Etravirine CAS 269055-15-4
Introduction：Basic information about Etravirine CAS 269055-15-4, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Etravirine Basic information
| Product Name: | Etravirine |
| Synonyms: | 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3, 5 –dimethylbenzonitrile;Etravirine;Etravirine（TMC-125）;R 165335;TMC 125;4-(6-amino-5-bromo-2-(4-cyanobenzyl)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile, Etravirine;4-[[6-AMino-5-broMo-2-[(4-cyanophenyl)aMino]-4-pyriMidinyl]oxy]-3,5-diMethyl-;4-[[6-aMino-5-broMo-2-[(4-cyanophenyl)aMino]-4-pyriMidinyl]oxy]-3, 5 –diMethylbenzonitrile/Etravirine |
| CAS: | 269055-15-4 |
| MF: | C20H15BrN6O |
| MW: | 435.28 |
| EINECS: | 682-331-6 |
| Product Categories: | Other APIs;All Inhibitors;Inhibitors;Intermediates & Fine Chemicals;Non-nucleoside Reverse Transcriptase;Pharmaceuticals |
| Mol File: | 269055-15-4.mol |
Etravirine Chemical Properties
| Melting point | .265°C (dec.) |
| Boiling point | 637.4±65.0 °C(Predicted) |
| density | 1.439 g/cm3 |
| storage temp. | Keep in dark place,Inert atmosphere,Store in freezer, under -20°C |
| solubility | DMSO (Slightly), Methanol (Slightly, Heated, Sonicated) |
| form | Solid |
| pka | 1.23±0.10(Predicted) |
| color | White to Off-White |
| InChI | InChI=1S/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) |
| InChIKey | PYGWGZALEOIKDF-UHFFFAOYSA-N |
| SMILES | C(#N)C1=CC(C)=C(OC2C(Br)=C(N)N=C(NC3=CC=C(C#N)C=C3)N=2)C(C)=C1 |
Safety Information
| WGK Germany | WGK 3 |
| Storage Class | 11 - Combustible Solids |
| Hazard Classifications | Aquatic Acute 1 Aquatic Chronic 1 |
| Description | Etravirine is a second-generation NNRTI. It is indicated for use incombination with other antiretroviral agents for treating HIV-1 infection intreatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to the currently available NNRTIs andother antiretroviral agents. The NNRTIs, along with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs), are importantcomponents of the combination regimens currently used to treat HIV-1infection. The NRTIs/NtRTIs act by competing with the natural nucleotidesubstrates of reverse transcriptase for incorporation into viral DNAand subsequent chain termination. By contrast, the NNRTIs bind to anallosteric site of the enzyme and disrupt the DNA polymerase function byinducing conformational changes to the catalytic site. The allostericbinding nature of NNRTIs generally results in improved safety profilesince there is no known human homolog for the drug-binding site ofthe enzyme. As with other NNRTIs, etravirine hasmany drug–drug interactions. It is a substrate of CYP3A4, CYP2C9,and CYP2C19, an inducer of 3A4, and an inhibitor of 2C9 and 2C19.Caution should be used with co-administration of inducers, inhibitors, orsubstrates of these enzymes. Etravirine can be synthesized starting from5-bromo-2,4,6-trichloropyrimidine through three successive nucleophilicsubstitution reactions. Initial displacement with 4-aminobenzonitrile usingHu¨nig’s base, followed by reaction with sodium salt of 4-hydroxy-3,5-dimethylbenzonitrile, and subsequent ammonolysis reaction with ammonia in dioxane under pressure affords etravirine. . |
| Chemical Properties | White to Off-White Solid |
| Originator | Janssen (United States) |
| Uses | Etravirine is a novel HIV reverse transcriptase inhibitor useful in treatment of HIV infection. |
| Uses | Etravirine is an antiretroviral (anti-HIV) drug that is part of the non nucleoside reverse transcriptase inhibitor (NNRTIs or Non Nukes) family. It is used together with other antiretrovirals in treatment-experienced adult patients, who have failed previous therapy, and have HIV-1 strains which are resistant to other retrovirals and NNRTIs. Etravirine is used to delay the progression of HIV infection. By using etravirine, your immune system should improve (increase in CD4 + count) and you will be better protected against opportunistic infections. Etravirine does not cure AIDS or completely kill the HIV virus, but helps to prevent further damage by slowing down the production of new viruses. Treatment with etravirine does not reduce the risk of passing infection on to others. You will still be able to pass HIV by sexual contact, by blood transfer or by sharing needles. You should always use appropriate precautions to prevent passing HIV on to others. |
| Uses | Etravirine (TMC125) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used for the treatment of HIV. |
| Definition | ChEBI: An aminopyrimidine that consists of 2,6-diaminopyrimidine bearing a bromo substituent at position 5, a 4-cyano-2,6-dimethylphenoxy substituent at position 4 and having a 4-cyanophenyl substituent attached to the 2-amino group. NNRTI of HIV-1, binds directl to RT and blocks RNA-dependent and DNA-dependent DNA polymerase activities |
| Brand name | Intelence |
| Acquired resistance | Various mutations are associated with a decreased virologicalresponse. Single codon substitutions at positions 100, 101and 181 are considered major mutations. A single K103Nmutation is not associated with resistance. |
| Pharmaceutical Applications | A comprehensive analysis of baseline resistance data fromthe DUET-1 and DUET-2 studies has identified a list of17 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 associatedwith 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 andreduces interpatient variability. It undergoes oxidative metabolismby cytochrome P450 systems. Around 93.7% and 1.2%of an administered dose can be retrieved in the feces andurine, respectively, mostly as unchanged drug. Details of distribution into CSF, semen and breast milkand recommendations for dose adjustment in patients withhepatic impairment are not yet available. |
| Clinical Use | Treatment of HIV-1 infection in adults (in combination with otherantiretroviral drugs) |
| Side effects | In the phase III studies around 15% of patients experiencederythematous or maculopapular rashes of mild or moderateseverity; most resolved with continued dosing, but treatmentwas discontinued in 2% of patients. Rare cases of Stevens–Johnson syndrome have been reported. Other common adverse events are diarrhea, nausea, headacheand fatigue. Dyslipidemia and raised pancreatic amylaseoccur in some patients. |
| Synthesis | Only the discoverysynthesis and small scale syntheses have been disclosed for this compound in the following scheme. Thelargest scale synthesis was initiated by the portionwise additionof cyanamide to a solution of the p-cyanoaniline hydrochloridesalt 73. The mixture was refluxed in diglyme to giveguanidine salt 74 in 85% yield after concentration of the reactionmixture and recrystallization from acetone. Reactionof guanidine 74 with diethylmalonate in the presence ofsodium ethoxide in refluxing ethanol gave pyrimidine diol75 in 57% yield, which upon refluxing in phosphorous oxychloridefor 30 min gave dichloride 76 in 97% yield. Brominationof dichloride 76 with NBS in chloroform at roomtemperature provided bromide 77 in 55% yield. Heating amixture of the dichlorobromide 77 with the sodium salt of2,5-dimethyl-4-cyanophenol 78, generated by reaction withsodium hydride in situ) in diglyme and NMP at 155 ??C gavethe coupled product 79 in 45% yield. Finally, reaction of thechloride 79 with ammonia in refluxing dioxane (or iPrOH) ina 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. |
Etravirine Preparation Products And Raw materials
| Raw materials | 6-Desamino 6-Chloro Etravirine-->4-hydroxy-3,5-dimethyl-benzenecarbonitrile-->Etravirine Impurity 11 |
