Dasatinib monohydrate

Description

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

Uses

Dasatinib Monohydrate is an orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. It is a COVID19-related research product. It is used in the treatment of patients with chronic myeloid leukemia who are resistant or intolerant to imatinib.

Definition

Dasatinib monohydrate is 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； dasatinib monohydrate) as well as to anhydrous dasatinib (INN). It has a role as an antineoplastic agent and a tyrosine kinase inhibitor. It contains a dasatinib (anhydrous).

brand name

Sprycel (Bristol-Myers Squibb).

Biological Activity

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.

Synthesis

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).

in vitro

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].

in vivo

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].

IC 50

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

References

[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 -