CN106995440A - A kind of beta-carboline compounds and its synthetic method and application - Google Patents
A kind of beta-carboline compounds and its synthetic method and application Download PDFInfo
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Abstract
The present invention relates to a kind of beta-carboline compounds and its synthetic method and application, belong to pharmaceutical technology field.The compound structure shown in formula I, shows that the anti-kidney fibrosis activity of Compound ira vitro is notable, with preferable potential medical value, the preparation available for various anti-kidney fibrosis, anti-chronic kidney disease medicine through preliminary experiment.
Description
【Technical field】
The present invention relates to pharmaceutical technology field, and in particular to a kind of 'Beta '-carboline compound and its synthetic method and application.
【Background technology】
CKD is lost with renal function progressive, extracellular matrix (ECM) largely builds up caused kidney fibrosis
It is characterized, mainly includes glomerulosclerosis and Tubulointerstitial fibrosis.Kidney region fibrosis is almost all chronic renal diseases
The final result of development, is in progress closely related with renal failure, is to cause the Etiological of end stage renal failure.If early stage is right
Renal fibrosis carries out therapeutic intervention, it will help delaying chronic kidney trouble is in progress, and greatly reduces the incidence of ESRD
And its complication, mitigate the social economical burden caused by it.
Research finds that the Smad signal paths of transforming growth factor-β (TGF-β) and its mediation are in kidney region fibrosis
Play an important role, it is considered to be most critical, most strong fibrosis inducible factor, in the links for participating in kidney fibrosis.It
Overexpression being capable of mesangial cells stimulated, a large amount of collagens (Collagen) of Stromal fibroblasts synthesis, fibronectin
(FN) and laminin (LN), stimulate fibroblast proliferation simultaneously to activate into myofibroblast, promote ECM secretion with it is heavy
Product.TGF-β can also mediate transdifferentiation (EMT) of the renal cells to interstitial cell.Clinically it there is no at present effective anti-
The treatment method of renal fibrosis.Antagonism TGF-β and its signal path of mediation, suppress ECM synthesis or promote it to degrade, may
An effective approach is provided to find treatment renal fibrosis.
Beta-carboline alkaloid is the one kind separated from Xinjiang medicinal plant harmel (Peganumharmala)
Active component.Pharmacological activity with wide spectrum, such as antianxiety, antidepression, anti-spasm and antitumor, anti-malarial, anti-parasitism
Worm, anti-AIDS etc..It is long-standing come treating cancer with seed of peganum harmala in Chinese herbal medicine formula.Beta-carboline alkaloid
Structural modification enjoys the concern of researcher always.It is generally believed that the planar conjugate structure of most of beta-carboline alkaloids
And the presence of different substituents group (such as benzyl (- C6H5), methoxyl group (- OCH3)) and its antitumor activity have notable pass
System.The research to beta-carboline alkaloid mainly includes the following aspects at present：One be based on natural product chemistry research from
Found in the plant of not equal category and carry out separating-purifying；Two be that beta-carboline alkaloid is carried out entirely by methodology of organic synthesis
Synthesis is semi-synthetic, and its structure is modified.It is other then be to its pharmacological activity (such as antitumor activity) carry out molecule mechanism
Research.DNA is such as inserted, suppresses topoisomerase, suppress CDK etc..But from the point of view of current progress, beta-carboline alkaloid
Content in natural plants is general all than relatively low, and extracts relatively complicated, is unfavorable for furtheing investigate it, and
Though organic semisynthesis, with certain advantage, is limited on yield by cost is produced, therefore at present to B-carboline
The expansion research of Alkaloid is still inadequate.Such compound has good development prospect, but yet there are no 1- pyrroles
Pyridine -6- methoxyl groups -9- (2,3,4,5- ptfe benzyl) B-carbolines and its relevant report of synthesis and application.
【The content of the invention】
The goal of the invention of the present invention is：For above-mentioned problem, there is provided a kind of 'Beta '-carboline compound and its synthesis
Methods and applications.Production process environmental protection of the present invention, production cost is low, and processing safety is high, and reaction condition is gentle, simple to operate；
Obtained 'Beta '-carboline compound can be used for preparing anti-kidney fibrosis medicine and/or anti-chronic kidney disease medicine.
To achieve these goals, the technical solution adopted by the present invention is as follows：
A kind of compound of Formulas I or its pharmaceutically acceptable salt：
The chemical name of compound is shown in above-mentioned Formulas I：1- pyridine -6- methoxyl groups -9- (2,3,4,5- ptfe benzyl) β -
Carboline.Molecular weight is：437.12.
Present invention also offers the synthetic method of the compound of the Formulas I, comprise the following steps：Sodium hydride is dissolved in N, N-
In dimethylformamide, compound 1- pyridine -6- methoxy-p-carbolines and 2,3,4,5- ptfe benzyls shown in formula II are then added
Bromine, in one pot reaction under normal temperature or heating condition, produces the compound of the Formulas I.
The synthetic route of above-mentioned synthetic method is as follows：
Shown in above-mentioned Formulas I the step of compound synthesis method in, raw material 1- pyridine -6- methoxy-p-carbolines and another original
It is usually 1 to expect the ratio between amount of material of 2,3,4,5- ptfe benzyl bromines：1.5 or 1:1, preferably 2,3,4,5- ptfe benzyl bromines rub
Your amount is slightly larger than the amount of the material of 1- pyridine -6- methoxy-p-carbolines, with the progress that reacts fully.
Further, the reaction is carried out under 40 DEG C to organic solvent of reflux temperature.Whether reaction can adopt completely
With thin-layer chromatography (TLC) tracing detection, generally control the reaction time appropriate for 20min~2h.The mode of reaction is preferred to use
Back flow reaction, when using back flow reaction, reaction is carried out more preferably under the reflux temperature of organic solvent.
Synthetic method of the present invention, in addition to separation and purification step, the separation and purifying are by one pot reaction
Products therefrom is added dropwise alkaline solution and is adjusted to neutral or alkalescence, is extracted with ethyl acetate or chloroform, collects organic phase, removes solvent,
Then purified by the way of silica gel column chromatography or recrystallization；When being purified by the way of silica gel column chromatography,
Using volume ratio as 1000：The eluant, eluent of 50~500 petroleum ether and ethyl acetate composition is eluted, and eluent removes solvent,
Obtain object after purification.
Present invention also offers described compound or its pharmaceutically acceptable salt prepare anti-kidney fibrosis medicine and/
Or the application in anti-chronic kidney disease medicine.
Present invention also offers a kind of pharmaceutical composition, it includes the compound described in the claim 1 of therapeutically effective amount
Or its pharmaceutically acceptable salt and pharmaceutically acceptable auxiliary material.
In summary, by adopting the above-described technical solution, the beneficial effects of the invention are as follows：
Compared with prior art, the invention provides a kind of 'Beta '-carboline compound and its synthetic method and application.Inventor
Anti- kidney fibrosis, anti-chronic kidney disease activity research to compound of the present invention show, the anti-kidney fibrosis of the Compound ira vitro
It is active notable, with preferable potential medical value, the preparation available for various anti-kidney fibrosis, anti-chronic kidney disease medicine.
【Brief description of the drawings】
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of final product made from the embodiment of the present invention 1；
Fig. 2 is the carbon-13 nmr spectra figure of final product made from the embodiment of the present invention 1；
Fig. 3 is the electrospray ionization mass spectrum spectrogram of final product made from the embodiment of the present invention 1；
Fig. 4 is the cell protein immunoblot experiment figure of final product made from the embodiment of the present invention 1.
【Embodiment】
The preparation of the structure of embodiment 1 compound shown in formula I
1) by 200mg (9.3mmol) NaH, it is dissolved in 1mLN, dinethylformamide, stirs 10min, and gradually add
Enter 275mg (1mmol) 1- pyridine -6- methoxy-p-carbolines, 10min is stirred at room temperature, 391.5mg is then added dropwise again
The 2 of (1.5mmol), 3,4,5- ptfe benzyl bromides, normal temperature continues to react about 20min；Reaction terminates rear products therefrom 300ml
Ammoniacal liquor adjust to neutrality, and be extracted with ethyl acetate, collect organic phase, removal of solvent under reduced pressure obtains the crude product of yellow oily；
2) crude product is with petroleum ether：Ethyl acetate=1000:The solvent of 100 (volume ratios) composition is used as eluant, eluent, silica gel
Column chromatography, obtains faint yellow fluffy solid (347mg, yield 79.4%, purity 99.94%).
Fluffy solid faint yellow to gained carries out nuclear-magnetism sign, and its proton nmr spectra and carbon spectrum are respectively such as Fig. 1 and 2 institutes
Show.
1HNMR (400MHz, CDCl3) δ 9.56 (d, J=5.1Hz, 1H), 9.51 (dt, J=4.9,1.2Hz, 1H), 9.04
(d, J=5.1Hz, 1H), 7.79-7.75 (m, 2H), 7.66 (t, J=1.5Hz, 1H), 7.35-7.30 (m, 1H), 7.23 (d, J
=1.5Hz, 2H), 6.09 (dd, J=5.4,2.6Hz, 1H), 5.53 (s, 2H), 3.96 (s, 3H)
13CNMR (101MHz, CDCl3) δ 157.79,154.92,149.05,142.71,139.57,137.25,
136.92,134.71,131.47,124.92,123.15,121.94,119.94,114.73,110.71,109.09,109.99,
103.72,77.35,77.23,77.03,76.71,65.15,56.04,42.50,31.93,29.71,22.70,14.11.
Fluffy solid faint yellow to gained carries out mass spectral analysis, as a result as shown in Figure 3.
Accordingly, it can be determined that above-mentioned faint yellow fluffy solid is：1- pyridine -6- methoxyl groups -9- (2,3,4,5- ptfe benzyl)
B-carboline, its chemical structural formula is as shown in following formula I：
The preparation of the structure of embodiment 2 compound shown in formula I
400mg (16.6mmol) NaH is dissolved in 1mLN, dinethylformamide, stirs 10min, and be gradually added into
550mg (2mmol) 1- pyridine -6- methoxy-p-carbolines, are stirred at room temperature 10min, 391.5mg are then added dropwise again
The 2 of (1.5mmol), 3,4,5- ptfe benzyl bromides, normal temperature continues to react about 20min；Reaction terminates rear products therefrom and used
400ml ammoniacal liquor is adjusted to neutrality, and is extracted with ethyl acetate, and collects organic phase, and removal of solvent under reduced pressure obtains yellow oily liquid
Crude product；
Crude product is with petroleum ether：Ethyl acetate=1000:The solvent of 100 (volume ratios) composition is used as eluant, eluent, silicagel column
Chromatography, obtains faint yellow fluffy solid (211mg, yield 48.3%, purity 99.91%).
The faint yellow fluffy solid of gained is characterized by nuclear-magnetism, is defined as 1- pyridines -6- methoxyl groups -9- of the present invention
(2,3,4,5- ptfe benzyl) B-carboline.
The preparation of the structure of embodiment 3 compound shown in formula I
1) by 200mg (9.33mmol) NaH, it is dissolved in 5mLN, dinethylformamide, stirs 10min, and gradually add
Enter 275mg (1mmol) 1- pyridine -6- methoxy-p-carbolines, 10min is stirred at room temperature, 524mg is then added dropwise again
The 2 of (2mmol), 3,4,5- ptfe benzyl bromides, normal temperature continues to react about 20min；Reaction terminates rear products therefrom with using 400ml
Ammoniacal liquor is adjusted to neutrality, and is extracted with ethyl acetate, and collects organic phase, and removal of solvent under reduced pressure obtains the thick production of yellow oily liquid
Thing；
2) crude product is with petroleum ether：Ethyl acetate=1000:The solvent of 50 (volume ratios) composition is used as eluant, eluent, silicagel column
Chromatography, obtains faint yellow fluffy solid (162mg, yield 37.1%, purity 99.90%).
The faint yellow fluffy solid of gained is characterized by nuclear-magnetism, is defined as 1- pyridines -6- methoxyl groups -9- of the present invention
(2,3,4,5- ptfe benzyl) B-carboline.
The preparation of the structure of embodiment 4 compound shown in formula I
1) by 200mg (9.33mmol) NaH, it is dissolved in 9mLN, dinethylformamide, stirs 10min, and gradually add
Enter 275mg (1mmol) 1- pyridine -6- methoxy-p-carbolines, 10min is stirred at room temperature, 261mg is then added dropwise again
The 2 of (1mmol), 3,4,5- ptfe benzyl bromides, normal temperature continues to react about 20min；Reaction terminates rear products therefrom with using 400ml
Ammoniacal liquor is adjusted to neutrality, and is extracted with ethyl acetate, and collects organic phase, and removal of solvent under reduced pressure obtains the thick production of yellow oily liquid
Thing；
2) crude product is with petroleum ether：Ethyl acetate=1000:The solvent of 200 (volume ratios) composition is used as eluant, eluent, silica gel
Column chromatography, obtains faint yellow fluffy solid (75mg, yield 17.2%, purity 99.96%).
The faint yellow fluffy solid of gained is characterized by nuclear-magnetism, is defined as 1- pyridines -6- methoxyl groups -9- of the present invention
(2,3,4,5- ptfe benzyl) B-carboline.
The preparation of the structure of embodiment 5 compound shown in formula I
1) by 200mg (9.33mmol) NaH, it is dissolved in 10mLN, dinethylformamide, stirs 10min, and gradually
275mg (1mmol) 1- pyridine -6- methoxy-p-carbolines are added, 20min is stirred at room temperature, 522mg is then added dropwise again
The 2 of (2mmol), 3,4,5- ptfe benzyl bromides, normal temperature continues to react about 40min；Reaction terminates rear products therefrom with using 500ml
Ammoniacal liquor is adjusted to neutrality, and is extracted with ethyl acetate, and collects organic phase, and removal of solvent under reduced pressure obtains the thick production of yellow oily liquid
Thing；
2) crude product is with petroleum ether：Ethyl acetate=1000:The solvent of 300 (volume ratios) composition is used as eluant, eluent, silica gel
Column chromatography, obtains faint yellow fluffy solid (227mg, yield 51.9%, purity 99.95%).
The faint yellow fluffy solid of gained is characterized by nuclear-magnetism, is defined as 1- pyridines -6- methoxyl groups -9- of the present invention
(2,3,4,5- ptfe benzyl) B-carboline.
The preparation of the structure of embodiment 6 compound shown in formula I
1) by 200mg (9.3mmol) NaH, it is dissolved in 1mLN, dinethylformamide, stirs 10min, and gradually add
Enter 275mg (1mmol) 1- pyridine -6- methoxy-p-carbolines, 10min is stirred at room temperature, 391.5mg is then added dropwise again
The 2 of (1.5mmol), 3,4,5- ptfe benzyl bromides are heated to 40 DEG C and continue to react about 20min；Reaction terminates rear products therefrom
Adjusted to alkalescence, and extracted with chloroform with 350ml ammoniacal liquor, collect organic phase, removal of solvent under reduced pressure obtains the thick production of yellow oily
Thing；
2) crude product is with petroleum ether：Ethyl acetate=1000:The solvent of 500 (volume ratios) composition is used as eluant, eluent, silica gel
Column chromatography, obtains faint yellow fluffy solid (127mg, yield 29.1%, purity 99.91%).
The faint yellow fluffy solid of gained is characterized by nuclear-magnetism, is defined as 1- pyridines -6- methoxyl groups -9- of the present invention
(2,3,4,5- ptfe benzyl) B-carboline 1- pyridine -6- methoxyl groups -9- (2,3,4,5- ptfe benzyl) B-carboline.
The structure of embodiment 7 compound 1- pyridines -6- methoxyl groups -9- (2,3,4,5- ptfe benzyl) B-carboline shown in formula I
Anti- kidney fibrosis experiment
First, 1- pyridines -6- methoxyl groups -9- (2,3,4,5- ptfe benzyl) B-carbolines are to the normal kidney fibroblast of rat
NRK-49F proliferation inhibition activity experiment：
1st, cell line and cell culture
The normal kidney fibroblast NRK-49F cell lines of rat are selected in this experiment.
Cell line culture used calf serum containing 10wt%, 100U/mL penicillin, 100U/mL streptomysins DMEM/F-
In 12 nutrient solutions, put in 37 DEG C of incubators of 5%CO2 containing volumetric concentration and cultivate.
2nd, the preparation of testing compound
1- pyridine -6- methoxyl groups -9- (2,3,4,5- ptfe benzyl) B-carboline used is that production is made in the embodiment of the present invention 1
Thing, gained, purity >=95% are purified by column chromatography.After test-compound to be measured is dissolved with DMSO, then use diameter d=0.22
μm filtering with microporous membrane it is degerming, be placed at 4 DEG C preserve.By its DMSO liquid storage (concentration is 0.002mol/L) by serum-free
DMEM/F-12 culture mediums are diluted to five concentration gradients successively, respectively 20,10,5,2.5,1.25 μm of ol/L, wherein cosolvent
DMSO final concentration≤1%.The inhibiting rate that target product first under test various concentrations is bred for NRK-49F cells, is considered as
Primary dcreening operation result；The Proliferation Ability degree of target product under different gradient concentrations to NRK-49F cells is tested respectively again, to be fitted
Calculation of half inhibitory concentration, i.e. IC50 values.
3rd, cell growth inhibition test (mtt assay)
(1) take the logarithm the cell in growth period, after Trypsin Induced, be configured to the nutrient solution containing 10% calf serum
Concentration is 5000/mL cell suspension, is inoculated in every μ L of hole 190 in 96 well culture plates, makes cell density to be measured to 1000
~10000/hole (edge hole is filled with sterile PBS)；
(2) 5%CO2,37 DEG C of incubation 12h, continue to cultivate after after cell attachment, changing serum-free DMEM/F-12 nutrient solutions
12h, the μ L of medicine 20 of finite concentration gradient are added per hole, and each concentration gradient sets 5 multiple holes；
(3) 5%CO2,37 DEG C are incubated 49 hours, are observed under inverted microscope；
(4) 10 μ L MTT solution (5mg/mLPBS, i.e. 0.5%MTT) is added per hole, continues to cultivate 4~8h；
(5) culture is terminated, nutrient solution in hole is carefully sucked, 200 μ LDMSO are added per hole and fully dissolve first a ceremonial jade-ladle, used in libation precipitation, vibration
With wavelength it is 570nm in ELIASA, reference wavelength is the OD value that 450nm determines each hole after device is mixed；
(6) while setting zeroing hole (culture medium, MTT, DMSO), (cell, the medicine dissolving of same concentrations are situated between control wells
Matter, nutrient solution, MTT, DMSO).
(7) according to the OD value (OD values) measured, to judge living cells quantity, OD values are bigger, and cytoactive is stronger.
Utilize formula：
Calculate the inhibiting rate of compounds on cell growth.Its test result is as shown in the following Table 1.
Table 1：Growth inhibition ratio (%) of the compound under various concentrations to NRK-49F cell lines
Further the inhibiting rate data of three concentration gradients are fitted by SPSS softwares, product are obtained to NRK-
The half-inhibition concentration (IC50 values, unit μm ol/L) of 49F cell lines, compound for NRK-49F cell lines IC50 values such as
Shown in table 2.
Table 2：IC50 value (μM) of the compound to NRK-49F cell lines
From the point of view of testing in vitro result, 1- pyridine -6- methoxyl groups -9- (2,3,4,5- ptfe benzyl) B-carboline to rat just
Normal kidney fibroblast NRK-49F cell lines all show significant proliferation inhibition activity, measured with mtt assay 20,10,5,
2.5th, inhibiting rate is respectively 67.05%, 59.02%, 54.59%, 48.46%, 29.67% during 1.25 μm of ol/L concentration, is calculated
IC50 values are obtained for 4.752 μM.
2nd, 1- pyridines -6- methoxyl groups -9- (2,3,4,5- ptfe benzyl) B-carbolines to Rat renal into brotic cells NRK-
The protein immunoblotting experiment of 49F kidney fibrosis GAP-associated protein GAP：
The present invention stimulates NRK-49F cells with TGF-β 1 (2ng/ml), sets up external fibrosis model, while adding different
Compound shown in above-mentioned (I) of concentration (4 μM, 9 μM, 12 μM), collective effect is after 49 hours, extract proteins after cell is cracked,
Carry out protein immunoblotting experiment, analysis fibronectin (Fibronectin, FN), α-smooth muscle actin (α-SMA),
The expression of the albumen such as collagen I (Collagen I), concrete operations are as follows：
1. protein extraction
(1) inoculating cell：The good NRK-49F cells of selection growth conditions, are planted in a diameter of 10cm culture dish,
37 DEG C are placed in, CO2 concentration is 5% constant incubator culture 12h, change serum-free DMEM/F-12 nutrient solutions and continue to cultivate 12h.
(2) it is administered：When cell attachment propagation reaches exponential phase, 2ng/ml TGF-β 1 and not consubstantiality is separately added into
Product, concentration are 2 × 10-3M chemical compounds I (being made by embodiment 1), are incubated after being sufficiently mixed uniformly in constant incubator
48h。
(3) cell is collected：After after cell administration processing 48h, it is 0.25% Trypsin Induced attached cell with concentration, turns
Move in 15mL centrifuge tubes, go to centrifuge, 2000rpm centrifugations 10min.
(4) cell is cracked：With cell pyrolysis liquid (RIPA)：PMSF (phenylmethylsulfonyl fluoride)=100:1 volume ratio difference
Add, mix suspension cell, be placed in 30~50min of cracking under low temperature environment on ice.
(5) albumen is collected：By 4 DEG C cracked of cell suspension low temperature, 12000r centrifugations 10min；Supernatant BCA albumen
Concentration measuring kit is (enhanced) to carry out protein quantification, -90 DEG C of storages.
2.SDS-PAGE electrophoresis
(1) preparation of concentration glue and separation gel：According to experiment needs, 10%, 12% separation gel and 5% concentration are prepared
Glue.Separation gel is poured into vertical glass groove, fluid-tight is carried out with distilled water.After separation gel solidification, distilled water is discarded, then will concentration
Glue pours into vertical glass groove insertion comb, treats that gelling is solid.After gelling to be separated is solid, comb is extracted, vertical electrophoresis device is put into
Waited in electrophoresis tank subsequently plus testing sample carries out electrophoresis.
(2) loading and electrophoresis：It is 4 by volume with 5 × sample-loading buffer to take 20 μ g samples:In 1 dilution proportion, boiling water bath
5min is heated, loading after cooling on the left of offset plate, adds 5 μ L albumen pre-dyed.Electrophoresis liquid is added, electrophoresis tank is filled, by concentration glue
60V, 60min, separation gel 90V, 160min carry out electrophoresis.
(3) transferring film：Glass plate is taken out, gel is peeled off and is dipped in transferring film buffer solution balances 10min；According to colored pre-dyed
Protein band carries out cutting glue.Take 9 filter paper be cut into transferring film sponge formed objects, soaked in transferring film buffer solution standby；Take
Suitable pore size (0.45 μm or 0.22 μm) cellulose acetate film (PVDF), is cut into the PAGE glue formed objects with cutting.
Take 9 filter paper be cut into transferring film sponge formed objects, soaked in transferring film buffer solution standby；Take suitable pore size (0.45 μ
M or 0.22 μm) cellulose acetate film (PVDF), it is cut into the PAGE glue formed objects with cutting.Transferring film is folded up into transferring film groove
In, transferring film buffer solution is added, constant current 200mA carries out transferring film electrophoresis.Treat that transferring film terminates, glue can be contaminated with Coomassie brilliant blue, the beautiful spring is used
Red dye liquor contaminates film, detects transferring film effect；After pvdf membrane is washed with clear water, next step operation is carried out.
(4) immune response：Treat that transferring film terminates, pvdf membrane closes 30min with quick closure fluid-tight again after being rinsed with PBS.PBST
Rinse 5min, go to the primary antibody fibronectin (Fibronectin, FN) configured by proper proportion, α-smooth muscle actin (α-
SMA), collagen I (Collagen I) and collagen III (COL3A1)) in solution, 4 DEG C of overnight incubations.Use secondary antibody dilution
Secondary antibody is diluted, about 1h is incubated on decolorization swinging table at room temperature, chemiluminescence reaction is carried out after being rinsed with PBST and PBS.
(5) chemiluminescence：Take chemical illuminating reagent (the super quick luminescent solutions of superECL, the limited public affairs of Puli's lema gene technology
Department), fully contact, develop in chemiluminescence imaging system with memebrane protein face.
Experimental result is as shown in Figure 4.
From the point of view of anti-kidney fibrosis test result, 1- pyridine -6- methoxyl groups -9- (2,3,4,5- ptfe benzyl) B-carboline can
FN, α-SMA, the Collagen I expression of the NRK-49F cells of the induction of TGF-β 1 are significantly inhibited, and in dose-dependence,
Show the anti-kidney fibrosis activity of the Compound ira vitro significantly, with preferable potential medical value, available for various anti-kidney fibers
Change, the preparation of anti-CKD medicine.
The pharmaceutical composition of embodiment 10
| Compound shown in the Formulas I that the present invention is provided | 15% |
| Starch | 40% |
| Microcrystalline cellulose | 25% |
| CMS is received | 19% |
| Magnesium stearate | 1% |
Above medicine and auxiliary material grinding and sieving, mixing are produced.
The pharmaceutical composition of embodiment 11
| Compound shown in the Formulas I that the present invention is provided | 8% |
| Starch | 47% |
| Microcrystalline cellulose | 22% |
| CMS is received | 20% |
| Magnesium stearate | 3% |
Above medicine and auxiliary material grinding and sieving, mixing are produced.
The pharmaceutical composition of embodiment 11
Above medicine and auxiliary material grinding and sieving, mix after tabletting on tablet press machine, produce.
The pharmaceutical composition of embodiment 11
| Compound shown in the Formulas I that the present invention is provided | 15% |
| Dried starch | 65% |
| Magnesium stearate | 20% |
Above medicine and auxiliary material grinding and sieving, are packed into hard gelatin capsule after mixing, produce.
The pharmaceutical composition of embodiment 12
| Compound shown in the Formulas I that the present invention is provided | 1% |
| Sodium chloride | 1% |
| Water for injection | 98% |
The compound plus sodium chloride and appropriate water for injection that the present invention is provided, stir, and add 0.1% pin activity
Decarburization is filtered in carbon, absorption, and benefit injects water to ormal weight, micro porous filtration membrane filtration, by 1mL/ branch embeddings, and 100 DEG C damp and hot to go out
Bacterium 20min, it is qualified through lamp inspection, produce.
The pharmaceutical composition of embodiment 13
| Compound shown in the Formulas I that the present invention is provided | 0.1% |
| Ethanol | 0.4% |
| Sodium chloride | 0.1% |
| Mannitol | 0.6% |
| Water for injection | 99% |
The compound plus ethanol stirring and dissolving that the present invention is provided, plus sodium chloride, mannitol and appropriate water for injection, stirring
Uniformly, 0.1% pin activated carbon is added, decarburization is filtered in absorption, and benefit injects water to ormal weight, and micro porous filtration membrane filtration is pressed
4mL/ branch is dispensed, and is freeze-dried, and encapsulation is qualified through examining, and produces.
Described above is the detailed description for the present invention preferably possible embodiments, but embodiment is not limited to this hair
The equal change or modification change completed under bright patent claim, the technical spirit suggested by all present invention, all should belong to
Cover the scope of the claims in the present invention.
Claims (7)
1. a kind of compound of Formulas I or its pharmaceutically acceptable salt：
2. the synthetic method of compound according to claim 1, it is characterised in that comprise the following steps：Sodium hydride is dissolved in
In DMF, 1- pyridine -6- methoxy-p-carbolines and 2,3,4,5- ptfe benzyl bromines, in normal temperature are then added
Or one pot reaction under heating condition, produce the compound of the Formulas I.
3. synthetic method according to claim 2, it is characterised in that：Backflow temperature of the reaction at 40 DEG C to organic solvent
Degree is lower to be carried out.
4. synthetic method according to claim 2, it is characterised in that also including separation and purification step, the separation and
Purify as one pot reaction products therefrom dropwise addition alkaline solution is adjusted into neutral or alkalescence, extracted, collected with ethyl acetate or chloroform
Organic phase, is removed solvent, is then purified by the way of silica gel column chromatography.
5. synthetic method according to claim 4, it is characterised in that the silica gel column chromatography uses petroleum ether and acetic acid second
The eluant, eluent of ester composition carries out elution chromatography, and the volume ratio of the petroleum ether and ethyl acetate is 1000：50~500.
6. the compound or its pharmaceutically acceptable salt described in claim 1 are preparing anti-kidney fibrosis medicine and/or resisted slow
Application in property nephrosis medicine.
7. a kind of pharmaceutical composition, it is characterised in that compound or its pharmacy described in the claim 1 including therapeutically effective amount
Upper acceptable salt and pharmaceutically acceptable auxiliary material.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107805247A (en) * | 2017-10-31 | 2018-03-16 | 临沂齐泽医药技术有限公司 | A kind of preparation technology and its application for being used to prepare the beta-carboline compounds of anti-kidney fibrosis medicine and/or anti-chronic kidney disease medicine |
| CN107936012A (en) * | 2017-10-31 | 2018-04-20 | 临沂齐泽医药技术有限公司 | A kind of preparation method for the beta-carboline compounds for being used to prepare anti-kidney fibrosis medicine and/or anti-chronic kidney disease medicine |
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| CN1308632A (en) * | 1998-06-12 | 2001-08-15 | 研究及应用科学协会股份有限公司 | 'Beta'-carboline compound |
| JP2013129632A (en) * | 2011-12-22 | 2013-07-04 | Ono Pharmaceut Co Ltd | Enpp2 inhibiting compound |
| CN106632421A (en) * | 2016-09-26 | 2017-05-10 | 广西师范大学 | Copper nitrate complex of 1-(2-pyridine)-9-(4-methylbenzyl)-beta-carboline and synthesizing method and application of copper nitrate complex |
| CN106632424A (en) * | 2016-09-26 | 2017-05-10 | 广西师范大学 | Copper chloride complex using 1-(2-pyridine)-9-hexyl-beta-carboline as ligand and synthesis method and application thereof |
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| CN1308632A (en) * | 1998-06-12 | 2001-08-15 | 研究及应用科学协会股份有限公司 | 'Beta'-carboline compound |
| JP2013129632A (en) * | 2011-12-22 | 2013-07-04 | Ono Pharmaceut Co Ltd | Enpp2 inhibiting compound |
| CN106632421A (en) * | 2016-09-26 | 2017-05-10 | 广西师范大学 | Copper nitrate complex of 1-(2-pyridine)-9-(4-methylbenzyl)-beta-carboline and synthesizing method and application of copper nitrate complex |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107805247A (en) * | 2017-10-31 | 2018-03-16 | 临沂齐泽医药技术有限公司 | A kind of preparation technology and its application for being used to prepare the beta-carboline compounds of anti-kidney fibrosis medicine and/or anti-chronic kidney disease medicine |
| CN107936012A (en) * | 2017-10-31 | 2018-04-20 | 临沂齐泽医药技术有限公司 | A kind of preparation method for the beta-carboline compounds for being used to prepare anti-kidney fibrosis medicine and/or anti-chronic kidney disease medicine |
| CN107936012B (en) * | 2017-10-31 | 2020-09-01 | 安徽和医天下医药科技有限公司 | Preparation method of beta-carboline compound for preparing anti-renal fibrosis drug and/or anti-chronic nephrosis drug |
| CN107805247B (en) * | 2017-10-31 | 2020-09-29 | 上海长征富民金山制药有限公司 | Preparation process and application of beta-carboline compound for preparing renal fibrosis resisting medicine and/or chronic nephrosis resisting medicine |
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| CN106995440B (en) | 2019-09-03 |
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