Lopinavir CAS 192725-17-0
Introduction：Basic information about Lopinavir CAS 192725-17-0, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Lopinavir Basic information
| Product Name: | Lopinavir |
| Synonyms: | LOPINAVIR;(2s)-n-[(2r,4s,5s)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenyl-hexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide;(aS)-N-[(1S,3S,4S)-4-[[2-(2,6-Dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-a-(1-methylethyl)-2-oxo-1(2H)-Pyrimidineacetamide;A 157378.0;ABT 378;Aluviran;Koletr;134368 |
| CAS: | 192725-17-0 |
| MF: | C37H48N4O5 |
| MW: | 628.81 |
| EINECS: | 200-001-8 |
| Product Categories: | Pharmaceutical;Other APIs;Anti-viral Compounds;Anti-virals;Intermediates & Fine Chemicals;Chiral Reagents;Non-nucleoside Reverse Transcriptase;Pharmaceuticals;Pepetides;ProteaseInhibitors;API;peptides;ABT-378 |
| Mol File: | 192725-17-0.mol |
Lopinavir Chemical Properties
| Melting point | 255.2-260.6 °F (124—127°C) |
| Boiling point | 924.1±65.0 °C(Predicted) |
| density | 1.163±0.06 g/cm3(Predicted) |
| storage temp. | 2-8°C |
| solubility | DMSO: soluble20mg/mL, clear |
| pka | 13.89±0.46(Predicted) |
| form | powder |
| color | white to beige |
| biological source | synthetic |
| Optical Rotation | [α]/D -20 to -27°, c = 0.4 in methanol |
| Stability: | Hygroscopic |
| InChIKey | KJHKTHWMRKYKJE-SXICDMDWNA-N |
| SMILES | [C@H](N1CCCNC1=O)(C(C)C)C(=O)N[C@H](C[C@H](O)[C@@H](NC(=O)COC1C(=CC=CC=1C)C)CC1C=CC=CC=1)CC1C=CC=CC=1 |&1:0,14,16,18,r| |
| CAS DataBase Reference | 192725-17-0(CAS DataBase Reference) |
Safety Information
| RIDADR | 3077 |
| WGK Germany | WGK 3 |
| HS Code | 29335990 |
| Storage Class | 11 - Combustible Solids |
| Hazardous Substances Data | 192725-17-0(Hazardous Substances Data) |
| Description | Lopinavir, the sixth HIV protease inhibitor in the “navir” class, was launched in coformulationwith ritonavir, another HIV protease inhibitor already marketed (Abbott, 1996);this original formulation was introduced as Kaletra for use in combination with eithernucleoside or non-nucleoside reverse transcriptase inhibitors for the treatment of AIDS inadults and children. Lopinavir is a peptidomimetic compound with a structural coreidentical to that of ritonavir, on which terminal groups, particularly a modified valine, wereintroduced by peptide coupling procedures. Lopinavir is a potent competitive inhibitor ofHIV-I protease exhibiting high potential against ritonavir-resistant mutations. In severalanimal species, pharmacokinetic studies with the lopinavirlritonavir association showedthat the modest properties of lopinavir were significantly improved in presence of ritonavir,in terms of Cmax and duration of action. Ritonavir inhibits the P450 isoenzyme CYP3A4and the human liver microsomal metabolism of lopinavir, so strongly amplifying plasmalevels of this latter component. In AIDS patients, the plasma HIV RNA level wasconsiderably reduced and the CD4+ T-cell counts increased after administration oflopinavir combined with relatively small doses of ritonavir. Kaletra is intended to be usedjointly with other antiretroviral agents. |
| Chemical Properties | Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. |
| Originator | Abbott (US) |
| Uses | Lopinavir has been used as a ZMPSTE24 and human immunodeficiency virus protease inhibitor. |
| Uses | A selective HIV protease inhibitor. An analogue of Ritonavir. Antiviral. |
| Uses | Lopinavir is a potent HIV protease inhibitor with Ki of 1.3 pM |
| Definition | ChEBI: Lopinavir is a dicarboxylic acid diamide that is amphetamine is substituted on nitrogen by a (2,6-dimethylphenoxy)acetyl group and on the carbon alpha- to nitrogen by a (1S,3S)-1-hydroxy-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyrimidin-1-yl)butanoyl]amino}-4-phenylbutyl group. An antiretroviral of the protease inhibitor class, it is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir. It has a role as an antiviral drug, a HIV protease inhibitor and an anticoronaviral agent. It is a member of amphetamines and a dicarboxylic acid diamide. |
| Indications | Lopinavir is available in the United States only as afixed-dose combination with ritonavir (Kaletra). In thisregimen, a low dose of ritonavir is used to inhibit therapid inactivation of lopinavir by CYP3A4. |
| Manufacturing Process | Manufacturing process for Lopinavir includes these steps as follows: Synthesis of 2,6-dimethylphenoxyaceticacid; 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 DMFwas 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) andtriethylamine (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 5hours. The mixture was diluted with 1000 ml of IPAC and quenched with 1000ml of water. The mixture was shaken and separated, the aq. layer wasextracted IPAC, the organics were washed with 10% HCl, solution of NaHCO3with 100 ml hexanes, then washed 500 ml water, and brine, dried overMgSO4, 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. |
| Brand name | Kaletra |
| Therapeutic Function | Antiviral |
| Antimicrobial activity | Lopinavir is active against HIV-1 and HIV-2. |
| Acquired resistance | Significant resistance to the antiretroviral efficacy of ritonavirbootedlopinavir occurs as a result of amino acid substitutionsat positions 32, 47 and 82 in the protease region. Proteaseinhibitor resistance is uncommon in patients identified withearly failure of combination therapy with ritonavir boostedlopinavirand nucleotide reverse transcriptase inhibitors. |
| General Description | Lopinavir is a protease inhibitor that has been approved foruse in combination with ritonavir for patients with HIV whohave not responded to other treatment modalities. Lopinaviris used in excess over ritonavir. Ritonavir at amounts givenhas no antiretroviral activity, Ritonavir inhibits lopinavir’smetabolism by CYP3A4, causing a higher level of lopinavirin the system. The combination is the first protease inhibitorapproved for patients as young as 6 months of age. |
| 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 otherantiretroviral agents) |
| Side effects | The most common adverse events seen in trials of complex antiretroviralregimens were diarrhea, nausea, headache, fatigue,vomiting and rash. Ritonavir-boosted lopinavir is associatedwith a dyslipidemia profile characteristic of those treated withother protease inhibitors boosted with 200 mg of ritonavir. |
| target | HIV protease |
| storage | -20°C |
| References | [1] Patent: CN108218791, 2018, A. Location in patent: Paragraph 0014 [2] Patent: EP1170289, 2002, A2. Location in patent: Page 42 [3] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 21, p. 3101 - 3103 [4] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2643 - 2645 [5] Patent: EP1170289, 2002, A2. Location in patent: Page 57 |
Lopinavir Preparation Products And Raw materials
| Raw materials | Sodium hydroxide-->Oxalyl chloride-->Benzyl chloroformate-->Hydrochloric acid-->1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-->L-VALINE METHYL ESTER-->(R*,S*)-(-)-8-Hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino)butyl)-2(1H)-quinolinone-->Lithium hydroxide-->Trifluoroacetic acid-->2,6-Dimethylphenol-->Palladium hydroxide-->Chloroacetic acid-->Topotecan-->Aluminium-nickel |
