CN103772317A - 2-methoxyl-3-substituted sulfonamido-5-(2-acetamido-6-benzothiazolyl) benzamide compound, preparation method and application thereof - Google Patents
2-methoxyl-3-substituted sulfonamido-5-(2-acetamido-6-benzothiazolyl) benzamide compound, preparation method and application thereof Download PDFInfo
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- CN103772317A CN103772317A CN201410003840.3A CN201410003840A CN103772317A CN 103772317 A CN103772317 A CN 103772317A CN 201410003840 A CN201410003840 A CN 201410003840A CN 103772317 A CN103772317 A CN 103772317A
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- sulfonamido
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- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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Abstract
The invention discloses a 2-methoxyl-3-substituted sulfonamido-5-(2-acetamido-6-benzothiazolyl) benzamide compound, a preparation method and application thereof. The compound is characterized in that the structural formula of the compound is shown in a formula in the specification, wherein R is alkyl or aryl. The compound has remarkable in-vitro and in-vivo anti-tumor activities and is applicable to preparation of anti-tumor medicinal preparations.
Description
Technical field
The invention belongs to antitumor drug technical field, relate to 2-methoxyl group-3-and replace sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound and preparation method thereof and purposes.
Background technology
Malignant tumour serious threat human health.Over nearly 20 years, the M & M of China's malignant tumour constantly rises, and the sickness rate of some tumour is up to 2,00/,100,000 people, and annual new cases reach 3,500,000, and death exceedes 2,000,000, more than controlling patient 6,000,000 people.
The treatment means of tumour remains traditional operative treatment, radiotherapy and pharmacological agent at present, but is still to a great extent take pharmacological agent as main.In recent years, along with the progress of molecular biology, RESEARCH ON CELL-BIOLOGY, tumorigenic Biological Mechanism has been had to more deep understanding, find the novel targets of many antitumor drug effects, make the exploitation of antitumor drug obtain many new achievements, as topoisomerase enzyme inhibitor, kinases inhibitor, PI3K inhibitor, mTOR inhibitors etc.
In most tumors cell, some kinases present high expression level or excessive activation.For this feature, the kinase whose antitumor drugs of target such as Gefitinib, imatinib, erlotinib, Conmana, Xarelto, Sutent and lapatinibditosylate are developed.But in clinical rear discovery, it is not efficient high in some medicinal application, some medicine that acts on single target spot easily produces resistance.Therefore, research and develop new antitumor drug or act on the antitumor drug of multiple target spots simultaneously significant.
Document J.Med.Chem.2011,54,1789 – 1811 report the chloro-3-(4-fluorophenyl of compound 2-acetylaminohydroxyphenylarsonic acid 6-[2-sulfonamido)-5-pyridyl] benzothiazole has the activity of good inhibition kinases PI3K and mTOR, experimentation on animals proves to have obvious antitumor action, but, such toxicity of compound is larger, and 3mg/kg can cause that Mouse Weight obviously declines.
Summary of the invention
The object of the invention is to provide a kind of 2-methoxyl group-3-and replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound and preparation method thereof and purposes, the present invention has replaced document J.Med.Chem.2011 by the fragment of benzoyl, 54, the chloro-3-(4-fluorophenyl of the 2-acetylaminohydroxyphenylarsonic acid 6-[2-sulfonamido of report in 1789 – 1811)-5-pyridyl] pyridine fragment in benzothiazole, obtained 2-methoxyl group-3-and replaced sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound.This compounds has obvious anti-tumor activity, and toxicity reduces greatly, and its synthesis material is easy to get, synthetic method easily realizes, and can be applicable to the preparation of antitumor drug.
The present invention is achieved through the following technical solutions:
2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound, it is characterized in that, the structural formula of this compounds is:
In formula, R is alkyl or aryl.
Described alkyl is cyclopropyl, cyclohexyl, propyl group.
Described aryl is 4-fluorophenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-, 2,4 difluorobenzene base.
A kind of 2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) preparation method of benzamide compound, it is characterized in that, comprise the following steps:
Midbody compound A and midbody compound B carry out suzuki reaction and obtain 2-methoxyl group-3-replacement sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound (I), its reaction formula is as follows:
In formula, in compd A, R is cyclopropyl, cyclohexyl, propyl group, 4-fluorophenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-, 2,4 difluorobenzene base.
Adopt suzuki reaction, at PdCl
2(dppf) under catalysis, compd A, compd B are mixed in solvent with an alkali metal salt, stirring and refluxing 1～5h under nitrogen protection, steam solvent, from reaction mixture, separate and obtain 2-methoxyl group-3-replacement sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound;
Described compd A is 2-methoxyl group-3-sulfonyl propyl amino-5-brombenzamide, 2-methoxyl group-3-cyclopropyl sulfonamido-5-brombenzamide, 2-methoxyl group-3-cyclohexyl sulfonamido-5-brombenzamide, 2-methoxyl group-3-(4-fluorophenyl sulfonamido)-5-brombenzamide, 2-methoxyl group-3-(4-aminomethyl phenyl sulfonamido)-5-brombenzamide, 2-methoxyl group-3-(4-chloro-phenyl-sulfonamido)-5-brombenzamide, 2-methoxyl group-3-(2,4-difluorophenyl sulfonamido)-5-brombenzamide;
Described compd B is 2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl pinacol borate;
Described solvent is one or more in tetrahydrofuran (THF), dioxane, glycol dimethyl ether, dimethyl formamide, water.
Described an alkali metal salt is sodium carbonate, salt of wormwood, cesium carbonate or sodium-acetate, and the mol ratio of itself and compd A is 1:1～5:1;
Described compd A and the mol ratio of compd B are 1:1; The compd A of 1 mole joins in the solvent of 5～10L and reacts; Catalyst P dCl
2(dppf) be the 5%-20% of compd A molar weight.
Described 2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound is in the application of preparing in antitumor drug.
2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamides adds auxiliary material and makes tablet, capsule or injection, wherein every or a preparation in contain 10～500mg 2-methoxyl group-3-replace sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound.
Described auxiliary material comprises one or more in additive, stablizer, solubilizing agent, lubricant, disintegrating agent.
Compared with prior art, the present invention has following useful technique effect:
1. novel structure.2-methoxyl group provided by the invention-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound has no bibliographical information.The present invention has replaced the structure fragment of pyridine ring with the structure fragment of benzamide, can obtain new antineoplastic compound.This compounds and J.Med.Chem.2011, the chloro-3-(4-fluorophenyl of the compound 2-acetylaminohydroxyphenylarsonic acid 6-[2-sulfonamido that 54,1789 – 1811 report)-5-pyridyl] benzothiazole has similar pharmacophore, also has anti-tumor activity.
2. there is obvious anti-tumor activity.Antitumor test in external, body all proves, compound provided by the invention has obvious anti-tumor activity.As compound 2-methoxyl group-3-(4-fluorobenzene sulfonamido)-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide (compound 4 in table 1) suppresses the IC of human breast cancer cell MCF-7
50be 0.50 μ mol/L.Patent " 2; 3,5-trisubstituted benzene Carbox amide and its production and use " (application number: 201210224812.5) compound 2-methoxyl group-3-(4-fluorobenzene sulfonamido of report)-5-(2-cyclopropyl formamido group-6-benzothiazolyl) benzamide suppresses the IC of human breast cancer cell MCF-7
50be 3.34 μ mol/L.Anti-mouse S-180 knurl in body, dosage is 30mg/kg, and the former tumour inhibiting rate is 80%, and the latter's tumour inhibiting rate is 45%.
Synthesis material inexpensive, be easy to get.Compared with pyridine derivate, benzamide derivatives is inexpensive, be easy to get; Compare with cyclopropyl formyl chloride, Acetyl Chloride 98Min. is inexpensive, be easy to get.
4. toxicity is little.J.Med.Chem.2011, the active best compound of 54,1789 – 1811 report is to mouse stomach administration 1 time, and 15mg/kg can cause dead mouse.Compound provided by the invention is to mouse stomach administration 1 time, and 400mg/kg does not cause dead mouse.
Accompanying drawing explanation
Fig. 1 is that 2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) the half-inhibition concentration contrast histogram of benzamide compound to human breast cancer cell MCF-7.
Fig. 2 is the tumor growth restraining effect of compound 4 to mouse S-180.
Embodiment
The invention provides 2-methoxyl group-3-and replace sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound and its production and use, the present invention has replaced the structure fragment of pyridine ring with the structure fragment of benzamide, can obtain new antineoplastic compound.Below this compound is further described.Should be noted that, following examples are used for explanation of the present invention and also unrestricted the present invention.Although the present invention is had been described in detail by preferred embodiment, those of ordinary skill in the art should be appreciated that under not departing from the scope of the present invention can modify, be out of shape or be equal to replacement to the present invention, all belong to protection scope of the present invention.
One class 2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound, the structural formula of this compounds is:
Wherein, R is alkyl or aryl.
Described alkyl is cyclopropyl, cyclohexyl, propyl group.
Described aryl is 4-fluorophenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-, 2,4 difluorobenzene base.
Provide some representative compound numberings, structure and HRMS data (structure of target compound is determined through high resolution mass spectrum HRMS) below, specifically as shown in table 1.
Some concrete compound number of table 1., structure and HRMS data
The synthetic method of above-claimed cpd is:
Carry out suzuki reaction with compd A and compd B and obtain 2-methoxyl group-3-replacement sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound, its reaction formula is as follows:
In formula I, in compd A, R is cyclopropyl, cyclohexyl, propyl group, 4-fluorophenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-, 2,4 difluorobenzene base.
Provide the synthetic example of above-claimed cpd below.
2-methoxyl group-3-cyclopropyl sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide (1) synthetic
Compd A: the preparation of 2-methoxyl group-3-cyclopropyl sulfonamido-5-brombenzamide (A)
Compound 2-methoxyl group-3-amino-5-brombenzamide (11g, 45mmol) is dissolved in pyridine (120mL), is cooled to 0 ℃, add corresponding SULPHURYL CHLORIDE (50mmol) in batches, mixture and stirring at room temperature 12h, pyridine is removed in decompression, in residue, adds water (200mL), leave standstill, suction filtration, solid washes with water, dry, obtain compd A, yield 82-92%.
Compd B: the preparation of 2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl pinacol borate (B)
Reference J.Med.Chem.2011, prepared by 54,1789 – 1811.
2-methoxyl group-3-cyclopropyl sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide (1) synthetic
In 100mL round-bottomed flask, add compd A: 2-methoxyl group-3-cyclopropyl sulfonamido-5-brombenzamide (A, 0.3g), compd B (0.5g), PdCl
2(dppf) (40mg), sodium carbonate (0.3g), water (6mL) and glycol dimethyl ether (12mL), mixture is stirring and refluxing 3h under nitrogen protection, steams solvent, and resistates silica gel column chromatography separates (chloroform: methyl alcohol=30:1) and obtains product 0.3g.
2-methoxyl group-3-sulfonyl propyl amino-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide (2) synthetic
With synthesizing of compound 1.Compd A replaces 2-methoxyl group-3-cyclopropyl sulfonamido-5-brombenzamide with 2-methoxyl group-3-sulfonyl propyl amino-5-brombenzamide; Replace glycol dimethyl ether with dioxane.
2-methoxyl group-3-cyclohexyl sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide (3) synthetic
With synthesizing of compound 1.Compd A replaces 2-methoxyl group-3-to encircle the third sulfonamido-5-brombenzamide with 2-methoxyl group-3-cyclohexyl sulfonamido-5-brombenzamide; Replace glycol dimethyl ether with tetrahydrofuran (THF).Replace sodium carbonate with salt of wormwood.
2-methoxyl group-3-(4-fluorophenyl sulfonamido)-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide (4) synthetic
With synthesizing of compound 1.2-methoxyl group-3-(4-fluorophenyl sulfonamido for compd A)-5-brombenzamide replaces 2-methoxyl group-3-to encircle the third sulfonamido-5-brombenzamide; Replace glycol dimethyl ether with dimethyl formamide.
2-methoxyl group-3-(4-fluorophenyl sulfonamido)-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide (5) synthetic
With synthesizing of compound 1.2-methoxyl group-3-(4-aminomethyl phenyl sulfonamido for compd A)-5-brombenzamide replaces 2-methoxyl group-3-to encircle the third sulfonamido-5-brombenzamide; Replace glycol dimethyl ether with dimethyl formamide.
2-methoxyl group-3-(4-chloro-phenyl-sulfonamido)-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide (6) synthetic
With synthesizing of compound 1.2-methoxyl group-3-(4-chloro-phenyl-sulfonamido for compd A)-5-brombenzamide replaces 2-methoxyl group-3-to encircle the third sulfonamido-5-brombenzamide; Replace sodium carbonate with cesium carbonate.
2-methoxyl group-3-(2,4-difluorophenyl sulfonamido)-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide (7) synthetic
With synthesizing of compound 1.2-methoxyl group-3-(2 for compd A, 4-difluorophenyl sulfonamido)-5-brombenzamide replaces 2-methoxyl group-3-to encircle the third sulfonamido-5-brombenzamide; Replace glycol dimethyl ether with dimethyl formamide.
Sodium carbonate or cesium carbonate in above-described embodiment are an alkali metal salt, and they can also replace with salt of wormwood or sodium-acetate, and the mol ratio of itself and compd A is all can within the scope of 1:1～5:1; Catalyst P dCl
2(dppf) be all can within the scope of the 5%-20% of compd A molar weight.On related chemical reagent market of the present invention, all can buy.
2-methoxyl group provided by the invention-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound, can be used in and prepare anti-tumor medicinal preparation, wherein every or this pharmaceutical preparation in contain 10-500mg.In the time utilizing active compound that the present invention provides to prepare anti-tumor medicinal preparation, this medicine can be made to tablet, capsule or injection.These pharmaceutical preparations can be made according to the conventional preparation technology of various preparations.For tablet or capsule, preferred content is 20-150mg.And can contain pharmaceutical excipient in the oral preparations the present invention relates to, comprise additive, stablizer, solubilizing agent, lubricant, disintegrating agent etc., as starch, dextrin, glucose, lactose, Mierocrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, pectin, cyclodextrin, twen-80, polyvinyl alcohol, Magnesium Stearate, talcum powder etc.
The checking of anti-tumor activity
In order to verify that 2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) anti-tumor activity of benzamide compound, specifically, with the positive control drug of BEZ235, adopt external mtt assay to measure the growth-inhibiting effect of compound 1-7 to human breast cancer cell MCF-7.
Verification method: tumour cell A549 is cultivated containing in the RPMI1640 substratum of 10% calf serum, include mould and have 100UmL
-1, Streptomycin sulphate 100 μ gmL
-1, in 37 ℃, 5%CO
2the cultivation of going down to posterity in incubator.Get the adherent tumour cell of 0.3% trysinization, containing the RPMI1640 nutrient solution preparation cell suspension of 10% calf serum, concentration is 6 × 10
3individual cells/ml.In 96 well culture plates, 200 μ L(are inoculated approximately containing 1000 tumour cells in every hole), cultivate 24h for 37 ℃.Administration group adds different concns medicine, and every medicine sets 10
-4, 10
-5, 10
-6, 10
-7, 10
-8 molL
-15 concentration, establish 5 parallel holes for every group.Control group adds and the isopyknic solvent of medicine, is placed in 37 ℃, 5%CO
2after cultivating 72h in incubator, discard nutrient solution, every hole adds 20 μ l5mgmL
-1mTT solution, hatch after 4h, abandoning supernatant, every hole adds DMSO150 μ L, measures optical density value (OD) after gentle agitation by microplate reader under 570nm.Result is calculated:
Take the tumour cell of solvent control processing as control group, ask according to the following formula the inhibiting rate of medicine to tumour cell.
And further adopt linear regression method calculation of half inhibitory concentration (IC
50).
IC
50measurement result as shown in Figure 1, can see that all compounds have obvious restraining effect to the growth of MCF-7, the wherein IC of some compound
50be worth suitable with BEZ235, the especially IC of compound 4
50=0.50 μ mol/L; The IC of positive drug BEZ235
50=0.55 μ mol/L, effect and BEZ235 are suitable.
The checking of anti-tumor in vivo activity
24 of S-180 tumor-bearing mices, are divided into 3 groups at random, i.e. group of solvents, compound 410mg/kg group and 30mg/kg.Compound 4 use NMP, PEG400 and water dissolution.Administration group mouse gastric infusion every day once, successive administration 8 days.Group of solvents mouse gavage every day solvent (20mL/kg) once.The 9th day, put to death mouse, peel off knurl piece, weigh, with group of solvents comparison, the results are shown in Figure 2.Illustrate that administration group tumor growth is subject to obvious inhibition.
Acute toxicity test
The part that the present embodiment does not describe in detail and english abbreviation belong to the common practise of the industry, can search on the net, here not narration one by one.
Claims (9)
1.2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound, it is characterized in that, the structural formula of this compounds is:
In formula, R is alkyl or aryl.
2. 2-methoxyl group as claimed in claim 1-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound, it is characterized in that, described alkyl is cyclopropyl, cyclohexyl, propyl group.
3. 2-methoxyl group as claimed in claim 1-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound, it is characterized in that, described aryl is 4-fluorophenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-, 2,4 difluorobenzene base.
4. 2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) preparation method of benzamide compound, it is characterized in that, comprise the following steps:
Midbody compound A and midbody compound B carry out suzuki reaction and obtain 2-methoxyl group-3-replacement sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound (I), its reaction formula is as follows:
In formula, in compd A, R is cyclopropyl, cyclohexyl, propyl group, 4-fluorophenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-, 2,4 difluorobenzene base.
5. 2-methoxyl group as claimed in claim 4-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) preparation method of benzamide compound, it is characterized in that, adopt suzuki reaction, at PdCl
2(dppf) under catalysis; compd A, compd B are mixed in solvent with an alkali metal salt; stirring and refluxing 1～5h under nitrogen protection; steam solvent, from reaction mixture, separate and obtain 2-methoxyl group-3-replacement sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound.
Described compd A is 2-methoxyl group-3-sulfonyl propyl amino-5-brombenzamide, 2-methoxyl group-3-cyclopropyl sulfonamido-5-brombenzamide, 2-methoxyl group-3-cyclohexyl sulfonamido-5-brombenzamide, 2-methoxyl group-3-(4-fluorophenyl sulfonamido)-5-brombenzamide, 2-methoxyl group-3-(4-aminomethyl phenyl sulfonamido)-5-brombenzamide, 2-methoxyl group-3-(4-chloro-phenyl-sulfonamido)-5-brombenzamide, 2-methoxyl group-3-(2,4-difluorophenyl sulfonamido)-5-brombenzamide;
Described compd B is 2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl pinacol borate;
Described solvent is one or more in tetrahydrofuran (THF), dioxane, glycol dimethyl ether, dimethyl formamide, water.
6. 2-methoxyl group as claimed in claim 5-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) preparation method of benzamides, it is characterized in that, described an alkali metal salt is sodium carbonate, salt of wormwood, cesium carbonate or sodium-acetate, and the mol ratio of itself and compd A is 1:1～5:1;
Described compd A and the mol ratio of compd B are 1:1; The compd A of 1 mole joins in the solvent of 5～10L and reacts; Catalyst P dCl
2(dppf) be the 5%-20% of compd A molar weight.
7. 2-methoxyl group claimed in claim 1-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound is in the application of preparing in antitumor drug.
8. application as claimed in claim 7; it is characterized in that; 2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamides adds auxiliary material and makes tablet, capsule or injection, wherein every or a preparation in contain 10～500mg 2-methoxyl group-3-replace sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound.
9. application as claimed in claim 8, is characterized in that, described auxiliary material comprises one or more in additive, stablizer, solubilizing agent, lubricant, disintegrating agent.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2716947A1 (en) * | 2008-02-29 | 2009-09-11 | Array Biopharma Inc. | Imidazo [4,5-b] pyridine derivatives used as raf inhibitors |
| WO2009114874A2 (en) * | 2008-03-14 | 2009-09-17 | Intellikine, Inc. | Benzothiazole kinase inhibitors and methods of use |
| CN102746241A (en) * | 2012-07-02 | 2012-10-24 | 西安交通大学 | 2, 3, 5-trisubstituted benzamide compound, and preparation method and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2716947A1 (en) * | 2008-02-29 | 2009-09-11 | Array Biopharma Inc. | Imidazo [4,5-b] pyridine derivatives used as raf inhibitors |
| WO2009114874A2 (en) * | 2008-03-14 | 2009-09-17 | Intellikine, Inc. | Benzothiazole kinase inhibitors and methods of use |
| CN102746241A (en) * | 2012-07-02 | 2012-10-24 | 西安交通大学 | 2, 3, 5-trisubstituted benzamide compound, and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
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| JINAN WANG ET AL.: "Molecular simulation of a series of benzothiazole PI3Kα inhibitors: probing the relationship between structural features, anti-tumor potency and selectivity", 《J. MOL. MODEL》 * |
| NOEL D. D’AMICO ET AL.: "Discovery and Optimization of a Series of Benzothiazole Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors", 《J. MED. CHEM.》 * |
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