Definition
ChEBI: The monomethanesulfonic acid salt of delavirdine, a non-nucleoside reverse transcriptase inhibitor with activity specific for HIV-1. Viral resistance emerges rapidly when delavirdine is used alone, so it is therefore used (as the methanesulfonic acid salt)
with other antiretrovirals for combination therapy of HIV infection.
Description
Rescriptor was launched in the US for HIV positive individuals. It can be
prepared in seven steps from 2-chloro-3-nitropyridine and piperazine. Rescriptor is a member of the bis(heteroaryl)piperazine (BHAP) class of non-nucleoside HIV-1
reverse transcriptase inhibitors (NNRTIs) of which it is a second generation drug. It
acts exclusively as an allosteric mixed inhibitor of both RNA- and DNA-directed
polymerase domains of RT and has a much higher binding affintiy for the enzymesubstrate
complex than for the free enzyme. Rescriptor does not inhibit RNase H
activity of RT. It prevented the spread of HIV significantly longer than AZT.
Development of resistance to Rescriptor can occur, however the mutated strain
becomes more vulnerable to other members of the NNRTIs. It is metabolized in the
liver by CYP3A.
Manufacturing Process
5-Nitroindole-2-carboxylic acid (0.86 g), 1-[3-(N-isopropyl)amino-2-
pyridinyl]piperazine (0.43 g), 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide
(0.45 g) and THF (4 ml), were stirred at 20-25°C for 3 hr; then the reaction
mixture was dissolved in chloroform (50 ml) and extracted with saturated
aqueous sodium bicarbonate, saline, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. Purification by flash column
chromatography (200 g silica) eluting with ethyl acetate/hexane (50/50), the
appropriate fractions were pooled and concentrated to give 1-[5-nitroindolyl2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine, mp 153°-
154°C.
1-[5-Nitroindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-
pyridinyl]piperazine (1.0 g) was dissolved in ethanol (60 ml) and THF (60 ml)
and palladium on carbon (10%, 0.15 g) was added. The reaction mixture was
hydrogenated at 40 psi for 14 hr, then filtered through celite and concentrated
under reduced pressure. Purification by flash chromatography, eluting with
ethyl acetate/hexane (50/50) pooling and concentrating the appropriate
fractions gave 1-[5-aminoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-
pyridinyl]piperazine, mp 212°-214°C.
1-[5-Aminoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-
pyridinyl]piperazine (0.075 mg) was dissolved in methylene chloride (0.4 ml)
and pyridine (0.016 g) was added and the reaction is cooled to 0°C. Then
methanesulfonyl chloride (0.023 g) was added. After 2.5 hr of stirring, the
reaction was diluted with chloroform and washed with saturated aqueous
sodium bicarbonate, saline, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The concentrate was dissolved in the
minimum amount of chloroform and passed through a small plug of silica gel
and then it is recrystallized with ethyl acetate/hexane to provide the 1-[5-
methansulfoneamidolyl-2-carbonyl]-4-[3-(1-methylethylenamino)-2-
pyridinyl]piperazine, mp 226°-228°C.
The mesylate salt may be formed by dissolving the free base in methanol and
methanesulfonic acid (1 eq) is added.
