AMPRENAVIR CAS 161814-49-9
Introduction：Basic information about AMPRENAVIR CAS 161814-49-9, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
AMPRENAVIR Basic information
| Product Name: | AMPRENAVIR |
| Synonyms: | KVX-478;AGENERASE;AMPRENAVIR;141W94;PROZEI;141W94, KVX-478, Agenerase, Prozei,;Carbamic acid, (1S,2R)-3-(4-aminophenyl)sulfonyl(2-methylpropyl)amino-2-hydroxy-1-(phenylmethyl)propyl-, (3S)-tetrahydro-3-furanyl ester;Angenerase |
| CAS: | 161814-49-9 |
| MF: | C25H35N3O6S |
| MW: | 505.63 |
| EINECS: | 827-179-5 |
| Product Categories: | Inhibitor;peptides;API;Anti-viral Compounds;Anti-virals;Inhibitors;Intermediates & Fine Chemicals;Non-nucleoside Reverse Transcriptase;Pharmaceuticals |
| Mol File: | 161814-49-9.mol |
AMPRENAVIR Chemical Properties
| Melting point | 72-74°C |
| density | 1.30±0.1 g/cm3(Predicted) |
| storage temp. | -20°C |
| solubility | DMSO: soluble20mg/mL, clear |
| form | powder |
| pka | 11.54±0.46(Predicted) |
| color | white to beige |
| Optical Rotation | [α]/D +8 to +12°, c = 0.5 in methanol |
| BCS Class | 2 |
| InChIKey | YMARZQAQMVYCKC-OEMFJLHTSA-N |
| SMILES | [S](=O)(=O)(N(C[C@@H](O)[C@@H](NC(=O)O[C@@H]3COCC3)Cc2ccccc2)CC(C)C)c1ccc(cc1)N |
Safety Information
| RIDADR | 3077 |
| WGK Germany | 3 |
| HS Code | 29350090 |
| Storage Class | 11 - Combustible Solids |
| Hazardous Substances Data | 161814-49-9(Hazardous Substances Data) |
| Description | Amprenavir was launched as Agenerase in the US for the treatment ofAIDS patients in combination with approved agent antiretroviral nucleosideanalogs. It is the fifth non-peptidic inhibitor of HIV-1 protease to be marketed inthis indication after the last approved Neflinavir. Amprenavir, designed via astructure-based process, is the smallest molecule in the 《navir》 class andexhibits a reduced peptidic character. An improved process for preparationcomprising four steps from a (1S, 2R)-2-hydroxy-3-aminopropylcarbamate hasbeen developed. Amprenavir is a potent inhibitor of HIV-1 aspartyl protease (Ki= 0.6nM), an enzyme required by the virus to cleave pro-form polyproteins tostructural proteins during the last stage in the replication process. Thecompound displays good oral bioavailability in humans and penetrates the CNS,which is an important advantage in long-term treatment. Its plasma half-life isapproximately 10h. Treatment with Amprenavir in combination with nucleosideanalog reverse transcriptase inhibitors considerably decreases viral load andrestores CD4+ T-cell counts in patients with HIV infection. |
| Description | Amprenavir is an inhibitor of HIV protease (Ki = 0.04 nM). It inhibits the cytopathic effects of HIV-1 in MT-4 cells (IC50 = 150 nM). Formulations containing amprenavir have been used in combination with other antiretroviral agents in the treatment of HIV-1 infection. |
| Chemical Properties | Off-White to Pale Yellow |
| Originator | Vertex Pharm (US) |
| Uses | A selective HIV protease inhibitor. An analogue of Ritonavir |
| Uses | Protease inhibitor, anti-HIV agent |
| Indications | Amprenavir (Agenerase) is administered twice daily,providing the patient with an advantage over other proteaseinhibitors that must be taken more frequently(e.g., indinavir, saquinavir). Common side effects of am-prenavir include nausea, vomiting, diarrhea, and perioralparaesthesias. Rash occurs in approximately 20 to30% of patients and can be mild or severe (Stevens-Johnson syndrome). |
| Definition | ChEBI: Amprenavir is a tetrahydrofuryl ester, a sulfonamide and a carbamate ester. It has a role as a HIV protease inhibitor and an antiviral drug. |
| Manufacturing Process | (1-Oxiranyl-2-phenylethyl)-carbamic acid t-butyl ester may be synthesizedfrom available starting materials (see B. E. Evans et al., J. Org. Chem., 50,p.4615 (1985)). The amprenavir may be preparated with the next steps. 1. (1-Benzyl-3-isobutylaminopropyl)-carbamic acid t-butylester. A solution of4.1 g of epoxide (1-oxiranyl-2-phenylethyl)-carbamic acid t-butyl ester in 30ml of ethanol was treated with 22.4 ml of isobutylamine and heated underreflux for 1 h. The mixture was concentrated to yield the title compound as awhite solid which was used without subsequent purification. 2. To a solution of the above compound (2.5 g, 7.43 mmol) in CH2Cl2 (50 ml)was added triethylamine (2.1 ml, 14.9 mmol) followed by addition of benzylchloroformate (1.2 ml, 8.1 mmol). The mixture was allowed to stir at ambienttemperature for 6 h. The solution was diluted with 1 L of CH2Cl2 and washedwith water. The organics were dried over anhydrous MgSO4, concentrated under reduced pressure, then purified via silica gel chromatography. Gradientsolvent system: CH2Cl2 followed by 3:97 methanol/CH2Cl2. (3-t-Butoxycabonylamino-4-phenylbutyl)-isobutylcarbamic acid benzyl ester (2.97g) was obtained as a colorless oil. TLC: Rf= 0.14, 3:97 methanol/CH2Cl2.3. BOC - protecting group was removed as followed: to a solution of 1.5 g(3.187 mmol) of the above compound of in ethyl acetate (25 ml) at - 20°Cwas bubbled anhydrous HCl gas for 10 min. The ice bath was removed andafter an additional 15 min the reaction mixture was sparged with nitrogen,then concentrated in vacuo to provide 1.29 g of deprotected product as awhite solid which was used directly for the next reaction TLC: Rf= 0.14, 10%methanol/CH2Cl2. 4. Isobutyl[4-phenyl-(S)-3-tetrahydrofuran-3-yl-oxycarbonylamino)-butyl]-carbamic acid benzyl ester. To a solution of 1.077 g of the above resultantcrude compound (2.647 mmol) in acetonitrile (10 ml) was added sequentiallyat ambient temperature under an atmosphere of nitrogen, 1.61 ml (9.263mmol) of diisopropylethylamine and 910 mg (3.97 mmol) of the Nsuccinimidyl-(S)-3-tetrahydrocfuryl carbonate. The last one was prepared fromphosgene and (S)-(+)-3-hydroxytetrahydrofuran by usual procedure. Afterstirring for 3 h, an additional 223 mg (0.973 mmol) of the N-succinimidyl-(S)-3-tetrahydrocfuryl carbonate was added. The mixture was stirred for 16 h andthen concentrated in vacuo. The residue was taken up in ethyl acetate andwashed with water, 0.5 N HCl, saturated sodium bicarbonate, saturated brine,dried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by low pressure silica gel column chromatography using agradient 10% to 25% ethyl acetate in CH2Cl2 eluent to yield 1.025 g of thetitle product as a white solid. TLC: Rf= 0.10, 10% ethyl acetate/CH2Cl2. 5. A solution of 872 mg (1.799 mmol) isobutyl[4-phenyl-(S)-3-tetrahydrofuran-3-yl-oxycarbonylamino)-butyl]-carbamic acid benzyl ester in(10 ml) of ethyl alcohol was added, at ambient temperature under a nitrogenatmosphere, to a slurry of 87 mg (10% by weight) of 10% palladium oncarbon in (5 ml) ethyl alcohol and hydrogenated for 16 h under a slightpositive pressure of hydrogen. The mixture was filtered and concentrated invacuo to yield 553.2 mg of the carbamic acid as a colorless glass which wasused directly for ensuing reaction. TLC: Rf = 0.46, 10% methanol/CH2Cl2. 6. A solution of 102 mg of the resultant compound of a step 5 in 4:1CH2Cl2/saturated aqueous NaHCO3 was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 65 mg of pnitrobenzenesulfonylchloride and 51 mg of sodium bicarbonate. The mixturewas stirred for 14 h, diluted with CH2Cl2, washed with saturated NaCl, thendried over MgSO4, filtered, and concentrated in vacuo. The residue waspurified by low pressure silica gel chromatography using 20% diethylether/CH2Cl2 as eluent to provide 124 mg of the 1-benzyl-3-[isobutyl-(4-nitrobenzenesylfonyl)-amino]-propylcarbamic acid tetrahydrofuran-3(S)-yl]ester as a white solid. TLC: Rf = 0.36, 20% diethyl ether/CH2Cl2, HPLC: Rt =15.15 min. (1H)-NMR (CDCl3) consist with structure. 7. A solution of 124 mg of the resultant compound of the step 6 in ethylacetate was treated, at ambient temperature, with 13 mg of 10% palladium on carbon. The mixture was stirred for 14 h under an atmosphere ofhydrogen, filtered through a pad of celite filter agent, and concentrated invacuo. The residue was subjected to preparative HPLC to yield 82 mg of the((1S,2R)-3-(((4-aminophenyl)sulfonyl)(2-methylpropyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-, (3S)-tetrahydro-3-furanyl carbamic ester a whitesolid. TLC: Rf= 0.10, 20% ether/CH2Cl2, HPLC: Rt= 13.16 min. (1H)-NMR(CDCl3) consistent with structure. |
| Brand name | Agenerase(GlaxoSmithKline). |
| Therapeutic Function | Antiviral |
| Acquired resistance | Mutations at position 50, 76 and 84 of the protease enzymegene are associated with significantly reduced susceptibility. |
| General Description | Amprenavir is a second-generation drug derived from hydroxyethylamine sulfonamide. |
| Pharmaceutical Applications | A synthetic compound formulated as the calcium salt of theoral prodrug fosamprenavir. |
| Biochem/physiol Actions | Protease inhibition results in inactive and immature virus. |
| Pharmacokinetics | Oral absorption: Not known/available Cmax 700 mg + ritonavir 100 mg:c. 6.08 mg/L twice daily Cmin 700 mg + ritonavir 100 mg:c. 2.12 mg/L twice daily Plasma half-life: c. 7.7 h Volume of distribution: c. 430 L Plasma protein binding: c. 90% Absorption Fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate by cellular phosphatases in the gut epithelium as it is absorbed. Absolute bioavailability has not been established. It can be taken without regard to food. Distribution It penetrates moderately well into the CNS. The semen:plasma ratio is negligible. It is not known if it is distributed into breast milk. Metabolism and excretion It is extensively metabolized by the cytochrome P450 (CYP) 3A4 enzyme system. Two major metabolites have been identified that appear to result from the oxidation of the tetrahydrofuran and aniline moieties. Around 14% of a dose is eliminated in the urine and 75% in feces, <3% as unchanged drug. Metabolites account for >90% of administered drug found in fecal samples. It should be used with caution and at reduced doses in adults with mild or moderate hepatic impairment; it is contraindicated in patients with severe hepatic impairment. |
| Clinical Use | Treatment of HIV infection (in combination with other antiretroviral drugs) |
| Side effects | The most common adverse events in patients receiving boostedfosamprenavir were diarrhea, nausea, headache, fatigue,vomitingand rash. Ritonavir-boosted fosamprenavir is associatedwith a dyslipidemia profile characteristic of thosetreated with other protease inhibitors boosted with 200 mgof ritonavir. |
| target | HIV Protease |
| References | [1] RONALD G. SHERRILL. Synthesis and antiviral activities of novel N-alkoxy-arylsulfonamide-based HIV protease inhibitors[J]. Bioorganic & Medicinal Chemistry Letters, 2005, 15 15: Pages 3560-3564. DOI: 10.1016/j.bmcl.2005.05.101 |
AMPRENAVIR Preparation Products And Raw materials
| Raw materials | Isobutylamine-->Benzyl chloroformate-->4-Nitrobenzenesulfonyl chloride-->PHOSGENE-->N,N-Diisopropylethylamine-->(S)-(+)-3-Hydroxytetrahydrofuran |
