- Organocatalytic and scalable synthesis of the anti-influenza drugs zanamivir, laninamivir, and CS-8958
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Zanamivir, laninamivir, and CS-8958 are three neuraminidase inhibitors that have been clinically used to combat influenza. We report herein a novel organocatalytic route for preparing these agents. Only 13 steps are needed for the assembly of zanamivir and laninamivir from inexpensive d-araboascorbic acid by this synthetic route, which relies heavily on a thiourea-catalyzed enantioselective Michael addition of acetone to tert-butyl (2-nitrovinyl)carbamate and an anti-selective Henry reaction of the resulting Michael adduct with an aldehyde prepared from d-araboascorbic acid. The synthetic procedures are scalable, as evident from the preparation of more than 3.5 g of zanamivir.
- Tian, Junshan,Zhong, Jiankang,Li, Yunsheng,Ma, Dawei
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- Acylguanidine derivatives of zanamivir and oseltamivir: Potential orally available prodrugs against influenza viruses
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Zanamivir (ZA) and guanidino-oseltamivir carboxylic acid (GOC) are very potent inhibitors against influenza neuraminidase (NA). The guanidinium moiety plays an important role in NA binding; however, its polar cationic nature also hinders the use of ZA and GOC from oral administration. In this study, we investigated the use of ZA and GOC acylguanidine derivatives as possible orally available prodrugs. The acylguanidine derivatives were prepared by coupling with either n-octanoic acid or (S)-naproxen. The lipophilic acyl substituents were verified to improve cell permeability, and may also improve the bioavailability of acylguanidine compounds. In comparison, the acylguanidines bearing linear octanoyl chain showed better NA inhibitory activity and higher hydrolysis rate than the corresponding derivatives having bulky branched naproxen moiety. Our molecular docking experiments revealed that the straight octanoyl chain could extend to the 150-cavity and 430-cavity of NA to gain extra hydrophobic interactions. Mice receiving the ZA octanoylguanidine derivative survived from influenza infection better than those treated with ZA, whereas the GOC octanoylguanidine derivative could be orally administrated to treat mice with efficacy equal to oseltamivir. Our present study demonstrates that incorporation of appropriate lipophilic acyl substituents to the polar guanidine group of ZA and GOC is a feasible approach to develop oral drugs for influenza therapy.
- Hsu, Peng-Hao,Chiu, Din-Chi,Wu, Kuan-Lin,Lee, Pei-Shan,Jan, Jia-Tsrong,Cheng, Yih-Shyun E.,Tsai, Keng-Chang,Cheng, Ting-Jen,Fang, Jim-Min
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supporting information
p. 314 - 323
(2018/05/29)
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- Preparation method of zanamivir intermediate and preparation method of zanamivir
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The invention relates to a preparation method of a zanamivir intermediate, namely an acetylation protected amino compound, and a preparation method of zanamivir. The preparation method of the zanamivir, provided by the invention, comprises the following steps: performing cyclization by taking sialic acid as a raw material and through group protection to produce a cyclization substance, treating the cyclization substance by a metal amino substance at one step to obtain the acetylation protected amino compound, and removing a hydroxyl protective agent acetic acid ester and removing guanidyl from imipyrozole reaction to obtain the zanamivir, wherein the process of treating the cyclization substance by the metal amino substance at one step to obtain the acetylation protected amino compound is great substantial breakthrough in preparation of the zanamivir, the synthesis steps are greatly shortened and the process operation is simplified. Ring opening is conducted by the cheap metal amino substance instead of expensive trimethylsilyl azid, so that the cost is reduced and the safety of the production process is guaranteed. According to thepreparation method of the zanamivir, provided by the invention, the total mass yield can reach 50 percent or above and is greatly increased as compared with that in the prior art.
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- PROCESS FOR THE PREPARATION OF ZANAMIVIR
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The present invention provides a process for preparing 5-(acetylamino)-4-[(aminoiminomethyl)amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-enonic acid Formula (I), which process comprises reducing compound of Formula (IV) by Lindlar catalyst in presence of hydrogen to obtain compound of Formula (V). reacting compound of Formula (V) with pyrazole-1H-carboxamidine or its suitable salt to obtain compound of Formula (VIII). hydrolyzing the compound of Formula (VIII) to give compound of Formula (I). The present invention also provides compounds of formula (VIII) which may be used in the synthesis of zanamivir. The present invention also provides process for preparing compound of formula (VIII) and process involving the use of Formula (VIII), including in the synthesis of zanamivir.
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- Chemical insight into the emergence of influenza virus strains that are resistant to Relenza
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A reagent panel containing ten 4-substituted 4-nitrophenyl α-d-sialosides and a second panel of the corresponding sialic acid glycals were synthesized and used to probe the inhibition mechanism for two neuraminidases, the N2 enzyme from influenza type A virus and the enzyme from Micromonospora viridifaciens. For the viral enzyme the logarithm of the inhibition constant (Ki) correlated with neither the logarithm of the catalytic efficiency (kcat/Km) nor catalytic proficiency (kcat/Kmkun). These linear free energy relationship data support the notion that these inhibitors, which include the therapeutic agent Relenza, are not transition state mimics for the enzyme-catalyzed hydrolysis reaction. Moreover, for the influenza enzyme, a correlation (slope, 0.80 ± 0.08) is observed between the logarithms of the inhibition (Ki) and Michaelis (Km) constants. We conclude that the free energy for Relenza binding to the influenza enzyme mimics the enzyme-substrate interactions at the Michaelis complex. Thus, an influenza mutational response to a 4-substituted sialic acid glycal inhibitor can weaken the interactions between the inhibitor and the viral neuraminidase without a concomitant decrease in free energy of binding for the substrate at the enzyme-catalyzed hydrolysis transition state. The current findings make it clear that new structural motifs and/or substitution patterns need to be developed in the search for a bona fide influenza viral neuraminidase transition state analogue inhibitor.
- Shidmoossavee, Fahimeh S.,Watson, Jacqueline N.,Bennet, Andrew J.
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supporting information
p. 13254 - 13257
(2013/09/24)
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- Catalytic asymmetric anti-selective nitroaldol reaction en Route to Zanamivir
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Battling the flu: Zanamivir (Relenza) is widely prescribed as an anti-influenza drug. It contains a vicinal amino alcohol, which is in an anti orientation, and is readily accessed by an anti-selective catalytic asymmetric nitroaldol (Henry) reaction promoted by a heterobimetallic complex (see scheme; PMB=p-methoxybenzyl). Additional synthetic manipulation of the nitroaldol product allowed the enantioselective synthesis of zanamivir. Copyright
- Nitabaru, Tatsuya,Kumagai, Naoya,Shibasaki, Masakatsu
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p. 1644 - 1647
(2012/04/05)
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- Concise synthesis of zanamivir and its C4-thiocarbamido derivatives utilizing a [3+2]-cycloadduct derived from d-glucono-δ-lactone
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A concise synthesis of zanamivir (GG167, 1) has been accomplished utilizing the adduct of a highly diastereoselective 1,3-dipolar cycloaddition between methyl acrylate and the nitrone derived from d-glucono-δ-lactone. Azide-free introduction of C4 nitrogen functionality and one-pot selective O-acetylation followed by straightforward generation of dihydropyran moiety are two advantages in this synthesis. Using the established methodology and common intermediate, two representative C4-thiocarbamido derivatives of zanamivir were also synthesized.
- Zhu, Xue-Bin,Wang, Meng,Wang, Shaozhong,Yao, Zhu-Jun
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experimental part
p. 2041 - 2044
(2012/04/10)
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- PROCESS FOR THE PREPARATION OF ZANAMIVIR
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The present invention provides a process for preparing 5-(acetylamino)-4- [(aminoiminomethyl)amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non- enonic acid Formula (I), which process comprises reducing compound of Formula (IV) by Lindlar catalyst in presence of hydrogen to obtain compound of Formula (V). reacting compound of Formula (V) with pyrazole-lH-carboxamidine or its suitable salt to obtain compound of Formula (VIII). hydrolyzing the compound of Formula (VIII) to give compound of Formula (I). The present invention also provides compounds of formula (VIII) which may be used in the synthesis of zanamivir. The present invention also provides process for preparing compound of formula (VIII) and process involving the use of Formula (VIII), including in the synthesis of zanamivir.
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- Process for Preparing Zanamivir and Intermediates for Use in the Process
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The present invention provides a process for preparing methyl 5-acetamido-4-amino-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate (V), which process comprises reducing methyl 5-acetamido-4-azido-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate (IV) in the presence of a reducing agent selected from the group consisting of lithium aluminium hydride, sodium borohydride, zinc/ammonium chloride, zinc-ferric chloride and ferric chloride/sodium iodide. The present invention also provides compounds of formula (VIII) and (IX) which may be used in the synthesis of zanamivir. The present invention also provides processes for preparing compounds (VIII) and (IX) and processes involving their use, including in the synthesis of zanamivir.
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Page/Page column 8
(2011/10/31)
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- PROCESS FOR PREPARING ZANAMIVIR AND INTERMEDIATES FOR USE IN THE PROCESS
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The present invention provides a process for preparing methyl 5-acetamido-4-amino-6- (1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate (V), which process comprises reducing methyl 5-acetamido-4-azido-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2- carboxylate (IV) in the presence of a reducing agent selected from the group consisting of lithium aluminium hydride, sodium borohydride, zinc/ammonium chloride, zinc-ferric chloride and ferric chloride/sodium iodide. The present invention also provides compounds of formula (VIII) and (IX) which may be used in the synthesis of zanamivir. The present invention also provides processes for preparing compounds (VIII) and (IX) and processes involving their use, including in the synthesis of zanamivir.
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Page/Page column 15
(2010/06/17)
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- Drug delivery device containing neuraminidase inhibitor and an H1 antagonist
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The present invention provides a dual release solid dosage form containing a first composition that releases a neuraminidase inhibitor, such as oseltamivir, zanamivir, or peramivir, in a controlled manner and a second composition that releases an H1 antagonist in a rapid and/or immediate manner. A wide range of H1 antagonist antihistamines, especially fexofenadine and loratadine, can be used in this device. Particular embodiments of the invention provide osmotic devices having predetermined release profiles. The device is useful for the treatment of respiratory congestion and other viral infection associated symptoms.
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- Synthesis of the potent influenza neuraminidase inhibitor 4-guanidino Neu5Ac2en. X-Ray molecular structure of 5-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-D-erythro-L-gluco-nononic acid
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An efficient and high-yielding synthesis of 4-guanidino Neu5Ac2en, the potent anti-influenza A and B compound, is described.The route exploits a stereospecific introduction of the key nitrogen functionality at C-4 via an oxazoline intermediate.Three different methods for the final-step conversion of the 4-amino into 4-guanidino derivatives are described.To explore the structure-activity relationship in this region of the molecule, a series of substituted guanidino derivatives were synthesized and their activity is described.
- Chandler, Malcolm,Bamford, Mark J.,Conroy, Richard,Lamont, Brian,Patel, Bina,et al.
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p. 1173 - 1180
(2007/10/02)
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- The synthesis of 2,3-didehydro-2,4-dideoxy-4-guanidinyl-N- acetylneuraminic acid: A potent influenza virus sialidase inhibitor
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The synthesis of a number of 5-acetamido-2,6-anhydro-3,5-dideoxy-D-galacto-non-2-enonic acid (Neu5Ac2en, 1) analogues has received considerable attention over the past decade. We have recently reported the design and biological evaluation of 5-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-D-glucero-D-galacto-no n-2- enonic acid (4-amino-Neu5Ac2en, 2) and 5-acetomido-2,6-anhydro-4-guanidino- 3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid (4-guanidino-Neu5Ac2en, 3) as influenza virus sialidase inhibitors. The synthetic strategy that we adopted for the preparation of 3 required the introduction of nitrogen at C-4 of 1.
- Von Itzstein,Wu,Jin
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p. 301 - 305
(2007/10/02)
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