Novel dual peptidase inhibitors as prodrugs for the therapy of inflammatory and other disorders
A configuration, residue technology, applied in the field of new substances and compounds, can solve problems such as reducing effect
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Embodiment 1
[0353] The preparation of the compound of general formula (1)
[0354] Compounds of general formula (1) are prepared using the following method:
[0355] (a) Compound II (Scheme 12)
[0356] 440mg (1mmol) (Boc-Cys-OH) 2 1 was dissolved in 5 ml of anhydrous THF. Under argon, 158 μl (2 mmol) of thiazolidine was added to the solution, and after 25 minutes at 0°C, 460 mg (2,4 mmol) of N'-(3-dimethylaminopropyl)-N-ethyl Carbodiimide (EDC). Conversion was controlled by thin layer chromatography (TLC) at room temperature. After 6 hours, further activation was performed at 0° C. with 460 mg (2.4 mmol) EDC and 79 μl (1 mmol) thiazolidine. After 20 hours, THF was removed by distillation and the solid residue was dissolved in ethyl acetate. with 5% KHSO 4 The ethyl acetate phase was washed three times with NaCl solution, washed once with saturated NaHCO 3 The solution was washed 3 times, and washed 3 times with NaCl solution. place it in Na 2 SO 4 dried, filtered and concentra...
Embodiment 2
[0384] The preparation of the compound of general formula (2)
[0385] Compounds of general formula (2) were prepared using the following method:
[0386] (a) Compound VII (Scheme 14)
[0387] (i) Synthesis of 6
[0388] 188 mg (0.5 mmol) of Boc-Cys(Npys)-OH 5 were dissolved in 2.5 ml dry THF. At 0° C. under argon, 40 μl (0.5 mmol) of thiazolidine were added, and 115 mg (0.6 mmol) of EDC were gradually added. The reaction was followed by TLC at room temperature and terminated after 4 hours. For this purpose, the reaction batch was concentrated, the solid residue was dissolved in ethyl acetate, followed by washing with 5% KHSO 4 The organic phase was washed 3 times with NaCl solution, washed once with saturated NaHCO 3 The solution was washed 3 times and washed 3 times with NaCl solution. in Na 2 SO 4 After drying, it was filtered and the ethyl acetate phase was concentrated.
[0389] Yield: 191 mg (86%) 6.
[0390] (ii) Synthesis of VII
[0391] 29 mg (0.065 mmol) o...
Embodiment 3
[0452] Inhibition of Phytohemagglutinin-Induced Monocyte (MNZ) Proliferation of Healthy Donors by Compounds V to XIII (Tables 3 and 4)
[0453] MNZ were isolated from peripheral blood of healthy donors by density gradient centrifugation and stimulated with 1 μg / ml phytohemagglutinin (PHA) in serum-free medium (AIMV). In a microplate at 37°C and 5% CO 2 , cultured 5×10 in the presence of different inhibitor concentrations (three measurements) 4 MNZ 48 hours. Under the same conditions, unstimulated cells and PHA-stimulated MNZ without inhibitors were cultured as controls. Cell proliferation rate was determined by adding bromodeoxyuridine to newly synthesized DNA (Biotrak-Assay, GE Healthcare).
[0454] The curves shown in Figure 1 represent proliferation data (relative values based on PHA-stimulated cells in the absence of inhibitor) respectively for at least three different donors.
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