863127-77-9

Dasatinib monohydrate is a highly potent, ATP competitive, orally active dual Src/Bcr-Abl inhibitor with potent antitumor activity.

antineoplastic

ChEBI: A hydrate that is the monohydrate of dasatinib. It is used for the treatment of chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia. Note that the name 'dasatinib' is used to refer to the monohydrate (USAN) as well as to anhyd ous dasatinib (INN).

Sprycel (Bristol-Myers Squibb).

chronic myeloid leukemia (cml) is a disease characterized by the presence of the philadelphia (ph+) chromosome and its oncogenic product, bcr-abl, that is present in >90% of the patients. dasatinib (bms-354825) is a novel, potent, and multitargeted kinase inhibitor that targets abl, src, kit, pdgfr, and other tyrosine kinases.

General procedure: to a mixture of N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide (4.00 g, 10.14 mmol) and N-hydroxyethylpiperazine (6.60 g, 50.69 mmol) in n-butanol (40 mL) was added N,N-diisopropylethylamine (DIPEA, 3.53 mL, 20.26 mmol). The reaction mixture was heated with stirring at 118 °C for 4.5 h, followed by slow cooling to room temperature. The precipitated solid was collected by vacuum filtration and washed with n-butanol (5 mL) and subsequently dried. The crude product (5.11 g) was dissolved in hot 80% ethanol-water (80 mL) and the solution was clarified by filtration. The hot filtrate was slowly diluted with water (15 mL) and slowly cooled to room temperature. The precipitated solid was collected by vacuum filtration, washed with 50% ethanol-water (5 mL) and dried to afford N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-5-thiazolecarboxamide hydrate 4.27 g in 83.2% yield.1H NMR (400 MHz, DMSO -d6) δ 2.23 (s, 3H), 2.40 (s, 3H), 2.42 (t, 2H, J = 6 Hz), 2.48 (t, 4H, J = 6.3 Hz), 3.50 (m, 4H), 3.53 (q, 2H, J = 6 Hz), 4.45 (t, 1H, J = 5.3 Hz), 6.04 (s, 1H), 7.25 (t, 1H , J = 7.6 Hz), 7.27 (dd, 1H, J = 7.6, 1.7 Hz), 7.40 (dd, 1H, J = 7.6, 1.7 Hz), 8.21 (s, 1H), 9.87 (s, 1H), 11.47 (s, 1H).

dasatinib is a potent atp-competitive inhibitor in biochemical assays with broad-spectrum antiproliferative activities against hematological and solid tumor cell lines. dasatinib was more potent than imatinib at inhibiting nonmutated bcr-abl kinase activity. in addition, the kinase activity of 14 out of 15 different clinically relevant, imatinib-resistant bcr-abl isoforms was successfully inhibited [1].

mice were dosed with dasatinib or vehicle alone by gavage for 2 weeks, beginning 3 days after injection of ba/f3 cells. all vehicle-treated mice developed progressive disease. in contrast, dasatinib–treated mice harboring nonmutant bcr-abl or the clinically common imatinib-resistant mutation m351t appeared healthy with no evidence of weight loss, lethargy, or ruffled fur and showed more than one log lower levels of bioluminescent activity after 2 weeks of therapy [2].

0.55 and 3.0 nm for src and bcr-abl tyrosine kinases, respectively

[1] shah np, tran c, lee fy, chen p, norris d, sawyers cl. overriding imatinib resistance with a novel abl kinase inhibitor. science. 2004 jul 16;305(5682):399-401.
[2] monika conchon, carla maria boquimpani de moura freitas, maria aparecida do carmo rego, and josé wilson ramos braga junior. dasatinib -