Syntéza NK1 antagonistů

Syntéza NK1 antagonistů Lucie Puchnerová Katedra organické a farmaceutické chemie, Farmaceutická fakulta, Univerzita Seville Antagonisté NK-1 receptorů jsou doposud zastupovány pouze jediným na trhu dostupným léčivem Aprepitant, který je používán k prevenci pocitu nevolnosti a zvracení způsobených chemoterapií. Nicméně se předpokládá, že látky schopné antagonizace receptoru NK-1 by se mohly v budoucnu uplatnit také při terapii migrény, revmatické artritidy, astmatu, zánětlivých onemocněních střev, Parkinsonovy choroby, úzkosti anebo deprese. Tato práce se zabývá asymetrickou syntézou několika derivátů 2-amino-4H-pyranu, které díky své substituci odpovídají struktuře farmakoforu NK-1 antagonistů. Jako výchozí látka pro jejich přípravu byl použit methyl-(p-tolyl)sulfon a menthyl-(S)- p-toluensulfinát, z kterého byl nukleofilní substitucí nasyntetizován (R)-methyl-(p- tolyl)sulfoxid. Tyto sloučeniny byly podrobeny reakci s ethyl-2-pikolinátem za vzniku příslušného β- ketosulfoxidu a β-ketosulfonu, z kterých jsme prostřednictvím Michaelovi adice získali 2-amino-4H-pyrany. U derivátů nasyntetizovaných z β-ketosulfoxidu jsme nadále provedli redukci sulfoxidové skupiny a trifluoracetylaci aminoskupiny, čímž jsme získali sloučeniny, u kterých byl prokázán agonistický účinek na NK-1 receptory. Tímto byla potvrzena...Synthesis of NK-1 antagonists Lucie Puchnerová Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy University of Seville NK-1 receptor antagonists are represented so far by only one drug, Aprepitant, which is available on the market for prevention of chemotherapy-induced nausea and vomiting. Nevertheless, it is assumed that NK-1 antagonists will be able to participate in treatment of migraine, rheumatoid arthritis, asthma, pain, inflammatory bowel disease, Parkinson's disease, anxiety and depression in future. This thesis is concerned with asymmetric synthesis of derivatives of 2-amino-4H-pyran, which thanks their substitutions are in accordance with structure of pharmacophore of NK-1 antagonists. As a starting material for their preparation has been used commercial methyl p-tolyl sulfone and (R)-methyl p-tolyl sulfoxide, which was synthesized from menthyl-(S)-p- toluenesulfinate by nucleophilic substitution. These compounds were subjected to reaction with ethyl 2-picolinate. From prepared β- ketosulfoxide and β-ketosulfone were obtained 2-amino-4H-pyrans by Michael addition. The derivatives proceeding from β-ketosulfoxide were subjected to reduction of the sulfoxide and trifluoroacetylation of the amine group on the carbon 2 of the pyran ring. Prepared derivatives had agonistic activity...Department of Pharmaceutical Chemistry and Drug ControlKatedra farmaceutické chemie a kontroly léčivFaculty of Pharmacy in Hradec KrálovéFarmaceutická fakulta v Hradci Králov

Synthesis of NK1 antagonists.

Synthesis of NK-1 antagonists Lucie Puchnerová Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy University of Seville NK-1 receptor antagonists are represented so far by only one drug, Aprepitant, which is available on the market for prevention of chemotherapy-induced nausea and vomiting. Nevertheless, it is assumed that NK-1 antagonists will be able to participate in treatment of migraine, rheumatoid arthritis, asthma, pain, inflammatory bowel disease, Parkinson's disease, anxiety and depression in future. This thesis is concerned with asymmetric synthesis of derivatives of 2-amino-4H-pyran, which thanks their substitutions are in accordance with structure of pharmacophore of NK-1 antagonists. As a starting material for their preparation has been used commercial methyl p-tolyl sulfone and (R)-methyl p-tolyl sulfoxide, which was synthesized from menthyl-(S)-p- toluenesulfinate by nucleophilic substitution. These compounds were subjected to reaction with ethyl 2-picolinate. From prepared β- ketosulfoxide and β-ketosulfone were obtained 2-amino-4H-pyrans by Michael addition. The derivatives proceeding from β-ketosulfoxide were subjected to reduction of the sulfoxide and trifluoroacetylation of the amine group on the carbon 2 of the pyran ring. Prepared derivatives had agonistic activity..