Nucleoside reverse transcriptase inhibitors preparations

Efavirenz (1) was chosen over compound 2 as a developmental candidate in 1993 based on its better antivirus activities, especially against resistant strains [1, 17]. Efavirenz is the first HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) which was approved by the FDA on September 21, 1998. The original Medicinal Chemistry method to prepare Efavirenz is depicted in Scheme 1.14. 

A number of novel spiro heterocycles, including the triazepinethione 146 have been derived from 3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one 145 by condensation with active methylene compounds <00SC1257>. A condensation process was also used to prepare tricyclic triazepinones related to the non-nucleoside reverse transcriptase inhibitor nevirapine <00JHC1539>. 

Aubry, A.F., Sebastian, D., Hobson, T., Xu, J.Q., Rabel, S., Xie, M., and Gray, V., In-use testing of extemporaneously prepared suspension of second generation non-nucleoside reversed transcriptase inhibitors in support of Phase I clinical studies, /. Pharm. Biomed. Anal., 23,535,2000. 

Tetrazole thioacetanilides 595 (HIV non-nucleoside reverse transcriptase inhibitors) <2006BML2748> and derivatives of cyclic ureas 596 (nonpeptide inhibitors of HIV protease) have been prepared <1998JME2019>. 

In the laboratory of E.B. Pedersen, several 2-methylsulfanyl-1H-imidazoles were prepared and tested for their activity against HIV-1 These compounds can be regarded as novel non-nucleoside reverse transcriptase inhibitors. The required a-aminoketone hydrochloride building blocks were prepared using the Dakin-West reaction. L-Cyclohexylalanine was dissolved in excess pyridine and propionic anhydride and was kept at reflux overnight. The resulting a-propionylamino ethyl ketone was hydrolyzed with concentrated hydrochloric acid and the a-aminoketone hydrochloride was heated with one equivalent of potassium thiocyanate in water to afford 4-cyclohexylmethyl-5-ethyl-1,3-dihydroimidazole-2-thione. This material was then advanced to 4-cyclohexylmethyl-1-ethoxymethyl-5-ethyl-2-methylsulfanyl-IH-imidazole. 

Several ADAM (alkenyidiarylmethane) II non-nucleoside reverse transcriptase inhibitors were prepared by M. Cushman and co-workers. The McMurry reaction was the key transformation that enabled the coupling of the diaryl ketone with a variety of aldehydes in good yield. The commercially available TiCU-THF (2 1) and zinc dust was used to prepare the low-valent titanium reagent in refluxing THF. To this suspension was added the diaryl ketone and the aldehyde successively. 

The synthesis of diaryl-1,3i5-triazines 10, a new class of potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) has been reported. The requisite amidines 8 were readily prepared from the corresponding phenylacelonitrilcs, while the isourea partners 9 were obtained in modest yields by the reaction of diphenyl cyanocarbonimidate with the appropriate aniline <01BMCL2229>. 

In the area of 2, 3 -didehydro-2, 3 -dideoxycompounds (d4 systems), a previous method for their synthesis from 5 -protected 2, 3 -di-0-mesyl-nucIeosides by treatment with arylselenyl anions (Vol. 31, p. 272) has now been modified by the use of bis(4-perfluorohexylphenyl) diselenide and sodium borohydride, which permits the use of the diselenide in catalytic quantities, and also its ready recovery. The method was used for the synthesis of d4-uridine. Analogues of d4T with potential linker arms at C-5, for attachment of either a fluorescent tag or a non-nucleoside reverse transcriptase inhibitor, have been prepared either from 5-(hydroxymethyl)uridine or from the 2,2 -anhydronucleoside of 5-(methoxycarbonyhnethyl)uridine (Vol. 28, p, 265-266). Addition of iodine at C-2 and C-3 of protected pyrimidine nucleosides under Arbuzov reaction conditions has led to a new route to d4 systems, and d4-uridine has been prepared from 2 -deoxyuridine using elimination from the 3, 5 -dimesylate. ... 

Kauffman GS, Harris GD, Dorow RL, Stone BR, Parsons RL Jr, Pesti JA, Magnus NA, Fortunak JM, Confalone PN, Nugent WA (2000) An efficient chiral moderator prepared from inexpensive (+)-3-carene synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963. Org Lett 2 3119-3121... 

Zagreb antivenom is a non-proprietary antivenom preparation that can be used as an injected ANTIDOTE to the poison from an adder s bite. However, the systemic allergic and other effects of the venom are rarely serious enough to warrant the use of the antivenom, zalcitabine [ban, inn, usan] (ddC DDC Hivid ) is a synthetic nucleoside analogue, a REVERSE TRANSCRIPTASE INHIBITOR which acts as an ANTIVIRAL AGENT. It is active orally as an ANTI-HIV AGENT. 

Dihydroquinazolinones 89 have been shown to represent a novel type of non-nucleoside HlV-1 reverse transcriptase inhibitors [94JMC(37)2437], Hexa-hydropyrimidines of type 90 were prepared as nonpeptidic HIV-1 protease inhibitors [94M1(4)1247. Antiviral activity has b n observed also with pyrimidinones of type 91 (94CCC(59)683j. Acyloxypyrimidines 92 have been found to inhibit human and herpetic DNA glycosylases [94T(S0)3603. ... 

Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase, dipyrido[2,3-/)]diazepinones, were prepared by J.R. Proudfoot and co-workers.These compounds are isomeric to the potent inhibitor nevirapine and available via the Smiles rearrangement of substrates that are intermediates used for the synthesis of nevarpine analogs. The deprotonated amide functionality in the rearrangement products displaces the chlorine at the 2-position to give the desired heterocycles in moderate to good yield. 

Analogues 249 (X = H, OH) of UDP-GlcNAc have been prepared as potential inhibitors of chitin synthetases. The synthetic route involved a C-allyl derivative of GlcNAc, which was elaborated by ozonolysis, Wittig reaction and coupling with the nucleoside, followed by hydrogenation or hydroxylation as appropriate. The corresponding amides were also prepared from 5 -amino-5 -deoxyuridine. Lipophilic amino acid methyl esters and methylamides have been coupled to 0-5 of AZT by carbamate links. The products showed anti-HIV activity, but this was not due to carbamate hydrolysis or to direct inhibition of reverse transcriptase, and the mechanism of action may be one not previously observed with nucleoside antivirals. ... 

Although the 5 -triphosphate of ddU is a potent inhibitor of reverse transcriptase, the parent nucleoside is inactive because it is a poor substrate for thymidine kinase. In an attempt to by-pass this phosphorylation step, the bis(pivaloyloxymethyl) triester of ddU 5 -monophosphate (44, Nu = 5 -ddU) was prepared [59]. This membrane-permeable prodrug is active against HIV-1 in either MT-4 or thymidine kinase-deficient CEM cells, and it has been shown to release the 5 -monophosphate of ddU in both cell lines. 

The S -triphosphates and a-thio-triphosphates of 2 -0-methylribonucleosides have been synthesized with the nucleoside attached via 0-3 to the surface of controlled pore glass.260 A range of imido-analogues of AZT triphosphate, 197 (X, Y = O, NH) have been prepared, together with similar derivatives of TIP itself the TIP analogue with X = O, Y = NH proved the best inhibitor of HTV 1 reverse transcriptase.26i... 

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