Anti-influenza Drugs oseltamivir

A highly useful and important regioselective reduction of substrate 84 leads to a mixture of 3-hydroxy ethers 85 and 86 in a 32 1 ratio (Eq. 306). Compound 85 is further converted to the anti-influenza drug oseltamivir phosphate, better known as Tamiflu .498... 

Hill G, Cihlar T, Oo C, et al. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos 2002 30 13-19. 

In pursuit of a rapid and cost-effective synthesis of the anti-influenza drug (—)-oseltamivir (83) (Tamiflu , as phosphate), Hayashi and coworkers have developed an innovative synthesis involving three one-pot processes (Scheme 7.15) [56]. A large-scale synthesis of Tamiflu is considered so profoundly important today with... 

The heterogeneous, catalytic hydrogenation of substituted aromatic rings is a powerful means for the preparation of cis-substituted cycloalkanes in a highly stereoselective fashion [16]. An elegant example has been reported by researchers at Roche in a synthesis of the anti-influenza drug oseltamivir phosphate (Tamiflu, 20, Scheme 8.4) [35]. Diester 18 was reduced at elevated pressure, exclusively affording the all-cis-substituted meso-cyclohexane 19. 

In comparison with the asymmetric epoxide-opening reactions described above in Section 9.4, catalytic desymmetrizations of meso-aziridines have relatively limited precedence [151]. Kanai and Shibasaki have disclosed a number of promising results obtained with lanthanide complexes of the chiral phosphinoxide ligand 193 (Scheme 9.24) [152, 153]. These efforts were showcased in the desymmetrization of meso-aziridine 192 with TMSN j to provide azide 194 in 96% yield and 91 % ee. Adduct 194 was subsequently converted into the anti-influenza drug oseltamivir phosphate (Tamiflu, 195) [153]. 

Influenza A viruses cause severe infections in the respiratory system and are responsible for seasonal epidemics and sporadic pandemics. The primary method for prevention is through vaccination but vaccine production by current methods cannot be carried out in time to stop the progress of a new strain of the influenza virus. Therefore, effective antiviral agents are used for prophylactic and therapeutic treatments. Among several viral molecular targets for anti-influenza drugs, the surface glycoprotein neuraminidase appears particularly attractive. Selective inhibitors of this enzyme have been developed and two of which, oseltamivir phosphate 18 (Tamiflu ) " and zanamivir 19 (Relenza ), have been approved for human use (Scheme 6). 

Wiltshire, H. Wiltshire, B. Citron, A. Clarke, T. Serpe, C. Gray, D. Herron, W. Development of a high-performance liquid chromatographic-mass spectrometric assay for the specific and sensitive quantification of Ro 64-0802, an anti-influenza drug, euid its pro-drug, oseltamivir, in human and animal plasma and urine, J.Chromatogr.B, 2000, 745, 373-388. 

In contrast to zanamivir (8), oseltamivir (9) is an oral anti-viral drug for the treatment cf uncomplicated influenza in patients whose flu symptoms have not lasted more than 2 days (15, 16). This product treats types A and B influenza however, the majority of patients in the United States are infected with type A. FTTit ay of oseltamivir (9) in the treatment of influenza in subjects with chronic cardiac disease and/or respiratory disease has not been established. Oseltamivir (9) is also approved for the prevention of influenza in adults and adolescents older than 13 years. Efficacy of oseltamivir (9) for the prevention of influenza has not been established in immune-compromisedpatients. 

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