CN106916143B - It is a kind of prevent and treat coronary heart disease drug and its application - Google Patents
It is a kind of prevent and treat coronary heart disease drug and its application Download PDFInfo
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- CN106916143B CN106916143B CN201710151840.1A CN201710151840A CN106916143B CN 106916143 B CN106916143 B CN 106916143B CN 201710151840 A CN201710151840 A CN 201710151840A CN 106916143 B CN106916143 B CN 106916143B
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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 effect.This kind of compound includes compound shown in Formulas I or its pharmaceutically acceptable salt:
Description
Technical field
The present invention relates to a kind of with excellent lecithin-cholesterol acetyltransferase (i.e. LCAT) activation effect, excellent
Select the indolinone derivative or its pharmaceutically acceptable salt of reversible LCAT activation effect, the compound can be used for preventing and
Treat cardiovascular and cerebrovascular disease, such as coronary heart disease, artery sclerosis etc..
Background technique
The cardiovascular and cerebrovascular disease as caused by hypertension, dyslipidemia, diabetes etc. is the significant problem faced at present.Anti- height
Blood pressure, anti-lipid obstacle and antidiabetic for treating hypertension, dyslipidemia and hyperglycemia disease, such as diuresis respectively
Agent, calcium antagonist, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe and A-II antagonist etc. can be used as antihypertensive, HMG-CoA reductase inhibitor, niacin
Derivative and clofibrate class etc. can be used as anti-lipid obstacle medicine, insulin, sulfonylurea, melbine, glitazone and wait can
As antidiabetic, these medicines help to adjust blood pressure or lipid or glucose level in blood.But themselves is not
Effect well can be generated to certain cardiovascular and cerebrovascular diseases such as coronary heart disease.Therefore, it is necessary to develop for the better of these diseases
Therapeutic agent.
The direct risk factors of cardiovascular disease are atherosclerosis related with artery wall thickening.The low-density of oxidation
Accumulation in the macrophage of lipoprotein (i.e. LDL) cholesterol in arterial wall etc. causes patch to be formed, and causes this thicken
(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 inhibits blood flow and promotes thrombus
It is formed.
Many epidemiological studies the result shows that, the serum-concentration of lipoprotein and such as dyslipidemia and artery sclerosis
Disease it is related (Badimon, J.Clin.Invest., 1990, Vol.85, p.1234-1241).Increased LDL gallbladder 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 on HDL by LCAT, to generate 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 increasing the active drug of LCAT 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 active drug of increase LCAT with realize to cardiovascular and cerebrovascular disease such as coronary heart disease,
The prevention and treatment of artery sclerosis.
Summary of the invention
There is excellent LCAT activation effect it is an object of the present invention to provide one kind and directly facilitate cholesterol from huge
The compound or its pharmaceutically acceptable salt of phagocyte outflow.
It is a further object to provide a kind of methods for preparing the compound.
It is also another object of the present invention to provide one kind include at least one compound or its is pharmaceutically acceptable
Pharmaceutical composition of the salt as active constituent.
A further object of the present invention is to provide the compound or its pharmaceutically acceptable salt in medicine preparation
Using.
In order to achieve the goal above, the present invention provides shown in a kind of formula 1, the compound with LCAT activation effect or
Its pharmaceutically acceptable salt:
[formula 1]
Wherein:
W1、W2Can be identical or different, it is each independently N or CR3；
R1、R2、R3Can be identical or different, be each independently hydrogen, halogen, hydroxyl, cyano, nitro, amino, carboxyl,
C1-4 alkyl, C1-4 alkoxy, C3-7 naphthenic base, halogenated c1-4 alkyl, methylol, C1-4 alkyl-carbonyl, C1-4 alkoxy carbonyl
Base, C1-4 alkyl amino, two (C1-4 alkyl) amino or C1-4 alkyl sulphonyl；
R indicates 0,1,2 or 3；
S indicates 0,1,2 or 3；
T indicates 0,1,2 or 3.
The present invention also provides a kind of preparation method of compound shown in formula 1, which is comprised the steps of:
Step 1. reacts compound shown in formula 2 with compound shown in formula 3 with compound shown in preparation formula 4, such as following anti-
It answers shown in formula 1:
[reaction equation 1]
In reaction equation 1, R1、R2, r, s as defined in formula 1, X indicates halogen, preferably chlorine or bromine.
Step 2. reacts compound shown in formula 4 with compound shown in formula 5 with compound shown in preparation formula 1, such as following anti-
It answers 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
The compound of the present invention can effectively serve as a kind of therapeutic agent, can activate LCAT, and can also be significant
It is horizontal to increase HDL, can be consequently used for treatment cardiovascular and cerebrovascular disease, such as coronary heart disease, artery sclerosis etc..
Specific embodiment
It hereafter will be described in detail the present invention.
Unless otherwise defined, all technical and scientific terms used in this application have and fields technology people of the present invention
Member is generally understood identical meaning.All patents and publications that the application refers to is incorporated herein by reference.
The present invention provides shown in a kind of formula 1, the compound with LCAT activation effect or its be pharmaceutically subjected to
Salt:
[formula 1]
Wherein:
W1、W2Can be identical or different, it is each independently N or CR3；
R1、R2、R3Can be identical or different, be each independently hydrogen, halogen, hydroxyl, cyano, nitro, amino, carboxyl,
C1-4 alkyl, C1-4 alkoxy, C3-7 naphthenic base, halogenated c1-4 alkyl, methylol, C1-4 alkyl-carbonyl, C1-4 alkoxy carbonyl
Base, C1-4 alkyl amino, two (C1-4 alkyl) amino or C1-4 alkyl sulphonyl；
R indicates 0,1,2 or 3；
S indicates 0,1,2 or 3；
T indicates 0,1,2 or 3.
In some embodiments of the compounds of this invention, W1、W2It is all N.
In some embodiments of the compounds of this invention, W1For N, W2For CH.
In some embodiments of the compounds of this invention, R1For methyl, methylol, hydroxyl, trifluoromethyl or ethyoxyl.
In some embodiments of the compounds of this invention, R2For hydrogen, methyl sulphonyl or nitro.
In some embodiments of the compounds of this invention, R3For hydrogen, methoxyl group, cyclopropyl, cyano 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 branch and straight chained alkyl or cyclic hydrocarbon group or they
Combination.Alkyl is fully saturated and may include two-and multivalence group, has the carbon atom specified number (that is, C1-C4
Referring to has 1,2,3 or 4 carbon).Common alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl
Base, tert-butyl etc..
Term " halogen " or refer to fluorine, chlorine, bromine or iodine.
Term " naphthenic base ", which refers to, can have 3 to 10 carbon, such as the cyclic aliphatic ring structure of 3 to 7 carbon, such as
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
Select the acid-addition salts formed by pharmaceutically acceptable free acid.Herein, the pharmaceutically acceptable salt indicates any such as formula 1
The organic or inorganic addition salts of compound represented to patient's relative nontoxic, and have harmless activity, and 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, succinic acid, tartaric acid, galacturonic acid, pa not acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) apple
Acid, methanesulfonic acid, ethanesulfonic acid, 4- toluenesulfonic acid, salicylic acid, citric acid, benzoic acid and malonic acid.Salt as described herein includes alkali
Metal salt (sodium salt, sylvite etc.) and alkali salt (calcium salt, magnesium salts etc.).For example, the example of acid-addition salts are as follows: acetate, day
Aspartic acid 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, ethanol amine, 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
Close any possible salt, isomer, hydrate and the solvate constructed in object.
Acid-addition salts of the present invention can be prepared by conventional method well known in the art.For example, 1 chemical combination of formula
Object is dissolved in water-miscible organic solvent such as acetone, methanol, ethyl alcohol or acetonitrile, and excessive organic acid or inorganic is added thereto
The acidic aqueous solution of acid is to induce precipitating or crystallization.Then, solvent or excessive acid are evaporated from mixture and is removed, then led to
It crosses drying composite or filters the salt of Precipitation to obtain addition salts.
Some compounds shown in formula 1 contain chiral centre or geometric isomer center (E and Z isomer).It should
Understand, the present invention includes all optical isomer, diastereomer and geometric isomers with LCAT activation effect.
The present invention also provides a kind of preparation method of compound shown in formula 1, which is comprised the steps of:
Step 1. reacts compound shown in formula 2 with compound shown in formula 3 with compound shown in preparation formula 4, such as following anti-
It answers shown in formula 1:
[reaction equation 1]
In reaction equation 1, R1、R2, r, s as defined in formula 1, X indicates halogen, preferably chlorine or bromine；
The reaction carries out in the presence of base, and the alkali includes inorganic base, such as sodium hydroxide, potassium hydroxide, carbonic acid
Sodium, potassium carbonate, sodium bicarbonate or saleratus；And organic base, such as triethylamine, pyridine or piperidines.
Step 2. reacts compound shown in formula 4 with compound shown in formula 5 with compound shown in preparation formula 1, such as following anti-
It answers 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 carries out in the presence of alkali and palladium catalyst, the alkali include sodium carbonate, potassium carbonate, sodium bicarbonate or
Saleratus；The palladium catalyst includes tetrakis triphenylphosphine palladium or palladium acetate.
In addition, described pharmaceutical composition includes chemical combination shown at least one formula 1 the present invention provides a kind of pharmaceutical composition
Object or its pharmaceutically acceptable salt are as active constituent.
Compound shown in formula 1 is proven to have excellent LCAT activation effect, specifically, the compound activation LCAT's
EC50For 0.1nM-10000nM, preferably 0.5nM-1000nM, more preferable 1nM-100nM can be specifically 2nM-50nM.Formula 1
Shown compound can also dramatically increase HDL level, specifically, increment rate 300%-1500%, preferably 400%-1000%,
More preferable 500%-900%.The compound as shown in formula 1 has excellent LCAT activation effect and increases HDL level
Effect, therefore can be used as coronary heart disease, artery sclerosis, arteriography, cranial vascular disease, peripheral vascular disease,
Dyslipidemia, low HDL cholesterolemia, high LDL cholesterol mass formed by blood stasis therapeutic agent.
Contain the pharmaceutical composition of the invention of compound shown in formula 1 or its pharmaceutically acceptable salt as active constituent
Object, can be administered orally or Parenteral administration, and with the use of 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, suspension, emulsion, sugar
Starch agent, granule etc..These preparations may include diluent (for example, lactose, dextrose, sucrose, sweet dew in addition to the active ingredient (s
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 may include binder such as aluminium-magnesium silicate, gelatinized corn starch, gelatin, methylcellulose, carboxylic first
Base sodium cellulosate and/or polyvinylpyrrolidone, if it is necessary, also may include disintegrating agent such as starch, agarose, alginic acid or
Its sodium salt or azeotropic mixture and/or adsorbent, colorant, flavoring agent and sweetener can also be included therein.
The effective dose of the compounds of this invention can be according to age, weight, gender, medication, health status and illness
Severity determines.For example, the dosage of the adult of an individual weight 70kg is 0.1-1,000mg/ days, preferably 1-500mg/
It.Such administration can execute once a day to multiple according to the decision of doctor or pharmacists.
Practical and presently preferred embodiment of the invention 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- benzo [d] imidazoles -7- base) methylene) -5- methyl -6- (pyridine -2- base) indoles
Quinoline -2- ketone (compound I)
Step 1: 1H- benzo [d] imidazoles -7- formaldehyde (2.19g, 15.0mmol) being placed in 500ml eggplant-shape bottle, is added
After the dissolution of 150ml dehydrated alcohol, the chloro- 5- methyl indol quinoline -2- ketone of 6- and 2ml triethylamine are added, reacts 3h at room temperature, occurred
A large amount of precipitatings.It filters, a small amount of dehydrated alcohol washing, dry, obtaining yellow solid (Z) -3-, ((1H- benzo [d] imidazoles -7- base) is sub-
Methyl) the chloro- 5- methyl indol quinoline -2- ketone 4.15g of -6-, yield 89.2%, content 98.1%.ESI-MS:310.07 [M+H]+。
Step 2: (Z) -3- ((1H- benzo [d] imidazoles -7- base) methylene)-is added into dry Schlenk reaction tube
The chloro- 5- methyl indol quinoline -2- ketone (3.09g, 10.0mmol) of 6-, pyridine -2- ylboronic acid dimethyl ester (1.66g, 11.0mmol), four
(triphenylphosphine) palladium (0.12g, 0.1mmol), Na2CO3Isosorbide-5-Nitrae-dioxy six is added under nitrogen protection in (2.12g, 20.0mmol)
Ring (50mL), water (5mL), 55 DEG C of reaction 5h.After reaction, solvent is removed under reduced pressure, residue is used after being dissolved with ethyl acetate
Silica gel column chromatography separation, 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]+
Elemental 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- base) methylene
Base) -6- (pyrimidine -2-base) indole-2-ketone (compound II)
According to the method for embodiment 1, it is replaced with 1- (5- (methyl sulphonyl) -1H- benzo [d] imidazoles -7- base)-formaldehyde
1H- benzo [d] imidazoles -7- formaldehyde replaces the chloro- 5- methyl indol quinoline -2- ketone of 6- with 6- bromo- 5- (methylol) indole-2-ketone,
Pyridine -2- ylboronic acid dimethyl ester is replaced with pyrimidine -2-base trimethyl borate, obtains the title compound of white solid, two steps are total
Yield 63.9%.
ESI-MS:448.47 [M+H]+
Elemental 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
Part (the 1.125 < specific gravity being made of HDL3 are obtained from the blood plasma of the people of health by density gradient centrifugation separation
< 1.210/mL).By the part of acquisition to phosphate-buffered saline (pH 7.4) dialysis and as LCAT enzyme source and by
Body.Each testing drug is prepared by being dissolved in dimethyl sulfoxide.DTNB (Ellman reagent, ultimate density: 0.5mM), mercapto will be contained
Base ethyl alcohol (ultimate density: 12.5mM) and 0.6% bovine serum albumin(BSA) [14C] cholesterol is added to containing 1mg/mL HDL3's
Phosphate-buffered saline (pH 7.4), and it is added to it the testing drug of various concentration further total amount is adjusted to 80 μ L.
The mixture is cultivated at 37 DEG C about 16 hours.Then, be added to it hexane and isopropanol mixed solution (mixing ratio=3: 2) with
Stop reaction.After stirring, hexane layer is collected, and evaporates the layer to dry.It is added to it 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) being unfolded.Using imaging analysis instrument BAS-2500, measurement corresponds to the radioactivity of the part of cholesterol acid ester.Similarly
Processing 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 is living
Property, calculate the EC of LCAT activation50Value.As the result is shown in the following table 1.
[equation 1]
The bottom Y=+(Top-Bottom)/(1+10LogEC50-X)
Wherein X represents the logarithm of the concentration of testing drug；
Y represents the responsiveness (i.e. LCAT activity) of testing drug；
Top represents maximum value；
Bottom represents minimum value；With
EC50Represent 50% effective concentration.
The LCAT agonist activity of 1 target compound of table
| Test compound | EC50(nm) |
| 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 effect, can be used for preventing and treating heart and brain
Vascular diseases, such as coronary heart disease and artery sclerosis.
Testing example 2: the efficacy testing in macaque
Each testing drug is dissolved in 80 mixed solution of propylene glycol-Tween [4/1 (v/v)] or 0.5% (w/v) Methyl cellulose
Plain aqueous solution, and the solution is administered orally 1 day to macaque or 7 days.The 1st day during administration or the 7th day, before administration and
Blood is collected after administration, and obtains blood plasma.Use the cholesterol level in commercially available assay kit measurement blood plasma.It is logical
Cross HPLC analysis lipoprotein distribution.HDL cholesterol and non-HDL cholesterol level: HDL gallbladder are calculated according to following calculation expression
In cholesterol level × (HDL cholesterol peak area/peak summation) non-HDL cholesterol level=blood plasma in sterol content=blood plasma
Cholesterol level × (peak area of non-HDL cholesterol/peak summation)
With administration before compared with, 10mg/kg single dose administration after HDL level increment rate (%) by before being administered with
24 hours AUC are determined after administration.As a result it is shown in following table 2:
Table 2: influence of the target compound to HDL level
The above results show that the compounds of this invention can dramatically increase HDL level, can be used for preventing and treating cardiovascular and cerebrovascular
Disease, such as coronary heart disease and artery sclerosis.
The foregoing describe the preferred embodiment for the present invention, and however, it is not to limit the invention.Those skilled in the art couple
Embodiment disclosed herein can carry out the improvements and changes without departing from scope and spirit.
Claims (4)
1. a kind of compound, is selected from:
Compound I:
Compound II:
Or its pharmaceutically acceptable salt.
2. a kind of pharmaceutical composition containing compound according to claim 1 or its pharmaceutically acceptable salt.
3. the application of compound or its pharmaceutically acceptable salt in medicine preparation according to claim 1, the drug
For treating cardiovascular and cerebrovascular disease.
4. application according to claim 3, which is characterized in that the drug is for treating coronary heart disease, artery sclerosis.
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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 |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| CN101970426A (en) * | 2007-12-21 | 2011-02-09 | 大学健康网络 | Indazolyl, benzimidazolyl, benzotriazolyl substituted indolmone derivatives as kinase inhibitors useful in the treatment of cancer |
| 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 |
-
2017
- 2017-03-14 CN CN201710151840.1A patent/CN106916143B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| CN101970426A (en) * | 2007-12-21 | 2011-02-09 | 大学健康网络 | Indazolyl, benzimidazolyl, benzotriazolyl substituted indolmone derivatives as kinase inhibitors useful in the treatment of cancer |
| 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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