CN103819483A - Drug for preventing and treating pulmonary artery hypertension, synthesis and applications thereof - Google Patents
Drug for preventing and treating pulmonary artery hypertension, synthesis and applications thereof Download PDFInfo
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Abstract
The invention discloses a drug for preventing and treating pulmonary artery hypertension, synthesis and applications thereof. The drug has a structural formula (I) which is represented in the description, wherein the R1 and R2 are independently selected from -CH3 and -CH2CH3. The compound is prepared by the following steps: making phenylacetic acid derivatives and benzoic acid derivatives carry out a Perkin reaction in the presence of acetic anhydride and an alkaline catalyst so as to obtain an intermediate, and then making the intermediate carry out condensation reactions with isosorbide mononitrate so as to obtain the compound represented by the structural formula (I). The structure of a primer namely iso-resveratrol is modified so as to strengthen the stability, thus the biological utilization degree of the iso-resveratrol is increased and the drug has a long-acting effect; furthermore, the shortages of easy oxidation and difficult storage of resveratrol with hydroxyl structure are overcome.
Description
Technical field
The present invention relates to the different trans-resveratrol benzyl of a kind of alkylation 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 (chronic obstructive pulmonary disease, COPD), plateau pneumochysis (high altitude pulmonary edema, HAPE) etc., belong to pharmaceutical chemistry field.
background technology
Pulmonary hypertension (pulmonary arterial hypertension, PAH) be important pathologic, physiologic link during clinical numerous cardiopulmonary and vascular disease develops, raise as the disease performance of feature take pulmonary artery pressure and carrying out property of pulmonary vascular resistance, 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, carrying out property expiratory dyspnea, pectoralgia, faint, fatigue and peripheral edema etc., is that one is treated difficulty large, 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 a large class cardiovascular disorder that obtains gradually attention.Although existing prostacyclin (PGI2) and analogue thereof, 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, treats the also method without 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 (HAPE) due to hypoxemia, illustrate the formation mechanism of PAH and the control PAH medicine of seeking of ideal is the focus in the diseases prevention and treatment such as COPD, HAPE research always.
Existing research is thought: the pathological factor that causes PAH is a lot, but all kinds of PAH has common pathophysiological features, i.e. vasoconstriction, primary thrombus and Pulmonary vascular cell reconstruct, and wherein lung blood vessel 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 PAH patient's symptom, can not delay the development process of PAH.Over nearly 20 years, newly medicine constantly occurs, make PAH patient's prognosis have obvious improvement, survival rate is also greatly improved, 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 thereof, ET-1 receptor antagonist, phosphodiesterase-5(PDE-5) inhibitor.In recent years, also emerge the target therapeutic agent of a large amount of novelties, as kinase inhibitor, soluble guanylate cyclase activators etc., become gradually the study hotspot in PAH field.But in above-mentioned new drug, clinical application exists a lot of drawbacks, as patient need implant central venous catheter, and use portable infusion pump etc.In addition, expensive price, serious untoward reaction and complicated administering mode have all limited their application greatly.
Summary of the invention
The object of this invention is to provide one and there is dual collaborative reduction pulmonary hypertension, improve hemorheology, the different trans-resveratrol benzyl of the alkylation position nitric ether nitric oxide donator type compound of anti-chronic obstructive pulmonary disease, plateau pneumochysis;
Another object of the present invention is to provide the preparation method of the different trans-resveratrol benzyl of abovementioned alkylization position nitric ether nitric oxide donator type compound;
A further object of the invention is to provide the medicinal use of the different trans-resveratrol benzyl of abovementioned alkylization 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 react and obtain intermediate 3 under the effect of acetic anhydride and basic catalyst;
(2) intermediate 3 and isosorbide mononitrate are carried out to 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 carries out condensation reaction with isosorbide mononitrate under thionyl chloride exists.
In above-mentioned steps (2), intermediate 3 carries out condensation reaction with isosorbide mononitrate under isobutyl chlorocarbonate exists.
In above-mentioned steps (2), intermediate 3 carries out condensation reaction with isosorbide mononitrate under condensing agent and catalyzer existence, 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 nitrate esters NO donor and primer coupling, designs and synthesizes new NO donor type derivant by different methods of attachment; (2) by the structural modification to the different trans-resveratrol of primer, energy enhanced stability, increases its bioavailability, and impels prolonged drug, and the trans-resveratrol that has improved hydroxyl structure is oxidizable, is difficult for the shortcoming of preserving; (3), by the combination of primer and NO donor medicine, likely in bringing into play drug effect separately, reduce the generation of side effect; (4) be the target site of NO sensitivity for pulmonary vascular endothelial cell, in conjunction with the pharmacological action of lead compound, be expected to bring into play dual collaborative drug effect, thereby become the ideal medicament of the disease such as COPD, HAPE due to control PAH; (5) synthesis technique of the present invention is simple, and raw material is cheap and 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;
The section of Fig. 6 BZ-1 high dose group SD lung tissue of rats.
Specific embodiments
Embodiment 1
the preparation of intermediate 3
Get 8.00g 3,4-dimethoxyphenylacetic acid (1), 6.00g aubepine (2), 15mL acetic anhydride and 6mL anhydrous triethylamine, stir and be heated to 130 ℃, backflow 6h.Leave standstill after room temperature, add 22.00g salt of wormwood and 90mL distilled water, after stirring, reheat to 130 ℃ of backflow 0.5h.Leave standstill after room temperature, adjust pH to 4.0 with concentrated hydrochloric acid, solid is leached, solid recrystallizing methanol, yield is 46.65%.
chloride method synthesising target compound
Get 6.28g intermediate 3 in clean 100mL single port bottle, be cooled to 0 ℃, under nitrogen atmosphere, add 6mLSOCl
2, stir 15min, remove nitrogen, after 79 ℃ of reflux 2 ~ 3h, make the solution of acid chloride of intermediate 3.Hang after room temperature, solution is spin-dried for for subsequent use at 40 ℃.Take 3.82g Ismo 20 simultaneously and be dissolved in 20mL dry methylene chloride, be cooled to 0 ℃ and under nitrogen atmosphere, slowly drip the solution of acid chloride of the intermediate 3 making, dropwise ice bath reaction 6h.Be spin-dried for after solvent, gained sample carries out silica gel column chromatography, collects elutriant, obtains light yellow crystal 5.99g after purifying, and yield is 61.5%.
1?H-NMR?
δ：7.75（s，H，C=C-H），6.07~7.06（m，7H，Ar-H），5.34~5.36（br?s，2H，Cy-H），4.95（br?s，H，Cy-H），4.52（br?s，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 ℃, under nitrogen atmosphere, add 2.54mL isobutyl chlorocarbonate, stir 15min.Take 3.82g Ismo 20 and be dissolved in 20mL dry methylene chloride, under nitrogen atmosphere, slowly drop to reaction solution, dropwise rear continuation reaction 12h.Be spin-dried for solvent, gained sample carries out silica gel column chromatography, collects elutriant, obtains light yellow crystal 6.15g after purifying, and yield is 63.2%.
condensation method synthesising target compound
Get 6.28g intermediate 3 and be dissolved in the methylene dichloride that 20 mL are dry, be cooled to 0 ℃.Under nitrogen atmosphere, add 4.96g condensing agent DCC(N, N-dicyclohexyl imines) and 0.24g catalyzer DMAP(4-N, N-lutidine), at this temperature, stir 15 min, 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, after purifying, obtain light yellow crystal 6.14g, yield is 63.0%.
Embodiment 2
Get 8.00g 3,4-dimethoxyphenylacetic acid (1), 6.00g p-methoxy phenylacetaldehyde (2), 15mL acetic anhydride and 6mL anhydrous pyridine, stir and be heated to 130 ℃, backflow 6h.Leave standstill after room temperature, add 22.00g salt of wormwood and 90mL distilled water, after stirring, reheat to 130 ℃ of backflow 0.5h.Leave standstill after room temperature, adjust pH to 4.0 with concentrated hydrochloric acid, solid is leached, solid recrystallizing methanol, obtains following compound, and yield is 46.65%.
Above-claimed cpd further takes method of condensing similar to Example 1 can prepare following compound,
Embodiment 3: embodiment 1 prepares pharmacological evaluation and the result of target compound
1. external nitrogen protoxide burst size is measured: nitrate compound is at sour environment and have under the condition that excessive sulfhydryl compound exists, and can discharge NO.The nitrite ion NO that NO generates through oxidation
2 -, measure its concentration by Griess method, indirectly reflect the nitrogen protoxide releasability 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, the effect that discharges NO to investigate it, and 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 its optical density value at 540nm wavelength place, 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, use 5%(volume ratio) phosphoric acid solution be settled to 100mL, preparation becomes 1% Sulphanilic Acid solution; Take 0.1046g N-(1-naphthyl)-quadrol, be settled to 100mL with distilled water, preparation becomes 0.1% N-(1-naphthyl)-ethylenediamine solution.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 ℃ preservation.
The drafting of external NO release standard curve: precision takes the Sodium Nitrite that 345mg is dry (5mmol), is settled to 50mL with distilled water, and it is 1 × 10 that dilution is mixed with concentration
-4mol/L Sodium Nitrite storing solution.Precision measures standard reserving solution, and being mixed with concentration is the Sodium Nitrite standard operation liquid of 0.02,0.025,0.032,0.05,0.1mmol/L.Inhale respectively the standard operation liquid of the each concentration of 2mL, with 2mLGriess reagent (1% Sulphanilic Acid solution 1.0mL, 0.1% N-(1-naphthyl)-ethylenediamine solution 1.0 mL) mix, after placement 15min, under 540nm, measure its absorbance.Through linear regression, obtain 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 between concentration and absorbancy within the scope of 0.02-0.10 mmol/L.
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, with a small amount of DMSO dissolving, 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 respectively the each 1.0mL of above-mentioned sample liquid to air-tight bottle, separately get PBS solution 1.0mL to air-tight bottle as blank, add respectively lungs homogenate 0.1mL, PBS(1mol/L, pH=4) 8.9 mL, vortex mixed is even, in 37 ℃ of water-baths, hatch, respectively 20, 40, 60, 80, 100, 120, 160, 180, 240, 250min extracts reaction solution 1mL with syringe, add Griess reagent (the 1% Sulphanilic Acid 0.5mL of 1mL, 0.1%N-(1-naphthyl)-quadrol 0.5mL), mix, place 10min, regulate zero point with reagent blank, survey the absorbancy of each sample solution in 540nm place, calculate optical density A=A
sample-A
empty, draw corresponding NO by typical curve equation
2 -concentration, is sample and discharges the concentration of 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 highlyest at 250min, and BZ-1 burst size is higher than isosorbide mononitrate, but is weaker than Sodium Nitroprusside.
2. experiment in body, 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, guarantees 12-12 hour diurnal cycle, the water of freely ingesting.26 ℃～28 ℃ of room temperatures, humidity 60%～70%, guarantees 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, Becton Dickinson, USA); Axioskop-40 Zeiss image collection processing system (Germany, MIC00152); Pressure transmitter (GEFRAN-KS, Italy); RM-6280 type intelligence eight road physiology record and analysis process systems (Chengdu Instruement Factory); Sartorius electronic balance (Germany, sensibility reciprocal 0.1mg), ka T10-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 grouping: rat is placed in IVC(independent ventilation cage box) feeding system, Artificial Control is time 12h round the clock, 20.3～23.1 ℃ of temperature, pressure reduction 20Pa(air intake 180, air-out 160), relative humidity 40～50%, pre-adaptation starts experiment after one week.By 50 of SD rats, be divided at random Normal group, pulmonary hypertension model group (PAH), the basic, normal, high dosage group of BZ-1.The disposable ip equal-volume of Normal group physiological saline, other each group disposable ip Monocrotalines (MCT) 60 mg/kg (Hanhua Gao, Can Chen, Shi ' an Huang, Bo Li. Quercetin attenuates the progression of monocrotaline-induced pulmonary hypertension in rats[J]. Journal of Biomedical Research. 2012,26 (2): 98-102.).Respectively ip BZ-1 5,15,25mg/kg of intervention group next day, Normal group and PAH group ip equal-volume physiological saline, once a day, continue 4 weeks.
Detect index: experiment terminal, measure NO concentration and NOS vigor in each group of rat mean pulmonary arterial pressure (mPAP), the plump index of right ventricle (RVHI), hemorheology index and serum, lung tissue homogenate; The per-cent (WA%) of the blood vessel total area is calculated the ratio (WT%) of lung arteriole blood vessel thickness and blood vessel external diameter and tube wall area and accounts in HE dyeing.
mean pulmonary arterial pressure and hypertrophy of right heart index detect:
Experimental rat was raised to the specified time, with after 3% vetanarcol anesthesia, lie on the back after fixing and do neck median incision, separate right external jugular vein and do the little otch of V-type, insert 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, conduit outer end Bonding pressure sensor and physiograph, the pressure wave mode shown according to physiograph changes the position that judges conduit.Record respectively 10,30, Ppa pulmonary artery pressure when 60min, getting its mean value is mPAP.After pressure measurement, core dirty and remove atrium, separating right ventricle (RV) and left ventricle+interventricular septum (LV+S), washing away blood, blotting and weigh respectively afterwards with filter paper, calculating the RV/(LV+S that reacts Right ventricular hypertrophy degree) ratio, result is as shown in table 1.
Result show the middle and high dosage of tested medicine BZ-1 can significantly reduce the mean pulmonary arterial pressure of rat model and hypertrophy of right heart index (
p<0.05,
p<0.01), compared with model group, BZ-1 low dosage demonstrates the effect that reduces 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
By the rat of measuring after Ppa pulmonary artery pressure, abdomen cardinal vein is got blood 2 mL in being added with the anticoagulant tube of 400 μ L1% heparin sodium aquas, gets 1 mL and detect whole blood viscosity and erythrocyte aggregation index after mixing, and 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); The middle and high dosage group of BZ-1 each numerical value compared with model group all decreases, have 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 can significantly 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 tissue 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 tissue homogenate centrifuged supernatant, measure according to the operation steps of NO testing cassete specification sheets, the sample not detecting is placed in-4 ℃ of freezing preservations.
The mensuration NOS catalysis L-Arg of NOS vigor and molecular oxygen reaction generate NO, and NO and nucleophilicity material generate colored compound, under 530nm wavelength, measure absorbancy, calculate NOS vigor according to the large I of absorbancy.Get rat blood serum and lung tissue homogenate centrifuged supernatant, measure the operation steps of test kit specification sheets measure according to NOS, the sample not detecting is placed in-4 ℃ of freezing preservations, and result is as shown in table 3.
Result show: the middle and high dosage group of BZ-1 compared with model group, significantly promote the serum of SD rat and the NO content of lung tissue homogenate and NOS vigor (
p<0.05,
p<0.01); The statistics there was no significant difference of BZ-1 low dose group compared with model group (
p, but to NO content and NOS effect of vigor, BZ-1 low dose group is compared model group and promoted to some extent >0.05).
each group Pulmonary Vessels in Rats histopathological examination
After rat blood sampling, get 10% neutral formalin liquid for rat right lung (formaldehyde: physiological saline=1:9) and fix one week, draw materials along hilus pulumonis is cross-section, specimens paraffin embedding slices, HE dyeing; Micro-Microscopic observation combining image analysis software is measured Aldosterone situation, every group of section selected 5 at random, measure Pulmonary arteriole thickness of pipe and account for the per-cent (WT%) of blood vessel external diameter and the per-cent (WA%) of tube wall area and the blood vessel total area, result is as shown in table 4.
Result show: WT/%, WA/% value are learned processing by statistics, the middle and high dosage group of BZ-1 have compared with model group significant difference (
p<0.05,
p<0.01), illustrate that the middle and high dosage of BZ-1 can expand the lung blood vessel of rat model effectively; The statistical result showed of BZ-1 low dose group and model group is close, there was no significant difference between the two (
p>0.05).
Each group Pulmonary Vessels in Rats histopathological examination result: morphological observation is found, in pathologic section, normal group alveolar structure is clear, alveolar epithelium is complete, and bubble wall capillary vessel is without dilatation and congestion, in chamber without exudate, the a small amount of inflammatory cell infiltration of interstitial, lung arteriole vessel wall is without thickening, and lumen of vessels is without narrow, without polyangitis (Fig. 2).And model group lung arteriole tube wall thickens, luminal stenosis is even inaccessible, lung tissue segment inflammatory cell infiltration is very obvious, and accompanies polyangitis, and alveolar capillary dilatation and congestion has edematous fluid in chamber, is pneumonia sample and changes (Fig. 3).After the intervention of the middle and high dosage group of BZ-1, lung arteriole and right ventricle wall thickening alleviate, and lung tissue inflammatory cell infiltration alleviates.In chamber, almost without edematous fluid, be only slight pneumonia sample and change (seeing respectively Figure of description 5,6).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, be slight pneumonia sample and change (Fig. 4), illustrate that the injury of lung pathologic that this dosage group can not effectively be resisted due to 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 react and obtain intermediate 3 under the effect of acetic anhydride and basic catalyst;
Intermediate 3 and isosorbide mononitrate are carried out to 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), intermediate 3 carries out condensation reaction with isosorbide mononitrate under thionyl chloride exists.
5. preparation method according to claim 2, is characterized in that: in step (2), intermediate 3 carries out condensation reaction with isosorbide mononitrate under isobutyl chlorocarbonate exists.
6. preparation method according to claim 2, it is characterized in that: in step (2), intermediate 3 carries out condensation reaction with isosorbide mononitrate under condensing agent and catalyzer existence, 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 claimed in 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 in preparation treatment pulmonary hypertension disease medicament described in claim 1.
9. application according to claim 8, is characterized in that: described pulmonary hypertension disease is chronic obstructive pulmonary disease or plateau pneumochysis.
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