CN103819483B - The control medicine of pulmonary hypertension and synthesis thereof and application - Google Patents
The control medicine of pulmonary hypertension and synthesis thereof and application Download PDFInfo
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- CN103819483B CN103819483B CN201410052946.2A CN201410052946A CN103819483B CN 103819483 B CN103819483 B CN 103819483B CN 201410052946 A CN201410052946 A CN 201410052946A CN 103819483 B CN103819483 B CN 103819483B
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- C07—ORGANIC CHEMISTRY
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Abstract
The invention discloses compound, wherein R shown in general structure (I)
1, R
2independently selected from-CH
3,-CH
2cH
3.This compound phenylacetic acid derivatives and benzaldehyde derivative is carried out Perkin under the effect of acetic anhydride and basic catalyst be obtained by reacting intermediate, and intermediate and isosorbide mononitrate carry out condensation reaction and obtain compound shown in general structure (I).The present invention is by the structural modification to the different trans-resveratrol of primer, and energy enhanced stability, increase its bioavailability, and impel prolonged drug, the trans-resveratrol improving hydroxyl structure is oxidizable, the shortcoming of not easily preserving.
Description
Technical field
The present invention relates to a kind of alkylation different trans-resveratrol benzyl position nitric ether nitric oxide donator type compound, this compounds can be used as prevention or treatment pulmonary hypertension relative disease medicine, as chronic obstructive pulmonary disease (chronicobstructivepulmonarydisease, COPD), plateau pneumochysis (highaltitudepulmonaryedema, HAPE) etc., medicinal chemistry art is belonged to.
Background technology
Pulmonary hypertension (pulmonaryarterialhypertension, PAH) be pathologic, physiologic link important during clinical numerous cardiopulmonary and vascular disease develops, the disease indicia for feature is raised with pulmonary artery pressure and pulmonary vascular resistance Progressive symmetric erythrokeratodermia, its pathological change comprises pulmonary vascular endothelial cell damage, the plumpness of middle film hyperplasia and adventitia, finally causes the obstruction of lung arteriole tube chamber.Clinical manifestation is right heart insufficiency, Progressive symmetric erythrokeratodermia expiratory dyspnea, pectoralgia, faint, tired and peripheral edema etc., it is large to be that one treats difficulty, poor prognosis, the disease that patient's case fatality rate is high.Right heart failure is that all types PAH patient is disabled, lethal common pathway, and PAH is also the main reason of right heart failure.In western countries, pulmonary hypertension has become the large class cardiovascular disorder obtaining gradually paying attention to.Although existing prostacyclin (PGI2) and analogue, endothelin (ET) receptor antagonist, phosphodiesterase-5(PDE-5 at present) inhibitor etc. is for the clinical treatment of PAH, and 1 year case fatality rate of PAH patient is still up to 15%.Its pathogenesis is not yet all illustrated at present, may relate to multiple approach and the levels such as cell, circulatory mediator and molecular genetic, and treatment is also without the method for special efficacy.PAH is the key link that chronic obstructive pulmonary disease (COPD) causes chronic pulmonary heart disease, also be the main pathogenesis of plateau pneumochysis caused by hypoxemia (HAPE), the control PAH medicine of the Forming Mechanism and seeking of ideal of illustrating PAH is the focus in the diseases prevention and treatment researchs such as COPD, HAPE always.
Existing research is thought: cause the pathological factor of PAH a lot, but all kinds of PAH has common pathophysiological features, i.e. vasoconstriction, primary thrombus and Pulmonary vascular cell reconstruct, wherein Pulmonary Vascular excess shrinkage is an important feature of PAH.This excessive vasoconstriction is relevant with endothelial tissue malfunction.Traditional PAH medicine comprises antithrombotics, diuretic(s), calcium channel blocker etc.Although these medicines can improve the symptom of PAH patient, the development process of PAH can not be delayed.Over nearly 20 years, new medicine constantly occurs, the prognosis of PAH patient is had obvious improvement, and survival rate there has also been larger raising, and 1,3,5 annual survival rates are increased to 86%, 69%, 61% from 68%, 48%, 34% respectively.These novel drugs comprise prostacyclin and analogue, ET-1 receptor antagonist, phosphodiesterase-5(PDE-5) inhibitor.In recent years, also emerge a large amount of novel target therapeutic agent, as kinase inhibitor, soluble guanylate cyclase activators etc., become the study hotspot in PAH field gradually.But in above-mentioned new drug, clinical application exists a lot of drawback, as patient need implant central venous catheter, and use portable infusion pump etc.In addition, the administering mode of expensive price, serious untoward reaction and complexity all greatly limit their application.
Summary of the invention
The object of this invention is to provide one to there is dual collaborative reduction pulmonary hypertension, improve hemorheology, the alkylation different trans-resveratrol benzyl position nitric ether nitric oxide donator type compound of anti-chronic obstructive pulmonary disease, plateau pneumochysis;
Another object of the present invention is to the preparation method that abovementioned alkylization different trans-resveratrol benzyl position nitric ether nitric oxide donator type compound is provided;
A further object of the invention is the medicinal use providing abovementioned alkylization different trans-resveratrol benzyl position nitric ether nitric oxide donator type compound.
Object of the present invention is achieved through the following technical solutions:
Compound shown in general structure (I),
Wherein, R
1, R
2independently selected from-CH
3,-CH
2cH
3.
The preparation method of above-claimed cpd, comprises the following steps:
(1) phenylacetic acid derivatives 1 and benzaldehyde derivative 2 carry out Perkin and are obtained by reacting intermediate 3 under the effect of acetic anhydride and basic catalyst;
(2) intermediate 3 and isosorbide mononitrate are carried out condensation reaction and obtain compound shown in general structure (I)
。
In above-mentioned steps (1), described basic catalyst is selected from triethylamine, pyridine, salt of wormwood, sodium carbonate.
In above-mentioned steps (2), intermediate 3 and isosorbide mononitrate carry out condensation reaction under thionyl chloride exists.
In above-mentioned steps (2), intermediate 3 and isosorbide mononitrate carry out condensation reaction under isobutyl chlorocarbonate exists.
In above-mentioned steps (2), intermediate 3 and isosorbide mononitrate carry out condensation reaction under condensing agent and catalyzer exist, described condensing agent is selected from 1,3-dicyclohexylcarbodiimide, 1,3-DIC, 1-ethyl-(3-dimethylaminopropyl) carbodiimide; Described catalyzer is selected from DMAP, I-hydroxybenzotriazole, 1-hydroxyl-7-azo benzotriazole.
A kind of pharmaceutical composition, it contains above-claimed cpd and pharmaceutically acceptable carrier or vehicle, and described pharmaceutical composition is inhalation powder spray, tablet, capsule, powder, pill, granule or emulsion.
Above-claimed cpd can be used for preparation treatment pulmonary hypertension disease medicament, and described pulmonary hypertension disease is chronic obstructive pulmonary disease or plateau pneumochysis.
Advantage of the present invention: (1), based on NO donor research strategy, by different method of attachment by nitrate esters NO donor and primer coupling, designs and synthesizes new NO donor type derivant; (2) by the structural modification to the different trans-resveratrol of primer, energy enhanced stability, increase its bioavailability, and impel prolonged drug, the trans-resveratrol improving hydroxyl structure is oxidizable, the shortcoming of not easily preserving; (3) by the combination of primer and NO donor medicine, while playing respective drug effect, the generation of side effect is likely reduced; (4) for pulmonary vascular endothelial cell be the target site of NO sensitivity, in conjunction with the pharmacological action of lead compound, be expected to play dual collaborative drug effect, thus become the ideal medicament of the diseases such as control COPD, HAPE caused by PAH; (5) synthesis technique of the present invention is simple, and cheaper starting materials is easy to get.
Figure of description
Fig. 1 is BZ-1 NO burst size in lungs tissue homogenate;
Fig. 2 is the section of normal group SD lung tissue of rats;
Fig. 3 is the section of model group SD lung tissue of rats;
Fig. 4 is the section of BZ-1 low dose group SD lung tissue of rats;
Dosage group SD lung tissue of rats section in Fig. 5 BZ-1;
Fig. 6 BZ-1 high dose group SD lung tissue of rats is cut into slices.
Specific embodiments
Embodiment 1
The preparation of intermediate 3
Get 8.00g3,4-dimethoxyphenylacetic acid (1), 6.00g aubepine (2), 15mL acetic anhydride and 6mL anhydrous triethylamine, stir and be heated to 130 DEG C, backflow 6h.After leaving standstill room temperature, add 22.00g salt of wormwood and 90mL distilled water, reheat after stirring to 130 DEG C of backflow 0.5h.After leaving standstill room temperature, adjust pH to 4.0 with concentrated hydrochloric acid, leached by solid, solids with methanol recrystallization, yield is 46.65%.
Chloride method synthesising target compound
Get 6.28g intermediate 3 in clean 100mL single port bottle, be cooled to 0 DEG C, add 6mLSOCl under nitrogen atmosphere
2, stir 15min, remove nitrogen, after 79 DEG C of reflux 2 ~ 3h, the solution of acid chloride of obtained intermediate 3.After hanging room temperature, solution is spin-dried for for subsequent use at 40 DEG C.Take 3.82g Ismo 20 simultaneously and be dissolved in 20mL dry methylene chloride, be cooled to the solution of acid chloride that 0 DEG C also slowly drips the intermediate 3 made under nitrogen atmosphere, dropwise, ice bath reaction 6h.After being spin-dried for solvent, gained sample carries out silica gel column chromatography, collects elutriant, and obtain light yellow crystal 5.99g after purifying, yield is 61.5%.
1H-NMRδ：7.75（s，H，C=C-H），6.07~7.06（m，7H，Ar-H），5.34~5.36（brs，2H，Cy-H），4.95（brs，H，Cy-H），4.52（brs，H，Cy-H），3.92~4.14（m，7H，OCH
3，Cy-H），3.78~3.91（m，6H，OCH
3）;IR（cm
-1）：745，1017，1021，1016，1202，1229，1247，1288，1346，1423，1459，1469，1482，1545，1577，1636，1790；HRMS([M+H]
+):488.20。
Mixed anhydride method synthesising target compound
Get 6.28g intermediate 3 in clean 100mL single port bottle, be cooled to 0 DEG C, add 2.54mL isobutyl chlorocarbonate under nitrogen atmosphere, stir 15min.Take 3.82g Ismo 20 and be dissolved in 20mL dry methylene chloride, slowly drop to reaction solution under nitrogen atmosphere, dropwise rear continuation reaction 12h.Be spin-dried for solvent, gained sample carries out silica gel column chromatography, collects elutriant, and obtain light yellow crystal 6.15g after purifying, yield is 63.2%.
Condensation method synthesising target compound
Get 6.28g intermediate 3 to be dissolved in the methylene dichloride of 20mL drying, be cooled to 0 DEG C.Under nitrogen atmosphere, add 4.96g condensing agent DCC(N, N-dicyclohexyl imines) and 0.24g catalyzer DMAP(4-N, N-lutidine), stir 15min at this temperature, then get 3.82g Ismo 20, stirring at room temperature 24h, suction filtration, gained filtrate decompression evaporate to dryness, gained sample carries out silica gel column chromatography, collects elutriant, obtain light yellow crystal 6.14g after purifying, yield is 63.0%.
Embodiment 2
Get 8.00g3,4-dimethoxyphenylacetic acid (1), 6.00g p-methoxy phenylacetaldehyde (2), 15mL acetic anhydride and 6mL anhydrous pyridine, stir and be heated to 130 DEG C, backflow 6h.After leaving standstill room temperature, add 22.00g salt of wormwood and 90mL distilled water, reheat after stirring to 130 DEG C of backflow 0.5h.After leaving standstill room temperature, adjust pH to 4.0 with concentrated hydrochloric acid, leached by solid, solids with methanol recrystallization, obtain following compound, yield is 46.65%.
Above-claimed cpd takes method of condensing similar to Example 1 can prepare following compound further,
。
Embodiment 3: embodiment 1 prepares pharmacological evaluation and the result of target compound
1. external nitric oxide releasing flow measurement: nitrate compound, at sour environment with under having excessive sulfhydryl compound existent condition, can discharge NO.The nitrite ion NO that NO generates through oxidation
2 -, measure its concentration by Griess method, indirectly reflect the nitric oxide releasing ability of compound, this method is easy, quick, favorable reproducibility.This experiment adopts this method to measure the external NO burst size of target compound BZ-1, and to investigate the effect of its release NO, control drug is isosorbide mononitrate, Sodium Nitroprusside.Utilize nitrite ion NO
2 -can with Griess reagent generation diazotization, coupled reaction, generate red-purple product, survey it at 540nm wavelength place and absorb angle value, indirect measurement NO burst size, it is lung tissue of rats homogenate environment that NO discharges environment.
Experimental technique:
The preparation of Griess reagent: take 1.0014g Sulphanilic Acid, uses 5%(volume ratio) phosphoric acid solution be settled to 100mL, preparation become 1% Sulphanilic Acid solution; Take 0.1046gN-(1-naphthyl)-quadrol, be settled to 100mL with distilled water, preparation becomes N-(1-the naphthyl)-ethylenediamine solution of 0.1%.Preparation before two developers use, and lucifuge is placed.
The preparation of lungs homogenate: take out rat tissue's sample (lungs), weigh rapidly, according to 1:10 weightmeasurement ratio (g/mL), add PBS(1mol/L, pH=4), miniature homogenizer grinds to form homogenate, the centrifugal 25min of 3000r/min, gets supernatant liquor-28 DEG C preservation.
The drafting of external NO release standard curve: precision takes the Sodium Nitrite (5mmol) of 345mg drying, is settled to 50mL with distilled water, it is 1 × 10 that dilution is mixed with concentration
-4mol/L Sodium Nitrite storing solution.Precision measures standard reserving solution, is mixed with the Sodium Nitrite standard working solution that concentration is 0.02,0.025,0.032,0.05,0.1mmol/L.Inhale the standard working solution of each concentration of 2mL respectively, with 2mLGriess reagent (the Sulphanilic Acid solution 1.0mL of 1%, N-(1-the naphthyl)-ethylenediamine solution 1.0mL of 0.1%) mix, under 540nm, measure its absorbance after placing 15min.Linear recurrence, obtains typical curve equation: A=7.0021C-0.0089, R
2=0.9819.A is absorbancy, and C is NO concentration, and result shows that Sodium Nitrite concentration has good linear relationship within the scope of 0.02-0.10mmol/L between concentration and absorbancy.
Take 0.5mg target compound BZ-1, its chemical name is (E)-6-(nitrooxy) six hydrogen [3,2-b] furans-3-base-2-(3,4-Dimethoxyphenyl)-3-(4-p-methoxy-phenyl) acrylate, dissolves with a small amount of DMSO, with PBS(1mol/L, pH=4) constant volume is in 100ml volumetric flask, pipette the volumetric flask that the above-mentioned solution of 5mL is placed in 100mL, as solution to be measured, concentration is 0.25mg/L.Sodium Nitroprusside and isosorbide mononitrate same treatment, be made into the reference substance solution to be measured of 0.25mg/L.Draw each 1.0mL of above-mentioned sample liquid respectively in air-tight bottle, separately get PBS solution 1.0mL to air-tight bottle as blank, add lungs homogenate 0.1mL respectively, PBS(1mol/L, pH=4) 8.9mL, vortex mixed is even, hatch in 37 DEG C of water-baths, respectively 20, 40, 60, 80, 100, 120, 160, 180, 240, 250min syringe extracts reaction solution 1mL, add Griess reagent (the 1% Sulphanilic Acid 0.5mL of 1mL, 0.1%N-(1-naphthyl)-quadrol 0.5mL), mix, place 10min, zero point is regulated with reagent blank, the absorbancy of each sample solution is surveyed in 540nm place, calculate optical density A=A
sample-A
empty, draw corresponding NO by typical curve equation
2 -concentration, is the concentration of sample release NO, the results are shown in shown in specification sheets Fig. 1.As can be seen from the figure target compound BZ-1 extends with incubation time, and NO discharges increase, reaches the highest to 180min burst size, and wherein reference substance Sodium Nitroprusside NO burst size reaches the highest at 250min, and BZ-1 burst size higher than isosorbide mononitrate, but is weaker than Sodium Nitroprusside.
2. experiment in vivo, determination of pharmacological activity
Healthy male SD rat, SPF level, body weight (220 ± 30) g, is provided by The Fourth Military Medical University's Experimental Animal Center, produces conformity certification number: SCXK(Shan) No. 2008-002nd, word.Sub-cage rearing, ensures 12-12 hour diurnal cycle, water of freely ingesting.Room temperature 26 DEG C ~ 28 DEG C, humidity 60% ~ 70%, ensures to ventilate.
Instrument reagent: rat IVC(independent ventilation cage box) feeding system (Shanghai Shaofeng Experimental Animal Equipment Co., Ltd.); LG-R-80A blood viscosity instrument (Beijing Zhong Qinshidi scientific instrument company limited); Right external jugular vein intubate conduit (PE10, BectonDickinson, USA); Axioskop-40 Zeiss image collection processing system (Germany, MIC00152); Pressure transmitter (GEFRAN-KS, Italy); RM-6280 type intelligence eight road physiology records and analysis process system (Chengdu Instruement Factory); Sartorius electronic balance (Germany, sensibility reciprocal 0.1mg), kaT10-Basic homogenizer (Germany);
Monocrotaline (monocrotaline, MCT, Sigma company); Nitrogen protoxide (NO), nitricoxide synthase (NOS) test kit (company is built up in Nanjing); Other chemical reagent (Tianjin chemical reagent one factory).
Animal divides into groups: rat is placed in IVC(independent ventilation cage box) feeding system, Artificial Control is time 12h round the clock, temperature 20.3 ~ 23.1 DEG C, pressure reduction 20Pa(air intake 180, air-out 160), relative humidity 40 ~ 50%, pre-adaptation starts experiment after one week.By SD rat 50, be divided into Normal group, pulmonary hypertension model group (PAH), the basic, normal, high dosage group of BZ-1 at random.Normal group disposable ip equal-volume physiological saline, other are disposable ip Monocrotaline (MCT) 60mg/kg(HanhuaGao of group respectively, CanChen, Shi ' anHuang, BoLi.Quercetinattenuatestheprogressionofmonocrotaline-in ducedpulmonaryhypertensioninrats [J] .JournalofBiomedicalResearch.2012,26 (2): 98-102.).Next day intervention group respectively ipBZ-15,15,25mg/kg, Normal group and PAH group ip equal-volume physiological saline, once a day, lasting 4 weeks.
Testing index: experimental endpoints, measures NO concentration and NOS vigor in each group of rat mean pulmonary arterial pressure (mPAP), the plump index (RVHI) of right ventricle, hemorheology index and serum, lung homogenate; HE dyeing calculates the per-cent (WA%) that the ratio (WT%) of lung arteriole blood vessel thickness and artery outer diameter and tube wall area account for the blood vessel total area.
Mean pulmonary arterial pressure and hypertrophy of right heart index detect:
Experimental rat was raised to the specified time, after 3% vetanarcol anesthesia, lie on the back after fixing and do neck median incision, be separated right external jugular vein and do V-type minimal incision *, inserting the polyethylene catheter of full 1% heparin solution 1mm, through right side external jugular vein, slowly be pushed into right ventricle, then enter pulmonary artery, external catheter end Bonding pressure sensor and physiograph, the pressure wave mode change according to physiograph judges the position of conduit.Record 10 respectively, 30,60min time Ppa pulmonary artery pressure, getting its mean value is mPAP.After pressure measurement, core dirty and remove atrium, being separated right ventricle (RV) and left ventricle+interventricular septum (LV+S), washing away blood, blotting with filter paper and to weigh respectively afterwards, calculate the RV/(LV+S reacting Right ventricular hypertrophy degree) ratio, result is as shown in table 1.
The middle and high dosage of result display test medicine BZ-1 significantly can reduce mean pulmonary arterial pressure and the hypertrophy of right heart index (P<0.05 of rat model, P<0.01), compared with model group, BZ-1 low dosage demonstrates the effect reducing mean pulmonary arterial pressure and hypertrophy of right heart index, but both there was no significant differences (P>0.05).
The detection of hemorheology of rat index and erythrocyte aggregation index
To measure the rat after Ppa pulmonary artery pressure, abdomen cardinal vein gets blood 2mL in the anticoagulant tube being added with 400 μ L1% heparin sodium aquas, and get 1mL after mixing and detect whole blood viscosity and erythrocyte aggregation index, result is as shown in table 2.
Result shows: under the different shear rates of whole blood viscosity value, model group Normal group is compared all significant difference (P<0.05); BZ-1 middle and high dosage group each numerical value compared with model group all decreases, and has significant difference (P<0.05, P<0.01); BZ-1 low dose group each numerical value compared with model group decreases, but there was no significant difference (P>0.05).Illustrate that the middle and high dosage of BZ-1 significantly can reduce whole blood viscosity value and the erythrocyte aggregation index of rat model.
The mensuration of NO concentration, NOS vigor in rat blood serum and lung homogenate
The detection NO of NO level meets oxygen and water generates nitrate and nitrite, and the latter two meet nitrate developer can generate incarnadine azo-compound, can indirectly predict NO concentration by colorimetric.Get rat blood serum and lung homogenate centrifuged supernatant, measure according to the operation steps of NO testing cassete specification sheets, the sample do not detected is placed in-4 DEG C of freezen protective.
The mensuration NOS catalysis L-Arg of NOS vigor and molecular oxygen reaction generation NO, NO and nucleophilic species generate colored compound, and under 530nm wavelength, measure absorbancy, the large I according to absorbancy calculates NOS vigor.Get rat blood serum and lung homogenate centrifuged supernatant, the operation steps measuring test kit specification sheets according to NOS measures, and the sample do not detected is placed in-4 DEG C of freezen protective, and result is as shown in table 3.
Result shows: the middle and high dosage group of BZ-1, compared with model group, significantly promotes the serum of SD rat and the NO content of lung homogenate and the vigor (P<0.05, P<0.01) of NOS; The statistics there was no significant difference (P>0.05) of BZ-1 low dose group compared with model group, but to NO content and NOS effect of vigor, BZ-1 low dose group is compared model group and is promoted to some extent.
Each group of Pulmonary Vessels in Rats histopathological examination
After rat blood sampling, get rat right lung 10% neutral formalin liquid (formaldehyde: physiological saline=1:9) and fix one week, draw materials along hilus pulumonis is cross-section, specimens paraffin embedding slices, HE dyes; Basis of microscopic observation combining image analysis software measures Aldosterone situation, often group section Stochastic choice 5, measure Pulmonary arteriole thickness of pipe and account for the per-cent (WT%) of artery outer diameter and the per-cent (WA%) of tube wall area and the blood vessel total area, result is as shown in table 4.
Result shows: WT/%, WA/% value is through statistical procedures, the middle and high dosage group of BZ-1 has significant difference (P<0.05 compared with model group, P<0.01), illustrate that the middle and high dosage of BZ-1 can expand the Pulmonary Vascular of rat model effectively; The statistical result showed of BZ-1 low dose group and model group is close, therebetween there was no significant difference (P>0.05).
Each group of Pulmonary Vessels in Rats histopathological examination result: morphological observation finds, in pathologic section, normal group alveolar structure is clear, alveolar epithelium is complete, steeps wall capillary vessel without dilatation and congestion, without exudate in chamber, the a small amount of inflammatory cell infiltration of interstitial, lung arteriole vessel wall without thickening, lumen of vessels without narrow, without polyangitis (Fig. 2).And model group lung arteriole tube wall thickening, luminal stenosis are even inaccessible, lung tissue segment inflammatory cell infiltration clearly, and accompanies polyangitis, and alveolar capillary dilatation and congestion, has edematous fluid in chamber, changes (Fig. 3) in pneumonia sample.After the intervention of BZ-1 middle and high dosage group, lung arteriole and right ventricle wall thickening alleviate, and lung tissue inflammatory cell infiltration alleviates.Almost without edematous fluid in chamber, only change (seeing Figure of description 5,6 respectively) in slight pneumonia sample.BZ-1 low dose group is compared with model group, still visible arteriole vessel wall slightly thickens, lumen of vessels is slightly narrow, companion's polyangitis, lung tissue segment has more inflammatory cell infiltration, and alveolar capillary dilatation and congestion, has edematous fluid in chamber, change (Fig. 4) in slight pneumonia sample, illustrate that the injury of lung pathologic that this dosage group can not effectively be resisted caused by MCT changes.
Claims (9)
1. compound shown in general structure (I),
Wherein, R
1, R
2independently selected from-CH
3,-CH
2cH
3.
2. the preparation method of compound shown in claim 1, is characterized in that comprising the following steps:
(1) phenylacetic acid derivatives 1 and benzaldehyde derivative 2 carry out Perkin and are obtained by reacting intermediate 3 under the effect of acetic anhydride and basic catalyst;
(2) intermediate 3 and isosorbide mononitrate are carried out condensation reaction and obtain compound shown in general structure (I)
。
3. preparation method according to claim 2, is characterized in that: in step (1), described basic catalyst is selected from triethylamine, pyridine, salt of wormwood, sodium carbonate.
4. preparation method according to claim 2, is characterized in that: in step (2), and intermediate 3 and isosorbide mononitrate carry out condensation reaction under thionyl chloride exists.
5. preparation method according to claim 2, is characterized in that: in step (2), and intermediate 3 and isosorbide mononitrate carry out condensation reaction under isobutyl chlorocarbonate exists.
6. preparation method according to claim 2, it is characterized in that: in step (2), intermediate 3 and isosorbide mononitrate carry out condensation reaction under condensing agent and catalyzer exist, described condensing agent is selected from 1,3-dicyclohexylcarbodiimide, 1,3-DIC, 1-ethyl-(3-dimethylaminopropyl) carbodiimide; Described catalyzer is selected from DMAP, I-hydroxybenzotriazole, 1-hydroxyl-7-azo benzotriazole.
7. a pharmaceutical composition, it contains compound according to claim 1 and pharmaceutically acceptable carrier or vehicle, and described pharmaceutical composition is inhalation powder spray, tablet, capsule, powder, pill, granule or emulsion.
8. the application of compound described in claim 1 in preparation treatment pulmonary hypertension disease medicament.
9. apply according to claim 8, it is characterized in that: described pulmonary hypertension disease is chronic obstructive pulmonary disease or plateau pneumochysis.
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