Diazepines scaffold

The utility of the Paal-Knorr reaction allows it to stiU remain at the forefront of organic chemistry for the preparation of highly complex substrates and drug-like compounds. The Paal-Knorr reaction was used to synthesize iV-aryl pyrroles 25 with an azide group on the aryl ring. These substrates were subsequently employed in a tandem azide-alkyne 1,3-dipolar cycloaddition reaction to synthesize medicinally important molecules with a diazepine scaffold 27 (14OL560). 

A. Barge, S. Fuzerooa, D. Upadhaya, D. GareUa, S. Aime, L. Tei, G. Cravotto, A new, easy access to the 6-aminoperhydro-l,4-diazepine scaffold under ultrasound and microwave irradiation. Synthesis (2008) 1879. 

Trisubstituted l,4-diazepin-2-ones have been used as -turn peptide mimics. Reductive amination of functionalised amino ketones 95 afforded functionalised diazepin-2-ones 96 ready for elaboration to peptide mimics <07JOC8980>. As an alternative to the classical benzodiazepine scaffold, 1,4-diazepane derivatives can also be considered dipeptidomimetics by rigidification of an intramolecular hydrogen bond in a -turn. Henichart and co-workers described the synthesis of dihydro-1,4-diazepan-5-ones, 1,4-diazepan-5-ones and mono-Boc protected 1,4-diazepanes <07TL2583>. 

A more complex structure class with activity at PR is represented by the tetrahydro-1 [H]-dibenzo[fo, /]pyrido[l,2-d][l,4]oxazepine scaffold (62) [77]. This scaffold was modified mainly at the two aromatic systems and the 1-amino functionality. In addition, the central oxazepine ring has been modified to a thiazepine (63), a diazepine and an azepane ring in some examples. Comparable decorations of the whole system delivered active compounds with all these modified central ring systems. The acylation of the 1-amino function, especially with the trifluoroacetyl group (64), resulted in enhanced activity compared to free amino or alkyl substitution. Trifluorothioacetate was essential for agonism of the compounds, while thioureas... 

The Ugi-4CR is one of the most versatile tools for the construction of scaffolds with biological properties, such as diazepines [44] and peptoids or peptide-peptoid backbones [45]. hi this context, the group of Andrade has prepared functionalized peptoids by combining methyl isocyanoace-tate, paraformaldehyde, Al-Cbz-glycine, and different primary amines (Scheme 7.17) [45c]. This procedure allowed the synthesis of several peptoids 41 in high yields (78-92%) and... 

Huge success of benzodiazepenes as pharmaceutical scaffolds has prompted preparation and evaluation of het-erocyde-annulated benzodiazepine derivatives. A tandem Michael addition-condensation sequence xmder MW irradiation was also proved to be useful for the synthesis of amino-substituted pyrimidine-fused diazepine derivatives of the type 96 from 4,5,6-triaminopyrimidine and chalcones [57]. Similarly, the pyridine-fused derivatives (97) were prepared xmder MW-assisted solvent and catalyst-free condition [58], Condensation of thiadiazole-annulated phen-ylene diamines with appropriate carbonyl compounds using sulfamic acid as organocatalyst led to the formation of corresponding diazepine derivatives 98 in excellent yields [59] (Figure 4). 

A three-component approach to dibenzodiazepine derivatives in aqueous medium has also been reported because of several important pharmaceutical properties of such scaffolds. Sangshetti and coworkers have developed an oxalic acid-catalyzed condensation of diamine, dicarbonyl compound, and an aromatic aldehyde in water [101] (Scheme 31). The reaction proceeded rapidly and almost in near-quantitative yield. Newly prepared dibenz[l,4]-diazepine-l-one derivatives 148 were evaluated for biological activity and some of the prepared compounds were found to have promising anxiolytic activity. 

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