Synthesis of a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.
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.
Tucker
T J
TJ
Merck Research Laboratories, West Point, Pennsylvania 19486.
Lyle
T A
TA
Wiscount
C M
CM
Britcher
S F
SF
Young
S D
SD
Sanders
W M
WM
Lumma
W C
WC
Goldman
M E
ME
O'Brien
J A
JA
Ball
R G
RG
D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors
D011799:Quinazolines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase