CN107118250A - A kind of NO donator types oleanolic acid derivate and its production and use - Google Patents
A kind of NO donator types oleanolic acid derivate and its production and use Download PDFInfo
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Abstract
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, specifically related to a kind of NO donator types oleanolic acid derivate, NO donors being capable of effectively vasodilator, and CDDO classes compound can suppress pulmonary arterial vascular reconstruct, and in particular to a kind of NO donors vasodilator suppresses drug combination strategy, synthesis and the anti-pulmonary hypertension activity rating of vascular remodeling with CDDO and its derivative.Pulmonary artery pressure is raised caused by such compound can be used for pulmonary vascular resistance increase.Drug regimen the invention further relates to the preparation method of this kind of compound and containing them.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, it is related to a kind of NO donator types oleanolic acid derivate, has
It is high with drug combination strategy, synthesis and the anti-pulmonary artery that CDDO-Me suppresses vascular remodeling that body is related to a kind of NO donors vasodilator
Press activity rating.Pulmonary artery pressure is raised caused by such compound can be used for pulmonary vascular resistance increase.The invention further relates to
The preparation method of this kind of compound and the drug regimen containing them.
Background technology
Pulmonary hypertension (Pulmonary arterial hypertension, PAH) is class pulmonary vascular resistance increase,
Pulmonary artery pressure is raised, and ultimately results in right heart failure even the malignant progression disease of death.In recent years, sent out with to PAH
The further investigation of the interpretation of the cause, onset and process of an illness and the listing of corresponding medicine, the mean survival time of PAH patient is by the 80's of last century
6.7 years extended till now for 2.8 years.But up to the present PAH treatment does not make a breakthrough yet, the higher incidence of disease
The title of " malignant tumour of cardiovascular system " is made it have with the death rate, the life and health of the mankind is seriously endangered.
Oleanolic acid (oleanolic acid, OA) and its derivative are the important pentacyclic triterpene compounds of a class, are had
Anti-inflammatory, antitumor and antiviral etc. multiple biological activities.By carrying out structure of modification to OA, A rings have been synthesized containing α-cyano group-α,
Derivative CDDO, CDDO-Me and CDDO- of alpha, beta-unsaturated ketone (α-cyano- α, β-unsaturated ketone, CUK)
IM。
Compound CDDO-Me shows extremely strong bioactivity, is a semi-synthetic oleanolic acid derivate.It is clinical
Preceding research finds that it not only reduces ET-1 secretion and ETA expression of receptor and vasodilator by suppressing NF- κ B paths, and
And the apoptosis of arteria pulmonalis smooth muscle cells can be promoted, produce the effect for suppressing pulmonary artery reconstruct；Importantly, CDDO-Me is
Nrf2 derivant, with potent anti-inflammatory, antioxidation, improves metabolic disorder, suppresses blood vessel hyperplasia, prevent pulmonary artery
Vascular remodeling.Reata Pharmaceuticals companies of the U.S. have completed the II that CDDO-Me treats pulmonary hypertension in the recent period
Phase clinical research.Oral CDDO-Me (2.5-10mg/ days) can be obviously improved PAH patient symptoms.Compared with placebo, 6MWD
(6 minutes walking distances, the classical way for clinical evaluation patient's PAH cardio-pulmonary function) averagely adds 21.4 meters；In addition,
CDDO-Me shows good tolerance in clinical test, has no that it is treated and goes out in diabetic nephropathy III clinical trial phases
Existing fluid retention and other adverse reactions.During α, β-beta-unsaturated ketone are many bioactive natural products and chemical synthesis small molecule
Pharmacophore, michael acceptor and internal a variety of large biological molecule nucleophilic group (mercaptos of such as cysteine residues can be used as
Base) occur addition reaction, by covalent bond, intracellular numerous signal paths are adjusted, are played and its extensive biological activity
And disease treatment effect.Research shows that CDDO-Me produces anti-inflammatory activity by activating ARE-Nrf2-Keap1 signal paths, studies carefully
The A ring alpha-cyano-α of its molecule mechanism, mainly CDDO-Me, alpha, beta-unsaturated ketone (α-cyano- α, β-unsaturated
Ketone, CUK) occur Michael addition reaction with 151, regions of Keap1 protein B TB CYS sulfydryl caused by.
Pharmacological research shows that CDDO and its derivative suppress inflammatory factor under pM-nM concentration, protect normal cell；
Under 100-300nM concentration, cancer/Carcinoma cell differentiation before promoting suppresses growth of tumour cell；Under 0.02-2 μM of concentration, suppress
Tumor cell proliferation；Under 1-5 μM of concentration, apoptosis of tumor cells can be selectively induced, normal cell is not made significant difference.
CDDO and its derivative are by activating Nrf2-ARE paths, and to many, disease has protection caused by inflammation and oxidative stress
Effect, mainly including tumour, alzheimer disease (Alzheimer's disease, AD), Parkinson's (Parkinson's
Disease, PD), chronic obstructive disease (chronic obstructive pulmonary disease, COPD), asthma,
Diabetes and its complication, multiple sclerosis (multiple sclerosis, MS), osteoarthritis and rheumatoid are closed
Section scorching (rheumatoid arthritis, RA) etc..In addition, this kind of compound is also to smoking, ultraviolet, ischemia-reperfusion etc.
Ophthalmic injuries have protective effect caused by many reasons.Except these cover slow/acute illness of main organs, CDDO
And its derivative also has protective effect to the injury that radiation and chemical reagent are caused, while also having to immune and metabolic system
There is adjustment effect.
Using CDDO as lead compound, its C28 carboxyl is modified, derivative CDDO-IM anti-inflammatory activity ratios are found
CDDO and CDDO-Me improve tens or even hundreds of times, and the clinical test of compound is mainly for cancer of pancreas, leukaemia, black
The tumor diseases such as plain knurl, and chronic inflammatory diseases etc. caused by the concurrent chronic kidney disease of type ii diabetes, smoking.
NO gases are also widely used in PAH treatment.The NO of suction is produced from alveolar disperse to arteria pulmonalis smooth muscle cells
Vasorelaxation action, remaining NO can enter blood and quickly be removed by hemoglobin (Hb).Therefore, suction NO advantage is its blood
Pipe diastole activity is largely limited in lung.NO inhalations are used by U.S. FDA and European drugs administration approved
In clinical treatment neonate Observation of persistent Pulmonary Hypertension (PPNH).In addition, NO inhalations can also be used for stablizing the disease after openheart surgery
People, treats acute respiratory failure and chronic PAH etc..But suck NO and there are some defects, limit its extensive use.For example, NO
Rapid-action, clearance rate is also fast, it is necessary to repeatedly suction；Excessive NO enters can react after blood with hemoglobin, cause siderosis red eggs
White mass formed by blood stasis.It is different from being directly sucked in NO gases, the NO donor medicines of Neulized inhalation can realize slowly, smoothly discharge NO, make
The effect for reducing pulmonary arterial pressure is more lasting, is not likely to produce toxic side effect.Medicament for expanding vascellum is played in past PAH treatments
Leading role, and suppress pulmonary arterial vascular reconstruct research in recent years and deepened the understanding to PAH pathogenesis, and have developed one
A little related drugs enter clinical research.
In view of this, the present invention proposes with diastole pulmonary arterial vascular and suppressed the medicine ratio of pulmonary artery remodeling double action
The medicine of single effect has more preferable PAH therapeutic effects.
The content of the invention
Purpose：The present invention provides a kind of NO donator types oleanolic acid derivate and its production and use, vasodilator
With drug combination design, synthesis and the anti-pulmonary hypertension activity rating for suppressing vascular remodeling.Pharmacological evaluation proves that such is changed
Compound has good anti-pulmonary hypertension activity, therefore, and they can be used for prevention and treatment hypertensive pulmonary arterial disease.
Technical scheme：In order to solve the above technical problems, the technical solution adopted by the present invention is：
The invention discloses a kind of NO donator types oleanolic acid derivate, it is characterised in that：Compound shown in formula I
Or its optical isomer, enantiomer, diastereomer, racemic modification or racemic mixture, or its pharmaceutically acceptable salt or
Ester：
Wherein：
R represents hydrogen atom or C1-C10 straight or branched alkyls；
Five chiral centres (being represented respectively with * 1, * 2, * 3, * 4 and * 5) indicated in Formulas I are R configurations or S configurations.
Further, the compound shown in formula 1, it is characterised in that：
R represents methyl, ethyl, propyl group, isopropyl, the tert-butyl group, phenyl, benzyl；
Chiral centre * 1 is S configurations in Formulas I, and chiral centre * 2 is R configurations, and chiral centre * 3 is S configurations, chiral centre *
4 be S configurations, and chiral centre * 5 is R configurations；
Specifically, compound shown in formula I preferably is selected from following compounds：
1- Isosorbide Mononitrate -2- cyano group -3- acetoxyl group -12- oxos oleananes -2 (3), 9 (11)-diene -
28- carboxylate methyl ester (compound numbers：I1):
1- Isosorbide Mononitrate -2- cyano group -3- acetoxyl group -12- oxos oleananes -2 (3), 9 (11)-diene -
28- carboxylic acid (compound numbers：I2):
1- Isosorbide Mononitrate -2- cyano group -3- propionyloxy -12- oxos oleananes -2 (3), 9 (11)-diene -
28- carboxylic acid (compound numbers：I3)
1- Isosorbide Mononitrate -2- cyano group -3- acetoxyl group -12- oxos oleananes -2 (3), 9 (11)-diene -
28- acylimidazole (compound numbers：I4):
1- Isosorbide Mononitrate -2- cyano group -3- propionyloxy -12- oxos oleananes -2 (3), 9 (11)-diene -
28- acylimidazole (compound numbers：I5)
The code name of compound is equal to the compound corresponding to code name herein in pharmacological evaluation below.
Another object of the present invention is to provide the preparation method of compound described in formula I of the present invention, it is characterized in that be,
Comprise the following steps：
CDDO-Me obtains enolization compound III, enol III through DMF/ alkali process with Isosorbide Mononitrate II reactions
Target compound I is obtained with compound IV reactions；Synthetic route is as follows：
Preferably, the preparation method of the compound of Formula I,
From compound II prepare compounds IV reaction, solvent is selected from anhydrous acetonitrile, anhydrous methylene chloride, chloroform, second
Acetoacetic ester, steams one kind in acetone, anhydrous tetrahydro furan, anhydrous DMF, dimethyl sulfoxide or dioxane again
Or it is a variety of；Alkali is selected from potassium carbonate, sodium carbonate, sodium acid carbonate, sodium hydroxide, potassium hydroxide, pyridine, 4- methylamino pyridines, three second
Amine, N, N- diisopropyl methylamines；Reaction temperature is -20 DEG C to being heated to reflux；
From compound IV prepare compounds I reaction, solvent is selected from anhydrous acetonitrile, anhydrous methylene chloride, chloroform, second
Acetoacetic ester, steams one kind in acetone, anhydrous tetrahydro furan, anhydrous DMF, dimethyl sulfoxide or dioxane again
Or it is a variety of；Alkali is selected from potassium carbonate, sodium carbonate, sodium acid carbonate, sodium hydroxide, potassium hydroxide, pyridine, 4- methylamino pyridines, three second
Amine, N, N- diisopropyl methylamines；Reaction temperature is -20 DEG C to being heated to reflux.
As it is further preferred that the preparation method of the compound of Formula I,
From compound II prepare compounds IV reaction, solvent selects anhydrous DMF, alkali selection carbon
Sour potassium, reaction temperature is room temperature；
From compound IV prepare compounds I reaction, solvent selects anhydrous DMF, alkali selection carbon
Sour potassium, reaction temperature is room temperature.
These compounds can be purified according to conventional isolation techniques.
Another object of the present invention is to provide the compounds of this invention I answering in prevention or treatment hypertensive pulmonary arterial disease is prepared
With.
Drug combination strategy is used herein, it is distributed in lung by nebulizer administration, in lung's lysyl oxidation
Enzyme (LOX) or the lower release CDDO-Me and appropriate NO of esterase effect, diastole pulmonary arterial vascular, while suppressing NF- κ B paths and swashing
Nrf2 paths living, generation anti-inflammatory, effect that is anti-oxidant and suppressing pulmonary arterial vascular reconstruct, reach the purpose of drug combination.
Beneficial effect：The present invention provides NO donator type oleanolic acid derivate therapeutic alliances and has been successfully applied to hypertension,
Such as PAH is this highly complex and the disease of progressive progress, is proved to be effective always without a kind of single medicine.For
This, several clinical tests combine, it has been shown that increased effect and improved result.The present invention designs, has synthesized NO
Donator type oleanolic acid derivate, a kind of nitric oxide donors of new generation and dihydrotestosterone methyl compound, being proved to can be with
The CDDO classes compound and NO gases in lung tissue are resolved into, dual anti-inflammatory is produced, prevention oxidative stress and expansion are pulmonary vascular
Effect.Pharmaceutical composition containing target compound and their medical usage are particularly high in prevention and treatment pulmonary artery
Press in related disease, have a good application prospect.
Brief description of the drawings
Fig. 1：(A) it is serum starvation model；(B) it is the serum starvation model of anoxic；
Fig. 2：The inhibitory action that CDDO-NO and CDDO-Me breeds to PASMCs
Fig. 3：For the situation of change of mean pulmonary arterial pressure；
Fig. 4：For the situation of change of right ventricular systolic pressure；
Fig. 5：For the situation of change of Right ventricular hypertrophy index；
Fig. 6：The lung fibroblast tissue picture and pulmonary artery inner thickness (PAMT) (A) for being HE dyeing are what HE was dyed
Lung fibroblast tissue picture；(B) pulmonary artery inner thickness.
Embodiment
In order to which the present invention is furture elucidated, a series of embodiments are given below, these embodiments be entirely it is illustrative, it
Only be used for the present invention specific descriptions, be not construed as limitation of the present invention.
The pharmacological experimental method and result of the compounds of this invention I anti-pulmonary hypertensions are as follows：
CDDO classes compound has protective effect to PAEC damages
It has studied I1The protective effect damaged to pulmonary artery endothelial cell (PAEC).As shown in Figure 1A, in serum starvation mould
In type, I is found1Concentration has protective effect in≤0.5 μM of concentration to the endothelial cell damage that serum starvation is induced. I1≤
At 0.25 μM, protective effect is proportionate with drug concentration, and protective effect is most obvious in 24h.(the figure in weary oxygen model
1B), I1There is protective effect to the endothelial injuries cell that weary oxygen is induced in≤0.125 μM of concentration, protective effect is dense with medicine
Degree is proportionate.
CDDO classes Compound ira vitro has obvious inhibiting effect to PASMC propagation
It has studied the influence that compound is bred to human pulmonary artery smooth muscle cells (PASMC).It was found that I1Exist with CDDO-Me>
Under 0.75 μM of concentration, PASMC propagation (Fig. 2) can be significantly inhibited in 24h and 48h.
Anti-pulmonary hypertension activity in CDDO class compound bodies
Experimental method：Using male Sprague-Dawley (SD) rat (weight is between 200-250g), MCT is pressed
The intraperitoneal disposable injection (model group) of 60mg/kg dosage, while setting up MCT medium (solvent group), and does not inject any molten
Agent is used as blank control group (blank group).During modeling, one day entry rat body weight of interval and death condition.I1By it is low, in,
High three dosage groups are through nebulizer administration, and it is special that body weight is put into SCIREQ under the SD rat waking states between 250-400g
With in mouth and nose exposure limits device bucket, rat can freely breathe.Medicine is given by ultrasonic atomizer atomization, rat only mouth
Nose is exposed in atomization medicine.Ultrasonic atomizer nebulization efficiency is adjusted to 60%, and atomized flow speed is adjusted to 2L per minute, medicine
Cumulative volume is diluted to for 1mL using distilled water before atomization, nebulisation time 15 minutes.Atomized medicine introducing concentration calculation formula is as follows：Mist
Change administration concentration=medicine mother concentration × drug dilution front volume/(2 L × 15min), animal suction intrapulmonary drug dose=dynamic
Thing minute ventilation × 15min × atomized medicine introducing concentration.Control group is oral group of CDDO-Me, CDDO-Me atomization groups, NO donors
Fragment atomization group, the oral+NO donor fragments atomization drug combination groups of CDDO-Me, and CDDO-Me atomization+NO donor fragment mists
Change drug combination group.In addition, being also used as positive control drug by the use of (suctions) such as existing treatment PAH first-line drug such as Wan Tawei.
The acute effect and chronic effect of each administration group are detected, the former refers mainly to Acute Hemodynamic detection, including average lung is moved
The indexs such as pulse pressure (mPAP), right ventricular systolic pressure power (RVSP), cardiac output, pulmonary vascular resistance (PVR) and heart rate.The latter master
Show to pulmonary artery, the influence of cardiopulmonary institutional framework after medicine, including determine right ventricle and left ventricle+interventricular septum weight ratio
(RV/LV+S, the plump degree of reaction right ventricle).
Using 2% yellow Jackets, it is administered by 50mg/kg body weight, rat is fully anaesthetized.Separation right side vena jugularis externa,
Microguide (PE10, Becton Dickinson, USA) of the insertion full of heparin-saline, in the guiding of pressure waveform
Under, through right side vena jugularis externa, atrium dextrum, right ventricle to pulmonary artery, the other end and pressure sensor (the TSD104A blood pressures of conduit
Transducer, BIOPAC Systems, USA) it is connected, using 16 passage physiological signal record analysis system (MP100, BIOPAC
Systems, USA) right ventricular systolic pressure (RVSP) (Fig. 3) and pulmonary artery pressure are determined, and calculate mean pulmonary arterial pressure (mPAP)
(Fig. 4).Complete to put to death rat after mPAP and RVSP is determined, leave and take blood specimen, separation right lung is fixed, makes paraffin section after
Continuous tissue pathology checking.Separate left lung be put into liquid nitrogen after snap frozen place -80 DEG C of refrigerators treat that subsequent experimental is used.By the heart
It is dirty to remove, separation right ventricle (right ventricular, RV) and left ventricle and interventricular septum (left ventricular+
Septum, LV+S), calculate I1With the Right ventricular hypertrophy index (RV/LV+S) (Fig. 5) of each control group.
CDDO classes compound improves the pulmonary artery remodeling (PVR) of MCT inductions
Pulmonary arterial vascular reconstruct (PVR) is the outstanding feature of pulmonary hypertension, and the increase of pulmonary arterial wall thickness is presented in it,
Lung tissue's abnormal muscle and fibrosis.Compared with control group, its pulmonary arterial wall average thickness of the PAH rats of MCT inductions is bright
Aobvious increase (Fig. 6 A) (p<0.01).It is worth noting that, CDDO-NO can significantly mitigate the blood vessel in Rats of Pulmonary Hypertension lung
Surrounding annulus and abnormal muscle (Fig. 6 A) (p<0.01)；Similarly, CDDO-NO can also reduce pulmonary hypertension (PAH)
In pulmonary artery average thickness (PAMT) (Fig. 6 B) (p<0.01).Sum it up, CDDO-NO is obviously improved MCT inductions in vivo
Pulmonary hypertension (PAH) in pulmonary arterial vascular reconstruct.
Above pharmacology data is shown, of the present invention a kind of about NO compound donators vasodilator and CDDO classes
The restructuring compound I that compound suppresses pulmonary artery remodeling can play significant function of anti-pulmonary hypertension, pass through a series of bodies
Interior external experiment shows that its effect is all more notable than the effect of other control groups under equal conditions.
Embodiment 1
1- Isosorbide Mononitrate -2- cyano group -3- acetoxyl group -12- oxos oleananes -2 (3), 9 (11)-diene -
28- carboxylate methyl esters
CDDO-Me (100mg, 0.2mmol) is dissolved in 2.5ml dry DMF, Isosorbide Mononitrate is added
(57.3mg, 0.3mmol), K2CO3(41mg, 0.3mmol) is stirred overnight at room temperature, and the next morning adds compound V
(23.6mg, 0.3mmol) continues to stir 6h, and reaction solution adds q. s. methylene chloride (50mL) dilution, saturated sodium bicarbonate solution
Respectively washed with saturated aqueous common salt 3 times.Organic layer anhydrous sodium sulfate drying, filtering, filtrate is concentrated to give white solid, through quick
White solid I is made in silica gel column chromatography1(35mg, 35%).
mp:247-248℃；1H NMR(300MHz,CDCl3,25℃,TMS):δ5.84(s,1H),4.69(s,1H),
4.53 (s, 1H), 4.21 (d, J=10.2Hz, 2H), 4.05 (q, 2H), 3.86 (d, J=4.8Hz, 2H), 3.61 (s, 3H),
2.97 (d, J=13.5Hz, 1H), 2.85 (s, 1H), 2.25 (s, 3H), 2.00 (d, J=18.3Hz, 3H), 1.80 (d, J=
13.2Hz,3H),1.45(m,10H),1.26,1.21,1.19,1.14,1.05,0.97,0.86(s,each 3H) ppm；
13CNMR(CDCl3,25℃,TMS):δ198.7,177.8,170.7,170.6,169.9,166.6,124.4,116.1,
100.8,86.8,82.5,81,80.8,80.4,78.6,72.8,68.2,59.5,51.3,49.3,46.8,45.0,43.8,
41.3,39.5, 35.3,34.0,32.7,32.3,31.0,30.2,30.0,29.7,29.1,27.9,26.8,23.4,
22.9ppm；EIMS(70eV) m/z:739.5[M+H]+,761.5[M+Na]+；HRMS(m/z):[M+Na]+calculated
C40H54N2O11761.3728Found:761.3637,PPM error 5.0.
Embodiment 2
1- Isosorbide Mononitrate -2- cyano group -3- acetoxyl group -12- oxos oleananes -2 (3), 9 (11)-diene -
28- carboxylic acids
CDDO (100mg, 0.2mmol) is dissolved in 2.5ml dry DMF, Isosorbide Mononitrate is added
(57.3mg, 0.3mmol), K2CO3(41mg, 0.3mmol) is stirred overnight at room temperature, and the next morning adds compound V
(23.6mg, 0.3mmol) continues to stir 6h, and reaction solution adds q. s. methylene chloride (50mL) dilution, saturated sodium bicarbonate solution
Respectively washed with saturated aqueous common salt 3 times.Organic layer anhydrous sodium sulfate drying, filtering, filtrate is concentrated to give white solid, through quick
White solid I is made in silica gel column chromatography2(35mg, 35%).
Embodiment 3
1- Isosorbide Mononitrate -2- cyano group -3- propionyloxy -12- oxos oleananes -2 (3), 9 (11)-diene -
28- carboxylic acids
CDDO (100mg, 0.2mmol) is dissolved in 2.5ml dry DMF, Isosorbide Mononitrate is added
(57.3mg, 0.3mmol), K2CO3(41mg, 0.3mmol) is stirred overnight at room temperature, and the next morning adds compound V
(27.8mg, 0.3mmol) continues to stir 6h, and reaction solution adds q. s. methylene chloride (50mL) dilution, saturated sodium bicarbonate solution
Respectively washed with saturated aqueous common salt 3 times.Organic layer anhydrous sodium sulfate drying, filtering, filtrate is concentrated to give white solid, through quick
White solid I is made in silica gel column chromatography3(35mg, 35%).
Embodiment 4
1- Isosorbide Mononitrate -2- cyano group -3- acetoxyl group -12- oxos oleananes -2 (3), 9 (11)-diene -
28- acylimidazoles
CDDO-IM (100mg, 0.2mmol) is dissolved in 2.5ml dry DMF, Isosorbide Mononitrate is added
(57.3mg, 0.3mmol), K2CO3(41mg, 0.3mmol) is stirred overnight at room temperature, and the next morning adds compound V
(23.6mg, 0.3mmol) continues to stir 6h, and reaction solution adds q. s. methylene chloride (50mL) dilution, saturated sodium bicarbonate solution
Respectively washed with saturated aqueous common salt 3 times.Organic layer anhydrous sodium sulfate drying, filtering, filtrate is concentrated to give white solid, through quick
White solid I is made in silica gel column chromatography4(35mg, 35%).
Embodiment 5
1- Isosorbide Mononitrate -2- cyano group -3- propionyloxy -12- oxos oleananes -2 (3), 9 (11)-diene -
28- acylimidazoles
CDDO-IM (100mg, 0.2mmol) is dissolved in 2.5ml dry DMF, Isosorbide Mononitrate is added
(57.3mg, 0.3mmol), K2CO3(41mg, 0.3mmol) is stirred overnight at room temperature, and the next morning adds compound V
(27.8mg, 0.3mmol) continues to stir 6h, and reaction solution adds q. s. methylene chloride (50mL) dilution, saturated sodium bicarbonate solution
Respectively washed with saturated aqueous common salt 3 times.Organic layer anhydrous sodium sulfate drying, filtering, filtrate is concentrated to give white solid, through quick
White solid I is made in silica gel column chromatography5(35mg, 35%).
Described above is only the preferred embodiment of the present invention, it should be pointed out that：For the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications
It should be regarded as protection scope of the present invention.
Claims (9)
1. a kind of compound, be compound or its optical isomer shown in formula I, enantiomer, diastereomer, racemic modification or
Racemic mixture, or its pharmaceutically acceptable salt：
Wherein：
R1Represent hydrogen atom H, C1-C10 straight or branched alkyl；R2Represent alkoxy, hydroxyl or amido；
Five chiral centres indicated in Formulas I, are represented with * 1, * 2, * 3, * 4 and * 5 respectively, and chiral centre is R configurations or S configurations.
2. compound according to claim 1, it is characterised in that：R1Represent hydrogen atom, methyl, ethyl, propyl group, isopropyl,
The tert-butyl group, phenyl, benzyl；R2Represent hydroxyl, methoxyl group, 1 imidazole radicals；
Chiral centre * 1 is S configurations in Formulas I, and chiral centre * 2 is R configurations, and chiral centre * 3 is S configurations, and chiral centre * 4 is S
Configuration, chiral centre * 5 is R configurations.
3. compound according to claim 1, it is characterised in that：The compound is selected from following compound：
1- Isosorbide Mononitrate -2- cyano group -3- acetoxyl group -12- oxos oleananes -2 (3), 9 (11)-diene -28- carboxylics
Sour methyl esters；
1- Isosorbide Mononitrate -2- cyano group -3- acetoxyl group -12- oxos oleananes -2 (3), 9 (11)-diene -28- carboxylics
Acid；
1- Isosorbide Mononitrate -2- cyano group -3- propionyloxy -12- oxos oleananes -2 (3), 9 (11)-diene -28- carboxylics
Acid；
1- Isosorbide Mononitrate -2- cyano group -3- acetoxyl group -12- oxos oleananes -2 (3), 9 (11)-diene -28- acyls
Base imidazoles；
1- Isosorbide Mononitrate -2- cyano group -3- propionyloxy -12- oxos oleananes -2 (3), 9 (11)-diene -28- acyls
Base imidazoles.
4. the preparation method of the NO donator type oleanolic acid derivates described in claim 1 shown in formula I, comprises the following steps：
Compound II obtains enolization compound IV, enol IV and chemical combination through DMF/ alkali process with Isosorbide Mononitrate III reactions
Thing V reactions obtain target compound I；Synthetic route is as follows：
5. the preparation method of compound of Formula I according to claim 4, it is characterised in that：
From compound II prepare compounds IV reaction, solvent is selected from anhydrous acetonitrile, anhydrous methylene chloride, chloroform, acetic acid second
Ester, steams one kind or many in acetone, anhydrous tetrahydro furan, anhydrous DMF, dimethyl sulfoxide or dioxane again
Kind；Alkali be selected from potassium carbonate, sodium carbonate, sodium acid carbonate, sodium hydroxide, potassium hydroxide, pyridine, 4- methylamino pyridines, triethylamine, N,
N- diisopropyl methylamines；Reaction temperature is -20 DEG C to being heated to reflux；And/or,
From compound IV prepare compounds I reaction, solvent is selected from anhydrous acetonitrile, anhydrous methylene chloride, chloroform, acetic acid second
Ester, steams one kind or many in acetone, anhydrous tetrahydro furan, anhydrous DMF, dimethyl sulfoxide or dioxane again
Kind；Alkali be selected from potassium carbonate, sodium carbonate, sodium acid carbonate, sodium hydroxide, potassium hydroxide, pyridine, 4- methylamino pyridines, triethylamine, N,
N- diisopropyl methylamines；Reaction temperature is -20 DEG C to being heated to reflux.
6. the preparation method of compound of Formula I according to claim 5, it is characterised in that：
From compound II prepare compounds IV reaction, solvent selects anhydrous DMF, and alkali selects potassium carbonate,
Reaction temperature is room temperature；And/or,
From compound IV prepare compounds I reaction, solvent selects anhydrous DMF, and alkali selects potassium carbonate,
Reaction temperature is room temperature.
7. a kind of pharmaceutical composition, wherein the NO donator types shown in formula I described in the claim 1 containing therapeutically effective amount are neat
Pier fruit acid derivative or its optical isomer, enantiomer, diastereomer, racemic modification or racemic mixture, or it is pharmaceutically
Acceptable salt and pharmaceutically useful carrier, adjuvant or mediator.
8. the compound described in claim any one of 1-3 is preparing the medicine of prevention or the treatment disease relevant with diabetic nephropathy
Application in thing.
9. purposes according to claim 8, the relevant disease of diabetic nephropathy includes hypertensive pulmonary arterial disease.
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| CN111518028A (en) * | 2020-05-12 | 2020-08-11 | 中国药科大学 | Nitric oxide donor type ripassail derivative and preparation method and application thereof |
| CN113603743A (en) * | 2021-08-06 | 2021-11-05 | 南通大学 | CDDO/ligustrazine heterozygote with combined treatment effect and preparation method and application thereof |
| WO2021227898A1 (en) * | 2020-05-12 | 2021-11-18 | 中国药科大学 | Nitric oxide donor type fasudil derivative, preparation method therefor and use thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111518028A (en) * | 2020-05-12 | 2020-08-11 | 中国药科大学 | Nitric oxide donor type ripassail derivative and preparation method and application thereof |
| WO2021227898A1 (en) * | 2020-05-12 | 2021-11-18 | 中国药科大学 | Nitric oxide donor type fasudil derivative, preparation method therefor and use thereof |
| WO2021227895A1 (en) * | 2020-05-12 | 2021-11-18 | 中国药科大学 | Nitric oxide donor-type ripasudil derivative, preparation method therefor, and use thereof |
| CN113603743A (en) * | 2021-08-06 | 2021-11-05 | 南通大学 | CDDO/ligustrazine heterozygote with combined treatment effect and preparation method and application thereof |
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| CN107118250B (en) | 2019-06-21 |
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