| Autor: |
Tucker TJ; Merck Research Laboratories, West Point, Pennsylvania 19486., Lyle TA, Wiscount CM, Britcher SF, Young SD, Sanders WM, Lumma WC, Goldman ME, O'Brien JA, Ball RG, et. al. |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 1994 Jul 22; Vol. 37 (15), pp. 2437-44. |
| DOI: |
10.1021/jm00041a023 |
| Abstrakt: |
As part of an ongoing effort to prepare novel non-nucleoside inhibitors of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT), a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin -2(1H)-ones 4aa-l has been prepared. Target compounds 4a-e were synthesized via addition of various 1-lithio-2-(aryl)alkyne nucleophiles to a 1-protected-4-cyclopropylquinazolin-2(1H)-one (7), followed by deprotection. The 3-methyl compound 4aa was prepared in an analogous manner, with the 3-alkylation performed prior to deprotection. Alternatively, the target compounds 4f-l were prepared by addition of 1-lithio-2-(trimethylsilyl)acetylene to 7, followed by deprotection and subsequent palladium-catalyzed coupling with various aryl halides. By incorporating an aryl group onto the end of the 4-acetylene functionality, the requirement for a metabolically labile 3-methyl group on the dihydroquinazolinone nucleus has been eliminated. A number of the target compounds were shown to be potent inhibitors of HIV-1 RT. Compound 4a, which had exhibited the most favorable overall biological profile, was resolved via a four-step procedure to provide the enantiomers 13a and 13b. Compound 13a having the (-)-4(S) configuration was shown to be the active enantiomer and was selected as a candidate for further investigation. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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