Combination therapy for the treatment of prostate cancer
A technology for prostate cancer, therapy, applied in the field of combination therapy for the treatment of prostate cancer, which can solve the problem of unpredictable overall profile, etc.
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Embodiment 1
[0167] Embodiment 1: the synthesis of compound I
[0168] Step A: 5-Bromo-N 3 Synthesis of -(phenylmethylene)pyridine-2,3-diamine (compound B)
[0169]
[0170] Starting material A was dissolved in methanol and acetic acid. The solution was cooled to 0°C to 5°C and benzaldehyde was added dropwise. Once the reaction is complete, add treated water and NaHCO dropwise 3 solution, kept at low temperature (0°C to 5°C). The solid was filtered off and washed with methanol / water (1:1) followed by drying to give compound B in 94% yield and +99% purity (by HPLC). 1 H-NMR (DMSO-d 6 ): δ8.75(1H), 8.04(2H), 7.93(1H), 7.65(1H), 7.50-7.60(3H).
[0171] Step B: N 3 -Synthesis of benzyl-5-bromopyridine-2,3-diamine (compound C)
[0172]
[0173] Compound B was dissolved in ethanol and NaHB was added portionwise 4 , keeping the temperature between 15°C and 25°C. The reaction mixture was stirred for 8 to 15 hours until completion as monitored by HPLC. The HCl solution was added to...
Embodiment 2
[0186] Example 2: Crystalline Mesylate Salt of Compound I
[0187] About 5 g of compound I was dissolved in ethanol (115 mL) and a solution of methanesulfonic acid in ethanol (10 mL, 158.7 mg / mL) was added according to a 1:1 molar ratio. The mixture was shaken at 50°C for 2 hours, then concentrated to half volume and stirred overnight. The solid formed (mesylate salt of compound I / co-crystal Form I) was isolated, dried and characterized.
[0188] The mesylate salt / co-crystal Form I of Compound I was also obtained from other solvents and solvent mixtures including acetone and acetonitrile.
[0189] The mesylate / co-crystal form I of Compound 1 was characterized by XRPD as comprising the following peaks in 2Θ: 8.4±0.2, 10.6±0.2, 11.7±0.2, 14.5±0.2, 15.3±0.2, 16.9±0.2, 18.2±0.2 0.2, 19.0±0.2, 19.9±0.2, 20.5±0.2, 22.6±0.2, 23.8±0.2, 24.5±0.2 and 27.6±0.2, such as using Cu-K α The radiation tube was measured on a diffractometer ( Figure 4 ).
[0190] The mesylate / co-crystal fo...
Embodiment 3
[0192] Example 3: Synergistic inhibition of VCaP cell viability by combining Compound I with Enzalutamide
[0193] VCaP cells (CRL-2876) were plated at a density of 10,000 cells per well on a 96-well flat-bottomed plate with D-MEM medium (containing 10% charcoal-removed FBS and penicillin / streptomycin), and incubated at 37°C for 5 %CO 2 Incubate for 24 hours. The medium was replaced with D-MEM and incubated at 37°C, 5% CO 2 For 3 to 7 days under incubation, the D-MEM contained 10% charcoal-depleted FBS, and had a constant ratio of Compound I or enzalutamide as a single agent or at four different concentrations (2×IC50, 1×IC50, 0.5×IC50, 0.25×IC50) of 0.1 nM R1881 treated with the combination of the two drugs. If cells were grown for 7 days, they were reprocessed on day 3 or 4 as described above. If cells were grown for 7 days, they were reprocessed on day 3 or 4 as described above. Triplicate wells were used for each concentration and wells containing only medium with 0.1...
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