269055-15-4 Usage
Description
4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile, also known as Etravirine, is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of HIV-1 infection. It is a white to off-white solid with a complex chemical structure, featuring a 2,6-diaminopyrimidine core with various substituents. Etravirine works by binding directly to the reverse transcriptase enzyme, blocking both RNA-dependent and DNA-dependent DNA polymerase activities, thus inhibiting the replication of the HIV virus.
Uses
Used in Antiviral Applications:
Etravirine is used as an antiretroviral drug for the treatment of HIV-1 infection in treatment-experienced adult patients. It is particularly effective against HIV-1 strains that are resistant to other NNRTIs and antiretroviral agents. Etravirine is used in combination with other antiretroviral agents to delay the progression of HIV infection, improve the immune system (increase in CD4+ count), and protect against opportunistic infections. However, it does not cure AIDS or completely kill the HIV virus, and patients should still take precautions to prevent the transmission of the virus to others.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, Etravirine is used as a key component of combination regimens for treating HIV-1 infection. Its allosteric binding nature to the reverse transcriptase enzyme results in an improved safety profile, as there is no known human homolog for the drug-binding site of the enzyme. Etravirine is also synthesized through a series of nucleophilic substitution reactions, starting from 5-bromo-2,4,6-trichloropyrimidine, making it an important compound in the development of new antiretroviral drugs.
Brand Name:
Etravirine is marketed under the brand name Intelence.
Originator
Janssen (United States)
Acquired resistance
Various mutations are associated with a decreased virological
response. Single codon substitutions at positions 100, 101
and 181 are considered major mutations. A single K103N
mutation is not associated with resistance.
Pharmaceutical Applications
A comprehensive analysis of baseline resistance data from
the DUET-1 and DUET-2 studies has identified a list of
17 etravirine resistance associated mutations: V901, A98G,
L100L, K101E/H/I, V1061, E138A, V179D/F/T, Y181C/L/V,
G190A/S, and M230L. A single K103N mutation is not associated
with resistance to etravirine.
Mechanism of action
Etravirine binds directly to reverse transcriptase and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine does not inhibit the human DNA polymerases alpha, beta, and gamma.
Pharmacokinetics
Oral absorption: Not known/available
Cmax 200 mg oral twice daily: c. 959 ng/mL
Cmin 200 mg oral twice daily: c. 469 ng/mL
Plasma half-life: c. 36 h
Volume of distribution: Not known/available
Plasma protein binding: >99%
Administration with food improves the bioavailability and
reduces interpatient variability. It undergoes oxidative metabolism
by cytochrome P450 systems. Around 93.7% and 1.2%
of an administered dose can be retrieved in the feces and
urine, respectively, mostly as unchanged drug.
Details of distribution into CSF, semen and breast milk
and recommendations for dose adjustment in patients with
hepatic impairment are not yet available.
Clinical Use
Treatment of HIV-1 infection in adults (in combination with other
antiretroviral drugs)
Side effects
In the phase III studies around 15% of patients experienced
erythematous or maculopapular rashes of mild or moderate
severity; most resolved with continued dosing, but treatment
was discontinued in 2% of patients. Rare cases of Stevens–
Johnson syndrome have been reported.
Other common adverse events are diarrhea, nausea, headache
and fatigue. Dyslipidemia and raised pancreatic amylase
occur in some patients.
Synthesis
Only the discovery
synthesis and small scale syntheses
have been disclosed for this compound in the following scheme. The
largest scale synthesis was initiated by the portionwise addition
of cyanamide to a solution of the p-cyanoaniline hydrochloride
salt 73. The mixture was refluxed in diglyme to give
guanidine salt 74 in 85% yield after concentration of the reaction
mixture and recrystallization from acetone. Reaction
of guanidine 74 with diethylmalonate in the presence of
sodium ethoxide in refluxing ethanol gave pyrimidine diol
75 in 57% yield, which upon refluxing in phosphorous oxychloride
for 30 min gave dichloride 76 in 97% yield. Bromination
of dichloride 76 with NBS in chloroform at room
temperature provided bromide 77 in 55% yield. Heating a
mixture of the dichlorobromide 77 with the sodium salt of
2,5-dimethyl-4-cyanophenol 78, generated by reaction with
sodium hydride in situ) in diglyme and NMP at 155 °C gave
the coupled product 79 in 45% yield. Finally, reaction of the
chloride 79 with ammonia in refluxing dioxane (or iPrOH) in
a sealed tube gave etravirine (IX) in 41% yield after purification.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration increased by
clarithromycin, also concentration of clarithromycin
reduced; concentration of both drugs reduced with
rifabutin; avoid concomitant use with rifampicin.
Antivirals: concentration possibly reduced by
efavirenz and nevirapine - avoid concomitant use;
concentration of fosamprenavir increased, consider
reducing fosamprenavir dose; possibly reduces
bosutinib and indinavir concentration - avoid
concomitant use; concentration of dolutegravir
reduced; possibly reduces concentration of
maraviroc; concentration reduced by tipranavir
and tipranavir concentration increased - avoid
concomitant use.
Clopidogrel: possibly reduced antiplatelet effect.
Guanfacine: possibly reduces concentration of
guanfacine - increase guanfacine dose.
Orlistat: absorption possibly reduced by orlistat.
Metabolism
Etravirine is extensively metabolised by hepatic
microsomal enzymes, mainly by the cytochrome P450
isoenzymes CYP3A4, CYP2C9, and CYP2C19, to
substantially less active metabolites.Unchanged etravirine accounted for 81.2-86.4% of the
administered dose in faeces. Unchanged etravirine was
not detected in urine.
Check Digit Verification of cas no
The CAS Registry Mumber 269055-15-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,6,9,0,5 and 5 respectively; the second part has 2 digits, 1 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 269055-15:
(8*2)+(7*6)+(6*9)+(5*0)+(4*5)+(3*5)+(2*1)+(1*5)=154
154 % 10 = 4
So 269055-15-4 is a valid CAS Registry Number.
InChI:InChI=1/C20H15BrN6O/c1-11-7-14(10-23)8-12(2)17(11)28-19-16(21)18(24)26-20(27-19)25-15-5-3-13(9-22)4-6-15/h3-8H,1-2H3,(H3,24,25,26,27)
269055-15-4Relevant articles and documents
A etravirine preparation method
-
, (2017/05/26)
The invention discloses a preparation method for etravirine. The method comprises the following steps: performing nucleophilic substitution on a pyrimidine ring to generate an intermediate IV under the action of an alkali by taking a compound II and a compound III as initial raw materials; performing the nucleophilic substitution on the intermediate IV and aminobenzonitrile under an alkaline condition to generate a key intermediate V; performing ammoniation on the key intermediate V in a microwave reactor to generate an intermediate VI; performing bromination on the intermediate VI to generate a target product, namely the etravirine I. The preparation method disclosed by the invention is high in reaction selectivity and easy to operate; compared with the original synthetic method, the reaction time is greatly shortened; the energy consumption is reduced; the reaction yield is improved; the overall yield reaches 38.5 percent; the preparation method is suitable for industrial large-scale production.
C-H FLUORINATION OF HETEROCYCLES WITH SILVER (II) FLUORIDE
-
, (2015/02/19)
The present invention provides compositions and methods for the selective C-H fluorination of nitrogen-containing heteroarenes with AgF2, which has previously been considered too reactive for practical, selective C-H fluorination. Fluorinated heteroarenes are prevalent in numerous pharmaceuticals, agrochemicals and materials. However, the reactions used to introduce fluorine into these molecules require pre-functionalized substrates or the use of F2 gas. The present invention provides a mild and general method for the C-H fluorination of nitrogen-containing heteroarene compounds to 2-fluoro-heteroarenes with commercially available AgF2. In various embodiments, these reactions occur at ambient temperature within one hour and occur with exclusive selectivity for fluorination at the 2-position. Exemplary reaction conditions are effective for fluorinating diazine heteroarenes to form a single fluorinated isomer.
Synthesis and late-stage functionalization of complex molecules through C-H fluorination and nucleophilic aromatic substitution
Fier, Patrick S.,Hartwig, John F.
, p. 10139 - 10147 (2014/08/05)
We report the late-stage functionalization of multisubstituted pyridines and diazines at the position α to nitrogen. By this process, a series of functional groups and substituents bound to the ring through nitrogen, oxygen, sulfur, or carbon are installed. This functionalization is accomplished by a combination of fluorination and nucleophilic aromatic substitution of the installed fluoride. A diverse array of functionalities can be installed because of the mild reaction conditions revealed for nucleophilic aromatic substitutions (SNAr) of the 2-fluoroheteroarenes. An evaluation of the rates for substitution versus the rates for competitive processes provides a framework for planning this functionalization sequence. This process is illustrated by the modification of a series of medicinally important compounds, as well as the increase in efficiency of synthesis of several existing pharmaceuticals.