Benzodiazepines scaffolds

Scheme 10 Recent UAC approaches to benzodiazepine scaffolds as mimics of P-tum peptide...

This is indeed the case. In addition to gamma-aminobutyric acid (GABA), opiate and cholecystokinin receptor activities, the benzodiazepine scaffold is also found in muscle relaxants, antidepressants, neuroleptics, hypnotics, NK-1 receptor and vasopressin receptor antagonists, integrin antagonists, farnesyl transferase and phosphodiesterase inhibitors, potassium channel modulators, and others. 

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>. 

Other type III peptidomimetic inhibitors of this enzyme have also been reported. Inhibitor (112) (Fig. 15.47) was developed by replacing the A1A2 dipeptidyl sequence with a benzodiazepine scaffold (209). Later, SAR modifications of the benzodiazepine nucleus that included a hydrophilic 7-cyano group and a 4-sulfonyl group provided the potent, orally available and in vivo active (113) (210). 

The benzodiazepine scaffold is a classic example. Although the underlying basis for this privileged standing is not well understood, it has been suggested that conservation of protein folds may contribute toward this [25, 27],... 

Figure 21 Benzodiazepine scaffold (left) and a statine-base peptomimetic (middle) are typical asymmetric scaffolds. Benzene triacylchloride scaffold (right) is a typical symmetric scaffold.

The series of compounds containing the tetrahydro-1,4-benzodiazepine scaffold are an important class of prototypical privileged structures associated with various biological... 

Howard HR, Sarges R, Siegel TW, Beyer TA (1992) Synthesis and aldose reductase inhibitory activity of substituted 2(lH)-benzimidazolone- and oxindole-l-acetic acids. Eur J Med Chem 27(8) 779-789. doi 10.1016/0223-5234(92)90112-E Huang Y, Khoury K, Chanas T, Doemling A (2012) Multicomponent synthesis of diverse 1,4-benzodiazepine scaffolds. Org Lett 14(23) 5916-5919. doi 10.1021/ol302837h Hudkins RL (1995) Synthesis of lH-indolyl-2-benzimidazoles and lH-indolyl-2-benzothiazoles. 

Tautens et al. (2005) used allyl acetates and carbonates for a microwave-assisted intramolecular coupling with aryl iodides for the synthesis of some seven membered N- and 0-containing heterocycles. Conventional reaction conditions involves reflux heating of allyl carbonates in the presence of Pd2(dba)3, tri-o-tolylphosphine and N,N-dimethylbutylamine in CHgCN-H O, but with low yield (49%) of the cyclized products. However, increased yield (72%) has been reported under microwave irradiation. This 1,4-benzodiazepine scaffold is an important component of pharmaceuticals used for treatment of neurological disorders. 

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