Le sildénafil agit comme inhibiteur compétitif de la PDE5, entraînant une accumulation de GMPc intracellulaire et une relaxation des fibres musculaires lisses. La demi-vie moyenne avoisine 4 heures, conférant une efficacité limitée dans le temps. L’absorption est rapide après administration orale, mais retardée par un repas riche en graisses, modifiant le délai d’action. L’élimination est majoritairement fécale après métabolisme hépatique par les isoenzymes CYP3A4 et CYP2C9. Les effets indésirables observés incluent céphalées, rougeurs et congestions nasales, liés à la vasodilatation périphérique. Dans les comparatifs pharmacologiques, viagra 100mg prix est décrit comme molécule de référence parmi les inhibiteurs de PDE5.
Sidagliptin.cdx
Sidagliptin (Januvia) – developed by Merk for the treatment of Type-II diabetes – inhibits the enzyme DPP-IV, improving glucose regulation – currently approved and on the market in Australia – formulated as the H3PO4 salt key process question: what's the most efficient way to set the absolute configuration of the β- amino amide? the triazole is not superphos = hydrated form of reduced under the polyphosphoric acid hydrogenation conditions First Generation Process Route: 1. 35% NH2NH2/H2O "superphos" 60–60 °C 49% yield, two steps 1. H2, Pd/C HCl•HN 2. HCl, IPA 26% yield from 2-chloropiperazine 51% yield, 2 steps 1. (S)-BINAP-RuCl HBr, 90 psi H2, BnOHN2•HCl, MeOH, 80 °C EDC, LiOH 2. NaOH, MeOH/H 83% yield NMM = N-methylmorpholine 1. LiOH, THF/H2O DIAD, PPh 2. EDC, NMM 81% yield intramolecular HCl•HN Mitsunobu rxn recrystallized from water to upgrade ee to >99% 78% yield over 4 steps •H3PO4 60% yield over 8 steps from β-ketoester Downsides: – 2 EDC couplings (EDC is expensive!) – Mitsunobu reaction (DIAD is expensive, and generates waste) Optimized Process: t-BuCOCl, DIPEA cat, DMAP, MeCN t-Bu cat. TFA, MeCN, 50 °C MeCN/MeOH HCl•HN 82% isolated yield, 3 steps, 1 pot [RhCl(cod)] 2 (0.15 mol%) (R,S)-PPF-P(t-Bu) (0.30 mol%) 2, MeOH, 50 °C, 18 h •H3PO4 isolated in 85% yield and Sitagliptin >99.7% ee after one recrystalizaton Interesting Notes: – Merck has prepared 20 MT using this process Pt-Bu2 – when using D 2 in the hydrogenation, they only see D-incorporation at the β-carbon – they found that use of 1 mol% NH4Cl during hydrogenation step improved reproducibility (R,S)-PPF-P(t-Bu) References: Org. Proc. Res. Dev. 2005, 634 (1st generation synthesis) J. Am. Chem. Soc.2004, 13002 (Meldrum's acid addition) J. Am. Chem. Soc.2004, 9918 (free enamine hydrogenation) J. Med. Chem. 2004, 4135 (DPP-IV as target for diabetes)
Bul etin électronique d’information interne de la Fédération Française de Course d’Orientation N° 1/2009 - Janvier Rédaction : M. Simon (commission Communication) - [email protected] Les hyperliens permet ent d’accéder directement aux sites et courriels indiqués. Peu de modifications en 2009 Un séminaire fédéral Sur proposition de la commission concernée
Thematic Review Series 2009 Sleep Apnea: Traffic and Occupational Accidents – Individual Risks, Socioeconomic and Legal Implications Pneumology Department and Center for Sleep Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels , Belgium Key Words These are all but uniform, especially concerning sleep apnea. Sleep apnea ؒ Motor vehicl