816444-90-3

Upstream product

• 101968-85-8 (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid 
• 20859-02-3 L-tert-Leucine 
• 943516-56-1 6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-ene 
• 1606175-05-6 1-tert-butyl-3-((2S)-1-(2-cyano-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)urea 
• 1606175-06-7 methyl 3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 
• 1159791-82-8 3-chloro-6,6-dimethyl-3-azabicyclo[3.1.0]hexane 
• 62965-35-9 N-tert-butyloxycarbonyl-L-tert-leucine 
• 394735-28-5 (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 
• 134107-65-6 (3R,7aS)-3-phenyl-3,7a-dihydro-1H-pyrrolo[1,2-c]oxazol-5-one 
• 394735-26-3 (1R,2S,5S)-3-((S)-2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-6,6-dimethyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid methyl ester 
• 569679-06-7 3-(tert-butyl) 2-methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate 
• 394735-27-4 methyl (1R,2S,5S)-3-((S)-2-(3-(tert-butyl)-ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 
• 219753-99-8 (1S,2S,4S,7R)-6-aza-3,3-dimethyl-8-oxa-7-phenyltricyclo<4.3.0.0>nonan-5-one 
• 219754-02-6 (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid 

Downstream Products

• 394730-60-0 boceprevir 
• 3651-67-0 N-methylmorpholine hydrochloride 
• 877381-80-1 C₂₉H₄₃N₅O₆S 
• 1034917-71-9 C₈H₁₇N*C₁₉H₃₃N₃O₄ 
• 394735-28-5 (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 

Relevant academic research and scientific papers

SARS-COV-2 MAIN PROTEASE INHIBITORS

The present disclosure relates to certain molecules, pharmaceutical compositions containing them, and methods of using them to treat viral infections.

Synthesis and Process Optimization of Boceprevir: A Protease Inhibitor Drug

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

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

Design and synthesis of deuterated boceprevir analogs with enhanced pharmacokinetic properties

As part of an ongoing effort to apply the Deuterated Chemical Entity Platform (DCE Platforma) to clinically validated drugs, the synthesis of deuterated analogs of the hepatitis C virus protease inhibitor boceprevir was carried out. The devised synthetic routes allowed for site-selective deuterium incorporation with high levels of isotopic purity. Application of the DCE Platforma to boceprevir enabled the identification of several deuterated analogs that display marked levels of in vitro metabolic stabilization. Most notably, analog 1g exhibits a near doubling of in vitro half-life in human liver microsomal assays. The details of the convergent synthetic route to the boceprevir isotopologs and the results of the metabolic stability assays are described herein.

Potent inhibitors of HCV-NS3 protease derived from boronic acids

Chronic hepatitis C infection is the leading causes for cirrhosis of the liver and hepatocellular carcinoma, leading to liver failure and liver transplantation. The etiological agent, HCV virus produces a single positive strand of RNA that is processed with the help of serine protease NS3 to produce mature virus. Inhibition of NS3 protease can be potentially used to develop effective drugs for HCV infections. Numerous efforts are now underway to develop potent inhibitors of HCV protease that contain ketoamides as serine traps. Herein we report the synthesis of a series of potent inhibitors that contain a boronic acid as a serine trap. The activity of these compounds were optimized to 200 pM. X-ray structure of compound 17 bound to NS3 protease is also discussed.

PROCESS FOR PREPARING (1R,2S,5S)-N-[(1S)-3-AMINO-1-(CYCLOBUTYLMETHYL)-2,3-DIOXOPROPYL]-3-[(2S)-2-[[[(1,1-DIMETHYLETHYL)AMINO]-CARBONYL]AMINO]-3,3-DIMETHYL-1-OXOBUTYL]-6,6-DIMETHYL-3-AZABICYCLO[3.1.0]HEXANE-2-CARBOXAMIDE

The present invention relates also to a process for the preparation of intermediate compounds useful in preparing the compounds of Formula (I) using the process of Scheme (II).

Pharmaceutical formulations and methods of treatment using the same

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

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.

METHOD OF TREATING INTERFERON NON-RESPONDERS USING HCV PROTEASE INHIBITOR

A method of treating, preventing or ameliorating one or more symptoms associated with hepatitis C virus (HCV) in a patient in whom either the HCV is of Genotype 1 and/or the patient was previously treated with interferon and the previous interferon therapy was ineffective to treat the one or more symptoms associated with HCV, comprising administering to such a patient an effective amount of at least one compound of formulae I-XXVI of which the structural formula (I) is exemplary or a pharmaceutically acceptable salt, solvate or ester thereof. Optional combined administration of said at least one compound with an interferon or pegylated interferon and/or ribaviron is also contemplated.

ASYMMETRIC DOSING METHODS

A method of treating, preventing or ameliorating one or more symptoms of hepatitis C, or inhibiting cathepsin activity, in a subject is provided, in which at least one compound (e.g., a HCV protease inhibitor) is administered in one or more discrete dosages over a twenty-four hour time interval in an asymmetric pattern as to dosage amount and/or timing of dosage, wherein the at least one compound is selected from the group consisting of compounds of Formulae I-XXVI, described herein. Methods of modulating the activity of hepatitis C virus protease in a subject are also provided. Asymmetric dosing as to amount of dose and/or timing of dose permits adjustment of dosing to accommodate variations in drug metabolism and/or viral activity caused by viral cell division or a patient's circadian rhythms, thus delivering the maximum amount of dose at the time or times it is most effective.