Carboxamides fragmentation

Table VII illustrates the entry format for the carboxamide fragment. Measurements from a number of solutes have established the values for many of its bond environments and its susceptibility to proximity effects. Table VIII shows the fragment data for N-oxy-urea. It is immaterial which direction the operator chooses to enter the fragment structure, because the program develops a unique sequence for fragments just as it does when dealing with complete structures. Of course the operator must use care to associate the correct bonding designations with the appropriate data. Two calculations using this fragment will serve to illustrate some features of the program.

Lithio-l-arenesulfonyUndole intermediates are also prone to ring fragmentation. Lithiated 1-phenylsulfonylindole-2-carboxamides fragment at —78°C <86H(24)2127>. 3-Lithiated indoles with A-alkyl substituents are much less susceptible to fragmentation. This relative stability relationship presumably reflects the anion stabilization provided by the sulfonyl group. 

Partly saturated pyrazino[l,2-r-]pyrimidines were prepared by formation of the pyrazine ring. 2-Substituted-8-hydroxy-3,4-dihydro-177,277-pyrazino[l,2-r-]pyrimidin-l-ones were prepared by a [6+0] synthesis involving cyclization of 6-hydroxy-pyrimidine-4-(fV-hydroxyethyl)carboxamides <2005W02005/087766>. The 2/7-pyra-zino[l,2-c]pyrimidine-3-carboxamide 164 (Y = NH) was formed from [5+1] atom fragments via the uracil derivative 163 (Y = NH) and DMF-dimethyl acetal. Compounds 163 were prepared from 6-chloromethyluracil and glycine methyl ester 162 (Y = NH) (Scheme 20) <2004W02004/014354>. 

However, the redox potentials of the Ni(II) complexes of the aza-cyclam (3b-3g) containing carboxamide or sulfonamide functional groups are reported to be influenced by the nature of the functional group. In particular, the amide fragment controls the reduction potential for the Nim/Nin and NiI1/NiI redox couples, which may be attributed to the it interaction between the nickel ion and the amido group 14). 

As shown in Figure 8.3, the principal metabolites of nicotinamide are A( -methyl nicotinamide and methyl pyridone carboxamides. AT -Methyl nicotinamide is actively secreted into the urine by the proximal renal tubules. Nicotinamide A(-methyltransferase is an S-adenosylmethionine-dependent enzyme that is present in most tissues. Very high intakes of nicotinamide may deplete tissue pools of one-carbon fragments - indeed, this was the basis for the use of nicotinamide in the treatment of schizophrenia (Section 8.8). 

The 5 -triphosphate deoxynucleoside derivatives of pyrrole-3-carboxamide and pyrrole 3,4-dicarboxamide have been incorporated into DNA with DNA polymerases. They are preferentially incorporated with Klenow fragment where they are incorporated as either dA or dC. The base analogue 1,2,4-triazole-3-carboxamide (124) can exist in four different conformations by rotation about the glycosidic or carboxamide bonds, and thus can in principle behave as a universal base. The analogue has been examined by NMR in duplexes opposite G and T where it is anticipated that it would adopt syn and anti conformations, respectively. NMR showed that in both duplexes, the complementary nucleotide adopted a syn conformation, and the carboxamide group is able to adopt two rotational isomers. 

Wyatt PG, Woodhead AJ, Berdini V et al (2008) Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-lH-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design. J Med Chem 51 4986-4999... 

The fragment N-C —pyridine-N-C is also present in 3-isocyanatopyridine-2-carboxamides, which are intermediates in degradation reactions of 2,3-dicarbofunctional pyridines135, l36 425 (see Section 7.2.2.2.1.1.3.). 

Standard one-letter abbreviations are used. pE is pyroglutamyl (5-oxoprolyl) and -NH2 at the right indicates a C-termlnal carboxamide. Ring and tail fragments of oxytocin. 

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