174484-41-4 Usage
Uses
Used in Antiviral Applications:
Tipranavir is used as an antiviral agent for the treatment of HIV-1 infected adults with evidence of viral replication and demonstrated resistance to multiple protease inhibitors. It is administered with a booster dose of ritonavir, which inhibits CYP3A4, causing the levels of tipranavir to increase. The drug is effective in reducing viral load and preserving immune function when used in combination with at least one nucleoside reverse transcriptase inhibitor.
Used in Pharmaceutical Industry:
Tipranavir is used as a non-peptidic HIV protease inhibitor in the pharmaceutical industry for the development of antiretroviral drugs. Its unique chemical structure and increased flexibility make it less susceptible to cross-resistance compared to peptidomimetic compounds, making it a valuable addition to the arsenal of antiretroviral medications.
Originator
Pharmacia &Upjohn (US)
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.
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.
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.
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.
Check Digit Verification of cas no
The CAS Registry Mumber 174484-41-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,7,4,4,8 and 4 respectively; the second part has 2 digits, 4 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 174484-41:
(8*1)+(7*7)+(6*4)+(5*4)+(4*8)+(3*4)+(2*4)+(1*1)=154
154 % 10 = 4
So 174484-41-4 is a valid CAS Registry Number.
InChI:InChI=1/C31H33F3N2O5S/c1-3-16-30(17-15-21-9-6-5-7-10-21)19-26(37)28(29(38)41-30)25(4-2)22-11-8-12-24(18-22)36-42(39,40)27-14-13-23(20-35-27)31(32,33)34/h5-14,18,20,25,36-37H,3-4,15-17,19H2,1-2H3/t25-,30-/m1/s1
174484-41-4Relevant articles and documents
Process for asymmetric hydrogenation
-
, (2008/06/13)
The present invention is a process for the preparation of a compound of the formula: where R3, R4 and n are defined in the specification which comprises hydrogenating a compound of the formula: the E-geometrical isomer thereof or a mixture of the Z- and E-isomers in the presence of catalyst containing Rh, a chiral ligand with at least one phosphorous atom where the hydrogenation is conducted in the presence of a base.
Process to produce a protease inhibitor
-
, (2008/06/13)
Disclosed is a novel process and novel intermediates to prepare [R-(R*,R*)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide (XIX) which is a protease inhibitor useful in treating humans infected with the HIV virus.
Tipranavir (PNU-140690): A potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class
Turner, Steve R.,Strohbach, Joseph W.,Tommasi, Ruben A.,Aristoff, Paul A.,Johnson, Paul D.,Skulnick, Harvey I.,Dolak, Lester A.,Seest, Eric P.,Tomich, Paul K.,Bohanon, Michael J.,Horng, Miao-Miao,Lynn, Janet C.,Chong, Kong-Teck,Hinshaw, Roger R.,Watenpaugh, Keith D.,Janakiraman, Musiri N.,Thaisrivongs, Suvit
, p. 3467 - 3476 (2007/10/03)
A broad screening program previously identified phenprocoumon (1) as a small molecule template for inhibition of HIV protease. Subsequent modification of this lead through iterative cycles of structure-based design led to the activity enhancements of pyrone and dihydropyrone ring systems (II and V) and amide-based substitution (III). Incorporation of sulfonamide substitution within the dihydropyrone template provided a series of highly potent HIV protease inhibitors, with structure-activity relationships described in this paper. Crystallographic studies provided further information on important binding interactions responsible for high enzymatic binding. These studies culminated in compound VI, which inhibits HIV protease with a K(i) value of 8 pM and shows an IC90 value of 100 nM in antiviral cell culture. Clinical trials of this compound (PNU-140690, Tipranavir) for treatment of HIV infection are currently underway.
A convergent, scalable synthesis of HIV protease inhibitor PNU-140690
Fors, Kristina S.,Gage, James R.,Heier, Richard F.,Kelly, Robert G.,Perrault, William R.,Wicnienski, Nancy
, p. 7348 - 7356 (2007/10/03)
PNU-140690, an inhibitor of the HIV protease enzyme undergoing clinical evaluation as a chemotherapeutic agent for treatment of AIDS, was synthesized by a convergent approach amenable to large-scale preparation in a pilot plant environment. The key step is the aldol addition of nitroaromatic ester (+)-8 to aldehyde 19e. The two stereocenters present in the target molecule were each set independently by resolution of enantiomers. Intermediates along the synthetic routes were chosen to maximize opportunities for isolation and purification by crystallization.
