Oseltamivir compounds

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... 

The neuramidase inhibitor oseltamivir phosphate was discovered by Gilead Sciences and developed by Roche Pharmaceuticals under the name of Tamiflu (Scheme 5.13) to be used as an orally active antiviral compound for prevention and treatment of influenza infections. Because of the recent emergence of the avian flu, the demand for Tamiflu has gained momentum. Two industrially feasible syntheses are known, starting from (—)-shikimic acid and (—)-quinic acid, respectively (Scheme 5.13) [45]. 

Neuraminidase is an essential viral glycoprotein for virus replication and release. The neuraminidase inhibitors zanamivir and oseltamivir have recently been approved for the treatment of acute uncomplicated influenza infection. When a 5-day course of therapy is initiated within 36-48 hours after the onset of symptoms, use of either agent shortens the severity and duration of illness and may decrease the incidence of respiratory complications in children and adults. Unlike amantadine and rimantidine, zanamivir and oseltamivir have activity against both influenza A and influenza B. Zanamivir is administered via oral inhaler. The compound displays poor oral bioavailability, limited plasma protein binding, rapid renal clearance, and absence of significant metabolism. Nasal and throat discomfort may occur—as well as bronchospasm in patients with reactive airway disease. 

As shown in Table 1, none of the compounds had the ability to inhibit HSV, while only quercetin-3,7-O-a-L-dirhamnoside had inhibitory activity against PI-3 in the range 8-32 pg/mL of maximum and minimum cytopathogenic effect (CPE) inhibitory concentrations, respectively. The inhibitory concentration range of this compound is on a vast scale, which resembles that of oseltamivir (32 to < 0.25 pg/mL). Besides, its maximum non-toxic concentration (MNTC) (64 pg/mL) was observed to be better than oseltamivir (32 pg/mL). 

An X-ray crystal structure of peramivir (24) in complex with influenza A N9 showed interactions of the 3-pentyl group with S4 and S5 [117]. Due to the different stereochemistry of the guanidino moiety of 24 compared to zanamivir, a water molecule was displaced from S2 when 24 was bound. The different binding mode of the guanidine moiety within the active site provided the reason by which 24 showed inhibitory activity also for zanamivir-resistant influenza virus sialidase strains [117,120], Compound 24, which showed comparable or better efficacy in vivo than zanamivir and oseltamivir [121, 122], successfully completed animal studies and is in phase III clinical trials. 

Karpf, M. et al. New, Azide-Free Transformation of Epoxides into 1,2-Diamino Compounds Synthesis of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu). 3.4.4 2001 [135]... 

Two agents, oseltamivir and zanamivir, are approved for the management of Influenza A and B infection. Both are potent neuraminidase inhibitors responsible for inhibiting viral replication. These agents differ in their structural compounds, enabling oseltamavir to have greater bioavailabihty and be the only oral option. There have been no reports of nephrotoxicity with the use of either agent. 

Prompted by the success achieved with simple carbocyclic compounds (e.g., 35), which are potent inhibitors of influenza neuraminidase, several other Neu5Ac2en mimetics of this kind were studied. The isomeric carbocyclic derivatives 37 and 38 are selective for influenza A sialidase, but only 38 showed signihcant inhibition (IC50 = 2 X 10 M) [87]. Other carbocyclic neuraminidase inhibitors include the guanidino substituted cyclohexene 39 [88] and amine derivatives [89] such as 40, which was found to be an inhibitor of influenza B neuraminidase comparable with oseltamivir 35, but was not as potent against influenza A virus [89a]. 

These efforts have culminated in the hve-membered carbocyclic compound peramivir 41, which is an orally available influenza neuraminidase inhibitor, obtained by rational design [90]. In a comprehensive study, 41 has been shown to possess neuraminidase activity comparable with both zanamivir 28 and oseltamivir 35 against a number of influenza strains. Furthermore, 41 was found to be very selective for influenza neuraminidase over mammalian, bacterial or other viral neuraminidases. Peramivir 41 is currently undergoing clinical evaluation as an oral treatment for influenza in humans [90b]. 

Quinic acid will reappear in Chapter 43 as a synthetic precursor to the important anti-flu compound oseltamivir. 

The drug oseltamivir (Tamiflu), developed by the companies Gilead and Roche, is a neuraminidase inhibitor. Like the HIV proteases described above, it has enough structural similarity with the enzyme s substrate to bind to the enzyme, but once bound it blocks the enzyme s activity. No-one knows how much oseltamivir might be needed if ever a flu pandemic took hold, but clearly the safest course of action is to stockpile the compound in readiness for such an event. The first manufacturing route to oseltamivir made use of the natural product (-)-quinic acid as a naturally derived starting material. Quinic acid is found in coffee beans, but is not available in sufficient quantities for widespread use. 

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