Tetrahydro-imidazo benzodiazepin-2

X-ray structures of HIV RT, so structure-based design did not seem to play a role in their discovery. The discovery of NNRTIs appears to have started with selective screening of the compound library in cell culture at Janssen Phar-maceutica in 1987, which led to the discovery of the first generation NNRTIs, the TIBO (tetrahydro-imidazo[4,5,l-jk][l,4]-benzodiazepin-2(lH)one) compounds. Two of these first generation NNRTIs, tivirapine, a TIBO deriva-... 

Mellors JW, Im G-J, Tramontano E, Winkler SR, Medina DJ, Dutschman GE, Bazmi HZ, Piras G, Gonzalez CJ, Cheng Y-C. A single conservative amino acid substitution in the reverse transcriptase of human immunodeficiency virus-1 confers resistance to ( + )- (5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,l-y ][l,4]benzodiazepin-2(lH)-thione (TIBO R82150). Mol Pharmacol 1993 43 11-16. 

Separately, 3.0 g (27.1 mmol) of potassium t-butylate are dissolved in 9.0 ml of dry dimethylformamide, cooled in an acetone/dry-ice bath, treated with 3.9 g (27.1 mmol) of t-butyl isocyanoacetate and the solution obtained is added dropwise at -15°C to the mixture obtained according to the preceding paragraph. The mixture is warmed to 15°C, neutralized with 1.5 ml of glacial acetic acid, poured into 100 ml of water and extracted four times with methylene chloride. The methylene chloride solution is washed twice with water, dried over magnesium sulfate, evaporated and the crude product obtained is chromatographed on silica gel using ethyl acetate for the elution. By recrystallization from ethyl acetate/n-hexane there is obtained t-butyl (S)-8-bromo-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo[l,5-a]pyrrolo[2,l-c] [ 1,4] benzodiazepine-1-carboxylate. 

C27H2ftCl3FN, 03S, 8-Chloro-trans-6-(2-fluorophenyl)-5-nitroso-1 -(((4-methylphenyl)sulphonyl)methylene)imidazo[1,5-a](1,4)benzodiazepine dichloromethane solvate, 44B, 266 C27H25F3N2O, dl-8-Fluoro-5-(4-fluorophenyl)-2-[4-hydroxy-4-(4-fluorophenyl)butyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 46B, 286... 

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