CN106674150A - Dasatinib derivative with anti-tumor activity and application thereof - Google Patents

Dasatinib derivative with anti-tumor activity and application thereof Download PDF

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Publication number
CN106674150A
CN106674150A CN201611238771.XA CN201611238771A CN106674150A CN 106674150 A CN106674150 A CN 106674150A CN 201611238771 A CN201611238771 A CN 201611238771A CN 106674150 A CN106674150 A CN 106674150A
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chloro
dasatinib
thiazole
derivant
methyl
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姚志艺
王庆宣
舒启胜
薛楠楠
杨燕
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Shanghai Institute of Technology
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Shanghai Institute of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention belongs to the technical field of medicine chemistry and particularly relates to a dasatinib derivative with anti-tumor activity and application thereof. The dasatinib derivative provided by the invention has a very good inhibition effect on tyrosine kinase and has a very good application prospect for developing in the anti-tumor aspect.

Description

Dasatinib derivant with anti-tumor activity and its application
Technical field
The present invention relates to a class has the Dasatinib derivant of anti-tumor activity and its application, belong to pharmaceutical chemistry technology Field.
Background technology
Become the second killer for threatening human life with tumor, die from evil in the population of the whole world more than 50 hundred million every year on average Property tumor person up to 6,900,000 people, new case is 8,700,000, and the number is also increasing year by year.Therefore, national governments, research institution and Drugmaker is paid much attention to tumor research and antitumor drug always for a long time, in antitumor drug research and development, mesh It is front achieved with major progress.
With the continuous development of medicine and pharmacology, people achieve achievement obvious to all for the treatment of numerous disease.Cancer These diseases, are nowadays still a great problem for perplexing medical circle.For the research of antitumor drug is carried out in high gear.
In recent years, cytobiology, molecular biology, molecular pharmacology, the development of oncology make tumor essence by Step is illustrated；The invention of the advanced technologies such as extensive rapid screening, combinatorial chemistry, genetic engineering and application acceleration drug development enters Journey；The research and development of antitumor drug have been enter into a brand-new epoch.
The new antitumoral medicine that antitumor drug is just being acted on from traditional cytotoxic drug to the too many levels for mechanism Thing develops.Antitumor drug new development in recent years, including cytotoxic anti-tumor drug, with cellular signal transduction molecule as target spot The swift and violent of the life sciences such as antitumor drug, angiogensis inhibitor, tumor drug resistance reversal agent, endocrine therapy medicine send out Exhibition, the understanding and successful prevention deep to tumor produces new opportunity.
As to the continuous research of antitumor drug and developing rapidly for oncobiology, people gradually recognize that cell is sent out The essence of raw canceration is Cell signal propagation pathways imbalance, so as to cause the unlimited hypertrophy of cell.Research and development focus is also just from tradition Cell toxicity medicament is turned to for numerous targeting links during tumor development.These target spot new drugs are directed to normal cell and swell Difference between oncocyte, can overcome that the poor selectivity of conventional cell cytotoxic drug, toxic and side effects are strong, be also easy to produce drug resistance etc. lacks Point, can reach high selectivity and hypotoxic therapeutic effect.Thus, antitumor drug enter a brand-new development- The research of anti-tumor drugs targeting.But new type antineoplastic medicine research and development to reach it is real cure tumor and also need to one overflow Long process.The invention provides a kind of have the new Dasatinib derivant structure of targeting anti-tumor activity, it is with L-Tyrosine The compound for having a biological activity that kinases is screened for target spot.With important development prospect.
The content of the invention
It is an object of the invention to provide a kind of Dasatinib derivant with anti-tumor activity and its application.The present invention Dasatinib derivant with tyrosine kinase as target spot, with important development prospect.
The technical solution used in the present invention is specifically described as follows.
The present invention provides a kind of Dasatinib derivant with anti-tumor activity, its structure such as formula (I), formula (II) or Shown in formula (III)：
Wherein：R is monosubstituted, two replacements or three replacements；R independences selected from halogen, nitro, methoxyl group, cyano group, methyl Or one or more in trifluoromethyl；Y is heterocyclic radical.
In the present invention, heterocyclic radical is any one in unsubstituted either mono-substituted oxygen-containing heterocycle or nitrogen heterocycle. Preferably, it is five-ring heterocycles, hexa-member heterocycle, benzo five-membered heterocycle or benzo hexa-member heterocycle.It is further preferred that being unsubstituted Either mono-substituted piperidyl, morpholinyl, indyl, imidazole radicals, pyrazolyl, piperazinyl or pyrrole radicals；When monosubstituted, replace Base independence selected from methyl or ethoxy.
The present invention also provides a kind of above-mentioned Dasatinib derivant with anti-tumor activity stated as tyrosine kinase Inhibitor, prepare treatment, prevention, alleviate tumor antitumor drug in application.Preferably, the antitumor drug is The medicine for the treatment of, prevention or palliating leukemia, colon cancer, pulmonary carcinoma, breast carcinoma, cervical cancer or hepatocarcinoma.Described antitumor drug For tablet, capsule, powder, pill, granule or Emulsion.
Compared to the prior art, the device have the advantages that as follows：The Dasatinib derivant life that the present invention is provided Thing Activity Results show that it has good inhibitory action to tyrosine kinase.
Specific embodiment
The Dasatinib derivant and biological activity of the present invention are described further with reference to example is embodied as, But protection scope of the present invention is not limited to that.
The preparation of the 2- amino-N- of embodiment 1 (the chloro- 6- aminomethyl phenyls of 2-) -5- thiazole carboxamides
(1) preparation of 2- (N- t-butoxycarbonyl amino) -5- thiazole ethyl formates
First, clean 50mL there-necked flasks one, a bag pan paper, an aluminum spatula is prepared；Needed raw material is found out And be placed on designated area and wait to weigh；After the completion of preparation, electronic balance on and off switch is opened, by there-necked flask after registration is stable It is put in balance and zero setting, with aluminum spoon thiazolamine -5- Ethyl formate 1.00g is added in the there-necked flask of 50m1, zero setting, Add DMAP 141.89mg to the there-necked flask of 50ml with clean aluminum spoon, the anhydrous THF for adding the weight of 15m1 steamed 15min is to mix homogeneously for stirring, weighs in the balance and takes Bis(tert-butoxycarbonyl)oxide 1.52g, in being dissolved in the anhydrous THF of 2ml, room temperature condition Under, Deca is dripped and is finished dissolved with the anhydrous THF solution (2m1) of Bis(tert-butoxycarbonyl)oxide, and 8h is stirred at room temperature, and is evaporated off molten in reactant liquor Agent is filtered to remaining about 1/5 volume, and filter cake is washed with a small amount of THF, and after being dried off-white powder product (1.3g) is obtained, and is received Rate 82.21%.
Net reaction is as follows:
Nuclear-magnetism and mass spectrometric data：1H NMR (500MHz, DMSO) δ 11.74 (s, 1H), 8.13 (s, 1H), 4.32 (d, J= 7.63, Hz, 2H), 1.49 (s, 9H), 1.49 (s, 9H), 1.34 (d, J=7.63, Hz, 3H)；HRMS calcd for C11H16N2O4S[M+H]+:273.0831,Found:273.0832.
(2) preparation of 2- (N- t-butoxycarbonyl amino) -5- thiazol formic-acids
THF (6m1) and ethanol (7m1) are added in the there-necked flask of 50m1, then will be weighed in the balance and be taken Cape-1 (1g) In adding there-necked flask, 20min is stirred under room temperature to mix homogeneously；Then reaction vessel is transferred to into cryogenic thermostat reactive bath technique In, 0 DEG C is cooled the temperature to, stir 15min；The NaOH aqueous solution 10m1 of the freshly prepared 2mol/L of Deca in reaction vessel, Finish, 10h is stirred at room temperature.The THF in reactant liquor is boiled off with Rotary Evaporators；Reaction vessel is transferred to into cryogenic thermostat reactive bath technique In, cool the temperature to 0 DEG C, Deca newly match somebody with somebody 10% hydrochloric acid conditioning solution PH to 1, separate out white precipitate, filter, filter cake is used Water washing, after being dried white solid product Cape-2 (0.875g), yield 97.55% are obtained final product.
Net reaction is as follows:
Nuclear-magnetism and mass spectrometric data：1H NMR(500MHz,DMSO)δ13.40(s,1H),11.81(s,1H),8.53(s, 1H),1.49(s,9H)；HRMS calcd for C9H12N2O4S[M+H]+:245.0518,Found:245.0519.
(3) preparation of [5- (the chloro- 6- aminomethyl phenyls carbamyls of 2-) thiazol-2-yl]-ammonia t-butyl formate
10m1 dichloromethane is added in the there-necked flask of 50m1, is then weighed in the balance and is taken the Cape-3 of 1g and be added to three mouthfuls In flask；Reaction vessel is transferred in cryogenic thermostat reactive bath technique, -5 DEG C are adjusted the temperature to, PhosphorodichloridicAcid Acid Phenyl Ester is dividedly in some parts (1.036g) with the chloro- 6- monomethylaniline .s (0.754g) of 2-；Then, Deca DIPEA 1.6g；Room temperature is warming up to, is stirred Mix reaction 14h.Reactant liquor concentrating under reduced pressure falls after organic solvent, adds 5m1 ethanol, stirring to pulp 30min；Finally, 10m1 is added Tap water, stirring and crystallizing, sucking filtration obtains 1.43g faint yellow solid Cape-3, yield 95%.
Net reaction is as follows:
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ11.74(s,1H),9.51(s,1H),8.13(s,1H), 7.37 (dd, J=7.63,2.03Hz, 1H), 7.28-7.20 (m, 2H), 2.21 (s, 3H), 1.49 (s, 9H)；HRMS calcd forC16H18ClN3O3S[M+H]+:368.0757,Found:368.0756.
(4) preparation of 2- amino-N- (the chloro- 6- aminomethyl phenyls of 2-) -5- thiazole carboxamides
5m1 dichloromethane and 5m1 trifluoroacetic acids are separately added in the there-necked flask of 50m1, reaction vessel are transferred to low In warm isothermal reaction bath, temperature to -5 DEG C is adjusted；Then, Cape-3 (1g) is added with charging hopper, stirs 30min, will be reacted Container is transferred under room temperature condition from cryogenic thermostat reactive bath technique and stirs, and reacts 10h；Solvent in reactant liquor is evaporated, is added 15m1 ethyl acetate dissolves, and is then washed twice with 5% sodium bicarbonate solution, washed once with the common salt aqueous solution of saturation, Organic faciess are dried, concentrating under reduced pressure falls solvent, obtain yellow solid Cape-4 (0.6188g), yield 85%.
Net reaction is as follows:
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ9.66(s,1H),7.87(s,1H),7.69(s,2H), 7.36 (d, J=7.5Hz, 1H), 7.24 (d, J=7.5Hz, 2H), 2.21 (s, 3H)；HRMS calcd for C11H10ClN3OS [M+H]+:268.0233,Found:268.0234.
The synthesis (A classes) of the Dasatinib derivant of embodiment 2
Weigh in the balance and take in Cape-4 (100mg) addition 50ml single port bottles, be subsequently adding the THF of the 7ml for steaming again, while plus Enter 113.39mg triethylamines, stir 5min, then reaction vessel is transferred in cryogenic thermostat reactive bath technique, cool the temperature to 0 DEG C, Stirring 15min；The 4- chloromethyl benzoic acid chlorides for weighing 84.73mg are dissolved in 1mlTHF, after the THF of 1ml is slowly dropped to instead In answering container, 3h is reacted, rear sucking filtration filters the salt of generation, and column chromatography can obtain 0.12g white solid products Cs ape-5, and yield is 76.44%.
Net reaction is as follows:
By above identical method with Cape-4 come with 4- chlorobenzoyl chlorides, 4- trifluoromethyl benzoyl chlorides, 2,4- bis- The bromo- 2- fluorobenzoyl chlorides of chloro- 5- fluorobenzoyl chlorides, anisoyl chloride, 4-, 2- naphthoyl chlorides, 4- nitrobenzoyl chlorides, 2,4 difluorobenzene formyl chloride, o-methoxy benzoyl chloride, meta-methoxy Benzenecarbonyl chloride. and 4- cyano-benzoyl chlorides, 4- toluyls Chlorine reacts, and 5b-5p is prepared into respectively.And respectively biological activity test is carried out to compound 5a-5p.
The yield of compound 5b-5p such as table 1 below
The yield of the compound 5b-5p of table 1
Table 1 The yield of compounds 5b-5p
The title and structural formula of 5a is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- [4- (chloromethyl) benzamido] thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-[4-(chloromethyl)benzamido]thiazole-5- carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.76(s,1H),10.21(s,1H),8.84(s, 1H), 7.92 (d, J=7.5Hz, 2H), 7.53 (dd, J=7.5,3.6Hz, 1H), 7.45 (d, J=7.8Hz, 2H), 7.17- 7.11(m,2H),4.64(s,2H),2.12(s,3H)；HRMS calcd for C19H15Cl2N3O2S[M+H]+:420.0262, Found:420.0261.
The title and structural formula of 5b is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (4- chloro-benzoyl aminos) thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-(4-chlorobenzamido)thiazole-5- carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.76(s,1H),10.24(s,1H),8.85(s, 1H), 7.93 (d, J=7.5Hz, 2H), 7.54 (dd, J=7.5,3.6Hz, 1H), 7.45 (d, J=7.8Hz, 2H), 7.18- 7.10(m,2H),2.12(s,3H)；HRMS calcd for C18H13Cl2N3O2S[M+H]+:406.0106,Found: 406.0105.
The title and structural formula of 5c is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- [4- (trifluoromethyl) benzamido] thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-[4-(trifluoromethyl)benzamido]thiazole- 5-carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.84(s,1H),10.21(s,1H),8.84(s, 1H), 7.82 (d, J=7.5Hz, 2H), 7.65 (d, J=7.8Hz, 2H), 7.53 (dd, J=7.5,3.6Hz, 1H), 7.17- 7.11(m,2H),2.12(s,3H)；HRMS calcd for C19H13ClF3N3O2S[M+H]+:440.0369,Found: 440.0367.
The title and structural formula of 5d is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (the chloro- 5- fluorobenzoyls amidos of 2,4- bis-) thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-(2,4-dichloro-5-fluorobenzamido) thiazole-5-carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.84(s,1H),10.21(s,1H),8.85(s, 1H), 7.83 (s, 1H), 7.53 (dd, J=7.6,2.5Hz, 1H), 7.49 (s, 1H), 7.17-7.11 (m, 2H), 2.12 (s, 3H)；HRMScalcd for C18H11Cl3FN3O2S[M+H]+:457.9622,Found:457.9621.
The title and structural formula of 5e is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (the bromo- 2- fluorobenzoyls amidos of 4-) thiazole -5- Methanamides
2-(4-bromo-2-fluorobenzamido)-N-(2-chloro-6-methylphenyl)thiazole-5- carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.81(s,1H),10.20(s,1H),8.84(s, 1H), 7.86 (d, J=8.7Hz, 1H), 7.57 (d, J=8.7Hz, 1H), 7.55 (s, 1H), 7.53 (dd, J=8.7,2.8Hz, 1H),7.17-7.11(m,2H),2.12(s,3H)；HRMS calcd for C18H12BrClFN3O2S[M+H]+:467.9506, Found:467.9507.
The title and structural formula of 5f is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (4- methoxy benzamide bases) thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-(4-methoxybenzamido)thiazole-5- carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.83(s,1H),10.21(s,1H),8.84(s, 1H), 8.13 (d, J=7.5Hz, 2H), 7.53 (dd, J=7.6,3.5Hz, 1H), 7.17-7.11 (m, 2H), 7.08 (d, J= 7.8Hz,2H),3.81(s,3H),2.12(s,3H)；HRMS calcd for C19H16ClN3O3S[M+H]+:402.0601, Found:402.0602.
The title and structural formula of 5g is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (2- naphthoyl amidos) thiazole -5- Methanamides
2-(2-naphthamido)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.82(s,1H),10.21(s,1H),8.84(s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 8.10 (d, J=7.8Hz, 1H), 8.06 (d, J=7.8Hz, 1H), 7.83-7.52 (m, 4H), 7.17-7.11 (d, J=9.6Hz, 2H), 2.12 (s, 3H)；HRMS calcd for C22H16ClN3O2S[M+H]+: 422.0652,Found:422.0651.
The title and structural formula of 5h is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (4- nitrobenzamide bases) thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-(4-nitrobenzamido)thiazole-5- carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.82(s,1H),10.21(s,1H),8.84(s, 1H), 8.39 (d, J=7.5Hz, 2H), 8.21 (d, J=8.2,3.6Hz, 2H), 7.53 (d, J=7.8Hz, 2H), 7.17-7.11 (m,2H),2.12(s,3H)；HRMS calcd for C18H13ClN4O4S[M+H]+:417.0346,Found:417.0347.
The title and structural formula of 5i is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (2,4 difluorobenzene formamido) thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-(2,4-difluorobenzamido)thiazole-5- carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.84(s,1H),10.21(s,1H),8.84(s, 1H), 7.95 (d, J=8.7Hz, 1H), 7.53 (d, J=7.8Hz, 1H), 7.25 (d, J=9.6Hz, 1H), 7.17-7.11 (m, 2H),2.12(s,3H)；HRMS calcd for C18H12ClF2N3O2S[M+H]+:408.0307,Found:408.0308.
The title and structural formula of 5j is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (2- methoxy benzamide bases) thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-(2-methoxybenzamido)thiazole-5- carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.83(s,1H),10.19(s,1H),8.85(s, 1H), 7.88 (d, J=8.1Hz, 1H), 7.57-7.53 (m, 2H), 7.23-7.11 (m, 4H), 3.93 (s, 3H), 2.12 (s, 3H)；HRMS calcd for C19H16ClN3O3S[M+H]+:402.0601,Found:402.0602.
The title and structural formula of 5k is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (3- methoxy benzamide bases) thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-(3-methoxybenzamido)thiazole-5- carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.84(s,1H),10.18(s,1H),8.84(s, 1H), 7.71 (dd, J=9.7,3.6Hz, 1H), 7.63 (d, J=7.8Hz, 1H), 7.18 (d, J=8.1Hz, 2H), 7.20- 7.11(m,3H),3.77(s,3H),2.12(s,3H)；HRMS calcd for C19H16ClN3O3S[M+H]+:402.0601, Found:402.0602.
The title and structural formula of 5l is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (4- Cyanophenacyl amidos) thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-(4-cyanobenzamido)thiazole-5- carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.82(s,1H),10.23(s,1H),8.86(s, 1H), 8.17 (d, J=9.2Hz, 2H), 8.10 (d, J=7.8Hz, 2H), 7.53 (d, J=8.7Hz, 1H), 7.17-7.11 (m, 2H),2.12(s,3H)；HRMS calcd for C19H13ClN4O2S[M+H]+:397.0448,Found:397.0447.
The title and structural formula of 5m is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (4- Cyanophenacyl amidos) thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-(4-cyanobenzamido)thiazole-5- carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.84(s,1H),10.21(s,1H),8.82(s, 1H), 8.16 (d, J=9.1Hz, 2H), 7.53 (d, J=8.7Hz, 1H), 7.37 (d, J=7.8Hz, 2H), 7.18-7.10 (m, 2H),2.12(s,3H)；HRMS calcd for C18H13ClFN3O2S[M+H]+:390.0401,Found:390.0402.
The title and structural formula of 5n is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- cinnamoyl amino-thiazol -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-cinnamamidothiazole-5-carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ13.63(s,1H),10.21(s,1H),8.84(s, 1H), 7.73 (s, 1H), 7.62 (d, J=8.7Hz, 2H), 7.53 (d, J=8.7Hz, 1H), 7.38-7.33 (m, 3H), 7.17- 7.11(m,2H),6.89(s,1H),2.12(s,3H)；HRMS calcd for C20H16ClN3O2S[M+H]+:398.04652, Found:398.0653.
The title and structural formula of 5o is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (4- toluyl amidos) thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-(4-methylbenzamido)thiazole-5- carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.84(s,1H),10.22(s,1H),8.84(s, 1H), 7.84 (d, J=7.6Hz, 2H), 7.53 (d, J=8.7Hz, 1H), 7.34 (d, J=7.6Hz, 2H), 7.17-7.11 (m, 2H),2.41(s,3H),2.12(s,3H)；HRMS calcd for C19H16ClN3O2S[M+H]+:386.0652,Found: 386.0651.
The title and structural formula of 5p is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- (4- bromo benzamidos) thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-(4-bromobenzamido)thiazole-5- carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.84(s,1H),10.21(s,1H),8.84(s, 1H), 8.07 (d, J=7.2Hz, 2H), 7.70 (d, J=7.2Hz, 2H), 7.54 (d, J=8.1Hz, 1H), 7.17-7.11 (m, 2H),2.12(s,3H)；HRMS calcd for C18H13BrClN3O2S[M+H]+:449.9600,Found:449.9601.
The synthesis (B classes) of the Dasatinib derivant of embodiment 3
First, the n-butyl alcohol of 6m1 is added in the there-necked flask of 50m1, then Cape-5 (0.1g) is added to into reaction In container, under room temperature 15min is stirred；Difference Deca triethylamine 72.23mg and N methyl piperazine (238.31mg), stirring is warming up to 120 DEG C, back flow reaction 5h is cooled to room temperature, and column chromatography can obtain 0.098g products Cs ape-6, yield 85.10%.
Net reaction is as follows：
By above identical method with Cape-5 come with hydroxyethyl piperazine, piperazine, pyrroles, morpholine, piperidines, indole, N- Methylimidazole., imidazoles, pyrazoles reaction, are prepared into respectively 6b-6k.And respectively biological activity test is carried out to compound 6a-6k.
The yield of compound 5b-5p such as following table 3.3-2
The yield of table 3.3-2 compound 6b-6k
Table 3.3-2 The yield of compounds 6b-6k
The title and structural formula of 6a is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- { 4- [(4- methylpiperazine-1-yls) methyl] benzamido } thiazole -5- first Amide
N-(2-chloro-6-methylphenyl)-2-{4-[(4-methylpiperazin-1-yl)methyl] benzamido}thiazole-5-carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.83(s,1H),10.21(s,1H),8.84(s, 1H), 7.92 (d, J=7.8Hz, 2H), 7.53 (dd, J=7.5,3.6Hz, 1H), 7.34 (d, J=7.8Hz, 2H), 7.17- 7.11 (m, 2H), 3.66 (s, 2H), 2.48 (t, J=9.5Hz, 4H), 2.34 (t, J=9.5Hz, 4H), 2.14 (s, 3H), 2.12 (s,3H)；HRMS calcd for C24H26ClN5O2S[M+H]+:483.1496,Found:484.1497.
The title and structural formula of 6b is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- { 4- [(4- (2- ethoxys) piperazine -1- bases) methyl] benzamido } thiophene Azoles -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-{4-[(4-(2-hydroxyethyl)piperazin-1-yl) methyl]benzamido}thiazole-5-carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.84(s,1H),10.21(s,1H),8.84(s, 1H), 7.92 (d, J=7.8Hz, 2H), 7.53 (dd, J=7.5,3.6Hz, 1H), 7.34 (d, J=7.8Hz, 2H), 7.17- 7.11 (m, 2H), 4.16 (s, 1H), 3.66 (s, 2H), 3.42 (t, J=7.8Hz, 2H), 2.57-2.48 (m, 6H), 2.29 (t, J =9.5Hz, 4H), 2.12 (s, 3H)；HRMS calcd for C25H28ClN5O3S[M+H]+:514.1601,Found: 514.1602.
The title and structural formula of 6c is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- [4- (piperazine -1- ylmethyls) benzamido] thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-[4-(piperazin-1-ylmethyl)benzamido] thiazole-5-carboxami-de
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.83(s,1H),10.21(s,1H),8.84(s, 1H), 7.92 (d, J=7.8Hz, 2H), 7.53 (dd, J=7.5,3.6Hz, 1H), 7.34 (d, J=7.8Hz, 2H), 7.17- 7.11 (m, 2H), 3.66 (s, 2H), 2.48 (t, J=9.5Hz, 4H), 2.34 (t, J=9.5Hz, 4H), 2.12 (s, 3H), 1.07 (s,1H)；HRMS calcd for C23H24ClN5O2S[M+H]+:470.1339,Found:470.1338.
The title and structural formula of 6d is as follows：
2- { 4- [(1H- pyrroles's -1- bases) methyl]-N- (the chloro- 6- aminomethyl phenyls of 2-) benzamido } thiazole -5- Methanamides
2-{4-[(1H-pyrrol-1-yl)methyl]-N-(2-chloro-6-methylphenyl)benzamido} thiazole-5-carboxa-mide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.84(s,1H),10.21(s,1H),8.84(s, 1H), 7.84 (d, J=7.8Hz, 2H), 7.53 (dd, J=7.5,3.6Hz, 1H), 7.35 (d, J=7.8Hz, 4H), 7.17- 7.11 (m, 2H), 6.22 (d, J=9.6Hz, 2H), 3.66 (s, 2H), 2.12 (s, 3H)；HRMS calcd for C23H19ClN4O2S[M+H]+:451.0917,Found:451.0918.
The title and structural formula of 6e is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- [4- (morpholinomethyl) benzamido] thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-[4-(morpholinomethyl)benzamido] thiazole-5-carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.83(s,1H),10.21(s,1H),8.84(s, 1H), 7.92 (d, J=7.8Hz, 2H), 7.53 (dd, J=7.5,3.6Hz, 1H), 7.34 (d, J=7.8Hz, 2H), 7.17- 7.11 (m, 2H), 3.66 (s, 2H), 3.57 (t, J=9.5Hz, 4H), 2.42 (t, J=9.5Hz, 4H), 2.12 (s, 3H)；HRMS calcd for C23H23ClN4O3S[M+H]+:471.1179,Found:471.1178.
The title and structural formula of 6f is as follows：
2- { 4- [(1H- imidazoles -1- bases) methyl]-N- (the chloro- 6- aminomethyl phenyls of 2-) benzamido } thiazole -5- Methanamides
2-{4-[(1H-imidazol-1-yl)methyl]-N-(2-chloro-6-methylphenyl)benzamido} thiazole-5-carbo-xamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.84(s,1H),10.21(s,1H),8.84(s, 1H), 7.84 (d, J=7.8Hz, 2H), 7.74 (s, 1H), 7.53 (dd, J=7.5,3.6Hz, 1H), 7.34 (d, J=7.8Hz, 2H), 7.17-7.10 (m, 3H), 6.86 (d, J=7.8Hz, 1H), 5.46 (s, 2H), 2.12 (s, 3H)；HRMS calcd for C22H18ClN5O2S[M+H]+:452.0870,Found:452.0871.
The title and structural formula of 6g is as follows：
2- { 4- [(1H- indole -1- bases) methyl]-N- (the chloro- 6- aminomethyl phenyls of 2-) benzamido } thiazole -5- Methanamides
2-{4-[(1H-indol-1-yl)methyl]-N-(2-chloro-6-methylphenyl)benzamido} thiazole-5-carboxa-mide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.83(s,1H),10.21(s,1H),8.84(s, 1H), 7.92-7.82 (m, 4H), 7.53 (dd, J=7.5,3.6Hz, 1H), 7.44-7.34 (m, 4H), 7.17-7.11 (m, 2H), 6.83 (dd, J=7.1,2.8Hz, 1H), 6.36 (d, J=10.7Hz, 1H), 5.56 (s, 2H), 2.12 (s, 3H)；HRMS calcd forC27H21ClN4O2S[M+H]+:501.1074,Found:501.1075.
The title and structural formula of 6h is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- [4- (piperidin-1-yl methyl) benzamido] thiazole -5- Methanamides
N-(2-chloro-6-methylphenyl)-2-[4-(piperidin-1-ylmethyl)benzamido] thiazole-5-carboxamid-e
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.84(s,1H),10.21(s,1H),8.84(s, 1H), 7.92 (d, J=7.8Hz, 2H), 7.53 (dd, J=7.5,3.6Hz, 1H), 7.34 (d, J=7.8Hz, 2H), 7.17- 7.11 (m, 2H), 3.66 (s, 2H), 2.45 (t, J=9.5Hz, 4H), 2.12 (s, 3H), 2.34 (m, 6H)；HRMS calcd for C24H25ClN4O2S[M+H]+:469.1387,Found:469.1386.
The title and structural formula of 6i is as follows：
N- (the chloro- 6- aminomethyl phenyls of 2-) -2- { 4- [(2- methyl-1 H-imidazole-1-groups) methyl] benzamido } thiazole - 5- Methanamides
N-(2-chloro-6-methylphenyl)-2-{4-[(2-methyl-1H-imidazol-1-yl)methyl] benzamido}thiazole-5-carboxamide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.84(s,1H),10.21(s,1H),8.84(s, 1H), 7.84 (d, J=7.8Hz, 2H), 7.53 (dd, J=7.5,3.6Hz, 1H), 7.34 (d, J=7.8Hz, 2H), 7.17- 7.10 (m, 3H), 6.86 (d, J=7.8Hz, 1H), 5.46 (s, 2H), 2.53 (s, 3H), 2.12 (s, 3H)；HRMS calcd for C23H20ClN5O2S[M+H]+:466.1026,Found:466.1027.
The title and structural formula of 6j is as follows：
2- { 4- [(1H- pyrazol-1-yls) methyl]-N- (the chloro- 6- aminomethyl phenyls of 2-) benzamido } thiazole -5- Methanamides
2-{4-[(1H-pyrazol-1-yl)methyl]-N-(2-chloro-6-methylphenyl)benzamido} thiazole-5-carbox-amide
Nuclear-magnetism and mass spectrometric data:1H NMR(500MHz,DMSO)δ12.83(s,1H),10.21(s,1H),8.84(s, 1H), 7.84-7.80 (m, 3H), 7.53 (dd, J=7.5,3.6Hz, 1H), 7.34-7.28 (m, 3H), 7.17-7.11 (m, 2H), 6.22 (d, J=9.2Hz, 1H), 5.48 (s, 2H), 2.12 (s, 3H)；HRMS calcd for C22H18ClN5O2S[M+H]+: 452.0870,Found:452.0871.
Cell bio-activity test experiments
1. experimental principle：Compound anticancer growth detail can be measured with Jing MTT methods.Mtt assay Principle is：Yellow Thiazolyl blue may pass through cell membrane and enter intracellular, and the succinate dehydrogenase in living cells mitochondria can allow outer Property MTT in source is reduced into the royal purple crystallization first a ceremonial jade-ladle, used in libation being deposited in cell, but dead cell is but without this function.It is sub- with dimethyl again Sulfone dissolves first a ceremonial jade-ladle, used in libation.At 570nm wavelength, its light absorption value is determined with enzyme-linked immunosorbent assay instrument, to obtain living cells quantity indirectly.
2. experiment material：K562 (human leukemia cell).With DMEM+10%FBS culture medium culturings or use respectively 1640+10%FBS is cultivated.
3. test method
Experimental group：The medicine (final concentration of 10 of the μ l variable concentrations of 190 μ l cell suspension+10-5~10-10)
Blank control group：200μl PBS
Negative control group：μ l 2%DMSO (final concentration of 0.1%) of DMSO of 190 μ l cell suspension+10
Positive controls：The compound of the μ l variable concentrations of 190 μ l cell suspension+10
4.MTT cell viability detecting steps
A. inoculating cell
In 37 DEG C, 5%CO2Under the conditions of, trained with the DMEM containing 10% hyclone, 1% penicillin and streptomycin Cultured cell line in foster base.The upper strata culture medium in culture dish is discarded, with PBS cell 2 times is washed, add pancreatin, be put into training 1-2min is digested in foster base, after the de- wall of cell, new culture medium is added, is gently blown and beaten, completely fall off cell, treat cell Enter the new culture medium of 5ml, gently blow and beat, cell concentration is calculated with cell counting, in being then inoculated in 96 orifice plates.
B. cell culture
96 orifice plates being inoculated with are positioned over into 37 DEG C, 5% CO2Overnight incubation in incubator, next day cell can be adherent.
C. dosing
The medicine of variable concentrations is added according to different experimental designs, 3~4 multiple holes are set per group, 10 μ l phases are added per hole The medicine of concentration is answered, then 96 orifice plates are put into into incubator and continue to cultivate.
D.MTT viability examinations
Cultivate after administration 24 hours, 48 hours, after 72 hours, the MTT of 10 μ l 5mg/ml is added per hole, after by 96 orifice plates In being positioned over incubator, take out after continuing to cultivate 4 hours, the careful supernatant drawn per hole adds the diformazan of 100 μ l per hole Base sulfoxide (DMSO) solution, places and be incubated in incubator after 10min, and concussion 40s or so is completely dissolved first a ceremonial jade-ladle, used in libation crystal.
E. survey absorbance and calculate IC50Value
96 orifice plates are placed in microplate reader, Detection wavelength is the light absorption value at 570nm and 630nm.With per 3~4 multiple holes The mean value calculation of absorbance its relative inhibition.According to suppression ratio, by software " Dose-Effect Analysis WithMicrocomputers " calculates half effective inhibition concentration (IC50).Every group of sample will do 3 parallel laboratory tests.
F.570nm reading, calculates cell survival rate, and according to result IC is calculated50, obtain table 1 below
The structural formula of compound of table 1 and activity data are following (μM)

Claims (7)

1. a kind of Dasatinib derivant with anti-tumor activity, it is characterised in that：Its structure such as formula (I), formula (II) or Shown in formula (III)：
Wherein：R is monosubstituted, two replacements or three replacements；R independences selected from halogen, nitro, methoxyl group, cyano group, methyl or three One or more in methyl fluoride；Y is heterocyclic radical.
2. Dasatinib derivant as claimed in claim 1, it is characterised in that heterocyclic radical is unsubstituted or mono-substituted contain In oxa- ring group or nitrogen heterocycle any one.
3. Dasatinib derivant as claimed in claim 2, it is characterised in that unsubstituted or mono-substituted oxygen-containing heterocycle Either nitrogen heterocycle is five-ring heterocycles, hexa-member heterocycle, benzo five-membered heterocycle or benzo hexa-member heterocycle.
4. Dasatinib derivant as claimed in claim 1 or 2, it is characterised in that heterocyclic radical is unsubstituted or monosubstituted Piperidyl, morpholinyl, indyl, imidazole radicals, pyrazolyl, piperazinyl or pyrrole radicals；When monosubstituted, the choosing of substituent group independence From methyl or ethoxy.
5. a kind of Dasatinib derivant with anti-tumor activity as described in one of claim 1-4 is used as tyrosine kinase Inhibitor, prepare treatment, prevention, alleviate tumor antitumor drug in application.
6. application as claimed in claim 5, it is characterised in that the antitumor drug is treatment, prevention or palliating leukemia, The medicine of colon cancer, pulmonary carcinoma, breast carcinoma, cervical cancer or hepatocarcinoma.
7. application as claimed in claim 6, it is characterised in that described antitumor drug is tablet, capsule, powder, ball Agent, granule or Emulsion.
CN201611238771.XA 2016-12-28 2016-12-28 Dasatinib derivative with anti-tumor activity and application thereof Pending CN106674150A (en)

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CN1348370A (en) * 1999-04-15 2002-05-08 布里斯托尔-迈尔斯斯奎布公司 Cyclic protein tyrosine kinase inhibitors
WO2007056023A2 (en) * 2005-11-02 2007-05-18 Targegen, Inc. Thiazole inhibitors targeting resistant kinase mutations
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