cas 302964-24-5, 2-Amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

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SUBSTITUTED ARYLUREA COMPOUNDS FOR INDUCING APOPTOSIS AND COMPOSITION FOR ANTICANCER COMPRISING THE SAME
The present invention relates to a substituted arylurea compound inducing apoptosis and an anticancer composition comprising the same. The present invention relates to a novel compound capable of preventing, treating and alleviating cancer diseases such as prostate cancer, breast cancer, lung cancer, colorectal cancer, and skin cancer by inhibiting apoptosis of cancer cells and inhibiting proliferation of cancer cells.
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(2021/08/17)

Protein kinase inhibitor and use thereof
The present invention provides a compound of formula 1 having an activity of inhibiting protein kinase and its use.
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Paragraph 0091; 0098-0099; 0135; 0138-0139

(2021/01/21)

Preparation process of dasatinib
The invention relates to a preparation process of dasatinib. The preparation process includes the following steps that 3-ethyl propionate reacts with 2-chlorine-6-methylaniline under an alkaline condition to obtain a compound 3; the compound 3, copper bromide and thiourea react under action of hydroxyethyl-beta-cyclodextrin to obtain 2-amino-N-(2-chlorine-6-methyl phenyl) thiazole-5-formamide through a heating reaction; secondly, 4,6-dichloro-2-methyl pyrimidine reacts with N-hydroxyethyl piperazine, 2-amino-N-(2-chloro-6-methyl phenyl) thiazole-5-formamide sequentially in the presence of alkali, a catalytic system and an organic solvent, and a compound 1, namely dasatinib, is obtained. The conditions are mild, the steps are simple, the process is environmentally friendly, the yield is high, and the process is suitable for industrial production.
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Paragraph 0055; 0056-0064; 0081; 0082; 0083; 0084-0086

(2019/06/27)

A reach [...] preparation method
The invention relates to a preparation method of up to [...], the method comprises the following steps: 3 - ethyl oxo propionic acid under alkaline condition first with 2 - chloro - 6 - methylaniline reaction, then adding [...] copper solution reaction, to obtain compound 3; with the thiourea reaction, from 2 - amino - N - (2 - chloro - 6 - methyl phenyl) thiazole - 5 - carboxamide; after the 4, 6 - dichloro - 2 - methyl pyrimidine in alkali, catalytic system, organic solvents, successively with the N - hydroxyethyl piperazine, 2 - amino - N - (2 - chloro - 6 - methyl phenyl) thiazole - 5 - carboxamide reaction, to obtain compound 1, has reached the [...]. Mild condition of this invention, the step is simple, short reaction time, speed, friendly to the environment and have high yield, is suitable for industrial production.
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Paragraph 0033; 0051-0056; 0071-0076

(2019/07/01)

Preparation method of dasatinib intermediate
The invention relates to a preparation method of a dasatinib intermediate. The method comprises the following steps: performing heating reflux on ethyl 3-oxopropanoate and 2-chloro-6-methylaniline under alkaline conditions, adding copper bromide, and performing warming reflux to obtain a compound 2; and cyclizing the compound 2 and thiourea in a solvent PEG 400 to obtain a target product, namely 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide. The method involved in the invention has mild conditions, simple steps, environmental friendliness and high yield, and is suitable for industrial production.
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Paragraph 0041-0048; 0053; 0054

(2019/04/04)

Preparation process of dasatinib
The invention relates to a preparation process of dasatinib. The method comprises the following steps: enabling 3-oxopropionic acid ethyl ester to react firstly with 2-chlo-6-methylaniline under an alkaline condition, then adding a solvent dissolved with cupric bromide, and reacting to obtain a compound 3; cyclizing the compound 3 and thiourea in solvent water to obtain 2-amino-N-(2-chlo-6-methylphenyl)thiazole-5-formamide; and then synthesizing dasatinib from 4,6-dichloro-2-methyl pyrimidine, N-ethoxyl piperazine, and 2-amino-N-(2-chlo-6-methyl phenyl)thiazole-5-formamide through a one-pot method under the actions of an alkali K3PO4 and a catalyst 1-butyl-3-methylimidazole glycinate. The conditions are mild, the steps are simple, and the preparation process is environmentally-friendly, high in yield and suitable for industrial production.
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Paragraph 0034; 0053-0064; 0079; 0080

(2019/05/08)

Method for preparing dasatinib tablets
The invention relates to a method for preparing dasatinib tablets. The method comprises the following steps: enabling 3-oxo-ethyl propionate to react with 2-chlorine-6-methylaniline under an alkali condition, further adding a solvent in which cupric bromide is dissolved to carry out a reaction, further adding thiourea, and cyclizing with a catalyst so as to obtain 2-amino-N-(2-chlorine-6-methyphenyl)thiazole-5-formamide; further synthesizing dasatinib tablets from 4,6-dichloro-2-methyl pyrimidine, N-ethoxy piperazine and 2-amino-N-(2-chlorine-6-methyphenyl)thiazole-5-formamide according to a one-pot method under the action of an alkali and an ionic liquid 1-butyl-3-methylimidazole glycinate. The method is mild in condition, simple in step, environmentally friendly, high in yield and applicable to industrial production.
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Paragraph 0043-0056; 0069-0074

(2019/04/04)

Process for preparing dasatinib
The invention relates to a process for preparing dasatinib. The process includes steps of carrying out heating reflux on 3-oxo-propionic acid ethyl ester and 2-chlorine-6-methylaniline under alkalineconditions, adding cupric bromide, carrying out temperature-rise reflux, adding thiourea and a catalyst heteropoly acid salt, and carrying out room-temperature stirring reaction to obtain 2-amine-N-(2-chlorine-6-methyl phenyl)thiazole-5-formamide; carrying out 'one-pot reaction' on the 2-amine-N-(2-chlorine-6-methyl phenyl)thiazole-5-formamide, 4, 6-dichloro-2-methylpyrimidine and N-hydroxyethyl piperazine under the effects of catalysts to obtain the dasatinib. The process has the advantages of mild condition, simple step, environmental friendliness, high yield and applicability to industrialproduction.
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Paragraph 0041-0048; 0056-0063

(2019/03/08)

Scalable and impurity-free process for dasatinib: Src and BCR-Abl inhibitor
An efficient, telescopic, impurity-free and scalable process for Bcr-Abl and Src family tyrosine kinase inhibitor for synthesis of Dasatinib with high yield and purity is described.
Buchappa,Sagar Vijay Kumar,Durga Prasad,Aparna
p. 1621 - 1628
(2018/06/12)

AN IMPROVED PROCESS FOR THE PREPARATION OF DASATINIB POLYMORPH
The present invention is related to an improved process for the preparation of dasatinib anhydrous crystalline Neat form N-6 with high purity and high yield. The present invention also relates to purification of dasatinib crystalline Neat form N-6.
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Page/Page column 9-10

(2018/06/22)

Tyrosine kinase inhibitor and preparation method and use thereof
The invention relates to a tyrosine kinase inhibitor and a preparation method and use thereof, and belongs to the technical field of pharmaceutical chemistry. The tyrosine kinase inhibitor having the structural features shown in the general formula I, or its pharmaceutically acceptable salts or stereoisomers can effectively inhibit tyrosine kinase activity, and can inhibit kinases such as DDR1, DDR2, Abl, Src, Btk and Kit. Compared with a positive contrast dasatinib, the tyrosine kinase inhibitor has higher half inhibitory concentration or the same half inhibitory concentration, and especially, aiming at DDR1, DDR2, Src, Btk and Kit, the compound 8j has lower K562 cell half inhibitory concentration. The tyrosine kinase inhibitor has good enzyme inhibitory activity and cell activity and has a large application prospect.
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Paragraph 0102; 0106; 0109

(2017/07/19)

CRYSTALLINE FORMS OF N-(2-CHLORO-6-METHY]PHENVN-2-[F6-[4-(2-HVDROXVETHVL)-L- PIPERAZINVIL-2-METHVL-4-PVRIMIDINVLLAMINOL-5-THIAZOLECARBOXAMIDE AND THEIR PROCESS THEREOF
The present invention relates to crystalline 1,2-Propanediol solvate of N-(2-chloro-6- methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]ainino]-5- thiazolecarboxamide compound of formula- lb, its process for the preparation and its use in the preparation of anhydrous crystalline form (N-6) and monohydrate of N-(2-chloro-6- methy lphenyl)-2- [ [6- [4-(2 -hydroxy ethyl)- 1 -piperazinyl] -2-methyl-4-pyrimidinyl]amino] -5 - thiazolecarboxamide. [formula] 1,2-Propanediol solvate Formula- lb
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Page/Page column 17; 18

(2017/01/26)

A convenient new and efficient commercial synthetic route for dasatinib (Sprycel)
A new and efficient synthetic route for dual-Src/Abl kinase inhibitor dasatinib (Sprycel), an anticancer drug, is described. This commercially viable process yields dasatinib monohydrate free of potential impurities with consistent yield of 68% in route A and 61% in route B with HPLC purity >99.80% over four stages.
Suresh, Garbapu,Nadh, Ratnakaram Venkata,Srinivasu, Navuluri,Yennity, Durgaprasad
supporting information
p. 1610 - 1621
(2017/09/08)

Dasatinib derivative with anti-tumor activity and application thereof
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.
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Paragraph 0032-0036

(2017/07/12)

EMS ANALOGUES OF LYN/SRC-TYROSINE KINASE INHIBITORS
Embodiments of the present invention are directed to compounds of the formula API―LG―ESM wherein "API" is a monovalent substituent group of an enzyme inhibitor; "LG" is a divalent substituent group of a linking group; and "ESM" is a monovalent substituent group of an esterase sensitive motif; or a pharmaceutically acceptable salt thereof. Other embodiments are directed to methods for using compounds of the formula API―LG―ESM to treat a number of medical conditions, including Alzheimer's disease.
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Paragraph 00105; 00106

(2017/07/06)

Preparation method for intermediate of anti-cancer drug dasatinib
The invention discloses a preparation method for an intermediate of the anti-cancer drug dasatinib. The preparation method comprises the following steps: mixing N-(2-chloro-6-methylphenyl)-3-ethyoxyacrylamide and cuprous bromide with 1-butyl-3-methylimidazole tetraborofluoride under stirring; and then adding thiourea into the mixture obtained in the previous step and carrying out a contact reaction so as to obtain the dasatinib intermediate 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-methanamide. The preparation method provided by the invention is simple in steps, mild in conditions, high in yield and substantially shortened in reaction time.
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Paragraph 0024; 0029; 0030

(2016/12/22)

2,3-dimethyl-6-urea -2H-indazoles and its preparation method and application
The invention discloses a 2, 3-dimethyl-6-urea-2H-indazole compound shown by the following general formula (I), medicinal salt or a solvent compound thereof, wherein Ar is substituted or unsubstituted phenyl or aromatic matrix. The invention also discloses a preparation method and application of the compound. The compound can regulate signal transduction of tyrosine kinase, inhibit bad cellular proliferation, and particularly has obvious curative effect for tumors.
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Paragraph 0221-0224

(2016/10/09)

Synthetic method of medicine namely parecoxib sodium for treating leukaemia
The invention discloses a synthetic method of a medicine namely parecoxib sodium for treating leukaemia. The method comprises the following steps of (1) stirring and mixing N-(2-chlorine-6-methylphenyl)-3-ethoxy acrylamide with iodine monobromide and 1-butyl-3-methyl bromide imidazolium so as to obtain a mixture, then adding thiourea to the mixture obtained by mixing, and performing a contact reaction so as to obtain 2-amino-N-(2-chlorine-6-methylphenyl) thiazole-5-formylamine; and (2) enabling the 2-amino-N-(2-chlorine-6-methylphenyl) thiazole-5-formylamine obtained in the step (1) and 1-methyl-4-chlorine-6-(4-hydroxyethyl-piperydyl) pyrimidine to be subjected to a reaction in the presence of alkali so as to obtain the parecoxib sodium. The method for preparing the parecoxib sodium disclosed by the invention is simple in steps, mild in conditions and high in yield, and besides, the reaction time is also greatly shortened.
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Paragraph 0029; 0030; 0031

(2017/01/19)

AN IMPROVED PROCESS FOR THE PREPARATION OF DASATINIB
The present invention relates to a novel synthetic route to N-(2-chloro-6-methylphenyl)- 2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl] -2-methyl-4-pyrimidyl] amino]-5- thiazolformamide of the formula I and also relates to the process for the preparation of novel amorphous forms of dasatinib (formula I).
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Page/Page column 20

(2015/04/22)

PROCESS FOR THE PREPARATION OF DASATINIB AND ITS INTERMEDIATES
The present invention relates to processes for the preparation of dasatinib and its intermediates.
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Page/Page column 17

(2014/07/21)

Synthesis and biological activities of 2-amino-thiazole-5-carboxylic acid phenylamide derivatives
In an attempt to develop potent and selective anti-tumor drugs, a series of novel 2-amino-thiazole-5-carboxylic acid phenylamide derivatives were designed based on the structure of dasatinib. All compounds were synthesized by a systematic combinatorial chemical approach. Biological evaluation revealed that N-(2-chloro-6-methylphenyl)-2-(2-(4-methylpiperazin-1-yl)acetamido) thiazole-5-carboxamide (6d) exhibited high antiproliferative potency on human K563 leukemia cells comparable to dasatinib. Against mammary and colon carcinoma cells 6d was either inactive (MDA-MB 231) or distinctly less active (MCF-7 and HT-29: IC50=20.2 and 21.6μM, respectively). Dasatinib showed at each cell line IC501μM. The results of this structure activity relationship study clearly documented that the pyrimidin-4-ylamino core of dasatinib is responsible for the anti-tumor activity against non-leukemia cell lines.
Liu, Wukun,Zhou, Jinpei,Qi, Fan,Bensdorf, Kerstin,Li, Zhiyu,Zhang, Huibin,Qian, Hai,Huang, Wenlong,Cai, Xueting,Cao, Peng,Wellner, Anja,Gust, Ronald
experimental part
p. 451 - 458
(2012/02/01)

Synthesis and cytotoxicity of novel 2-amino-5-thiazolecarboxamide derivatives
A series of novel 2-amino-5-thiazolecarboxamide derivatives have been designed and synthesised. All the compounds were evaluated for their antiproliferative activity against human leukaemia cancer HL 60 and K562 cell lines by standard MTT assay in vitro. Some of these compounds showed moderate cytotoxic potencies. Structure-activity relationships suggested that the piperazine moiety in the side chain of 2-amino-5-thiazolecarboxamide was associated with an increase in the cytotoxicity.
Li, Hu,Yue, Yun,Hu, Xiao-Jun,Zhao, Sheng-Yin
p. 416 - 419
(2011/10/08)

A new and efficient preparation of 2-aminothiazole-5-carbamides: Applications to the synthesis of the anti-cancer drug dasatinib
A new and efficient method has been developed for the synthesis of 2-amino-N-(-(2-chloro-6-methylphenyl)-thiazole-5-carboxamide. The new method involves a chemoselective α-bromination of β-ethoxyacrylamide followed by a one-pot treatment with thiourea to give the desired 2-aminothiazole-5-carboxylamide in excellent yield. Application of this new method to the efficient synthesis of the anti-cancer drug dasatinib was demonstrated.
Chen, Bang-Chi,Zhao, Rulin,Wang, Bei,Droghini, Roberto,Lajeunesse, Jean,Sirard, Pierre,Endo, Masaki,Balasubramanian, Balu,Barrisha, Joel C.
experimental part
p. 32 - 38
(2010/09/05)

TRIAZINE DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
The present invention comprises inter alia compounds as shown in formula (I) or a pharmaceutically acceptable salt thereof.
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Page/Page column 84

(2010/12/29)

TRIAZINE DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
The invention provides for Triazine derivatives and their use to modulate protein kinase activity in a variety of conditions and diseases.
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Page/Page column 53-54

(2008/12/06)

PROCESS FOR PREPARING N-(2-CHLORO-6-METHYLPHENYL)-2-[[6-[4-(2-HYDROXYETHYL)-1-PIPERAZINYL]-2-METHYL-4-PYRIMIDINYL]AMINO] -5-THIAZOLECARBOXAMIDE AND RELATED METABOLITES THEREOF
The present invention is directed to process for the preparation of metabolites as well as the parent compound of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazolecarboxamide, the compound of formula (I).
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Page/Page column 27; 28

(2010/11/28)

Preparation of 2-amino-thiazole-5-carboxylic-acid derivatives
A method for preparing a compound of the structure I,
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Page/Page column 3

(2008/06/13)

2-Aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6- [4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-1, 3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor
2-Aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 ～ 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFα production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Das, Jagabandhu,Chen, Ping,Norris, Derek,Padmanabha, Ramesh,Lin, James,Moquin, Robert V.,Shen, Zhongqi,Cook, Lynda S.,Doweyko, Arthur M.,Pitt, Sidney,Pang, Suhong,Shen, Ding Ren,Fang, Qiong,De Fex, Henry F.,McIntyre, Kim W.,Shuster, David J.,Gillooly, Kathleen M.,Behnia, Kamelia,Schieven, Gary L.,Wityak, John,Barrish, Joel C.
p. 6819 - 6832
(2007/10/03)

PROCESS FOR PREPARING 2-AMINOTHIAZOLE-5-AROMATIC CARBOXAMIDES AS KINASE INHIBITORS
The invention relates to processes for preparing compounds having the formula (I) and crystalline forms thereof, wherein Ar is aryl or heteroaryl, L is an optional alkylene linker, and R2, R3, R4, and R5, are as defined in the specification herein, which compounds are useful as kinase inhibitors, in particular, inhibitors of protein tyrosine kinase and p38 kinase.
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Page/Page column 51

(2008/06/13)

Cyclic protein tyrosine kinase inhibitors
Novel cyclic compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders.
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Page 94

(2010/02/06)

Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56Lck inhibitors
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy. A series of substituted 2-(aminoheteroaryl)- thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy.
Chen, Ping,Norris, Derek,Das, Jagabandhu,Spergel, Steven H.,Wityak, John,Leith, Leslie,Zhao, Rulin,Chen, Bang-Chi,Pitt, Sidney,Pang, Suhong,Shen, Ding Ren,Zhang, Rosemary,De Fex, Henry F.,Doweyko, Arthur M.,McIntyre, Kim W.,Shuster, David J.,Behnia, Kamelia,Schieven, Gary L.,Barrish, Joel C.
p. 6061 - 6066
(2007/10/03)

Discovery and initial SAR of 2-amino-5-carboxamidothiazoles as inhibitors of the Src-family kinase p56Lck
A novel series of 2-amino-5-carboxamidothiazoles were identified as inhibitors of Lck. Structure-activity studies demonstrate the structural requirements for potent Lck activity. Cyclopropylamide 11d is a potent Lck inhibitor having sub-micromolar activity in a PBL proliferation assay.
Wityak, John,Das, Jagabandhu,Moquin, Robert V.,Shen, Zhongqi,Lin, James,Chen, Ping,Doweyko, Arthur M.,Pitt, Sidney,Pang, Suhong,Shen, Ding Ren,Fang, Qiong,De Fex, Henry F.,Schieven, Gary L.,Kanner, Steven B.,Barrish, Joel C.
p. 4007 - 4010
(2007/10/03)