394730-60-0 Usage
Uses
Used in Pharmaceutical Industry:
Boceprevir is used as an antiviral agent for the treatment of chronic hepatitis C virus genotype 1 infection. It inhibits the HCV NS3-4A protease, an essential enzyme required by HCV for posttranslational processing of viral proteins into their mature forms, with a Ki of 14 nM. Boceprevir is also used in the treatment of HCV by reducing the cytopathic effects of SARS-CoV-2 in Vero cells (EC50 = 1.31 μM).
Used in COVID-19 Research:
Boceprevir is used as an inhibitor of SARS-CoV-2 main protease (Mpro) with a Ki of 1.8 μM, which contributes to the reduction of cytopathic effects of SARS-CoV-2 in Vero cells. This application makes Boceprevir a potential candidate for COVID-19-related research and treatment.
Originator
Merck/Schering (United States)
Clinical Use
Boceprevir is an oral inhibitor of HCV NS3/4A protease for the
treatment of the chronic hepatitis C genotype infection. It is approved
as combination therapy with Peg-IFN-alpha and ribavarin
to treat adult patients with compensated liver diseasewhoare either
treatment naive or who have experienced prior failed therapy with
interferon and ribavarin. Boceprevir was initially discovered by
Schering-Plough and developed and marketed by Merck & Co. since
its acquisition of Schering-Plough in 2009. Several publications have
highlighted the discovery of this drug, which evolved from a potent
initial undecapeptide lead structure to boceprevir (VII) as a drug
candidate with potent activity and desirable PK properties.
Synthesis
Several
publications and patents including process patents
describing the preparation of key fragments and a full synthesis of boceprevir, have been published. Retrosynthetically, the
drug can be broken down into 3 or 4 key fragments and assembled
in a convergent synthesis as depicted in the scheme.
Synthesis of t-butyl urea fragment 55 began with esterification
of t-butyl amino acid 58 with TMSCl and triethylamine to give silyl
ester 59. Silyl ester 59 was then reacted with t-butyl isocyanate 60
to provide urea 55 in 74–89% (2-steps).Although several routes for the preparation of the azbicyclo[
3.1.0]hexane ester 56 have been disclosed, the most recent
process-scale synthesis of this heterocyclic core was accomplished
using enzymatic desymmetrization of readily available azabicyclo[
3.1.0]hexane 61(the scheme). This was accomplished through
the enzymatic oxidation of 61 followed by trapping of the resulting
imine 62 with bisulfate to give the corresponding sulfonate 63. Sulfonate
63 was attained under manufacturing conditions in 95% and
99% ee. Without isolation, the sulfonate salt was reacted with sodium
cyanide in cyclopentyl methyl ether providing trans nitrile
64 in 90% yield from 61, presumably through an elimination of
the sulfonate to regenerate imine 62, followed by addition of the
nitrile group from the opposite face of the dimethylcyclopropyl
group. Nitrile 64 was reacted under Pinner conditions (HCl, MeOH) to give ester salt 56 in 56% overall yield with greater than 99% ee
after recrystallization from MTBE.Although several preparations of cyclobutyl amides 57 have
been disclosed, the process scale preparation is described
in the scheme. Benzophenone-derived imine 65 was alkylated
with bromomethylcyclobutane in the presence of base to give
the alkylated intermediate, which was immediately treated
in situ with HCl to furnish aminoester 66. This aminoester was
then protected as the Boc-carbamate 67 prior to reduction of the
ester to provide the corresponding alcohol 68 after crystallization
from heptane in 43% overall yield. This alcohol was then oxidized
with TEMPO, sodium bromide and sodium hypochlorite in DCM
at 5 to 0°C to give aldehyde 69 in 91% yield. After exchanging solvents,
aldehyde 69 was treated with acetone cyanohydrin at room
temperature to provide intermediate 70 which, after treatment with potassium carbonate to wash off excess cyanohydrin, was
hydrolyzed with hydrogen peroxide at 40°C to give 90% of amide
71. Hydroxyl amide 71 was deprotected under acidic conditions
to give the hydrochloride salt 73. Alcohol 71 was also oxidized
using EDCI, DMSO and dichloroacetic acid in ethyl acetate to afford
the keto amide 72 in 70% yield. Subsequent treatment with HCl in
isopropyl alcohol provided salt 57 in 91% yield.With all four key fragments in hand, the final target was rapidly
assembled in a convergent manner as described in the scheme. Carboxylic acid fragment 55 was first coupled to azbicyclo[
3.2.1]cyclohexane amine ester salt 56 using EDCI as the coupling
reagent under basic conditions to give amide 74. Hydrolysis
of the methyl ester with lithium hydroxide followed by salt formation
gave rise to carboxylate salt 75 in 90% overall yield. Under
acidic conditions, salt 75 was coupled directly with cyclobutyl keto amide salt 57 in the presence of EDCI, HOBt and N-methylmorpholine
in acetonitrile to give, after acidic and basic work-ups, boceprevir
(VII) in 85–90% yield. Alternatively, salt 75 could be
coupled with the cyclobutyl alcohol amide salt 73 using EDCI,
HOBt and diisopropylethyamine (DIPEA) to give alcohol 76 in
90% yield after acid and base work-ups and crystallization. Oxidation
of alcohol intermediate 76 with TEMPO and NaOCl in the presence
of KBr also furnished boceprevir (VII) in 93% yield.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration possibly reduced by
rifampicin - avoid.
Anticoagulants: avoid with apixaban.
Antiepileptics: concentration possibly reduced
by carbamazepine, fosphenytoin, phenobarbital,
phenytoin and primidone - avoid.
Antifungals: concentration increased by
ketoconazole.
Antimalarials: avoid with artemether and
lumefantrine.
Antipsychotics: avoid pimozide; possibly increases
lurasidone and quetiapine concentration - avoid.
Antivirals: reduces concentration of atazanavir;
avoid with daclatasvir, darunavir, fosamprenavir and
lopinavir; concentration of both drugs reduced with
ritonavir.
Anxiolytics and hypnotics: increased oral midazolam
concentration - avoid.
Ciclosporin: concentration of ciclosporin increased.
Cilostazol: possibly increases cilostazol
concentration.
Cytotoxics: possibly increases bosutinib
concentration - avoid or reduce bosutinib dose;
avoid with dasatinib, erlotinib, gefitinib, imatinib,
lapatinib, nilotinib, olaparib, pazopanib, sorafenib
and sunitinib; reduce dose of ruxolitinib.
Domperidone: possible increased risk of ventricular
arrhythmias - avoid.
Ergot alkaloids: avoid concomitant use.
Guanfacine: concentration possibly increased, halve
guanfacine dose.
Lipid-regulating drugs: enhances effects and toxicity
of atorvastatin, reduce atorvastatin dose; increases
pravastatin concentration; avoid with simvastatin.
Oestrogens: possibly causes contraception failure.
Sirolimus: possibly increases sirolimus concentration.
Tacrolimus: concentration of tacrolimus increased,
reduce tacrolimus dose.
Metabolism
Boceprevir mainly undergoes metabolism through the
aldo-ketoreductase mediated pathway to ketone-reduced
metabolites that are inactive against HCV. After a single
800 mg oral dose of 14C-boceprevir, the most abundant
circulating metabolites were a diasteriomeric mixture
of ketone-reduced metabolites with a mean exposure
approximately 4-fold greater than that of boceprevir.
Boceprevir also undergoes, to a lesser extent, oxidative
metabolism mediated by CYP3A4/5.
Mainly excreted by the liver - approximately 79% and 9%
of the dose was excreted in faeces and urine, respectively,
with approximately 8% and 3% eliminated as boceprevir
in faeces and urine.
References
1) Malcom et al. (2006), SCH 503034, a Mechanism-Based Inhibitor of Hepatitis C Virus NS3 Protease, Suppresses Polyprotein Maturation and Enhances the Antiviral Activity of Alpha Interferon in Replicon Cells; Antimicrob. Agents Chemother., 50 1013
2) Ma et al. (2020), Boceprevir, GC-376, and Calpain Inhibitors II, XII Inhibit SARS-CoV-2 Viral Replication by Targeting the Viral Main Protease; Cell Res.?30?678
Check Digit Verification of cas no
The CAS Registry Mumber 394730-60-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 3,9,4,7,3 and 0 respectively; the second part has 2 digits, 6 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 394730-60:
(8*3)+(7*9)+(6*4)+(5*7)+(4*3)+(3*0)+(2*6)+(1*0)=170
170 % 10 = 0
So 394730-60-0 is a valid CAS Registry Number.
394730-60-0Relevant academic research and scientific papers
Bhalerao, Dinesh S.,Arkala, Anil Kumar Reddy,Madhavi,Nagaraju,Gade, Srinivas Reddy,Kumar, U. K. Syam,Bandichhor, Rakeshwar,Dahanukar, Vilas H.
, p. 1559 - 1567 (2015)
Efforts toward the synthesis and process optimization of boceprevir 1 are described. Boceprevir synthesis was optimized by telescoping the first three steps and last two steps of the five-step process. Optimization of oxidation, which is one of the critical steps in the total synthesis, is discussed. A control strategy for the three impurities is described. A novel process for the synthesis of fragment A (2) has been developed, which is the key starting material for the synthesis of boceprevir.
PROCESS FOR PREPARATION OF BOCEPREVIR AND INTERMEDIATES THEREOF
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Page/Page column 15; 33-34; 41, (2014/05/07)
THE PRESENT INVENTION RELATES TO AN IMPROVED PROCESS FOR THE PREPARATION OF (1R,5S)-N-[3-AMINO-1-(CYCLOBUTYLMETHYL)-2,3-DIOXOPROPYL]-3-[2(S)-[[[(1,1-DIMETHYLETHYL)AMINO]CARBONYL] AMINO]-3,3-DIMETHYL-1-OXOBUTYL]-6,6-DIMETHYL-3-AZABICYCLO[3.1.0]HEXAN-2(S)-CARBOXAMIDE AND ITS INTERMEDIATES
PROCESS AND INTERMEDIATES FOR THE PREPARATION OF 3-AMINO-4-CYCLOBUTYL-2-HYDROXYBUTANAMIDE AND SALTS THEREOF
-
, (2013/05/22)
The present invention relates to synthetic processes useful in the preparation of a compound of Formula (I), and salts thereof. Compounds of Formula (I) and salts thereof have application in the preparation of inhibitors of the hepatitis C virus, such as (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide. The present invention also encompasses intermediates useful in the disclosed synthetic processes and the methods of their preparation.
BISULFITE PURIFICATION OF AN ALPHA-KETO AMIDE
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Page/Page column 27, (2008/12/06)
A process for purifying the alpha-keto amide is (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]-amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide via a bisulfite adduct is disclosed.
Oxidation process for the preparation of N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-{N-[(tert-butylamino)carbonyl]-3-methyl-L-valyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide and related compounds
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Page/Page column 6-7, (2008/06/13)
The present application relates to a process for preparing a compound of formula I: wherein R1 is alkyl; R2 is alkyl; and R3 is optionally substituted cycloalklylalkyl which comprises oxidizing a compound of the formula wherein R1, R2 and R3 are defined above to yield a compound of formula I.
Pharmaceutical formulations and methods of treatment using the same
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Page/Page column 453, (2010/11/25)
Pharmaceutical formulations containing at least one compound of Formulae I-XXVI herein and at least one surfactant. Pharmaceutically acceptable carriers and excipients may also be included in the formulations. The formulations of the present invention are suited for use in single unit dosages.
Liver/plasma concentration ratio for dosing hepatitis C virus protease inhibitor
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Page/Page column 516, (2010/11/25)
Compositions and therapeutic combinations are provided including at least one compound selected from the group consisting of compounds of Formulae I to XXVI as defined herein as well as methods of treatment, prevention or amelioration of one or more symptoms of hepatitis C, treating disorders associated with HCV virus, modulating activity of HCV protease, in which liver to plasma concentration ratio of the compound ranges from about 2:1 to about 10:1.
Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: A potential therapeutic agent for the treatment of hepatitis C infection
Venkatraman, Srikanth,Bogen, Stéphane L.,Arasappan, Ashok,Bennett, Frank,Chen, Kevin,Jao, Edwin,Liu, Yi-Tsung,Lovey, Raymond,Hendrata, Siska,Huang, Yuhua,Pan, Weidong,Parekh, Tejal,Pinto, Patrick,Popov, Veljko,Pike, Russel,Ruan, Sumei,Santhanam, Bama,Vibulbhan, Bancha,Wu, Wanli,Yang, Weiying,Kong, Jianshe,Liang, Xiang,Wong, Jesse,Liu, Rong,Butkiewicz, Nancy,Chase, Robert,Hart, Andrea,Agrawal, Sony,Ingravallo, Paul,Pichardo, John,Kong, Rong,Baroudy, Bahige,Malcolm, Bruce,Guo, Zhuyan,Prongay, Andrew,Madison, Vincent,Broske, Lisa,Cui, Xiaoming,Cheng, Kuo-Chi,Hsieh, Yunsheng,Brisson, Jean-Marc,Prelusky, Danial,Korfmacher, Walter,White, Ronald,Bogdanowich-Knipp, Susan,Pavlovsky, Anastasia,Bradley, Prudence,Saksena, Anil K.,Ganguly, Ashit,Piwinski, John,Girijavallabhan, Viyyoor,Njoroge, F. George
, p. 6074 - 6086 (2007/10/03)
Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-α or polyethylene glycol (PEG)-interferon-α alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.
Methods of treating hepatitis C virus
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Page/Page column 469, (2008/06/13)
Methods for preventing, ameliorating or treating one or more symptoms of Hepatitis C virus (HCV), modulating HCV protease activity and/or inhibiting cathepsin activity in a subject, wherein the methods comprise administering to a subject in need of such treatment a dosage formulation containing at least one compound of Formulae I-XXVI herein, wherein the dosage formulation is capable of maintaining an average Cmin plasma concentration of the compound at or above 10 ng/ml.
Controlled-release formulation
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Page/Page column 449, (2010/11/25)
Controlled-release dosage formulations including at least one compound of Formulae I to XXVI herein and a controlled-release carrier and methods of treatment using the same are provided.
![(1R,2S,5S)-N-(4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicylo[3.1.0]-hexane-2-carboxamide](/Databaselist/images/loading.webp)
