Host defense protein (HDP) mimetics for prophylaxis and/or treatment of inflammatory diseases of the gastrointestinal tract
A technology for inflammatory diseases and gastrointestinal tract, applied in allergic diseases, anti-inflammatory agents, drug combinations, etc., can solve problems such as lack of understanding of HDP molecular mechanism
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Embodiment 1
[0176] Embodiment 1: Preparation of brilacidin (PMX-30063)
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[0178] Scheme-1: Synthetic method for preparing PMX-30063
[0179] Step 1: N-Boc-3-pyrrolidinol (2.2 kg) was dissolved in tetrahydrofuran (11.2 kg) and cooled to 10°C. Potassium tert-butoxide (1.5 kg) was then added followed by 2-chloro-5-(trifluoromethyl)-1,3-dinitrobenzene (3.0 kg) in tert-butyl methyl ether (5.1 kg) solution. The resulting mixture was stirred at 10-17°C for 16 hours, then tert-butyl methyl ether (10.7 kg) and water (15.6 kg) were added. The organic layer was separated, washed by brine, and evaporated to dryness. The crude product was crystallized twice from ethanol / water to give 2.17 kg (46.3%) of (R)-3-(2,6-dinitro-4-trifluoromethylphenoxy) with expected HPLC purity of about 96.4%. base) pyrrolidine-1-carboxylic acid tert-butyl ester (3).
[0180] Step 2: Add 2.2 kg of compound 3 Dissolved in methanol (6.1 kg), then added 5% Pd-C (294 g) under nitrogen. The resulting reaction m...
Embodiment 2
[0185] Example 2: Preparation of delparantag:
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[0188] Scheme 2 - Synthetic strategy for the preparation of PMX-60056
[0189] Step 1: Preparation of Compound 11
[0190]Compound 9 (1665 g, 4.379 mol, 1.0 eq), compound 10 (817 g, 4.51 mol , 1.03eq) and a mixture of N-hydroxybenzotriazole (651g, 4.82mol, 1.1eq), followed by the addition of N-(3-dimethylaminopropyl)-N'-ethylcarbodiene in portions Amine hydrochloride (923 g, 4.82 mol, 1.10 eq). Reactions were run at 20°C and the progress of the reaction was monitored by in-process HPLC. After completion of the reaction, the reaction mixture was worked up by standard extraction procedure to provide compound 11 (2192 g, 92.1% yield). HPLC analysis is expected to show a purity of Compound 11 of about 97-98%. The chiral HPLC method was expected to show that the enantiomeric purity of compound 11 was maintained during step 1 (from compound 9). The undesired enantiomer was not expected to be detected.
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Embodiment 3
[0211] Example 3: PMX-30063 inhibits PDE4A
[0212] Phosphodiesterase type 4 (PDE4) is the major phosphodiesterase expressed in neutrophils, T cells and macrophages. PDE inhibitors show broad-spectrum anti-inflammatory effects in almost all inflammatory cells. PDE4 inhibitors block the degradative action of PDE4 on cAMP, thereby increasing intracellular levels of cAMP that mediate phosphorylation of protein kinases. PDE4 inhibitors reduce neutrophil chemotaxis, recruitment, and activation; inhibit activation of CD4+ and CD8+ T cells; and inhibit monocyte chemotaxis. Therefore, inhibition of PDEs is expected to have a therapeutic effect in inflammatory diseases such as those of the gastrointestinal tract. To test whether PMX-30063 can inhibit PDE4 phosphodiesterase, a PDE4 inhibition assay was performed using PMX-30063. according to figure 1 The described method uses 8 ng of PDE4B, 1 μM cAMP substrate and PMX-30063 for the PDE-Glo phosphodiesterase assay. Data are provided...
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