174484-41-4
Name | Tipranavir |
CAS | 174484-41-4 |
Molecular Formula | C31H33F3N2O5S |
Molecular Weight | 602.66 |
MOL File | 174484-41-4.mol |
Synonyms
Aptivus
Tipranavir
PNU-140690
Tipranavir(PNU-140690,Aptivus)
N-[3-[(1R)-1-[(6R)-2-Hydroxy-4-oxo-6-phenethyl-6-propyl-5H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)pyridine-2-sulfonamide
N-[3-[(1R)-1-[(6R)-5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide
2-PyridinesulfonaMide,N-[3-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoroMethyl)-
Chemical Properties
Appearance | White Solid |
Melting point | 86-890C |
alpha | D +20° (ethanol) |
Boiling point | 712.3±70.0 °C(Predicted) |
density | 1.313±0.06 g/cm3(Predicted) |
storage temp. | -20°C Freezer |
solubility | Methanol (Slightly) |
form | Solid |
pka | 4.50±1.00(Predicted) |
color | White to Pale Yellow |
Hazard Information
Chemical Properties
White Solid
Uses
Nonpeptidic HIV protease inhibitor (NPPI). Antiviral
Definition
ChEBI: A pyridine-2-sulfonamide substituted at C-5 by a trifluoromethyl group and at the sulfonamide nitrogen by a dihydropyrone-containing m-tolyl substituent. It is an HIV-1 protease inhibitor.
Description
Tipranavir, an oral non-peptidic HIV protease inhibitor, was granted accelerated
approval for use in combination with ritanovir and was subsequently launched the
same month in 2005. The targeted patient population includes HIV-1 infected
adults with evidence of viral replication and demonstrated resistance to multiple
protease inhibitors. As with other protease inhibitors, binding at the HIV-1
protease’s active site inhibits the virus-specific processing of the Gag and Gag-Pol
polyproteins in HIV-1-infected cells resulting in the production of non-infectious
virions. An effective regimen to reduce viral load and to preserve immune function
typically consists of a cocktail of a protease inhibitor and at least one nucleoside
reverse transcriptase inhibitor. It is believed that tipranavir has been effective where
other protease inhibitors have encountered resistance because, as a non-peptidic
inhibitor, it was designed by structure-based analysis to have increased flexibility
making it acquiescent to conformational alterations at the binding site. Boosting with ritonavir (200 mg) increased tipranavir Cmin
4-fold and Cmax 20-fold. The primary route of excretion is through the feces (83%)
with an effective mean elimination half-life of 4.8 h in healthy volunteers and 6.0 h
in HIV-infected adults. The efficacy of tipranavir/ritonavir combination therapy
has been evaluated in multiple clinical trials. In general, the adverse events included nausea, vomiting,
and diarrhea. While tipranavir is a CYP3A4 inducer and substrate, as previously
stated, its co-administration with the CYP3A4 inhibitor ritonavir results in net
inhibition; therefore, patients should avoid the concomitant use of drugs highly
dependent on CYP3A4 for clearance. The complete list of contraindicated
drugs can be found in the package insert, but the general classes include antiarrhythmics,
antihistamines, antimycobacterials, neuroleptics, sedatives, ergot derivatives,
GI motility agents, and the herbal supplement St. John’s wort. Finally, as
the elevated liver enzyme levels suggest, tipranavir should not be taken by patients
with severe liver disease. Patients with clinical symptoms of hepatitis should
immediately discontinue use of tipranavir. It is highly recommended that liver
function tests be performed prior to treatment and throughout the course of
therapy.
Originator
Pharmacia &Upjohn (US)
Brand name
Aptivus
Acquired resistance
In a study of 105 viruses resistant to other protease inhibitors,
90% exhibited a more than four-fold decrease in susceptibility and
2% high-level resistance (>10-fold decrease). The predominant
emerging mutations in use with ritonavir are L33F/I/V, V82T/L
and I84V. Combination of all three of these mutations is usually
required for reduced susceptibility. Mutations at positions 47, 58
and 74 are also associated with resistance.
General Description
Tipranavir is unique among the PIs because it is not a peptidomimeticcompound. It does appear to bind to the activesite of HIV-1 protease the same as the peptidomimetics do.The benefit of this agent is that, because it is a differentchemical structure, cross-resistance does not develop tothe same extent as seen with the peptidomimetics. Thedrug is administered with a booster dose of ritonavir. Thisprotocol inhibits CYP3A4, causing the levels of tipranavirto increase.
Pharmaceutical Applications
A non-peptidic protease inhibitor formulated as capsules or
solution for oral use.
Mechanism of action
Tipranavir appears to be bound to the same active site of HIV-1 protease as the peptidomimetics are, but because of its different chemical structure, cross-resistance is significantly less than that seen between the peptidomimetics. The drug suppresses viral replication in various strains of HIV-1 in vitro, and when combined with azothymidine or delaviridine, synergistic activity is noted in vitro. Tipranavir has an advantage over the other PIs in that it is not as strongly bound to plasma protein as the earlier PIs are, a property that reduces the 90% inhibition concentration.
Pharmacokinetics
Oral absorption: Not known/available
Cmax 500 mg + 200 mg ritonavir twice: c. 57.2 mg/L (female);
daily: 46.8 mg/L (male)
Cmin 500 mg + 200 mg ritonavir twice: c. 25.1 mg/L (female);
daily: 21.5 mg/L (male)
Plasma half-life: c. 5.5 h (female); 6 h (male)
Volume of distribution: Not known/available
Plasma protein binding: >99.9%
Absorption and distribution
The combination with ritonavir may be taken with or without food. No studies have been conducted to determine the distribution into human CSF, semen or breast milk.
Metabolism and excretion
Metabolism in the presence of 200 mg ritonavir is minimal. Around 82% is excreted in the feces and 4% in the urine. In mild hepatic impairment it should be used with caution; it should not be used in moderate or severe hepatic impairment.
Cmax 500 mg + 200 mg ritonavir twice: c. 57.2 mg/L (female);
daily: 46.8 mg/L (male)
Cmin 500 mg + 200 mg ritonavir twice: c. 25.1 mg/L (female);
daily: 21.5 mg/L (male)
Plasma half-life: c. 5.5 h (female); 6 h (male)
Volume of distribution: Not known/available
Plasma protein binding: >99.9%
Absorption and distribution
The combination with ritonavir may be taken with or without food. No studies have been conducted to determine the distribution into human CSF, semen or breast milk.
Metabolism and excretion
Metabolism in the presence of 200 mg ritonavir is minimal. Around 82% is excreted in the feces and 4% in the urine. In mild hepatic impairment it should be used with caution; it should not be used in moderate or severe hepatic impairment.
Clinical Use
Treatment (in combination with other antiretroviral drugs) of HIV-1 infection
in patients unresponsive to more than one other protease inhibitor
Side effects
Adverse effects include nausea, vomiting, diarrhea, fatigue
and headache. In studies of ritonavir-boosted regimens higher
rates of hepatotoxicity have been observed with tipranavir
than with other protease inhibitors. In addition, 14 reports of
intracranial bleeding (eight fatal cases) associated with tipranavir
have been reported. It has been associated with dyslipidemia
to a greater extent than other protease inhibitors.
Synthesis
Synthesis
of tipranavir was assembled by an aldol condensation
between two chiral key intermediates, 149 and 154. Condensation of 1-phenylhexan-3-one (141) with ethyl
acetate in the presence of butyllithium and diisopropylamine
in THF gave racemic 3-hydroxy-3-(2-phenylethyl)hexanoic
acid ethyl ester, which was directly hydrolyzed with NaOH
in methanol to corresponding free acid 142 in 94% yield.
The racemic 142 was subjected to optical resolution with (1R,
2S)-(-)-norephedrine to yield chiral compound 144 which
was alkylated with 4-biphenylyloxymethyl chloride (POMCl)
and diisopropylethylamine in toluene to give POM protected
ester 146 in 73% yield . The choice of POM protection group
is for the purification since the POM protected intermediates
were highly crystalline compounds. The ester group of 146
was reduced with diisobutylaluminum hydride in toluene to
give corresponding alcohol 147 in 78% yield, which was
oxidized with 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy
radical (TEMPO)/bleach (NaOCl) to yield corresponding
aldehyde 149 in 99% yield. The other chiral intermediate
154 was synthesized as described below. Racemic compound
150 was subjected to kinetic enzymatic resolution with a
lipase and isopropenyl acetate in dichloromethane to give
chiral alcohol 152 which was converted to its mesylate and
reacted with sodium diethyl malonate to give diester 153.
The diester 153 was decarboxylated under an acid condition
and re-esterified to give optical pure intermediate 154. Aldol
condensation of 149 and 154 with sodium hexamethyldisilazide
in THF at low temperature gave hydroxyester 155 in
90% yield as a mixture of four diastereomers. This mixture
was oxidized with pyridinium chlorochromate (PCC) in dichloromethane
to afford corresponding ketoester which was
subsequently treated with sulfuric acid in methanol to remove
the POM protecting group to yield hydroxy ketoester
156 in 84% yield. Compound 156 was cyclized with NaOH
in methanol/water to afford dihydropyranone 157 in 75%
yield. The nitro group of 157 was reduced with hydrogen
over Pd/C in THF to give corresponding aniline 158, which
was finally amidated with 5-(trifluoromethyl)pyridine-2-
sulfonyl chloride 159 and pyridine in DMSO to give tipranavir
(XXI) in 78% yield from compound 149.
Drug interactions
Potentially hazardous interactions with other drugs
Antacids: avoid giving for 2 hours after tipranavir administration.
Antibacterials: plasma concentration of clarithromycin and other macrolides increased - reduce dose of clarithromycin in renal impairment; concentration increased by clarithromycin; rifabutin concentration increased (risk of uveitis) - reduce dose; concentration possibly reduced by rifampicin - avoid; avoid with telithromycin in severe renal and hepatic failure.
Anticoagulants: avoid with apixaban and rivaroxaban.
Antidepressants: concentration possibly reduced by St John’s wort - avoid.
Antimalarials: use artemether/lumefantrine with caution; concentration of quinine increased.
Antipsychotics: possibly increases aripiprazole concentration - reduce aripiprazole dose; possibly increases quetiapine concentration - avoid.
Antivirals: reduces concentration of abacavir, dolutegravir, didanosine, fosamprenavir, lopinavir, saquinavir and zidovudine; concentration increased by atazanavir, also concentration of atazanavir reduced; concentration reduced by etravirine, also concentration of tipranavir increased - avoid.
Beta-blockers: avoid with metoprolol for heart failure.
Ciclosporin: levels possibly altered by tipranavir.
Cobicistat: concentration of both drugs reduced - avoid.
Lipid-lowering drugs: increased risk of myopathy with atorvastatin, max dose 10 mg; avoid with lomitapide; concentration of rosuvastatin increased - reduce rosuvastatin dose; concentration of simvastatin increased - avoid.1
Orlistat: absorption possibly reduced by orlistat.
Ranolazine: possibly increases ranolazine concentration - avoid.
Sirolimus: levels possibly altered by tipranavir.
Tacrolimus: levels possibly altered by tipranavir.
Ulcer-healing drugs: concentration of esomeprazole and omeprazole reduced.
Antacids: avoid giving for 2 hours after tipranavir administration.
Antibacterials: plasma concentration of clarithromycin and other macrolides increased - reduce dose of clarithromycin in renal impairment; concentration increased by clarithromycin; rifabutin concentration increased (risk of uveitis) - reduce dose; concentration possibly reduced by rifampicin - avoid; avoid with telithromycin in severe renal and hepatic failure.
Anticoagulants: avoid with apixaban and rivaroxaban.
Antidepressants: concentration possibly reduced by St John’s wort - avoid.
Antimalarials: use artemether/lumefantrine with caution; concentration of quinine increased.
Antipsychotics: possibly increases aripiprazole concentration - reduce aripiprazole dose; possibly increases quetiapine concentration - avoid.
Antivirals: reduces concentration of abacavir, dolutegravir, didanosine, fosamprenavir, lopinavir, saquinavir and zidovudine; concentration increased by atazanavir, also concentration of atazanavir reduced; concentration reduced by etravirine, also concentration of tipranavir increased - avoid.
Beta-blockers: avoid with metoprolol for heart failure.
Ciclosporin: levels possibly altered by tipranavir.
Cobicistat: concentration of both drugs reduced - avoid.
Lipid-lowering drugs: increased risk of myopathy with atorvastatin, max dose 10 mg; avoid with lomitapide; concentration of rosuvastatin increased - reduce rosuvastatin dose; concentration of simvastatin increased - avoid.1
Orlistat: absorption possibly reduced by orlistat.
Ranolazine: possibly increases ranolazine concentration - avoid.
Sirolimus: levels possibly altered by tipranavir.
Tacrolimus: levels possibly altered by tipranavir.
Ulcer-healing drugs: concentration of esomeprazole and omeprazole reduced.
Metabolism
Tipranavir is metabolised by the cytochrome P450 system (mainly the isoenzyme CYP3A4), although when given with ritonavir metabolism is minimal with the majority of tipranavir being excreted unchanged in the faeces.
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