Histone deacetylase inhibitor (E)-3-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetamido)-N-hydroxy-butyl-2-enamide and its preparation method and use
A chlorobenzoyl and deacetylase technology, which is applied in anti-inflammatory agents, drug combinations, antiviral agents, etc., can solve problems such as difficult absorption, poor pharmacokinetic properties, and short half-life
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Problems solved by technology
Method used
Image
Examples
preparation example Construction
[0016] The preparation method of described compound, reaction steps and reaction formula are as follows:
[0017] The preparation method comprises the following steps:
[0018] Synthetic route: using indomethacin as raw material, first condense with methyl 3-aminocrotonate, then react with hydroxylamine potassium nucleophile, and finally obtain the final product; the reaction formula is as follows:
[0019] synthetic route:
[0020]
[0021] Reagents in the reaction formula of the above synthetic route 2: (1) methyl 3-aminocrotonate, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid, triethylamine , dichloromethane; (2) potassium hydroxylamine, anhydrous methanol;
[0022] Preparation of the intermediate of the histone deacetylase inhibitor, the intermediate is: (E)-methyl 3-(2-(1-(4-chlorobenzoyl)-5-methoxy-2- Methyl-1hydro-indol-3-yl)acetamido)but-2-enoate.
[0023] Due to the high homology of the catalytic center of each subtype of zinc ion-dependent...
Embodiment 1
[0044] Synthesis of compounds of the present invention
[0045] synthetic route:
[0046] (E)-Methyl 3-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1hydro-indol-3-yl)acetamido)butan-2 -enoate
[0047] Indomethacin (1.97g, 5mmol) was dissolved in 50mL tetrahydrofuran, triethylamine (0.55g, 5.5mmol) was added, O-benzotriazole-N,N,N',N'-tetramethyl Urea tetrafluoroboric acid (TBTU) (1.8 g, 5.5 mmol). After reacting at room temperature for 20 minutes, methyl 3-aminocrotonate (1.8 g, 5 mmol) was added, followed by triethylamine (0.5 g, 5 mmol). After reacting at room temperature for 6 hours, distill off the tetrahydrofuran in the reaction liquid, dissolve the product with ethyl acetate, wash with 1 mol / L citric acid solution, saturated sodium bicarbonate solution, and saturated saline respectively three times, and dry over anhydrous magnesium sulfate. , The solvent was evaporated to dryness to obtain a crude product, which was recrystallized from ethyl acetate to obtain 1.37 g ...
Embodiment 2
[0051] Example 2 Target compound inhibits histone deacetylase activity test (Invitro)
[0052] The fluorescent analysis method of histone deacetylase (HDACs) activity is mainly divided into two steps: the first step is to use a lysine HDACs fluorescent substrate (Boc-Lys(acetyl)-AMC) containing an acetylated side chain, and use Hela cell extract samples of protein deacetylases (including HDAC1, HDAC2, HDAC3 and HDAC8) were incubated to deacetylate and activate substrates. In the second step, trypsin is used to hydrolyze Boc-Lys-AMC to generate AMC, a fluorescent group (ie, a chromophore), and the fluorescence intensity is measured at the emission wavelength / excitation wavelength (390nm / 460nm), so that according to the inhibitor group and control The inhibition rate was calculated from the fluorescence intensity of each group, and the IC50 value was calculated. For the principle of enzyme activity test, please refer to the relevant content of this patent specification. The ...
PUM
Login to View More Abstract
Description
Claims
Application Information
Login to View More