CN104151256B - Disubstituted benzenes Carbox amide and synthetic method thereof and application - Google Patents
Disubstituted benzenes Carbox amide and synthetic method thereof and application Download PDFInfo
- Publication number
- CN104151256B CN104151256B CN201410401139.7A CN201410401139A CN104151256B CN 104151256 B CN104151256 B CN 104151256B CN 201410401139 A CN201410401139 A CN 201410401139A CN 104151256 B CN104151256 B CN 104151256B
- Authority
- CN
- China
- Prior art keywords
- disubstituted benzenes
- preparation
- carbox amide
- compound
- application
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
- C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
Abstract
The invention discloses a kind of disubstituted benzenes Carbox amide and its preparation method and application, comprise the following steps: 1) by 2,4,6 three chlorotriazines or 2,4,6 trichloropyrimidines react with morpholine, obtain compound A;2) 2 replacement 5 brombenzamides or 3 replacement 5 brombenzamides are prepared as boric acid ester compound B;3) at PdCl2(dppf), under catalysis, compound A, compound B are mixed in a solvent with alkali metal salt, is stirred at reflux reaction under nitrogen protection, then steam solvent, isolated disubstituted benzenes Carbox amide.The disubstituted benzenes Carbox amide that the present invention provides, has the activity of suppression tumor cell proliferation and prepares the purposes of anti-tumor medicinal preparation.
Description
Technical field
The invention belongs to antitumor drug technical field, be specifically related to a kind of disubstituted benzenes Carbox amide and conjunction thereof
Become methods and applications.
Background technology
Tumor is one of malignant disease of serious threat human health.Over nearly 20 years, the sickness rate of China's malignant tumor and
Mortality rate constantly rises, and tumor incidence is about 2,00/,100,000 people, and annual new cases reach more than 2,200,000 people, and death is about more than 160
Ten thousand, controlling more than patient 6,000,000 people.
The treatment means of tumor remains traditional operative treatment, radiotherapy and Drug therapy at present, but at very great Cheng
It is still based on Drug therapy on degree.Therefore, new antitumor drug is researched and developed significant.
In recent years, along with oncomolecularbiology progress of research, tumor pathogenesis is had more understanding, has found
The novel targets of many antitumor drug effects, makes the development of antitumor drug obtain many new achievements, such as topoisomerase
Inhibitor, kinases inhibitor, PI3K inhibitor, mTOR inhibitors etc..
In most tumors cell, some kinases present high expressed or excessive activation.For this feature, have been developed for
The targeting such as gefitinib, imatinib, erlotinib, Conmana, Sorafenib, Sutent and Lapatinib are kinase whose anti-
Tumour medicine.But, some medicinal application finds that after clinic its effective percentage is the highest, and some acts on the medicine of single target spot
Easily produce drug resistance.Therefore, research and develop new antitumor drug or simultaneously act on the antitumor drug of multiple target spot there is weight
Want meaning.
Document ACS Med.Chem.Lett.2011,2,774 779 reports, BKM120 has well suppression kinases PI3K
Activity, zoopery proves that it has good anti-tumor activity, but, BKM120 synthetic agent is expensive, and synthetic yield is low.
Summary of the invention
It is an object of the invention to provide a kind of disubstituted benzenes Carbox amide and synthetic method thereof and application, these are two years old
Substituted benzene formyl aminated compounds has anti-tumor activity, and its synthesis material is easy to get, method simple, environmental friendliness, thus is suitable to
The preparation of application antitumor drug.
The present invention is to be achieved through the following technical solutions:
A kind of disubstituted benzenes Carbox amide, the structural formula of this compounds such as following formula:
Wherein, R is hydroxyl, methoxyl group, benzyloxy, trifluoromethoxy, trifluoromethyl or hydrogen, and R substituent is connected to phenyl ring
2-position or 3-position;X is CH or N.
The synthetic method of a kind of disubstituted benzenes Carbox amide, comprises the following steps:
1) by 2,4,6-tri-chlorotriazines or 2,4,6-trichloropyrimidines react with morpholine, obtain compound A;
2) 2-is replaced-5-brombenzamide or 3-replaces-5-brombenzamide and is prepared as boric acid ester compound B;
3) at PdCl2(dppf), under catalysis, compound A, boric acid ester compound B are mixed in a solvent with alkali metal salt
Close, be stirred at reflux reaction under nitrogen protection, then steam solvent, isolated disubstituted benzenes Carbox amide;Wherein,
The reaction mol ratio of compound A and boric acid ester compound B is (1:1)~(2:1).
Described compound A is 2,4-dimorpholine base-6-chloropyrimide or 2,4-dimorpholine base-6-chlorotriazine;Described borate
Compounds B is 2-methoxyl group-5-pinacol borate Benzoylamide, 2-benzyloxy-5-pinacol borate Benzoylamide, 3-
Methoxyl group-5-pinacol borate Benzoylamide, 3-trifluoromethyl-5-pinacol borate Benzoylamide or 3-trifluoro methoxy
Base-5-pinacol borate Benzoylamide.
Described solvent be the one in oxolane, dioxane, glycol dimethyl ether, dimethylformamide or water or
Several, and the solvent load that every mole compound A adds is 5~10L.
Described alkali metal salt is sodium carbonate, potassium carbonate, cesium carbonate or sodium acetate, and this alkali metal salt rubs with compound A's
Your ratio is (1:1)~(3:1).
The described time being stirred at reflux reaction is 2~10h.
The application in preparing antitumor drug of the disubstituted benzenes Carbox amide.
The application in preparation suppression human breast cancer cell line Bcap-37 pharmaceutical preparation of the disubstituted benzenes Carbox amide.
The application in preparation suppression human colon cancer cell HCT116 pharmaceutical preparation of the disubstituted benzenes Carbox amide.
Disubstituted benzenes Carbox amide interpolation adjuvant is made tablet, capsule, soft capsule or injection;Its
In, every or preparation in containing 10~500mg disubstituted benzenes Carbox amide;Described adjuvant is stable
One or more in agent, solubilizing agent, lubricant, disintegrating agent or correctives.
Compared with prior art, the present invention has a following useful technique effect:
Disubstituted benzenes Carbox amide disclosed by the invention is the wound made on compound BKM120 architecture basics
Newly.In the structure of BKM120, the oxygen atom of morpholine ring and the 2-amino of pyridine ring are its pharmacophore.The present invention uses Benzoylamide
Structure fragment instead of the aminopyridine fragment in BMK120, the amino in amide structure can with kinases formed hydrogen bond, thus
Obtain the compound with the novel structure of anti-tumor activity.Thus disubstituted benzenes Carbox amide disclosed by the invention with
The pharmacophore that BKM120 tool is similar, it may have suppression kinases PI3K and anti-tumor activity.
Synthesis BKM120 needs 2-amino-4-trifluoromethyl-5-bromopyridine, this expensive reagents, and the final step of synthesis
Productivity is low.And the preparation process of disubstituted benzenes Carbox amide disclosed by the invention uses heterocyclic carbamate derivatives to close
Becoming, raw material is inexpensive, be easy to get, and synthetic method the most easily realizes, and productivity is high, environmental friendliness.
The disubstituted benzenes Carbox amide that the present invention provides, has suppression tumor cell (such as human breast cancer cell
MCF-7) activity bred, wherein the activity of part of compounds is suitable with positive drug BKM120.Such as compound 3-trifluoromethyl-
The IC of the compound 2 in 5-(4,6-morpholinyls-1,3,5-triazines-2-base) Benzoylamide, i.e. table 150=0.97 μm ol/L,
The IC of BKM12050=1.02 μm ol/L.
The disubstituted benzenes Carbox amide that the present invention provides, it is possible to be used for preparing anti-tumor medicinal preparation, the most often
Containing 10-500mg in sheet or grain or this pharmaceutical preparation.Antitumor drug is prepared at the reactive compound utilizing the present invention to provide
During preparation, this medicine can be made tablet, capsule, soft capsule or injection.These pharmaceutical preparatioies can be according to various systems
The conventional fabrication process of agent is made.For tablet or capsule, preferred content is 20-150mg.And the medicine that the present invention relates to
Composition oral preparation can contain pharmaceutic adjuvant, including stabilizer, solubilizing agent, lubricant, disintegrating agent etc., such as starch, dextrin, Fructus Vitis viniferae
Sugar, lactose, cellulose, polyvinylpyrrolidone, crospolyvinylpyrrolidone, pectin, cyclodextrin, twen-80, polyethylene
Alcohol, magnesium stearate, Pulvis Talci etc..
Accompanying drawing explanation
Fig. 1 is the synthetic route schematic diagram of the disubstituted benzenes Carbox amide of the present invention.
Detailed description of the invention
The present invention provides disubstituted benzenes Carbox amide and preparation method and use thereof, with the structure sheet of Benzoylamide
Section instead of the aminopyridine fragment in BKM120 structure, thus obtains novel structure, and has the compound of anti-tumor activity.
Below such compound is further described.It should be noted that following example are for the present invention's
The illustrative and not limiting present invention.Although being described in detail the present invention by preferred embodiment, but this area is general
It is logical it will be appreciated by the skilled person that the present invention can modified without departing from the scope of the invention, deform or equivalent,
Belong to protection scope of the present invention.
One, disubstituted benzenes Carbox amide disclosed by the invention, the structural formula of this compounds is:
Wherein, R is methoxyl group, benzyloxy, trifluoromethoxy, trifluoromethyl or hydrogen, and R substituent can be connected to phenyl ring
2-position or 3-position, X is CH or N.
The synthetic method of a kind of disubstituted benzenes Carbox amide, it is characterised in that comprise the following steps:
Carry out suzuki reaction with compound A and compound B and obtain disubstituted benzenes Carbox amide, its reaction equation such as figure
Shown in 1;
2,4,6-tri-chlorotriazines or with 2,4,6-trichloropyrimidines react with morpholine, obtain compound A.2-(or 3-) is taken
In generation ,-5-brombenzamide was prepared as borate (B), and B is the most separated, directly carries out suzuki reaction obtain two replacements with compound A
Benzamide compound.
Wherein, R is methoxyl group, benzyloxy, trifluoromethoxy, trifluoromethyl or hydrogen, and R substituent can be connected to phenyl ring
2-position or 3-position.X is CH or N.
Some representative compound numbering, structure and MS data are given below, the most as shown in table 1.
Some concrete compound number of table 1., structure and MS data
Two, in table 1 synthetic example of enumerated compound is given below.
Embodiment 1
The synthesis of compound 3-(4, the 6-dimorpholine bases-1,3,5-triazines-2-base) Benzoylamide of numbered (1), including
Following steps:
1) preparation of compound A:2-chloro-4,6-dimorpholine base-1,3,5-triazine (A1)
By 2,4,6-tri-chlorotriazines (1.84g, 0.01mol) are dissolved in anhydrous propanone (10mL), and cryosel bath is cooled to-10 DEG C,
The mixed liquor of morpholine (1.74mL, 0.02mol) and triethylamine (2.02g, 0.02mol) is added drop-wise in reaction system, 0 DEG C of reaction
3h, room temperature reaction 3h.It is poured in trash ice, sucking filtration, washing, dries and obtain white solid 2.70g, productivity 94.4%.
2) preparation of 3-(4,6-dimorpholine base-1,3,5-triazine-2-base) Benzoylamide (1):
3-brombenzamide (0.15g), connection pinacol borate (0.21g), potassium acetate is added in 100mL round-bottomed flask
(0.20g), PdCl2(dppf) (0.04g) and anhydrous Isosorbide-5-Nitrae-dioxane (6mL), mixture is stirred at reflux under nitrogen protection
3h.Remove solvent under reduced pressure, the most separated, directly by chloro-for 2-4,6-dimorpholine base-1,3,5-triazines (A1) (0.18g), PdCl2
(dppf) (0.04g), sodium carbonate (0.22g), water (1mL) and glycol dimethyl ether (4mL) join in above-mentioned residue, reaction
Mixture is stirred at reflux 3h under nitrogen protection, reduces pressure and steams solvent, residue over silica gel pillar layer separation (chloroform: methanol=
30:1) obtain crude product, with ethyl alcohol recrystallization, obtain near-white solid 120mg, productivity 50.0%.
The preparation of embodiment 2 3-trifluoromethyl-5-(4,6-dimorpholine base-1,3,5-triazine-2-base) Benzoylamide (2)
Preparation method is with the synthesis of embodiment 1 compound 1.3-bromobenzene first is replaced with 3-bromo-5-trifluoromethyl benzamide
Amide;1,4-dioxane is replaced with oxolane.Productivity 54.5%.
The preparation of embodiment 3 3-hydroxyl-5-(4,6-dimorpholine base-1,3,5-triazine-2-base) Benzoylamide (3)
Preparation method is with the synthesis of embodiment 1 compound 1.3-brombenzamide is replaced with 3-hydroxyl-5-brombenzamide;
1,4-dioxane is replaced with dimethylformamide;Sodium carbonate is replaced with potassium carbonate.Productivity 64.3%.
The system of embodiment 4 3-trifluoromethoxy-5-(4,6-dimorpholine base-1,3,5-triazine-2-base) Benzoylamide (4)
Standby
Preparation method is with the synthesis of embodiment 1 compound 1.3-bromobenzene is replaced with 3-bromo-5-trifluoromethoxy Benzoylamide
Methanamide, productivity 59.8%.
The preparation of embodiment 5 2-benzyloxy-5-(4,6-dimorpholine base-1,3,5-triazine-2-base) Benzoylamide (5)
Preparation method is with the synthesis of embodiment 1 compound 1.3-Bromophenacyl is replaced with 2-benzyloxy-5-brombenzamide
Amine;Glycol dimethyl ether is replaced with dimethylformamide;Productivity 68.1%.
The preparation of embodiment 6 2-methoxyl group-5-(4,6-dimorpholine base-1,3,5-triazine-2-base) Benzoylamide (6)
Preparation method is with the synthesis of embodiment 1 compound 1.3-Bromophenacyl is replaced with 2-methoxyl group-5-brombenzamide
Amine;Add 2 times that mole is 2-methoxyl group-5-brombenzamide of compound A1.Final step reacting reflux time is by 3h
It is extended for 10h.Productivity 73.6%.
The preparation of embodiment 7 3-methoxyl group-5-(4,6-dimorpholine base-1,3,5-triazine-2-base) Benzoylamide (6)
Preparation method is with the synthesis of embodiment 1 compound 1.3-Bromophenacyl is replaced with 3-methoxyl group-5-brombenzamide
Amine;Potassium carbonate is replaced with cesium carbonate;The consumption of glycol dimethyl ether is increased to 10mL by 4mL.Final step reacting reflux time
It is extended for 6h productivity 70.6% by 3h.
The preparation of embodiment 8 3-trifluoromethyl-5-(2,4-dimorpholine base-6-pyrimidine radicals) Benzoylamide (8)
The preparation of compound A:4-chloro-2,6-dimorpholine yl pyrimidines (A2)
Preparation method is with the synthesis of compound A1 in embodiment 1.With 2,4,6-trichloropyrimidines replace 2,4,6-tri-chlorotriazines,
Productivity 92.3%.
The preparation of 3-trifluoromethyl-5-(2,4-dimorpholine base-6-pyrimidine radicals) Benzoylamide (8)
Preparation method is with the synthesis of embodiment 1 compound 1.A1 is replaced with A2;With 3-bromo-5-trifluoromethyl benzamide generation
For 3-brombenzamide;Final step reacting reflux time is shortened to 2h by 3h.Productivity 53.6%.
The preparation of embodiment 9 3-methoxyl group-5-(2,4-dimorpholine base-6-pyrimidine radicals) Benzoylamide (9)
Preparation method is with the synthesis of compound 8 in embodiment 8.The bromo-5-of 3-tri-is replaced with 3-methoxyl group-5-brombenzamide
Methyl fluoride Benzoylamide;The amount of sodium carbonate is increased to 0.70g by 0.22g.Productivity 71.4%.
The preparation of embodiment 10 3-trifluoromethoxy-5-(2,4-dimorpholine base-6-pyrimidine radicals) Benzoylamide (10)
Preparation method is with the synthesis of compound 8 in embodiment 8.3-tri-is replaced with 3-trifluoromethoxy-5-brombenzamide
Fluorine methoxyl group-5-brombenzamide, response time 5h.Productivity 66.1%.
The preparation of embodiment 11 2-benzyloxy-5-(2,4-dimorpholine base-6-pyrimidine radicals) Benzoylamide (11)
Preparation method is with the synthesis of compound 8 in embodiment 8.3-fluoroform is replaced with 2-benzyloxy-5-brombenzamide
Epoxide-5-brombenzamide;Productivity 54.8%.
The preparation of embodiment 12 2-(4-fluorobenzyloxy)-5-(2,4-dimorpholine base-6-pyrimidine radicals) Benzoylamide (12)
Preparation method is with the synthesis of compound 8 in embodiment 8.Replace with 2-(4-fluorobenzyloxy)-5-brombenzamide
3-trifluoromethoxy-5-brombenzamide.Productivity 38.7%.
The checking of anti-tumor activity:
In order to verify the anti-tumor activity of the disubstituted benzenes Carbox amide of benzene invention synthesis, with BKM120 it is specifically
Positive control medicine, uses external mtt assay to determine compound 1-12 to human breast cancer cell line Bcap-37 and human colon cancer cell
The growth inhibited effect of HCT116.
Verification method: tumor cell U87 is cultivated in the RPMI1640 culture medium containing 10% calf serum, includes penicillium sp
Have 100U mL-1, streptomycin 100 μ g mL-1, in 37 DEG C, 5%CO2Secondary Culture in incubator.Take 0.3% trypsinization
Adherent tumor cell, the RPMI1640 culture fluid preparation cell suspension containing 10% calf serum, concentration is 6 × 103Individual cell/
Milliliter.In 96 well culture plates, 200 μ L (containing about 1000 tumor cells) are inoculated in every hole, cultivate 24h for 37 DEG C.Administration group adds not
Same acute drug, every medicine sets 10-4、10-5、10-6、10-7、10-8mol·L-15 concentration, often group sets 5 parallel holes.Matched group
Add and the isopyknic solvent of medicine, be placed in 37 DEG C, 5%CO2Discarding culture fluid after cultivating 48h in incubator, every hole adds 20 μ l
5mg·mL-1MTT solution, after hatching 4h, abandoning supernatant, every hole adds DMSO 150 μ L, exists by microplate reader after gentle agitation
Optical density value (OD) is measured under 570nm.
Result calculates:
With solvent control process tumor cell as matched group, seek the suppression ratio of drug on tumor cell according to the following formula.
And use improvement karber's method to obtain half-inhibition concentration (IC further50)。
IC50Testing result as shown in table 2:
The table 2. compound 1-12 inhibitory activity (μm ol/L, n=3) to two kinds of human tumor cells
From the data of table 2 display it can be seen that most compounds has significantly suppression to the growth of two kinds of tumor cells
Effect, the IC50 value of some of which compound is suitable with positive drug BKM120, especially compound 2,3,4,8,10 couples of MCF-7's
Inhibitory activity is suitable with positive drug.
Thus, the disubstituted benzenes Carbox amide of the present invention coordinates with pharmaceutic adjuvant, it is possible to prepare for resisting
The pharmaceutical preparation of tumor, and described pharmaceutic adjuvant, including stabilizer, solubilizing agent, lubricant, disintegrating agent etc., such as starch, paste
Essence, glucose, lactose, cellulose, polyvinylpyrrolidone, crospolyvinylpyrrolidone, pectin, cyclodextrin, twen-80,
Polyvinyl alcohol, magnesium stearate, Pulvis Talci etc..
Claims (5)
1. one kind 3,5-disubstituted benzenes Carbox amide, it is characterised in that the structural formula of this compounds such as following formula:
Wherein, R is hydroxyl, methoxyl group, trifluoromethoxy, trifluoromethyl;X is CH or N.
2. the application in preparing antitumor drug of the 3,5-disubstituted benzenes Carbox amide described in claim 1.
Applying the most as claimed in claim 2, it is characterised in that described 3,5-disubstituted benzenes Carbox amide is in preparation
Application in the pharmaceutical preparation of suppression human breast cancer cell line Bcap-37.
Applying the most as claimed in claim 2, it is characterised in that described 3,5-disubstituted benzenes Carbox amide is in preparation
Application in the pharmaceutical preparation of suppression human colon cancer cell HCT116.
Applying the most as claimed in claim 2, it is characterised in that by 3,5-disubstituted benzenes Carbox amide adds adjuvant system
Piece agent, capsule or injection;Wherein, every or preparation in containing 10~500mg disubstituted benzenes benzamide type
Compound;
Described adjuvant is one or more in stabilizer, solubilizing agent, lubricant, disintegrating agent or correctives.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410401139.7A CN104151256B (en) | 2014-08-14 | 2014-08-14 | Disubstituted benzenes Carbox amide and synthetic method thereof and application |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410401139.7A CN104151256B (en) | 2014-08-14 | 2014-08-14 | Disubstituted benzenes Carbox amide and synthetic method thereof and application |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104151256A CN104151256A (en) | 2014-11-19 |
CN104151256B true CN104151256B (en) | 2016-08-24 |
Family
ID=51876917
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410401139.7A Expired - Fee Related CN104151256B (en) | 2014-08-14 | 2014-08-14 | Disubstituted benzenes Carbox amide and synthetic method thereof and application |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104151256B (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1735607A (en) * | 2002-11-21 | 2006-02-15 | 希龙公司 | 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in the treatment of cancer |
CN101014590A (en) * | 2004-07-09 | 2007-08-08 | 阿斯利康(瑞典)有限公司 | 2, 4, 6-trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in the treatment of cancer |
CN101389622A (en) * | 2006-01-20 | 2009-03-18 | 诺瓦提斯公司 | Pyrimidine derivatives used as pi-3 kinase inhibitors |
CN102209714A (en) * | 2008-11-10 | 2011-10-05 | 巴塞尔大学 | Triazine, pyrimidine and pyridine analogs and their use as therapeutic agents and diagnostic probes |
WO2012101654A2 (en) * | 2011-01-25 | 2012-08-02 | Sphaera Pharma Pvt. Ltd | Novel triazine compounds |
-
2014
- 2014-08-14 CN CN201410401139.7A patent/CN104151256B/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1735607A (en) * | 2002-11-21 | 2006-02-15 | 希龙公司 | 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in the treatment of cancer |
CN101014590A (en) * | 2004-07-09 | 2007-08-08 | 阿斯利康(瑞典)有限公司 | 2, 4, 6-trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in the treatment of cancer |
CN101389622A (en) * | 2006-01-20 | 2009-03-18 | 诺瓦提斯公司 | Pyrimidine derivatives used as pi-3 kinase inhibitors |
CN102209714A (en) * | 2008-11-10 | 2011-10-05 | 巴塞尔大学 | Triazine, pyrimidine and pyridine analogs and their use as therapeutic agents and diagnostic probes |
WO2012101654A2 (en) * | 2011-01-25 | 2012-08-02 | Sphaera Pharma Pvt. Ltd | Novel triazine compounds |
Non-Patent Citations (2)
Title |
---|
Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer;Matthew T. Burger,等;《ACS Med. Chem. Lett.》;20110826;第2卷;第774-779页 * |
PI3K/mTOR双重抑制剂的研究进展;宣伟,等;《现代药物与临床》;20120331;第27卷(第2期);第133-137页 * |
Also Published As
Publication number | Publication date |
---|---|
CN104151256A (en) | 2014-11-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Azizmohammadi et al. | 2H-chromene derivatives bearing thiazolidine-2, 4-dione, rhodanine or hydantoin moieties as potential anticancer agents | |
CN106883213B (en) | Dual inhibitor of EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) | |
Certal et al. | Discovery and optimization of new benzimidazole-and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers | |
JP6954567B2 (en) | 2-Substituted Aromatic Ring-Pyrimidine Derivatives and Their Preparation and Medical Use | |
CN103054869A (en) | Application of amino dithio formic ester compound with triazolyl in preparing medicine taking LSD1 (Lysine Specificity Demethylase 1) as target | |
Zhang et al. | Design, synthesis and biological evaluation of sulfamoylphenyl-quinazoline derivatives as potential EGFR/CAIX dual inhibitors | |
JP2015518864A (en) | N-aryl unsaturated condensed ring tertiary amine compound, preparation method thereof and antitumor use | |
CN104010501A (en) | Agpnistis of SRC homology-2 containing protein tyrosine phosphatase-1 and treatment methods using the same | |
CN104402831B (en) | -5-cyanopyrimidine derivative containing uride construction unit and its production and use | |
Wang et al. | Synthesis and antitumor activity of 5-(5-halogenated-2-oxo-1H-pyrrolo [2, 3-b] pyridin-(3Z)-ylidenemethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamides | |
CN105017159A (en) | 5-fluorine-2,4-bis-substituted aminopyrimidine derivative and preparation method and application thereof | |
CN104151256B (en) | Disubstituted benzenes Carbox amide and synthetic method thereof and application | |
CN102924450A (en) | 6-(5-pyridyl)-1,2,4-triazolopyridine compound, and preparation method and application thereof | |
CN101691353A (en) | N-Boc-3,5-(E)-diarylidene-4-piperidone and application thereof in preparation of anti-tumor drugs | |
CN109456279A (en) | Thiazoleamino benzamide acetic ester derivative and application thereof | |
JP6518833B2 (en) | Prinyl-N-hydroxy pyrimidine formamide derivatives, and methods for their preparation and use | |
CN103044460B (en) | 3,5,7-triphenyl-5H-thiazolo[3,2-a]pyrimidin derivatives and application thereof | |
CN102746241B (en) | 2, 3, 5-trisubstituted benzamide compound, and preparation method and application thereof | |
CN103214422A (en) | Preparation methods and anti-cancer effect of novel substituted amido imidazolone derivatives | |
CN109336828B (en) | Quinazoline derivative and preparation method and application thereof | |
CN103183627B (en) | 1,2-diaryl-5-replaces-1H-azoles and preparation method thereof and application | |
JP2018027897A (en) | 2-oxo-2h-chromene-3-carboxylic acid amid derivative | |
CN106083828A (en) | Arylamine pyrimidine derivatives containing ethylene imine ring side chain and preparation and application | |
CN105001167A (en) | 1-substituted phenyl-3-(4-substituted phenyl amino-6-quinazolinyl)urea compounds and preparation method and application thereof | |
CN104341407A (en) | Quinazoline compounds, preparation method and applications thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160824 Termination date: 20190814 |
|
CF01 | Termination of patent right due to non-payment of annual fee |