192725-17-0 Usage
Uses
Used in Pharmaceutical Industry:
Lopinavir is used as an antiviral agent for the treatment of HIV infections. It is used in combination with ritonavir, another HIV protease inhibitor, to enhance its effectiveness and overcome resistance.
Used in HIV Treatment:
Lopinavir is used as a potent HIV protease inhibitor with a Ki of 1.3 pM, exhibiting high potential against ritonavir-resistant mutations. It is used in combination with ritonavir to improve the pharmacokinetic properties, such as Cmax and duration of action, and to reduce plasma HIV RNA levels and increase CD4+ T-cell counts in AIDS patients.
Used in Combination Therapy:
Lopinavir is used as a component of fixed-dose combinations with ritonavir for the treatment of HIV infections. The combination therapy is intended to be used jointly with other antiretroviral agents to enhance the overall treatment efficacy.
Used in Pediatric HIV Treatment:
Lopinavir, in combination with ritonavir, is the first protease inhibitor approved for patients as young as 6 months of age, making it an important option for treating HIV in pediatric populations.
Indications
Lopinavir is available in the United States only as a
fixed-dose combination with ritonavir (Kaletra). In this
regimen, a low dose of ritonavir is used to inhibit the
rapid inactivation of lopinavir by CYP3A4.
Manufacturing Process
Manufacturing process for Lopinavir includes these steps as follows: Synthesis of 2,6-dimethylphenoxyacetic
acid; 2,6-
dimethylphenoxyacetyl chloride as an oil; synthesis of (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(tbutyloxycarbonylamino)-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-
amino-1,6-diphenylhexane as a white needles; synthesis of N-carbonylbenzyloxy-3-
aminopropanol;synthesis of N-carbonylbenzyloxy-3-aminopropanal solution; N-(N-
(benzyloxycarbonyl-3-amino)-propyl)valine methyl ester, oil state; synthesis of 2S-(1-tetrahydro-pyrimid-2-onyl)-3-
methyl butanoic acid methyl ester;synthesis of 2S-(1-
tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid methyl ester. The mixture of (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-
amino-1,6-diphenylhexane (100 g, 0.22 mol), 2S-(1-tetrahydro-pyrimid-2-
onyl)-3-methyl butanoic acid methyl ester (44.8 g, 0.22 mol) and 750 ml DMF
was cooled in an ice/water bath. N-Hydroxybenzotriazole (90.9 g, 0.67 mol),
1-ethyl-3-[3-dimethylaminopropyl]carbodiimide (86 g, 0.45 mol) and
triethylamine (62.5 ml, 0.45 mol) were added and the ice bath was removed,
allowing the reaction mixture to stir with warming to room temperature for 5
hours. The mixture was diluted with 1000 ml of IPAC and quenched with 1000
ml of water. The mixture was shaken and separated, the aq. layer was
extracted IPAC, the organics were washed with 10% HCl, solution of NaHCO3
with 100 ml hexanes, then washed 500 ml water, and brine, dried over
MgSO4, filtered and concentrated to provide. (2S,3S,5S)-2-(2,6-
dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-
3-methylbutanoyl)amino-1,6-diphenylhexane as a white foam.
Therapeutic Function
Antiviral
Antimicrobial activity
Lopinavir is active against HIV-1 and HIV-2.
Acquired resistance
Significant resistance to the antiretroviral efficacy of ritonavirbooted
lopinavir occurs as a result of amino acid substitutions
at positions 32, 47 and 82 in the protease region. Protease
inhibitor resistance is uncommon in patients identified with
early failure of combination therapy with ritonavir boostedlopinavir
and nucleotide reverse transcriptase inhibitors.
Biochem/physiol Actions
Lopinavir is an antiviral HIV Protease Inhibitor. Lopinavir has insufficient bioavailability alone, so it is used in therapy in combination with Ritonavir, a HIV protease inhibitor, which inhibits cytochrome P450-3A4 (CYP3A4), a liver enzyme that normally metabolizes protease inhibitors. Lopinavir also has an ability to inhibit ZMPSTE24 (zinc metallopeptidase STE24).
Pharmacokinetics
Oral absorption: Not known/available
Cmax 400 mg + ritonavir 100 mg twice daily: c. 9.6 mg/L
Cmin 400 mg + ritonavir 100 mg twice daily: c. 5.5 mg/L
Plasma half-life: c. 5–6 h
Volume of distribution: Not known/available
Plasma protein binding: c. 98–99%
Absorption and distribution
The absorption of lopinavir–ritonavir in capsule or liquid form is favorably affected by the presence of food, particularly if high in fat. The CNS penetration is good. It has a semen:plasma ratio of 0.07. It is distributed into breast milk.
Metabolism
Lopinavir is extensively metabolized by the CYP3A4 system, but this is inhibited by ritonavir.
Excretion
Over an 8-day period after single dosing with the combined formulation, around 10% and 83% of the administered dose is recovered in urine and feces, respectively. Less than 3% of the dose is recovered as unchanged drug in urine and 20% in feces. In mild to moderate hepatic impairment, an increase in exposure of approximately 30% is observed, but is probably not clinically relevant. It should be avoided in severe hepatic impairment.
Clinical Use
Treatment of HIV infection (in combination with ritonavir and other
antiretroviral agents)
Side effects
The most common adverse events seen in trials of complex antiretroviral
regimens were diarrhea, nausea, headache, fatigue,
vomiting and rash. Ritonavir-boosted lopinavir is associated
with a dyslipidemia profile characteristic of those treated with
other protease inhibitors boosted with 200 mg of ritonavir.
Drug interactions
Potentially hazardous interactions with other drugs
In combination with ritonavir - see ritonavir interactions.
Anti-arrhythmics: increased risk of ventricular
arrhythmias with flecainide - avoid; possibly
increased lidocaine concentration.
Antibacterials: concentration reduced by rifampicin
- avoid; concentration of delamanid increased;
avoid with telithromycin in severe renal and hepatic
impairment; AUC of bedaquiline increased by 22%,
avoid.
Anticoagulants: avoid with apixaban and
rivaroxaban.
Antidepressants: concentration reduced by St John’s
wort - avoid.
Antiepileptics: concentration possibly reduced by
carbamazepine, fosphenytoin, phenytoin, primidone
and phenobarbital.
Antimalarials: use artemether/lumefantrine with
caution.
Antipsychotics: possibly inhibits metabolism of
aripiprazole - reduce dose of aripiprazole; possibly
increases quetiapine concentration - avoid.
Antivirals: avoid with boceprevir, daclatasvir
and telaprevir; concentration of darunavir and
fosamprenavir reduced - avoid; in combination with
ritonavir concentration of elvitegravir increased -
reduce dose of elvitegravir; concentration reduced
by efavirenz, tipranavir and possibly nevirapine,
consider increasing lopinavir dose; concentration
of paritaprevir increased - avoid; increased risk of
ventricular arrhythmias with saquinavir - avoid;
concentration of tenofovir increased; concentration
of maraviroc increased, consider reducing maraviroc
dose.
Bosentan: concentration of bosentan increased,
consider reducing bosentan dose.
Ciclosporin: may increase concentration of
ciclosporin.
Cytotoxics: reduce dose of ruxolitinib.
Lipid lowering agents: increased risk of myopathy
with atorvastatin; possibly increased risk of
myopathy with rosuvastatin (reduce rosuvastatin
dose) and simvastatin - avoid; avoid with lomitapide.
Orlistat: absorption of lopinavir possibly reduced.
Ranolazine: possibly increases ranolazine
concentration - avoid.
Sirolimus: may increase concentration of sirolimus.
Tacrolimus: may increase concentration of
tacrolimus.
Metabolism
Lopinavir is extensively metabolised, mainly by oxidation
by cytochrome P450 isoenzyme CYP3A4; 13 metabolites
have been identified with some, such as 4-oxylopinavir
and 4-hydroxylopinavir, having antiviral activity.
Lopinavir is mainly excreted in faeces and to a smaller
extent in the urine; unchanged lopinavir accounts for
about 2.2% of a dose excreted in the urine and 19.8%
in the faeces. After multiple dosing, less than 3% of the
absorbed lopinavir dose is excreted unchanged in the
urine
Check Digit Verification of cas no
The CAS Registry Mumber 192725-17-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,9,2,7,2 and 5 respectively; the second part has 2 digits, 1 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 192725-17:
(8*1)+(7*9)+(6*2)+(5*7)+(4*2)+(3*5)+(2*1)+(1*7)=150
150 % 10 = 0
So 192725-17-0 is a valid CAS Registry Number.
InChI:InChI=1/C37H48N4O5/c1-25(2)34(41-20-12-19-38-37(41)45)36(44)39-30(21-28-15-7-5-8-16-28)23-32(42)31(22-29-17-9-6-10-18-29)40-33(43)24-46-35-26(3)13-11-14-27(35)4/h5-11,13-18,25,30-32,34,42H,12,19-24H2,1-4H3,(H,38,45)(H,39,44)(H,40,43)/t30-,31-,32-,34-/m0/s1
192725-17-0Relevant articles and documents
Preparation method of lopinavir
-
Paragraph 0004; 0007; 0008; 0010, (2021/10/05)
The invention provides a preparation method represented by formula (I) shown in the specification, and particularly provides a preparation method of (2S)-N-{(1S, 3S, 4S)-1-benzyl-4-[2-(2, 6-dimethylphenoxy)acetamido]-3-hydroxy-5-phenylamyl}-3-methyl-2-(2-oxotetrahydropyrimidin-1-yl)butyramide. The novel method is provided for preparing lopinavir.
Synthesis and characterization of novel analogues of lopinavir
Reddy, Peketi Rajesh,Musunuri, Sivanadh,Ramasekhara Reddy,Subrahmanyam Chittala,Murthy,Krishnamohan
, p. 151 - 158 (2021/01/06)
The present work describes the identification, origin, synthesis, characterization and control of four novel analogues of lopinavir viz. leucine analogue of lopinavir, isoleucine analogue of lopinavir, methyl analogue of lopinavir and dihydroxy analogue of lopinavir.
Novel crystal form of lopinavir and preparation method thereof
-
, (2021/05/26)
The invention discloses a novel crystal form of lopinavir and a preparation method thereof, belonging to the technical field of medicine crystal forms. According to the invention, lopinavir is prepared, and the novel crystal form of lopinavir is cultured; a real stereo structure of four chiral centers in a lopinavir molecule can be seen from an obtained single crystal structure; crystal data is recorded by a crystal database, namely CCDC 1969375, of the British Cambridge University for the first time; and compared with other detection methods reported at present, an X-ray single crystal diffraction method is the most direct and intuitive method for determining the absolute configuration and space structure of lopinavir.
Novel method for preparing lopinavir
-
Paragraph 0064-0067; 0082-0085, (2020/05/01)
The invention relates to a novel method for preparing lopinavir (I), a condensation reaction of a compound shown in a formula (II) and a compound shown in a formula (III) is carried out at room temperature under mild condensation reaction conditions, and heating or cooling is not needed; the preparation method does not need special chemical reagents, the special chemical reagents are solvents andreagents commonly used in laboratories, the total yield is higher than 85%, preferably higher than 90%, in some embodiments, the yield reaches 96%, and the preparation method is especially suitable for industrial production.
Preparation of lopinavir by one-pot method
-
, (2020/04/02)
The invention relates to preparation of lopinavir as shown in formula (I) by a one-pot method. 2, 6-dimethylphenoxyacetic acid, a carboxyl activator and a compound as shown in a formula (III) are subjected to a condensation reaction in an organic solvent under a mild condensation reaction condition, the reaction can be carried out at room temperature without heating or cooling. The preparation method does not need special chemical reagents, and the solvent and the reagents used in the method are commonly used in laboratories. The total yield is higher than 85%, preferably higher than 90%, andthe yield reaches 96% in some embodiments. The preparation method is especially suitable for industrial production.
AN IMPROVED PROCESS FOR PREPARATION OF LOPINAVIR AND ITS INTERMEDIATES THEREOF
-
, (2019/10/23)
The present invention generally relates to an improved process for preparation of lopinavir and its intermediates through formation of tartrate salt of compound of Formula (III).
Method used for preparing Lopinavir using one-pot method
-
Paragraph 0014, (2018/07/30)
The invention discloses a method used for preparing lopinavir using one-pot method. According to the method, under certain organic solvent conditions, (2S)-(1-Tetrahydropyramid-2-one)-3-methylbutanoicacid is reacted with thionyl chloride so as to obtain (2S)-(1-Tetrahydropyramid-2-one)-3-methyl butyryl chloride; a weak base acid binding agent and N-[(1S,2S,4S)-4-amino-2-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]-2-(2,6-dimethylphenoxy)acetamide are added into an obtained reaction system for amidation reaction; after amidation reaction, an obtained product is subjected to post-treatment so as toobtain lopinavir finished product. According to the method, on-pot method is adopted, the process is simple, production period is short, the finial products can be separated and purified easily, synthesis yield is high, the method is economical and is high in feasibility, and is suitable for industrialized production.
NOVEL POLYMORPHS OF LOPINAVIR
-
Page/Page column 3, (2011/12/13)
The present invention provides a novel cyclohexane solvate form of lopinavir, and a process for its preparation thereof. The present invention also provides a novel desolvated crystalline form of lopinavir, process for its preparation and to pharmaceutical composition containing it. Thus, for example, lopinavir cyclohexane solvate was heated at 100° C. for 10 hours to give lopinavir desolvated crystalline form H1.
PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE (2S,3S,5S)-5-AMINO-2-N,N-DIBENZYLAMINO-3-HYDROXY-1,6-DIPHENYLHEXANE
-
Page/Page column 5, (2010/12/29)
The present invention relates to the purification of (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III) by making its crystalline acid addition salt, which can be used as such to produce Lopinavir/Ritonavir with high purity and yield. Formula III
NOVEL POLYMORPHS OF LOPINAVIR
-
Page/Page column 7, (2010/08/18)
The present invention provides a novel cyclohexane solvate form of lopinavir, and a process for its preparation thereof. The present invention also provides a novel desolvated crystalline form of lopinavir, process for its preparation and to pharmaceutical composition containing it. Thus, for example, lopinavir cyclohexane solvate was heated at 100 °C for 10 hours to give lopinavir desolvated crystalline form H1.
