The global AIDS epidemic has claimed the lives of more than 20 million people since 1981. Another 10 million are now living with HIV and most of these are likely to develop AIDS over the course of the next decade. In spite of the various treatment protocols available, including the mainstream
Regulatory requests that marketing authorization holders for chemically
synthesized active substances risk assess their medicines for the
potential presence of N-nitrosamines have led to
a renewed interest in amine nitrosation. We have used published mechanistic
and kinetic studies of amine nitrosation to assess the risk that traces
of nitrite in the water used during active pharmaceutical ingredient
(API) manufacturing could give rise to significant levels of N-nitrosamines. We conclude that the levels of nitrite typically
found in water used for API manufacture are very low (<0.01 mg/L)
and will not give rise to significant levels of N-nitrosamines through reaction with basic secondary amines (pK
a > 9.5) in the majority of cases. The use of
less basic amines, elevated processing temperatures, or low pH conditions
in combination with elevated levels of nitrite have the potential
to generate levels of N-nitrosamines that could lead
to significant quantities being present in the isolated API if the
downstream processing does not provide an adequate purge. The kinetic
models described may be used to risk assess specific situations or
processes. For example, the addition of traces of dimethylamine to
a nitrosation reaction is predicted to lead to the rapid, quantitative
formation of N-nitroso dimethylamine. Simple tertiary
alkylamines can nitrosate via a dealkylative process, which is significantly
slower than secondary amine nitrosation. Therefore, they do not represent
a risk of N-nitrosamine formation under conditions
where there is no significant risk of secondary amine nitrosation.
Building from the results of a computational screen of a range of triazole-containing compounds for binding efficiency to human immunodeficiency virus type 1 protease (HIV-1-Pr), a novel series of potent inhibitors has been developed. The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), which provides ready access to 1,4-disubstituted-1,2,3-triazoles, was used to unite a focused library of azide-containing fragments with a diverse array of functionalized alkyne-containing building blocks. In combination with direct screening of the crude reaction products, this method led to the rapid identification of a lead structure and readily enabled optimization of both azide and alkyne fragments. Replacement of the triazole with a range of alternative linkers led to greatly reduced protease inhibition; however, further functionalization of the triazoles at the 5-position gave a series of compounds with increased activity, exhibiting Ki values as low as 8 nM.
As part of our ongoing research into the discovery and development of highly efficient, versatile reactions, [1] and inspired by the success of the copper-catalyzed 1,3-dipolar cycloaddition reaction between terminal alkynes and azides, [2] we became interested in the unusual reactivity of copper(i) acetylides towards sulfonyl azides. This initially surprising reactivity is illustrated by their conversion into N-sufonylamidines when the reaction is conducted in the presence of amines [3] and N-acylsulfonamides in the presence of water.[4]Herein, we describe the direct, stereoselective conversion of alkynes to N-sulfonylazetidin-2-imines by the initial reaction of copper(i) acetylides with sulfonyl azides, followed, in situ, by the formal [2+2] cycloaddition of a postulated N-sulfonylketenimine intermediate with a range of imines. We began our investigations by looking into the copper(i)-catalyzed reaction of phenylacetylene with para-toluenesulfonyl azide. With the expectation of forming the 1-sulfonyl-4-phenyl-1,2,3-triazole, the reaction was carried out in the absence of a nucleophile, under conditions that were known to promote dipolar cycloaddition between alkynes and alkyl or aryl azides.[2a] We were therefore surprised to find that the only isolated product was the cyclobutene derivative 1 (Scheme 1). The results of extensive NMR studies correlate with the proposed structure.Compound 1 could result from the dimerization of an initially formed toluenesulfonylketenimine intermediate folScheme 1. Formation of ketenimine dimer 1. Tol = p-tolyl.[*] Dr. M. Whiting, Prof.
The global AIDS epidemic has claimed the lives of more than 20 million people since 1981. Another 10 million are now living with HIV and most of these are likely to develop AIDS over the course of the next decade. In spite of the various treatment protocols available, including the mainstream
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.