- Design and synthesis of novel dasatinib analogues
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Design, synthesis, characterization and in vitro biological assay of a series of novel carboxylic acid and amino acid analogs of dasatinib (1) as anticancer agents are reported. Some of the synthesized analogs were identified as potent Src/Abl kinase inhibitors with greater antiproliferative activity against K652 and T315I cancer cell lines. The synthetic process involves condensation of N-(2-chloro-6-methylphenyl)-2-[[6-[4(-1-pipearazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide with carboxylic acids in the presence of dicyclohexylcarbodiimide and oxyma in organic solvent medium. Compounds were characterized and tested for anticancer activity on leukemia cancer cell lines K562 and Baf3/T315. Analogues of lactic acid, mandalic acid, leucine and proline have shown promising antiproliferative activity compared to dasatinib.
- Buchappa,Durgaprasad,Suneelkumar,Rani, P. Baby,Babu, K. Ravi,Rao, A. K. S. Bhujanga,Aparna
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Read Online
- HALOGENATED-HETEROARYL AND OTHER HETEROCYCLIC KINASE INHIBITORS, AND USES THEREOF
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The invention relates to kinase inhibitors, in particular inhibitors of protein kinases including the SIK-family CSF1R, ABL/BCR-ABL, SRC, HCK, PDGFR, KIT and/or their mutants. Although structurally similar to dasatinib, the kinase inhibitors of the invention are distinctive; possessing a particular class of halogenated heteroaryls. Such kinase inhibitors can display one or more certain properties distinct to dasatinib and other structurally similar kinase inhibitors. The kinase inhibitors of the invention or pharmaceutical compositions comprising them may be used in the treatment of a disorder or condition, such as a proliferative disorder, for example, a leukaemia or solid tumour. In particular, these and other structurally similar kinase inhibitors may be used in the treatment of a proliferative disorder - such as a mixed phenotype acute leukaemia (MPAL) - characterised by (inter-alia) the presence of MEF2C protein, a human chromosomal translocation at 11q23, and/or a KMT2A fusion oncoprotein. The kinase inhibitors or pharmaceutical compositions disclosed herein may be used topically to modulate skin pigmentation in a subject, for example to impart UV protection and reduce skin cancer risk.
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- HETEROCYCLIC KINASE INHIBITORS AND USES THEREOF
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The invention relates to kinase inhibitors, in particular inhibitors of protein kinases including the protein-tyrosine kinases LCK, ABL, SRC, KIT, SIK-family and/or their mutants. Although structurally similar to dasatinib, the kinase inhibitors of the invention can display one or more certain properties distinct to dasatinib. Also, the invention relates to pharmaceutical compositions that comprise one or more of the kinase inhibitors. The kinase inhibitors or pharmaceutical compositions of the invention may be used in the treatment of a disorder or condition, such as a proliferative disorder, for example, a leukaemia or solid tumour. The kinase inhibitors or pharmaceutical compositions may be used in a treatment regimen that corresponds to, is similar to or is distinct from that used with dasatinib for a corresponding disorder, and in particular may be used in a combination treatment regimen together with one or more additional therapeutic agents, such as immune-checkpoint inhibitors.
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- Synthesis method of dasatinib key intermediate
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The invention discloses a synthesis method of a dasatinib key intermediate. The synthesis method comprises the step of carrying out dehydration condensation reaction on a compound 2 and a compound 3 to generate a compound 4, i.e., the dasatinib key intermediate. By adopting the synthesis method of the dasatinib key intermediate, disclosed by the invention, the occurrence of side reaction is greatly reduced, the selectivity of the reaction is improved, and the final yield of dasatinib is improved; the synthesis method is suitable for industrial production. A formula is shown in the description.
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- Scalable and impurity-free process for dasatinib: Src and BCR-Abl inhibitor
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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
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p. 1621 - 1628
(2018/06/12)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF DASATINIB POLYMORPH
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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 10-11
(2018/06/22)
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- 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
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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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- New method for preparing dasatinib and dasatinib intermediates
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The invention discloses a new method for preparing dasatinib and dasatinib intermediates. The method is characterized in that dasatinib (1) is prepared from 2-aminothiazole (2) through substitution, hydroxymethylation, oxidation amidation, fixed site chlorination and amination reactions. The method has the advantages of short synthesis route, high reaction yield, cheap and easily available raw materials, great reduction of the production cost, mild reaction conditions, suitableness for industrial large-scale production, avoiding of use of acyl chloride, and reduction of environmental pollution.
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- A reach sha Tini synthesis of intermediates method (by machine translation)
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The invention belongs to the field of medical technology, in particular to a reach sha Tini intermediate N - (2 - chloro - 6 - methylphenyl) - 2 - [(6 - chloro - 2 - methyl - 4 - pyrimidinyl) amino] - 5 - thiazole carboxamide synthetic method, the specific method is, first under the low temperature condition, to the non-proton solvent, sequentially adding organic base, 2 - amino - N - (2 - chloro - 6 - methyl phenyl) thiazole - 5 - carboxamide and 2 - methyl - 4, 6 - two chlorine pyrimidine, then raise the temperature of the reaction process for preparing N - (2 - chloro - 6 - methylphenyl) - 2 - [(6 - chloro - 2 - methyl - 4 - pyrimidinyl) amino] - 5 - thiazole carboxamide, compared with the prior art, the present invention has higher yield and more low maximum shan Za content, is suitable for industrial production. (by machine translation)
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Paragraph 0016; 0026; 0027; 0029; 0031; 0033; 0035; 0037
(2017/08/26)
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- A convenient new and efficient commercial synthetic route for dasatinib (Sprycel)
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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
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supporting information
p. 1610 - 1621
(2017/09/08)
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- Preparation method of dasatinib
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The invention discloses a preparation method of dasatinib. The preparation method comprises the following steps: (1) preparing N-(2-chloro-6-methyl-phenyl)-2-[(6-chloro-2-methyl-4-pyrimidyl)amino]-5-thiazole carboxamides; (2) preparing a dasatinib crude product; (3) refining the dasatinib: adding the dasatinib crude product and absolute methanol into a reaction kettle, stirring, performing nitrogen displacement, heating to refluxing while stirring, cooling, adding a seed crystal, stirring materials uniformly, cooling to 5 to 10 DEG in a uniform-speed cooling way, stirring at a constant temperature, filtering the materials, leaching an obtained filter cake with a proper amount of methanol, and drying the filter cake in a gradient heating way to a constant weight to obtain a dasatinib product. The preparation method has the advantages of simple process, high product yield and high product purity; the prepared Dasatinib product of a Form I crystal form has high stability, and the bioavailability of the product is equivalent to an existing T1H1-7 crystal form product.
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Paragraph 0055; 0056; 0057
(2018/02/04)
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- Tyrosine kinase inhibitor and preparation method and use thereof
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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; 0110
(2017/07/19)
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- EMS ANALOGUES OF LYN/SRC-TYROSINE KINASE INHIBITORS
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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)
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- A is suitable for industrial production reaches Sha Tini method for the synthesis of
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The invention discloses a preparation method for dasatinib. The preparation method includes using an intermediate II as a starting raw material; preparing an intermediate III; preparing a thiourea derivative; synthesizing imide; performing cyclization to generate thiophene; performing condensation and the like to prepare the dasatinib. A novel ideal and the novel method are provided for synthesizing the dasatinib, and the preparation method has the advantages of simplicity and convenience in operation, mild reaction condition, convenience in purification and suitability for industrial manufacturing.
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Paragraph 0031; 0035
(2017/02/09)
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- PROCESS FOR PREPARING DASATINIB MONOHYDRATE
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The present invention provides an improved process for preparing N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate or Dasatinib monohydrate (Formula A).
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Paragraph 0067-0069
(2015/03/04)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF DASATINIB
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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)
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- Biological evaluation of 2-methylpyrimidine derivatives as active pan Bcr-Abl inhibitors
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We designed a series of 2-methylpyrimidine derivatives as new BCR-ABL inhibitors using scaffold-hopping strategy. These synthetic compounds exhibited significant inhibition against a broad spectrum of Bcr-Abl mutants including the gatekeeper T315I mutant. Compound 7u showed very potent kinase inhibitory activities against Bcr-Abl WT, Bcr-Abl E255K, Bcr-Abl Q252H, Bcr-Abl G250E and Bcr-Abl T315I, with IC50 values of 0.13 nM, 0.17 nM, 0.24 nM, 0.19 nM and 0.65 μM, respectively. This compound also displayed anti-proliferation activity against K562 cell line with an IC50 value of 1.1 nM, thus representing a new lead for further optimization.
- Zou, Dingbiao,Qiu, Yatao,Tu, Zhengchao,Liao, Chenzhong,Luo, Jinfeng,Meng, Qingqing,Yao, Risheng,Li, Zheng,Jiang, Sheng
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p. 823 - 832
(2014/06/24)
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- Design and synthesis of minimalist terminal alkyne-containing diazirine photo-crosslinkers and their incorporation into kinase inhibitors for cell- and tissue-based proteome profiling
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Less is more: A minimalist "clickable" photo-crosslinker (see scheme) was incorporated with numerous small-molecule kinase inhibitors. The resulting probes were used for both in vitro (cell lysates) and in situ (live cells) proteome profiling, for large-scale identification of their potential cellular kinase targets and shows improved outcomes over previous probes. Copyright
- Li, Zhengqiu,Hao, Piliang,Li, Lin,Tan, Chelsea Y. J.,Cheng, Xiamin,Chen, Grace Y. J.,Sze, Siu Kwan,Shen, Han-Ming,Yao, Shao Q.
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p. 8551 - 8556
(2013/09/12)
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- Cell-based proteome profiling of potential Dasatinib targets by use of affinity-based probes
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Protein kinases (PKs) play an important role in the development and progression of cancer by regulating cell growth, survival, invasion, metastasis, and angiogenesis. Dasatinib (BMS-354825), a dual Src/Abl inhibitor, is a promising therapeutic agent with oral bioavailability. It has been used for the treatment of imatinib-resistant chronic myelogenous leukemia (CML). Most kinase inhibitors, including Dasatinib, inhibit multiple cellular targets and do not possess exquisite cellular specificity. Recent efforts in kinase research thus focus on the development of large-scale, proteome-wide chemical profiling methods capable of rapid identification of potential cellular (on- and off-) targets of kinase inhibitors. Most existing approaches, however, are still problematic and in many cases not compatible with live-cell studies. In this work, we have successfully developed a cell-permeable kinase probe (DA-2) capable of proteome-wide profiling of potential cellular targets of Dasatinib. In this way, highly regulated, compartmentalized kinase-drug interactions were maintained. By comparing results obtained from different proteomic setups (live cells, cell lysates, and immobilized affinity matrix), we found DA-2 was able to identify significantly more putative kinase targets. In addition to Abl and Src family tyrosine kinases, a number of previously unknown Dasatinib targets have been identified, including several serine/threonine kinases (PCTK3, STK25, eIF-2A, PIM-3, PKA C-α, and PKN2). They were further validated by pull-down/immunoblotting experiments as well as kinase inhibition assays. Further studies are needed to better understand the exact relevance of Dasatinib and its pharmacological effects in relation to these newly identified cellular targets. The approach developed herein should be amenable to the study of many of the existing reversible drugs/drug candidates.
- Shi, Haibin,Zhang, Chong-Jing,Chen, Grace Y. J.,Yao, Shao Q.
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p. 3001 - 3014
(2012/04/10)
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- A new and efficient preparation of 2-aminothiazole-5-carbamides: Applications to the synthesis of the anti-cancer drug dasatinib
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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.
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experimental part
p. 32 - 38
(2010/09/05)
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- 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
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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)
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- 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
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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.
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p. 6819 - 6832
(2007/10/03)
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- PROCESS FOR PREPARING 2-AMINOTHIAZOLE-5-AROMATIC CARBOXAMIDES AS KINASE INHIBITORS
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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 51-52
(2008/06/13)
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- Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56Lck inhibitors
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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.
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p. 6061 - 6066
(2007/10/03)
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- Cyclic protein tyrosine kinase inhibitors
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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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- Discovery of N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays
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A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole- 5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.
- Lombardo, Louis J.,Lee, Francis Y.,Chen, Ping,Norris, Derek,Barrish, Joel C.,Behnia, Kamelia,Castaneda, Stephen,Cornelius, Lyndon A. M.,Das, Jagabandhu,Doweyko, Arthur M.,Fairchild, Craig,Hunt, John T.,Inigo, Ivan,Johnston, Kathy,Kamath, Amrita,Kan, David,Klei, Herbert,Marathe, Punit,Pang, Suhong,Peterson, Russell,Pitt, Sidney,Schieven, Gary L.,Schmidt, Robert J.,Tokarski, John,Wen, Mei-Li,Wityak, John,Borzilleri, Robert M.
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p. 6658 - 6661
(2007/10/03)
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