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The EGFR inhibitor erlotinib possesses high anti-tumor effect but despite the good clinical responses in most of the cases recrudescence occures. This can be attributed to a secondary, acquired mutation causing resistance to tyrosine kinase inhibitors. In our work we were looking for small-molecule inhibitors, which simultaneously affect on the proliferation of erlotinib-sensitive PC9 cells and PC9-ER erlotinib-resistant cells. A set of molecules were selected from Vichem Chemie Research Ltd.'s kinase inhibitor compound library (Nested Chemical Library™). According to the results of medium throughput screening (MTS) of this set of compounds, novel structures with pyrido[2,3-b]pyrazine core were designed. These compounds were proved to be effective inhibitors of resistant cells in phenotypic screening. Based on these results structure-activity relationships were set up. The pyrido[2,3-b]pyrazine core was synthesized by a condensation reaction, which resulting two asymmetric products. In the reaction two regioisomer intermediates formed, and one of the products is the intermediate of the effective compounds. This condensation reaction was optimized, the regioisomers were identified by NMR analysis and X-ray crystallography. As a result of optimization we found that lower reaction temperature and replacement of dimethylformamide solvent with trifluoroacetic acid provided the undesired isomer in less than 2 % ratio.

Oesophago-respiratory fistula in most instances in a complication of advanced malignant tumours of the oesophagus or the lung. In our patient group eleven oesophago-respiratory and one gastro-respiratory fistulas were encountered. Three patients were operated upon. In one of them with achalasia, early oesophageal carcinoma was discovered in the background of the fistula. Two patients had fistulas without of oesophageal narrowing, therefore, stent implantation into the trachea and bronchus was performed. One of them was previously managed endoscopically with lyodura plug and fibrin glue, but only temporary occlusion of the fistula was obtained. In five patients, seven conventional oesophageal prosthesis (6 Cook, 1 Rüsch) were used to close the fistulas. In one of these patients, three oesophago-respiratory fistulas developed one after the other at the level of the prosthesis funnel. They were closed with three prostheses connected with short silicone tubes. In the last two patients, Gianturco-Z stent was employed. Its advantages over the plastic prostheses include small basic and lager final luminal diameter, lesser predilatation, easier implantation, lower complication and mortality rate. The silicone coated and double funnel stent with expansile force is effective in fistulas closure. On implantation, stent shortening in minimal, allowing precise placement of the stent even in proximal malignant oesophageal stenosis with oesophago-bronchial fistula. The high price of the stent is compensated for by the lower complication rate, shorter hospitalization and subsequent reduction is hospital expenses. Therefore these metal stents should be financed by the National Health Service, at least in specialized centers for managing patients with dysphagia.