CN106916143A - A kind of medicine for preventing and treating coronary heart disease and its application - Google Patents
A kind of medicine for preventing and treating coronary heart disease and its application Download PDFInfo
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- CN106916143A CN106916143A CN201710151840.1A CN201710151840A CN106916143A CN 106916143 A CN106916143 A CN 106916143A CN 201710151840 A CN201710151840 A CN 201710151840A CN 106916143 A CN106916143 A CN 106916143A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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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
- C07D403/14—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 three or more hetero rings
Abstract
The present invention relates to a kind of with excellent lecithin cholesterol acetyltransferase (i.e. LCAT) activation effect, the indolinone derivative or its pharmaceutically acceptable salt of preferably reversible LCAT activation effects.This kind of compound includes compound shown in Formulas I or its pharmaceutically acceptable salt：
Description
Technical field
It is excellent the present invention relates to a kind of with excellent lecithin-cholesterol acetyltransferase (i.e. LCAT) activation effect
Select the indolinone derivative or its pharmaceutically acceptable salt of reversible LCAT activation effects, the compound can be used to preventing and
Treatment cardiovascular and cerebrovascular disease, such as coronary heart disease, artery sclerosis etc..
Background technology
The cardiovascular and cerebrovascular disease caused by hypertension, dyslipidemia, diabetes etc. is the significant problem for facing at present.Anti- height
Blood pressure, anti-lipid obstacle and antidiabetic are used for treatment hypertension, dyslipidemia and hyperglycemia disease, such as diuresis respectively
Agent, calcium antagonist, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe and A-II antagonists etc. can be used as antihypertensive, HMG-CoA reductase inhibitor, nicotinic acid
Derivative and CLOF class etc. can be used as anti-lipid obstacle medicine, insulin, sulfonylurea, melbine, glitazone and wait can
As antidiabetic, these medicines help to adjust the lipid or glucose level in blood pressure or blood.But, themselves is not
Effect well can be produced to some cardiovascular and cerebrovascular diseases such as coronary heart disease.Accordingly, it would be desirable to be developed for the more preferable of these diseases
Medicine.
The direct risk factors of angiocardiopathy are the atherosclerosis relevant with artery wall thickening.The low-density of oxidation
Accumulation in lipoprotein (i.e. LDL) macrophage of cholesterol in arterial wall etc. causes patch to be formed, and causes this thickening
(Ross, R., Annu.Rev.Physiol.1995, Vol.57, p.791-804；Steinberg, D.,
J.Biol.Chem.1997, Vol.272, p.20963-20966).The patch atherosclerosis suppresses blood flow and promotes thrombus
Formed.
The result of many epidemiological studies shows, the serum-concentration of lipoprotein and such as dyslipidemia and artery sclerosis
Disease it is relevant (Badimon, J.Clin.Invest., 1990, Vol.85, p.1234-1241).Increased LDL courages in blood
Both high density fat albumen (i.e. HDL) cholesterol concentrations reduced in sterol concentration and blood are the wind of coronary artery disease
Dangerous factor.
In peripheral tissues, HDL promotes Cholesterol Efflux, and cholesterol is then esterified by LCAT on HDL, to produce cholesteric
Alcohol ester.Increased LCAT activity promote cholesterol from macrophage outflow (Matsuura, F., J.Clin.Invest.2006,
Vol.116, p.1435-1442).It is therefore contemplated that the medicine for increasing LCAT activity can be used as treating or preventing such as coronary disease
The medicament of the disease of disease and artery sclerosis.
Therefore, it is necessary to develop a kind of medicine of increase LCAT activity with realize to cardiovascular and cerebrovascular disease such as coronary heart disease,
The prevention and treatment of artery sclerosis.
The content of the invention
There is excellent LCAT activation effects it is an object of the present invention to provide one kind and cholesterol is directly facilitated from huge
The compound or its pharmaceutically acceptable salt of phagocyte outflow.
It is a further object to provide a kind of method for preparing the compound.
At least one compound is included it is also another object of the present invention to provide one kind or its is pharmaceutically acceptable
Salt as active component pharmaceutical composition.
A further object of the present invention is to provide the compound or its pharmaceutically acceptable salt in medicine is prepared
Using.
In order to realize the above object the invention provides compound shown in a kind of formula 1, with LCAT activation effects or
Its pharmaceutically acceptable salt：
[formula 1]
Wherein：
W1、W2N or CR can be each independently with identical or different3；
R1、R2、R3Can with identical or different, be each independently hydrogen, halogen, hydroxyl, cyano group, nitro, amino, carboxyl,
C1-4 alkyl, C1-4 alkoxies, C3-7 cycloalkyl, halogenated c1-4 alkyl, methylol, C1-4 alkyl-carbonyls, C1-4 alkoxy carbonyls
Base, C1-4 alkyl aminos, two (C1-4 alkyl) amino or C1-4 alkyl sulphonyls；
R represents 0,1,2 or 3；
S represents 0,1,2 or 3；
T represents 0,1,2 or 3.
Present invention also offers the preparation method of compound shown in a kind of formula 1, the preparation method is comprised the steps of：
Step 1. reacts with compound shown in formula 4 compound shown in formula 2 and compound shown in formula 3, such as following anti-
Answer shown in formula 1：
[reaction equation 1]
In reaction equation 1, R1、R2, r, s as defined in formula 1, X represents halogen, preferably chlorine or bromine.
Step 2. reacts with compound shown in formula 1 compound shown in formula 4 and compound shown in formula 5, such as following anti-
Answer shown in formula 2：
[reaction equation 2]
In reaction equation 2, W1、W2、R1、R2、R3, r, s, t be as defined in formula 1.
Beneficial effect
Compound of the invention can effectively serve as a kind of therapeutic agent, and it can activate LCAT, and also can be notable
Increase HDL levels, can be consequently used for treating cardiovascular and cerebrovascular disease, such as coronary heart disease, artery sclerosis etc..
Specific embodiment
Hereafter will be described in detail the present invention.
Unless otherwise defined, all technologies used in this application and scientific terminology have and art technology people of the present invention
Member is generally understood identical implication.The all patents and publication that the application is referred to are incorporated herein by reference.
The invention provides compound shown in a kind of formula 1, with LCAT activation effects or its be pharmaceutically subjected to
Salt：
[formula 1]
Wherein：
W1、W2N or CR can be each independently with identical or different3；
R1、R2、R3Can with identical or different, be each independently hydrogen, halogen, hydroxyl, cyano group, nitro, amino, carboxyl,
C1-4 alkyl, C1-4 alkoxies, C3-7 cycloalkyl, halogenated c1-4 alkyl, methylol, C1-4 alkyl-carbonyls, C1-4 alkoxy carbonyls
Base, C1-4 alkyl aminos, two (C1-4 alkyl) amino or C1-4 alkyl sulphonyls；
R represents 0,1,2 or 3；
S represents 0,1,2 or 3；
T represents 0,1,2 or 3.
In some embodiments of the compounds of this invention, W1、W2All it is N.
In some embodiments of the compounds of this invention, W1It is N, W2It is CH.
In some embodiments of the compounds of this invention, R1It is methyl, methylol, hydroxyl, trifluoromethyl or ethyoxyl.
In some embodiments of the compounds of this invention, R2It is hydrogen, methyl sulphonyl or nitro.
In some embodiments of the compounds of this invention, R3It is hydrogen, methoxyl group, cyclopropyl, cyano group or methyl fluoride.
In some embodiments of the compounds of this invention, the compound is selected from：
Compound I：
Compound II：
Compound III：
Compound IV：
Compound V：
Compound VI：
Compound VII：
In all embodiments of the invention, term " alkyl " include side chain and straight chained alkyl or cyclic hydrocarbon group or they
Combination.Alkyl is fully saturated and may include two-and multivalence group, with carbon atom (that is, the C1-C4 for specifying number
Refer to 1,2,3 or 4 carbon).Common alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl
Base, tert-butyl group etc..
Term " halogen " or refer to fluorine, chlorine, bromine or iodine.
Term " cycloalkyl " refers to can have 3 to 10 carbon, such as 3 to 7 cyclic aliphatic ring structures of carbon, for example
Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl etc..
Compound shown in formula 1 can be used in the form of a kind of pharmaceutically acceptable salt, wherein the salt is excellent
The acid-addition salts that choosing is formed by pharmaceutically acceptable free acid.Herein, the pharmaceutically acceptable salt represents any such as formula 1
The organic or inorganic addition salts of shown compound, it has harmless activity to patient's relative nontoxic, and its side effect will not drop
The beneficial effect of basic compound shown in the low formula 1.Acid-addition salts described herein can be obtained from following item：Inorganic acid
Such as hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid and phosphoric acid；Or organic acids such as citric acid, acetic acid, lactic acid, maleic acid, richness
Horse acid, methanesulfonic acid, butanedioic acid, tartaric acid, galacturonic acid, handkerchief not acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) apple
Acid, methanesulfonic acid, ethyl sulfonic acid, 4- toluenesulfonic acids, salicylic acid, citric acid, benzoic acid and malonic acid.Salt as herein described includes alkali
Slaine (sodium salt, sylvite etc.) and alkali salt (calcium salt, magnesium salts etc.).For example, the example of acid-addition salts is：Acetate, day
Winter propylhomoserin salt, benzoate, benzene sulfonate, bicarbonate/carbonate, disulfate/sulfate, borate, citrate, second
Disulfonate, ethylate, formates, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphoric acid
Salt, hibenzate, hydrochloride/chloride, hydrobromate/bromide, hydriodide/iodide, isethionate, lactic acid
Salt, malate, maleate, malonate, methoxide, dimethyl suflfate, nicotinate, nitrate, Orotate, oxalic acid
Salt, palmitate, embonate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, sugar lime, stearate, succinate, wine
Stone hydrochlorate, toluene fulfonate, trifluoroacetate, aluminium, arginine, calcium, choline, diethylamine, diethanol amine, glycine, lysine,
Magnesium, meglumine, monoethanolamine, potassium, sodium, tromethamine and zinc salt.Wherein, preferably hydrochloride or trifluoroacetate.
Compound shown in formula 1 not only includes pharmaceutically acceptable salt, also comprising by conventional method from the change
Any possible salt, isomer, hydrate and the solvate built in compound.
Acid-addition salts of the present invention can be prepared by conventional method well known in the art.For example, the chemical combination of formula 1
Thing is dissolved in water-miscible organic solvent such as acetone, methyl alcohol, ethanol or acetonitrile, is added thereto to excessive organic acid or inorganic
The acidic aqueous solution of acid is precipitated or crystallized to induce.Then, the acid of solvent or excess is evaporated from mixture and is removed, then led to
The salt of drying composite or suction filtration Precipitation is crossed to obtain addition salts.
Some compounds shown in formula 1 contain chiral centre or geometric isomer center (E and Z isomers).Should
Understand, the present invention includes all optical isomers with LCAT activation effects, diastereomer and geometric isomer.
Present invention also offers the preparation method of compound shown in a kind of formula 1, the preparation method is comprised the steps of：
Step 1. reacts with compound shown in formula 4 compound shown in formula 2 and compound shown in formula 3, such as following anti-
Answer shown in formula 1：
[reaction equation 1]
In reaction equation 1, R1、R2, r, s as defined in formula 1, X represents halogen, preferably chlorine or bromine；
The reaction is carried out in the presence of base, and the alkali includes inorganic base, such as NaOH, potassium hydroxide, carbonic acid
Sodium, potassium carbonate, sodium acid carbonate or saleratus；And organic base, such as triethylamine, pyridine or piperidines.
Step 2. reacts with compound shown in formula 1 compound shown in formula 4 and compound shown in formula 5, such as following anti-
Answer shown in formula 2：
[reaction equation 2]
In reaction equation 2, W1、W2、R1、R2、R3, r, s, t be as defined in formula 1；
The reaction is carried out in the presence of alkali and palladium catalyst, the alkali include sodium carbonate, potassium carbonate, sodium acid carbonate or
Saleratus；The palladium catalyst includes tetrakis triphenylphosphine palladium or palladium.
Additionally, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition includes chemical combination shown at least one formula 1
Thing or its pharmaceutically acceptable salt are used as active component.
Compound shown in formula 1 is proven to have excellent LCAT activation effects, specifically, the compound activation LCAT's
EC50It is 0.1nM-10000nM, preferably 0.5nM-1000nM, more preferably 1nM-100nM can be 2nM-50nM specifically.Formula 1
Shown compound can also dramatically increase HDL levels, and specifically, increment rate is 300%-1500%, preferably 400%-1000%,
More preferably 500%-900%.Because compound shown in formula 1 has excellent LCAT activation effects and increases HDL levels
Effect, therefore can be used as coronary heart disease, artery sclerosis, arteriography, cranial vascular disease, peripheral vascular disease,
Dyslipidemia, low HDL cholesterolemia, the therapeutic agent of LDL-C mass formed by blood stasis high.
Containing compound shown in formula 1 or its pharmaceutically acceptable salt as active component drug regimen of the invention
Thing, can be administered orally or Parenteral administration, and be used with the general type of pharmaceutical preparation, but not limited to this.
The example of formulations for oral administration is tablet, pill, hard/soft capsule, solution, supensoid agent, emulsion, sugar
Slurry agent, granule etc..These preparations in addition to the active ingredient (s can be comprising diluent (for example, lactose, dextrose, sucrose, sweet dew
Alcohol, sorbierite, cellulose and/or glycine) and lubricant (for example, silica, talcum, stearate and its magnesium salts or calcium
Salt, and/or polyethylene glycol).Tablet can include binding agent such as aluminium-magnesium silicate, gelatinized corn starch, gelatin, methylcellulose, carboxylic first
Base sodium cellulosate and/or polyvinylpyrrolidone, if it is necessary, can also comprising disintegrant such as starch, agarose, alginic acid or
Its sodium salt or azeotropic mixture, and/or adsorbent, colouring agent, flavor enhancement and sweetener can also be included therein.
The effective dose of the compounds of this invention can be according to age, body weight, sex, medication, health status and illness
The order of severity determines.For example, the dosage of the adult of an individual weight 70kg is 0.1-1, preferably 000mg/ days, 1-500mg/
My god.Such administration can once a day to multiple, the decision execution according to doctor or pharmacists.
Of the invention practical and presently preferred embodiment is such as with lower section embodiment explanation.
It will be appreciated, however, that those skilled in the art can make within the spirit and scope of the present invention after considering the disclosure
Modification and improvement.
Embodiment
Embodiment 1：(Z) -3- ((1H- benzos [d] imidazoles -7- bases) methylene) -5- methyl -6- (pyridine -2- bases) indoles
Quinoline -2- ketone (compound I)
Step 1：1H- benzos [d] imidazoles -7- formaldehyde (2.19g, 15.0mmol) is placed in 500ml eggplant-shape bottles, is added
After 150ml anhydrous alcohol solutions, the chloro- 5- methyl indols quinoline -2- ketone of 6- and 2ml triethylamines are added, 3h is reacted at room temperature, occurred
A large amount of precipitations.Suction filtration, a small amount of absolute ethanol washing is dried, and ((1H- benzos [d] imidazoles -7- bases) is sub- to obtain yellow solid (Z) -3-
Methyl) the chloro- 5- methyl indols quinoline -2- ketone 4.15g of -6-, yield 89.2%, content 98.1%.ESI-MS：310.07[M+H]+。
Step 2：To in dry Schlenk reaction tubes add (Z) -3- ((1H- benzos [d] imidazoles -7- bases) methylene) -
The chloro- 5- methyl indols quinoline -2- ketone (3.09g, 10.0mmol) of 6-, pyridine -2- ylboronic acids dimethyl ester (1.66g, 11.0mmol), four
(triphenylphosphine) palladium (0.12g, 0.1mmol), Na2CO3(2.12g, 20.0mmol), under nitrogen protection, adds Isosorbide-5-Nitrae-dioxy six
Ring (50mL), water (5mL), 55 DEG C of reaction 5h.After reaction terminates, removal of solvent under reduced pressure is used after residue with ethyl acetate dissolving
Silica gel column chromatography is separated, and is eluted with petrol ether/ethyl acetate 8: 1, obtains the title compound 2.75g of white solid, yield
78.2%, content 98.9%.
ESI-MS：353.13[M+H]+
Elementary analysis：Theoretical value/measured value, C (57.66/57.51), H (3.33/3.41), N (29.24/29.27), O
(9.60/9.81)
1H NMR (400MHz, CDCl3) δ 12.34 (s, 1H), 11.24 (s, IH), 8.51 (d, 1H), 8.32 (s, 1H),
8.16 (s, 1H), 7.67 (s, 1H), 7.54 (q, 1H), 7.43 (d, 1H), 7.21-7.26 (m, 4H), 7.01 (q, 1H), 2.63
(s, 3H).
Embodiment 2：(Z) -5- (methylol) -3- ((5- (methyl sulphonyl) -1H- benzo [d] imidazoles -7- bases) methylenes
Base) -6- (pyrimidine -2-base) indole-2-ketone (compound II)
According to the method for embodiment 1, replaced with 1- (5- (methyl sulphonyl) -1H- benzo [d] imidazoles -7- bases)-formaldehyde
1H- benzos [d] imidazoles -7- formaldehyde, the chloro- 5- methyl indols quinoline -2- ketone of 6- is replaced with 6- bromo- 5- (methylol) indole-2-ketone,
Replace pyridine -2- ylboronic acid dimethyl esters with pyrimidine -2-base trimethyl borate, obtain the title compound of white solid, two steps are total
Yield 63.9%.
ESI-MS：448.47[M+H]+
Elementary analysis：Theoretical value/measured value, C (59.05/59.12), H (3.83/3.87), N (15.65/15.74), O
(14.30/14.22), S (7.17/7.05)
1H NMR (400MHz, CDCl3) δ 12.37 (s, 1H), 11.19 (s, 1H), 8.81 (d, 2H), 8.24 (s, 1H),
8.12 (s, 1H), 8.00 (s, 1H), 7.76 (s, 1H), 7.56 (s, 1H), 7.39 (s, 1H), 7.28 (q, 1H), 5.23 (s, 1H),
4.63 (s, 2H), 3.31 (s, 3H).
In a similar way, following compound is synthesized：
Testing example 1：Lecithin-cholesterol acetyltransferase (LCAT) external activity measurement
The blood plasma separated from the people of health by density gradient centrifugation obtains part (the 1.125 ＜ proportions being made up of HDL3
＜ 1.210/mL).By obtain part to phosphate-buffered saline (pH 7.4) dialysis and as LCAT enzyme source and receive
Body.Each testing drug is prepared by being dissolved in dimethyl sulfoxide (DMSO).DTNB (Ellman reagents, ultimate density will be contained：0.5mM), mercapto
Base ethanol (ultimate density：12.5mM) and 0.6% bovine serum albumin(BSA) [14C] cholesterol is added to and contains 1mg/mL HDL3's
Phosphate-buffered saline (pH 7.4), and be further added to the testing drug of various concentrations and be adjusted to 80 μ L with by total amount.
The mixture is cultivated at 37 DEG C about 16 hours.Then, be added to hexane and isopropanol mixed solution (mixing ratio=3: 2) with
Stop reaction.After stirring, hexane layer is collected, and evaporate the layer to dry.It is added to chloroformic solution (concentration：10mg/mL), and
Mixture is polished on thin layer silica gel plate, and using hexane, diethyl ether and ethyl acetate mixed solution (mixing ratio=85:
15: 2) launch.Use imaging analysis instrument BAS-2500, radioactivity of the measurement corresponding to the part of cholesterol acid ester.Similarly
Treatment and analysis do not supplement the sample of testing drug.According to equation 1, the LCAT relative to the sample for not supplementing testing drug lives
Property, calculate the EC of LCAT activation50Value.Result is shown below in table 1.
[equation 1]
Y=bottoms+(Top-Bottom)/(1+10LogEC50-X)
Wherein X represents the logarithm of the concentration of testing drug；
Y represents the response (i.e. LCAT activity) of testing drug；
Top represents maximum；
Bottom represents minimum value；With
EC50Represent 50% valid density.
The LCAT agonist activities of the target compound of table 1
| Test compound | |
| Compound I | 4.5 |
| Compound II | 17.9 |
| Compound III | 30.4 |
| Compound IV | 9.7 |
| Compound V | 12.7 |
| Compound VI | 40.3 |
| Compound VII | 18.0 |
The above results show that the compounds of this invention has excellent LCAT activation effects, can be used to prevent and treat heart and brain
Vascular diseases, such as coronary heart disease and artery sclerosis.
Testing example 2：Efficacy testing in macaque
Each testing drug is dissolved in the mixed solutions of propane diols-Tween 80 [4/1 (v/v)] or 0.5% (w/v) Methyl cellulose
The plain aqueous solution, and the solution 1 day or 7 days of being administered orally to macaque.The 1st day during being administered or the 7th day, before administration and
Blood is collected after administration, and obtains blood plasma.The cholesterol level in blood plasma is measured using commercially available assay kit.It is logical
Cross HPLC analysis lipoprotein distributions.HDL cholesterol and non-HDL cholesterol levels are calculated according to following calculation expression：HDL courages
In cholesterol level × (HDL cholesterol peak area/peak summation) non-HDL cholesterol levels=blood plasma in sterol content=blood plasma
Cholesterol level × (peak area of non-HDL cholesterol/peak summation)
Compared with before administration, after the administration of 10mg/kg single doses the increment rate (%) of HDL levels by before administration and
The AUC of 24 hours determines after administration.Result is shown in table 2 below：
Table 2：Influence of the target compound to HDL levels
The above results show that the compounds of this invention can dramatically increase HDL levels, can be used to prevent and treat cardiovascular and cerebrovascular
Disease, such as coronary heart disease and artery sclerosis.
The preferred embodiment for the present invention is the foregoing described, so it is not limited to the present invention.Those skilled in the art couple
Embodiment disclosed herein can carry out improvement and the change without departing from scope and spirit.
Claims (10)
1. compound shown in a kind of formula 1 or its pharmaceutically acceptable salt：
[formula 1]
Wherein：
W1、W2N or CR can be each independently with identical or different3；
R1、R2、R3Hydrogen, halogen, hydroxyl, cyano group, nitro, amino, carboxyl, C1-4 alkane can be each independently with identical or different
Base, C1-4 alkoxies, C3-7 cycloalkyl, halogenated c1-4 alkyl, methylol, C1-4 alkyl-carbonyls, C1-4 alkoxy carbonyls, C1-4
Alkyl amino, two (C1-4 alkyl) amino or C1-4 alkyl sulphonyls；
R represents 0,1,2 or 3；
S represents 0,1,2 or 3；
T represents 0,1,2 or 3.
2. compound according to claim 1, it is characterised in that the W1、W2All it is N.
3. compound according to claim 1, it is characterised in that the W1It is N, the W2It is CH.
4. compound according to claim 1, it is characterised in that the R1For methyl, methylol, hydroxyl, trifluoromethyl or
Ethyoxyl.
5. compound according to claim 1, it is characterised in that the R2It is hydrogen, methyl sulphonyl or nitro.
6. compound according to claim 1, it is characterised in that the R3It is hydrogen, methoxyl group, cyclopropyl, cyano group or fluorine first
Base.
7. compound according to claim 1, it is selected from：
Compound I：
Compound II：
Compound III：
Compound IV：
Compound V：
Compound VI：
Compound VII：
8. a kind of preparation method of compound shown in formula according to claim 11, the preparation method is comprised the steps of：
Step 1. reacts with compound shown in formula 4 compound shown in formula 2 and compound shown in formula 3, such as following reaction equations 1
It is shown：
[reaction equation 1]
In reaction equation 1, R1、R2, r, s as defined in formula 1, X represents halogen, preferably chlorine or bromine；
Step 2. reacts with compound shown in formula 1 compound shown in formula 4 and compound shown in formula 5, such as following reaction equations 2
It is shown：
[reaction equation 2]
In reaction equation 2, W1、W2、R1、R2、R3, r, s, t be as defined in formula 1.
9. it is a kind of to contain compound shown in formula 1 or its pharmaceutically acceptable salt conduct described in good grounds any one of claim 1-7
The pharmaceutical composition of active component.
10. according to claim any one of 1-7 compound shown in formula 1 or its pharmaceutically acceptable salt in medicine is prepared
Application, the medicine be used for treat cardiovascular and cerebrovascular disease, such as coronary heart disease, artery sclerosis.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108530433A (en) * | 2018-05-31 | 2018-09-14 | 马文军 | A kind of ester derivative and its application in preventing cardiovascular and cerebrovascular disease |
| CN108558847A (en) * | 2018-05-31 | 2018-09-21 | 马文军 | A kind of ester derivative and its application in preventing cardiovascular and cerebrovascular disease |
| CN108774242A (en) * | 2018-08-22 | 2018-11-09 | 牡丹江医学院 | A kind of drug of prevention and treatment of coronary heart disease and preparation method thereof |
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| CN104781257A (en) * | 2012-06-14 | 2015-07-15 | 第一三共株式会社 | Piperidinylpyrazolopyridine derivative |
| CN105873928A (en) * | 2013-12-13 | 2016-08-17 | 第三共株式会社 | 5-hydroxy-4-(trifluoromethyl)pyrazolopyridine derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108530433A (en) * | 2018-05-31 | 2018-09-14 | 马文军 | A kind of ester derivative and its application in preventing cardiovascular and cerebrovascular disease |
| CN108558847A (en) * | 2018-05-31 | 2018-09-21 | 马文军 | A kind of ester derivative and its application in preventing cardiovascular and cerebrovascular disease |
| CN108774242A (en) * | 2018-08-22 | 2018-11-09 | 牡丹江医学院 | A kind of drug of prevention and treatment of coronary heart disease and preparation method thereof |
| CN108774242B (en) * | 2018-08-22 | 2020-10-27 | 牡丹江医学院 | Medicine for preventing and treating coronary heart disease and preparation method thereof |
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| CN106916143B (en) | 2019-09-27 |
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