Compositions comprising DHODH inhibitors for treatment of acute myelogenous leukemia
A technology of DHODH and acute myeloid system, applied in the direction of drug combination, medical preparations containing active ingredients, organic active ingredients, etc., can solve the problems of unmet medical needs of acute myeloid leukemia
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[0146] Preparation of Compound A .
[0147] Intermediate 1: 3'-Butoxy-3-chloro-5-fluorobiphenyl-4-amine :
[0148] 4-Bromo-2-chloro-6-fluoroaniline (0.2 g, 0.89 mmol) and 3-butoxyphenylboronic acid (0.224 g, 1.16 mmol) to prepare the title compound (3'-butoxy-3-chloro-5-fluorobiphenyl-4-amine) (0.190 g). with N 2 The mixture was degassed for 30 minutes, and the mixture was refluxed until both starting materials disappeared, as monitored by TLC. post-processing (H 2 O / AcOEt) and purification gave the desired product (0.19 g) as a yellow solid. 1 H-NMR (δppm, DMSO-d 6 ,400MHz):7.44-7.41(m,2H),7.27(t,J 7.9,1H),7.17-7.10(m,2H),6.81-6.84(m,1H),5.50(s,2H),4.01( t, J 5.3, 2H), 1.72-1.65 (m, 2H), 1.50-1.41 (m, 2H), 0.93 (t, J 7.4, 3H).
[0149] Compound A: 2-(3'-butoxy-3-chloro-5-fluorobiphenyl-4-ylcarbamoyl)benzoic acid
[0150] Intermediate 1 (90 mg, 0.31 mmol) was dissolved in about 2 ml of acetic acid. Phthalic anhydride (90 mg, 0.6 mmol) was added to the mixture an...
Embodiment 1
[0155] Antiproliferative effect of compound A in AML cell lines (MTT assay)
[0156] Compound A was tested in a panel of AML cell lines (U937, HL-60, THP-1, KG-1 and MV411). Cells were plated in 96-well plates and incubated with the desired concentration of Compound A for 72 hours (h). At the end of the incubation period, MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)) was added. The plates were placed on a shaker for 5 minutes to mix the formazan and measure the optical density at 560 nM on a spectrophotometer. Plot data using Graphpad prism for calculating GI 50 concentration.
[0157] Results: All AML cell lines tested were sensitive to Compound A with GI 50 in the range between 2.4 μM and 7.6 μM. (see Table 1).
[0158] Table 1
[0159]
Embodiment 1A
[0161] Antiproliferative effect of Compound A in AML cell lines in the presence of uridine rescue (MTT assay)
[0162] In the absence of uridine (U937, HL-60, THP-1 and MV411 cell lines) or in the presence of uridine (100 μM for U937, HL-60 and MV411 and 100 μM for THP-1 Compound A was tested at 300 μM). Cells were plated in 96-well plates and incubated with the desired concentration of Compound A for 72h. At the end of the incubation period, MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)) was added. The plates were placed on a shaker for 5 minutes to mix the formazan and measure the optical density at 560 nM on a spectrophotometer. Plot data using Graphpad prism for calculating GI 50 concentration.
[0163] Results: Addition of 100 μM or 300 μM uridine caused the activity of Compound A to shift to the right, where GI 50 >10 μM. (See Table 1A).
[0164] Table 1A
[0165]
[0166] in conclusion. Compound A inhibited the growth of AML cell li...
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