CN109180651A - It is a kind of to can be used for preparing compound for treating coronary atherosclerosis drug and preparation method thereof, purposes - Google Patents
It is a kind of to can be used for preparing compound for treating coronary atherosclerosis drug and preparation method thereof, purposes Download PDFInfo
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- CN109180651A CN109180651A CN201811030555.5A CN201811030555A CN109180651A CN 109180651 A CN109180651 A CN 109180651A CN 201811030555 A CN201811030555 A CN 201811030555A CN 109180651 A CN109180651 A CN 109180651A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a kind of compounds that can be used for preparing treatment coronary atherosclerosis drug, and disclose preparation method and use.The present invention passes through pharmacological evaluation, it proves that the compound has no significant effect liver, lung, spleen, kidney substantially, has the advantages that toxic side effect is small, can be used for treating cardiovascular disease, have broad application prospects in terms of anti-coronary atherosclerosis, there is the apparent effect for inhibiting platelet aggregation.
Description
Technical field
The present invention relates to drug fields relevant to treatment cardiovascular disease.Specifically, the present invention relates to coronal dynamic
A kind of medicative compound of cinnamic acid skeletal of pulse atherosclerosis, preparation method and the pharmaceutical composition containing them
Object.
Background technique
Cardiovascular and cerebrovascular disease is exactly that cardiovascular and cerebrovascular disease are referred to as, refer to due to hyperlipidemia, blood is sticky,
Ischemic or hemorrhagic disease occur for heart caused by atherosclerosis, hypertension etc., brain and body tissue.It is a kind of
Seriously threaten the mankind, the common disease of especially 50 years old or more middle-aged and the old's health, even if the treatment that application is most advanced, perfect at present
Means can still have 50% or more cerebrovascular accident survivor life that cannot take care of oneself completely, and cardiovascular and cerebrovascular is died of in the whole world every year
The number of disease is up to 15,000,000 people, and it is the first to occupy the various causes of the death.
Wherein coronary sclerosis is a kind of extremely common cardiovascular and cerebrovascular disease, and atherosclerosis is artery sclerosis
Common most important one kind in angiosis, its main feature is that involvement arterial disease is since inner membrance.Generally first there is lipid and compound
Carbohydrate accumulation, bleeding and thrombosis, proliferation of fibrous tissue and calcinosis, and have the gradually transformation and calcification of arterial media,
Lesion often involves elastic and big medium muscular artery, is enough to block lumen of artery once developing to, then the tissue that the artery is supplied
Or organ is by ischemic or necrosis.Since the lipid appearance gathered in endarterium is athero- in yellow, because of referred to herein as Atherosclerosis
Change.
Atherosclerosis is one kind of artery sclerosis, and the yellow containing cholesterol, class fat etc. occurs in big or middle endarterium
Substance, mostly by fat metabolic disturbance, neural blood vessel functional disturbance causes.Often result in thrombosis, blood supply disorder etc..Also it cries athero-
Hardening.
The symptom of atherosclerosis depends mainly on vascular lesion and the degree of ischemia of afflicted organ, and aorta is athero- hard
Angina pectoris, myocardial infarction, the heart can be occurred if caliber is narrow up to 75% or more by changing normal asymptomatic, coronary atherosclerosis person
Restrain it is not normal, or even sudden death.Cerebral arteriovenous malformation can cause cerebral ischemia, encephalatrophy, or cause rupture of blood vessel in brain bleeding, and the arteria renalis is athero-
Hardening often causes enuresis nocturna, resistant hypertension, serious person that can have renal insufficiency.Superior mesenteric atherosclerosis can behave as satisfying
The symptoms such as postprandial abdominal pain hematochezia.Lower limb atherosclerosis causes lumen of vessels Serious Stenosis person to may occur in which intermittent claudication, instep
Arteriopalmus disappears, and even gangrene can occur for serious person.
The invention discloses a kind of compound of cinnamic acid skeletal, it is especially coronal to can be used for preparing treatment cardiovascular disease
The drug of atherosclerosis.
Summary of the invention
It is an object of the present invention to overcome the disadvantages of the prior art and insufficient, and providing one kind can be used in the preparation treatment heart
The compound of formula I of vascular diseases drug.
It is a further object to provide the methods of the compound of preparation formula I.
It is also another object of the present invention to provide contain the compound of Formulas I as effective component and it is one or more pharmaceutically
The Pharmaceutical composition of acceptable carrier, excipient or diluent is provided commonly for treatment cardiovascular disease.
The present invention has following structural formula with the compound I of Formulas I structure:
Compound of formula I of the present invention is synthesized by following steps:
Compound A carries out esterification, obtains compound B, compound B is handled to obtain compound C with bromide reagent, and C exists
It reacts to obtain compound D with tetrazole in the presence of alkali, D obtains compound I through amidation process.
The present invention determines the activity such as compound of formula I to cardiovascular disease by every test.The results showed Formulas I
The compound of structure can be used to prepare the drug for the treatment of cardiovascular disease, with good development and application prospects.
The present invention is described in further detail by the following examples, but protection scope of the present invention is not by specific reality
Any restrictions of example are applied, but are defined in the claims.
Detailed description of the invention
Fig. 1 is the structural formula for the compound I that the present invention is prepared.
The reaction equation for the compound I that the position Fig. 2 present invention is prepared.
Specific embodiment
Embodiment 1:
12mmol formic acid and 15mmol phosphorus oxychloride are added in 20mL ether, stirred 30 minutes at 50 DEG C, it is rear to add
Enter 10mmol compound A, 3mmol DCC stirring stir at 60 DEG C 30 minutes, react 10h after, reaction mixture is poured into
In 100mL ice water, stirring adjusts pH=6 with concentrated hydrochloric acid, is extracted with the dichloroethanes of 50mL × 3, merges extraction phase, salt washing
To wash primary, anhydrous sodium sulfate is dry, and solvent, which is boiled off, in Rotary Evaporators obtains residue, and rear pillar chromatographic purifying, obtain the pure of B
Product, ESI-MS, m/z=280.09 ([M+NH4]+)。
8mmol compound B is dissolved in 20mL toluene, slowly stirs under ice-water bath is cooling, 2.71g is slowly added dropwise
(10mmol)PBr3It is dissolved in solution made of the dry methylene chloride of 2mL, rear reaction mixture is added dropwise and is stirred at room temperature
It being poured into 100mL ice water, stirs after half an hour, extracted with the dichloroethanes of 50mL × 3, merge extraction phase, salt water washed once,
Anhydrous sodium sulfate is dry, boils off solvent in Rotary Evaporators and obtains residue, and rear pillar chromatographic purifying, obtains the sterling of C, ESI-
MS, m/z=342.01 ([M+H]+)。
6mmol compound C and 8mmol tetrazole is dissolved in 10mLDMF, is stirred, 3.32g (24mmol) K is added2CO3,
Continue stirring at 100 DEG C until consumption of raw materials finishes (10 hours).Reaction mixture is poured into 100mL ice water, stirring, with dense salt
Acid for adjusting pH=2 are extracted with the dichloroethanes of 50mL × 3, merge extraction phase, and salt water washed once, and anhydrous sodium sulfate is dry,
Rotary Evaporators boil off solvent and obtain residue, and rear pillar chromatographic purifying, obtain the sterling of D, ESI-MS, m/z=332.11 ([M
+H]+)。
5mmol compound D and 8mmol thionyl chloride is dissolved in 20mL toluene, is stirred to react at room temperature 30 minutes, after
3mmol TEA is added and reaction 5 hours is stirred at room temperature.Reaction mixture is poured into 100mL ice water, stirring, with 50mL ×
3 dichloroethanes extraction, merges extraction phase, and salt water washed once, and anhydrous sodium sulfate is dry, boils off solvent in Rotary Evaporators and obtains
To residue, and rear pillar chromatographic purifying, the sterling of I is obtained, ESI-MS, m/z=447.17 ([M-H]-)。
Its physical property:
1H-NMR:δH(DMSO):0.96(t,3H),1.75(t,2H),2.08(s,3H),3.94(s,2H), 6.67(d,
1H),6.8(d,1H),6.9(d,1H),7.58(d,1H),7.72(d,1H),7.82(d,1H), 8.0(s,1H),8.20(s,
1H),8.23(s,1H),8.92(s,1H),12.4(s,1H)。
Elemental analysis: theoretical value: C:59.05, H:4.73, O:14.30；
Measured value: C:58.98, H:4.76, O:14.28.
Embodiment 2:
The pharmacological evaluation and result of compound of formula I of the present invention
1, maximum tolerance test:
Mouse 40 of 20 ± 2g of weight, half male and half female are taken, the concentration by 0.8mg/20g stomach-filling such as compound of formula I is
The death condition of animal in 30 days is observed continuously in the suspension of 100mg/ml, as a result, in 30 days, all animal feeding activities are just
Often, without death, LD is not detected50, it is believed that its is nontoxic.
2, inhibit platelet aggregation test:
Taking weight is Wistar big white mouse 70 of 180-220g health, and half male and half female takes 10 rats to make physiology at random
Salt water negative control group, remaining 60 rat are randomly divided into two groups.Experimental group: intravenous injection compound of formula I, positive controls:
It is injected intravenously aspirin.Each group is all made of (300 μ g/kg, 500 μ g/kg, 800 μ g/kg) three dosage groups, is made into 1mg/
The solution of ml, successive administration six days.In third day, the 6th day each blood sampling 2ml, wherein 0.8ml blood adds 0.2ml sodium citrate
(3.8%) anticoagulant, it separately takes 0.8ml blood to add 0.2mlEDTA anticoagulant, blood specimen is put into platelet aggregation instrument and is induced with ADP, detect
The variation of its cohesiveness.
It was found that control group platelet aggregation power is apparently higher than compound of formula I group and aspirin group, and blood platelet restraint
Then be significantly lower than compound of formula I group and aspirin group, all there were significant differences (P < 0.04), Formulas I compound group with dosage
Aspirin group compares, and two groups also there were significant differences, and the blood platelet restraint of compounds of formula I is apparently higher than aspirin,
And its platelet aggregation power is then significantly lower than aspirin, and is positively correlated with dosage, the time that is administered continuously.
3, Platelets cGMP Concentration Testing:
Sample acquisition is as above.After PRP prepared by EDTA anticoagulation is made platelet count, take 200 μ lPRP that 10 μ are added
The ADP induced platelet aggregation of mol/L.It 3000 revs/min, is centrifuged 10 minutes, discards supernatant liquid, precipitating is slow with 4.75 acetic acid
Fliud flushing is put into that -20 DEG C of refrigerator freeze thawing are primary after suspending, and centrifuging and taking supernatant detects the cGMP of blood platelet with 125I-cGMP kit
Concentration.As a result compound of formula I group cGMP content rises and is positively correlated with dosage, and arginine methyl esters are added, cGMP
Content changes of contents compared with physiological saline group is little, with only to compound of formula I compared with have significant difference, further demonstrate
Compound of formula I can make the increased effect of cGMP content in tissue.
Show that compound of formula I of the invention is a kind of new compound by above-described embodiment, it is safer, can make for a long time
With toxicity is lower, and side effect is less, can effectively inhibit platelet aggregation, is suitable for treatment coronary atherosclerosis.
Claims (4)
1. a kind of compound of Formulas I structure:
2. the method for synthesizing the compound of Formulas I structure defined in claim 1, comprising the following steps:
3. the compound of Formulas I structure defined in claim 1 is in the purposes of preparation treatment cardiovascular disease medicine.
4. the compound of Formulas I structure as claimed in claim 4 is in the purposes of preparation treatment cardiovascular disease medicine, feature
It is that the cardiovascular disease is coronary atherosclerosis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811030555.5A CN109180651A (en) | 2018-09-05 | 2018-09-05 | It is a kind of to can be used for preparing compound for treating coronary atherosclerosis drug and preparation method thereof, purposes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811030555.5A CN109180651A (en) | 2018-09-05 | 2018-09-05 | It is a kind of to can be used for preparing compound for treating coronary atherosclerosis drug and preparation method thereof, purposes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109180651A true CN109180651A (en) | 2019-01-11 |
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ID=64914629
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811030555.5A Withdrawn CN109180651A (en) | 2018-09-05 | 2018-09-05 | It is a kind of to can be used for preparing compound for treating coronary atherosclerosis drug and preparation method thereof, purposes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109180651A (en) |
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2018
- 2018-09-05 CN CN201811030555.5A patent/CN109180651A/en not_active Withdrawn
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Application publication date: 20190111 |
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