving MTT formazon precipitations, after the mixing of miniature ultrasonic vibrator, microplate reader measures the optical density value at wavelength 570nm place.Growth of tumour cell inhibiting rate (%)=(OD
contrast-OD
experiment)/(OD
contrast-OD
blank) * 100%
Table 2 brown pore fungi lactone is to external Bel-7402 people's tumor cells of hepatocellular carcinoma Cell suppression test result
To in external Bel-7402 people's tumor cells of hepatocellular carcinoma Cell suppression test, that positive control drug is selected is 5 FU 5 fluorouracil (5-Fu), and the compounds of this invention is when 5 μ g/ml concentration and positive control drug IC
50value quite.
Claims (8)
1. the brown pore fungi lactone of the compound shown in formula I
2. the preparation method of compound as claimed in claim 1, it comprises the steps:
(1) get the brown pore fungi medicinal material of a certain amount of oblique life, the extraction using alcohol with 95% three times, decompression and solvent recovery, obtains ethanol extract;
(2) ethanol extract in step (1) is suspended in water, first uses chloroform extraction, be then extracted with ethyl acetate, finally use n-butanol extraction, final rough segmentation becomes four parts such as chloroform, ethyl acetate, propyl carbinol, water;
(3) by ethyl acetate extraction part concentrating under reduced pressure, and through silica gel column chromatography separating for several times, chloroform-acetone and chloroform-methanol system is used to carry out gradient elution, every 500ml is first-class part, detection, collection obtain brown pore fungi lactone (Phaeoporlactone) crude product, then obtain compound brown pore fungi lactone (Phaeoporlactone) sterling through preparation HPLC purifying.
3. method according to claim 2, wherein in step (3), the separation condition of preparation HPLC is methanol-water-formic acid (30:70:1, V:V:V), and flow velocity 8ml/min, 227nm wavelength detecting, gets 500 μ L sample introductions, at t
r=20min obtains brown pore fungi lactone (Phaeoporlactone) sterling.
4. a pharmaceutical composition, it comprises formula I as claimed in claim 1 and pharmaceutically acceptable carrier.
5. pharmaceutical composition according to claim 4, the formulation of described pharmaceutical composition is selected from tablet, capsule, granule, oral liquid, dripping pill, micropill or injection.
6. the application of compound according to claim 1 in the medicine of relative disease preparing protein tyrosine kinase.
7. application according to claim 6, it is characterized in that, the relative disease of described protein tyrosine kinase is selected from tumour, PCI postoperative restenosis, atherosclerosis, hypertension, multiple sclerosis, diabetic retinopathy, endometriosis, psoriasis and asthma.
8. application according to claim 6, is characterized in that, described tumour is selected from liver cancer.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006046071A1 (en) * | 2004-10-29 | 2006-05-04 | Nipri Limited | Compounds and compositions useful in the treatment of neoplasia |
| CN101391958A (en) * | 2008-11-10 | 2009-03-25 | 马宏达 | Extraction method of medicinal fungus inonotus obliquus component |
-
2014
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006046071A1 (en) * | 2004-10-29 | 2006-05-04 | Nipri Limited | Compounds and compositions useful in the treatment of neoplasia |
| CN101391958A (en) * | 2008-11-10 | 2009-03-25 | 马宏达 | Extraction method of medicinal fungus inonotus obliquus component |
Non-Patent Citations (2)
| Title |
|---|
| AAMER SAEED ET AL: "Total synthesis and cytotoxic activity of stellatin", 《OURNAL OF ASIAN NATURAL PRODUCTS RESEARCH》 * |
| 赵芬琴等: "桦褐孔菌的化学成分研究", 《时珍国医国药》 * |
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