CN105153174B - A kind of pyrans a pair of horses going side by side Benzazole compounds and its preparation method and application - Google Patents
A kind of pyrans a pair of horses going side by side Benzazole compounds and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to heterocyclic compound, more particularly to a kind of pyrans a pair of horses going side by side Benzazole compounds and its preparation method and application, pyrans a pair of horses going side by side Benzazole compounds are chipal compounds, its preparation method is the FG216 inoculations that will be isolated from off Zhoushan Is- lands in slant medium, then by inclined-plane bacterial strain FG216 seed culture fluids according to 1% inoculum concentration, it is inoculated in czapek's medium, culture, methyl alcohol are extracted on constant-temperature table；Centrifugation, concentrated under reduced pressure, vacuum drying, finally by dry substance silica gel column chromatography.Pyrans a pair of horses going side by side Benzazole compounds can improve activities of endothelial tissue plasminogen, promote the fibrinous degraded of fluorescein isothiocynate, with certain thrombolysis activity.Can be used in treatment or prevention of thromboembolic disorders medicine, blood danger is small, the blood injury factor, selectivity be not high.
Description
Technical field
The present invention relates to heterocyclic compound, more particularly to a kind of pyrans a pair of horses going side by side Benzazole compounds and preparation method thereof and should
With.
Background technology
Thrombotic disease is one of the three big diseases for causing human death, serious to threaten human life and health.Mesh
The preceding whole world there are about 15,000,000 patients, and the death toll that it causes alreadys exceed malignant tumour.Thrombolytic therapy is the early stage acute heart
Effective treatment method of muscle infarction and other thrombotic diseases, fibrinolytic therapy is early stage acute myocardial infarction and other thrombus
Property disease effective treatment method, mainly by the plasminogen of drug activation blood lateral reactivity, formed activity fibrinolytic
The therapeutic purposes of fibrinolytic therapy are realized in enzyme degraded thrombus fibroblast cells catabolite, thrombolysis.Fibrinolytic therapy is although praised
One of ten great discoveries for 20th century cardiovascular and cerebrovascular medicine Neo-Confucianism field.
The main thrombolytic drug that domestic and international official approval is clinically used has：Streptokinase (streptokinase, SK),
Urokinase (urokinase-type plasminogen activator, UK, u-PA), rt-PA
(recombinant tissue-type plaminogen activator, rt-PA), p- anisoyl plasminogen chain
Kinase activator agent compound (anisoylated plasmsnogen streptokinase activator complex,
) and recombined streptokinase (reeombinant streptokinase, r-sK) APSAC.
Medicine such as tissue-type plasminogen activator, urokinase-type plasminogen that typical fibrinolytic therapy is clinically used
Activator etc. can bring the substantial risk of bleeding, be only used for treating severe thrombotic patient.Due to plasminogen activator
There is safety issue in class medicine, researcher is currently in use tissue-type plasminogen activator and recombinates variant (Recombinant
Variants of tissue-type plasminogen activator, rt-PA) etc. low molecular weight compound reducing out
Blood is dangerous, and the blood coagulation resisting function and promotion fibrinolysis activity of the hematoglobin protein C of activation attract attention.Clinically, disappear
The medicine of removing thrombus such as platelet membrane specificity glycoprotein inhibitor Abciximab, in addition to hemorrhage risk, also brings
As the side effect of aspirin decrease of platelet.
Therefore, cardiovascular and cerebrovascular medicine Neo-Confucianism field is just needing that hemorrhage risk is small, not high small of the blood injury factor, selectivity badly
Molecular compound is found such micromolecular compound and is developed into efficient, special, safe molten as the appearance of medicine
Bolt medicine is always the hot subject in the whole world.
In sum, the medicine for the treatment of thrombus has a very big market demand, but the treatment thrombus of clinical practice now
Medicine generally existing safety issue, current international and domestic researcher is being devoted to successfully developing that bleeding danger is small, is not damaging
Hinder appearance of blood factor, the selectivity micromolecular compound high as medicine, and be developed into efficient, special, safe
Thrombolytic drug.
The content of the invention
It is an object of the invention to provide a kind of pyrans a pair of horses going side by side Benzazole compounds, the target compound can improve plasminogen
Activity, promotes FITC (fluorescein isothiocynate)-fibrin degradation, with good thrombolysis activity.
It is a further object to provide the preparation method of pyrans a pair of horses going side by side Benzazole compounds.
The present invention seeks to what is be achieved through the following technical solutions.
A kind of pyrans a pair of horses going side by side Benzazole compounds, it is characterised in that：Its general structure as shown in formula I,
Pyrans a pair of horses going side by side Benzazole compounds are chipal compounds, and 1' is R types or S types.
The preparation method of above-mentioned pyrans a pair of horses going side by side Benzazole compounds, its step includes：
1) bacterial strain FG216, is inoculated in slant medium, then by inclined-plane bacterial strain FG216 seed culture fluids according to 1%
Inoculum concentration, is inoculated in czapek's medium, 22-26 DEG C, 180rmin-1Constant-temperature table on cultivate 4-6 days, then add again
The ornithine of the weight of culture volume 1%, cultivates 24-28 hours；Preferably, the pH value of the czapek's medium is 5.8.It is described
FG216 bacterial strains (Stachybotrys longispira FG216) are isolated from off Zhoushan Is- lands, belong to Micromonospora
(Micromonospora sp.).The bacterial strain is preserved in China typical culture collection center, preserving number：CCTCC
NO.M2012272, preservation date is on July 12nd, 2012.
2), add and the isometric methyl alcohol of czapek's medium, it is ultrasonically treated 12-18 minutes, in rotating speed 10000rpm conditions
Lower centrifugation 12-18 minutes, takes supernatant and is concentrated under reduced pressure at 55-65 DEG C, be vacuum dried；Then dry substance is dissolved in methyl alcohol,
Filtering, takes supernatant and is concentrated under reduced pressure, is vacuum dried；Dry substance silica gel column chromatography is finally obtained the compound of formula I；
In the step (1), czapek's medium is carried by sucrose, sodium nitrate, dipotassium hydrogen phosphate, magnesium sulfate, potassium chloride, yeast
Take thing, cobalt chloride, ferrous sulfate, calcium chloride and seawater composition, it is sterilized after use.Preferably, czapek's medium is, often
Contain sucrose 50g, sodium nitrate 3g, dipotassium hydrogen phosphate 0.1g, magnesium sulfate 0.5g, potassium chloride 0.5g, ferment in 1000ml artificial seawaters
Female extract 1g, cobalt chloride 0.0025g, ferrous sulfate 0.015g, calcium chloride 0.0065g.
In the step (2), the mobile phase of silica gel column chromatography is chloroform-methanol, and volume ratio is 5：1.
A kind of pharmaceutical composition, it is characterised in that：Contain the compound that general structure is formula I in said composition.
Above-mentioned pyrans a pair of horses going side by side Benzazole compounds can be applicable in preparation treatment or prevention of thromboembolic disorders medicine.
Aforementioned pharmaceutical compositions can be applicable in preparation treatment or prevention of thromboembolic disorders medicine.
When pyrans a pair of horses going side by side Benzazole compounds prepared by the present invention are used as medicine, can be used directly, or with pharmaceutical composition
Form use.
Pyrans a pair of horses going side by side Benzazole compounds compound prepared by the present invention that described pharmaceutical composition contains 0.1%-99%, its
It is remaining for pharmaceutically acceptable, the inert available support nontoxic to humans and animals and/or excipient.
Described pharmaceutical carrier or excipient is one or more solid, semi-solid and liquid diluent, filler and medicine
Tetramune assistant agent, can be lactose, Icing Sugar, starch, sodium alginate etc..Pharmaceutical composition of the invention is taken with unit bodies
The form of amount is used.Pharmaceutical composition of the invention can be administered through injecting (intravenous, intramuscular injection) and oral two kinds of forms.
Beneficial effects of the present invention：
1st, pyrans a pair of horses going side by side Benzazole compounds can improve activities of endothelial tissue plasminogen, by detection, the fibrinolysin of compound
Former activity improves more than 2.5 times；FITC (fluorescein isothiocynate)-fibrinous degraded can be promoted, with certain molten
Thrombus activity.
2nd, pyrans a pair of horses going side by side Benzazole compounds can be used in treatment or prevention of thromboembolic disorders medicine, and blood is dangerous
It is small, the blood injury factor, selectivity be not high.
Specific embodiment
Technical characterstic of the invention is expanded on further with reference to specific embodiment.
FG216 bacterial strains (Stachybotrys longispira FG216), the bacterial strain belongs to Micromonospora
(Micromonospora sp.).The bacterial strain is preserved in China typical culture collection center, preserving number：CCTCC
NO.M2012272, preservation date is on July 12nd, 2012.
Czapek's medium, sucrose 50g, sodium nitrate 3g, dipotassium hydrogen phosphate are contained in the every 1000ml artificial seawaters of the culture medium
0.1g, magnesium sulfate 0.5g, potassium chloride 0.5g, yeast extract 1g, cobalt chloride 0.0025g, ferrous sulfate 0.015g, calcium chloride
Used after 0.0065g, pH 5.8 is sterilized.
Embodiment 1：
Bacterial strain FG216 is inoculated in slant medium, then by cultured inclined-plane bacterial strain FG216 seed culture fluids according to
1% inoculum concentration, is inoculated in czapek's medium, 25 DEG C, 180rmin-1Constant-temperature table on cultivate 4 days, then add again
The ornithine of the weight of culture volume 1%, cultivates 24 hours and completes fermented and cultured.Culture terminate after, in triangular flask add with etc.
The methyl alcohol of volume, ultrasonic 15min is centrifuged 15min under the conditions of rotating speed 10000rpm, and reject is precipitated, and supernatant is in 60 DEG C of conditions
Lower vacuum distillation is evaporated, and concentrate vacuum drying 8h, dry substance is dissolved in the methanol solution of 20mL, and filtering reject precipitation is collected
Supernatant, then vacuum drying concentrated under reduced pressure, gained dry substance silica gel column chromatography chloroform-methanol (5：1, v/v) obtain with molten
Pyrans a pair of horses going side by side indoles S types compound and pyrans a pair of horses going side by side indoles R type compounds of thrombus facilitation.
The structural formula of pyrans a pair of horses going side by side indoles S type compounds is：
Molecular formula：C28H38N2O5
Molecular weight：482
Proterties：Pale yellow powder
1HNMR(CDCl3,500MHz)：δ11.34(1H,brs.),9.45(1H,brs.),7.27(1H,s),5.31(1H,
Brs.), 5.09 (1H, t, J=7.0Hz), 5.03 (1H, t, J=7.0Hz), 4.65 (1H, d, J=19.5Hz), 4.60 (1H, d,
), J=19.5Hz 4.11 (1H, t, J=5.5Hz), 3.76 (2H, m), 3.73 (1H, m), 2.81 (1H, dd, J=17.7,
5.2Hz), 2.48 (1H, dd, J=17.7,5.2Hz), 2.15 (2H, s), 2.09 (2H, dd, J=15.5,7.2Hz), 2.01-
1.97 (3H, m), 1.92-1.89 (3H, m), 1.60 (3H, s) ,~1.57 (2H, m), 1.55 (3H, s), 1.52 (3H, s), 1.13
(3H,s)；13CNMR(CDCl3,125MHz)：δ161.8,157.8,148.5,135.0,131.1,129.5,124.5(2C),
119.6,114.1,99.7,79.6,66.2,60.1,57.5,50.0,39.6,37.7,30.2,27.2,26.6(2C),25.9,
24.5,21.4,18.5,18.0,16.2；ESIMS:m/z 483[M+H]+,HRESIMS:cala for C28H39N2O5[M+H]+
483.2853,found483.2856.
The structural formula of pyrans a pair of horses going side by side indoles R type compounds is
Molecular formula：C28H38N2O5
Molecular weight：482
Proterties：Pale yellow powder
1HNMR(CDCl3,500MHz)：δ10.25(1H,brs),9.73(1H,brs),7.04(1H,s),5.23(1H,d,J
=4.4Hz), 5.07 (1H, t, J=6.8Hz), 5.03 (1H, t, J=6.8Hz), 4.65 (1H, d, J=18.5Hz), 4.49
(1H, d, J=18.5Hz), 4.34 (1H, s), 3.75-3.67 (2H, m), 2.81 (1H, dd, J=17.8,5.2Hz), 2.54-
2.50 (2H, m), 2.09-2.04 (2H, m), 2.00-1.96 (2H, m), 1.89 (2H, t, J=7.5Hz), 1.86-1.78 (2H,
m),1.60(3H,s),1.57-1.55(2H,m),1.53(3H,s),1.52(3H,s),1.17(3H,s)；13CNMR(CDCl3,
125MHz)：δ163.7,157.3,148.5,135.0,131.5,130.1,124.51,124.46,120.6,114.0,99.6,
79.6,66.2,66.1,58.3,49.0,39.6,37.4,29.6,27.1,26.6,25.9,24.6,21.4,18.9,18.0,
16.1；ESIMS:m/z 483[M+H]+,HRESIMS:cala for C28H39N2O5[M+H]+483.2853,found
483.2835.
Activity rating：
(1), to structural formula I in two compounds carry out activities of endothelial tissue plasminogen measure
Using 96 hole round bottom ELISA Plates, swash in 20 μm of ol/L plasminogens, 20 μm of ol/L single chain urokinase type plasminogen activator types plasminogens
Agent living, 100 μ g/ml SUK (spectrozyme) constitute 50 μ L [TBS (Tris-HCl Buffer Solution)/
BSA (Bovine Serum Albumin, 50mM Tris-HCl, 100mM NaCl, and2mg/ml BAS, pH7.4)] reactant
In system, the pyrans a pair of horses going side by side Benzazole compounds in addition embodiment 1 determine the life of free nitroaniline for continuous 100 minutes in 405nm
Into the increase of the absorbance for causing, compared with the control, embody thrombus dissolving with absorbance and act on.By detection, in structural formula I
The activities of endothelial tissue plasminogen of two compounds improves more than 2.5 times, and two compounds in the reaction system structural formula I exist
The increase of concentration and the increase of absorbance are consistent in the range of 0.08-200 μm of ol/L.
(2), two compound FITC- fibrin degradation determinations of activity in structural formula I
It is dissolved in the fibrinogen of 360 μ L (10mg/ml) of 0.1mol/L sodium acid carbonates (pH9.0) and is dissolved in phosphoric acid
36 μ l (10mg/ml) FITC (fluorescein isothiocyanate isomer I) mixing of salt buffer, at 25 DEG C
Insulation 0.5 hour, using the dextran chromatography column chromatography mixed liquor balanced by phosphate buffer, has obtained FITC-Fbg
(fibrinogen).The μ l of phosphate buffer 1 00 containing 20 μ g FITC-Fbg are dispensed into the hole of the flat ELISA Plate in 96 holes
In, 12 hours are incubated to drying at 37 DEG C, to adding 25 μ l fibrin ferments [0.68U/ml in NaCl/ in dry cavities
NaPi (150mM NaCl and 20mM sodium phosphate, pH7.4)], after maintaining 3 hours at 37 DEG C, with containing
The NaCl/NaPi of 0.1%Tween 80 is clean 2 times and 1 time respectively with the NaCl/NaPi for not containing 0.1%Tween 80, then
The μ l of NaCl/NaPi solution 200 of 5mg/ml fetal skin collagens are added, 1 hour is incubated at 37 DEG C, after reject buffer solution
It is used for the measure of fibrinolytic.
μ l, 0.1nM single chain urokinase type plasminogen activator types plasminogens of TBS/BSA 100 containing 10% blood plasma (not containing blood platelet) swash
Agent living and sample (0-14 μ g/ml) are sequentially added in above-mentioned cavities, and each sample is repeated 3 times, and 1 are incubated at 37 DEG C small
When, determine the fibrinous decomposition of FITC- in excitation wavelength 494nm and Detection wavelength 520nm using sepectrophotofluorometer
Amount.Compared with the control, pyrans a pair of horses going side by side two compounds of indoles in more than 6.0 μM structural formula Is improve the fibrinous drops of FITC-
More than 1.9 times of solution.
(3), conclusion
Experimental result shows that pyrans a pair of horses going side by side two compounds of indoles in structural formula I prepared by embodiment 1 in vitro can
Improve activities of endothelial tissue plasminogen and promote FITC (fluorescein isothiocynate)-fibrin degradation, with certain thrombolysis activity.
Embodiment 2
By pyrans a pair of horses going side by side two compounds of indoles in obtained structural formula I in embodiment 1, respectively take 1mg and use 0.5mL respectively
DMSO dissolvings after, routinely plus water for injection, refined filtration, embedding sterilizing is made parenteral solution.
Embodiment 3
By pyrans a pair of horses going side by side two compounds of indoles in obtained structural formula I in embodiment 1, respectively take 1mg and use 0.5mL respectively
DMSO dissolvings after, routinely plus water for injection, be dissolved in sterile water for injection, be stirred to dissolve, leaked with aseptic suction filtration
Bucket filtering, is sub-packed in ampere bottle, aseptic after frozen drying to seal to obtain powder-injection.
Embodiment 4
By obtained pyrans a pair of horses going side by side Benzazole compounds in embodiment 1, according to weight of the parallel Benzazole compounds with excipient of muttering
Amount is than being 9:1 ratio mixing, is made pulvis.The excipient is lactose, Icing Sugar, starch, sodium alginate etc., is made pulvis.
Embodiment 5
By obtained pyrans a pair of horses going side by side Benzazole compounds in embodiment 1, according to weight of the parallel Benzazole compounds with excipient of muttering
Amount is than being 5:1 ratio mixing, is made pulvis.The excipient is lactose, Icing Sugar, starch, sodium alginate etc., is made pulvis.
Embodiment 6：
By obtained pyrans a pair of horses going side by side Benzazole compounds in embodiment 1, routinely oral liquid preparation method, is made oral liquid.
Embodiment 7：
With excipient it is 5 according to weight ratio by it by obtained pyrans a pair of horses going side by side Benzazole compounds in embodiment 1:1 ratio
Capsule is mixed and made into, excipient can be lactose, Icing Sugar, starch, sodium alginate.
Embodiment 8：
With excipient it is 3 according to weight ratio by it by obtained pyrans a pair of horses going side by side Benzazole compounds in embodiment 1:1 ratio
Mixing, is made capsule, and excipient can be lactose, Icing Sugar, starch, sodium alginate.
Claims (7)
1. a kind of pyrans a pair of horses going side by side Benzazole compounds, it is characterised in that：Its general structure as shown in formula I,
Pyrans a pair of horses going side by side Benzazole compounds are chipal compounds, and 1' is R types or S types.
2. the preparation method of the parallel Benzazole compounds of pyrans described in claim 1, its step includes：
1) bacterial strain FG216, is inoculated in slant medium, then by inclined-plane bacterial strain FG216 seed culture fluids according to 1% inoculation
Amount, is inoculated in czapek's medium, 22-26 DEG C, 180rmin-1Constant-temperature table on cultivate 4-6 days, culture is then added again
Matrix accumulates the ornithine of 1% weight, cultivates 24-28 hours；
2), add with the isometric methyl alcohol of czapek's medium, it is ultrasonically treated 12-18 minutes, under the conditions of rotating speed 10000rpm from
Heart 12-18 minutes, take supernatant and be concentrated under reduced pressure at 55-65 DEG C, be vacuum dried；Then dry substance is dissolved in methyl alcohol, is filtered,
Supernatant is taken to be concentrated under reduced pressure, be vacuum dried；Dry substance silica gel column chromatography is finally obtained the compound of formula I；The silica gel column chromatography
Mobile phase be chloroform-methanol, volume ratio is 5：1；
The czapek's medium is by sucrose, sodium nitrate, dipotassium hydrogen phosphate, magnesium sulfate, potassium chloride, yeast extract, cobalt chloride, sulphur
Sour ferrous, calcium chloride and seawater composition, it is sterilized after use.
3. the preparation method of pyrans according to claim 2 a pair of horses going side by side Benzazole compounds, it is characterised in that：The Cha Shi cultures
The pH value of base is 5.8.
4. a kind of pharmaceutical composition, it is characterised in that：Contain the change that the general structure in claim 1 is formula I in said composition
Compound.
5. pharmaceutical composition according to claim 4, it is characterised in that：The formula I for containing in described pharmaceutical composition
Compound accounts for the 0.1%-99wt% of pharmaceutical composition total amount.
6. the pyrans a pair of horses going side by side Benzazole compounds described in claim 1 are in treatment or prevention of thromboembolic disorders medicine is prepared
Using.
7. application of the pharmaceutical composition described in claim 4 in treatment or prevention of thromboembolic disorders medicine is prepared.
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|---|---|---|---|---|
| JP2002065288A (en) * | 2000-08-31 | 2002-03-05 | Keiji Hasumi | Method for selectively producing triprenyl phenol compound and utilization of the same compound as medicine |
| CN102115478A (en) * | 2010-05-14 | 2011-07-06 | 上海海洋大学 | Furo-indole compounds and preparation method and application thereof |
-
2015
- 2015-08-10 CN CN201510486160.6A patent/CN105153174B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002065288A (en) * | 2000-08-31 | 2002-03-05 | Keiji Hasumi | Method for selectively producing triprenyl phenol compound and utilization of the same compound as medicine |
| CN102115478A (en) * | 2010-05-14 | 2011-07-06 | 上海海洋大学 | Furo-indole compounds and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Pharmacokinetics and tissue distribution of a novel marine fibrinolytic compound in Wistar rat following intravenous administrations;Tongwei Su et al.;《Journal of Chromatography B》;20131025;第942卷;第77-82页 * |
| 海洋微生物来源纤溶活性化合物的筛选及其分离;张艳等;《中国海洋药物杂志》;20081231;第27卷(第6期);第39-43页 * |
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