394735-27-4

Usage

Uses

Used in Pharmaceutical Industry:
(1S,2S,5R)-Methyl 3-((S)-2-(tert-butoxycarbonylaMino)-3,3-diMethylbutanoyl)-6,6-diMethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate is used as a potential pharmaceutical candidate for [application reason], leveraging its unique structural features and the presence of chiral centers, which may contribute to its biological activity and selectivity.
Used in Organic Chemistry Research:
In the field of organic chemistry, (1S,2S,5R)-Methyl 3-((S)-2-(tert-butoxycarbonylaMino)-3,3-diMethylbutanoyl)-6,6-diMethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate is utilized as a research tool for [application reason], such as studying the synthesis of complex organic molecules, exploring the reactivity of chiral centers, or investigating the protective role of the tert-butoxycarbonyl group in amine chemistry.

Upstream product

• 2425-74-3 t-butylformamide 
• 62965-35-9 N-tert-butyloxycarbonyl-L-tert-leucine 
• 20859-02-3 L-tert-Leucine 
• 101968-85-8 (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid 
• 219754-00-4 tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate 
• 1026427-11-1 ((1R,2S,5S)-3-Benzyl-6,6-dimethyl-3-aza-bicyclo[3.1.0]hex-2-yl)-methanol 
• 103201-79-2 (3R,7aS)-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazol-5-one 
• 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 
• 1609-86-5 Tert-butyl isocyanate 
• 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

• 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 
• 394730-60-0 boceprevir 
• 816444-90-3 (1R,2S,5S)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid 

Relevant academic research and scientific papers

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.

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

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

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.

Medicaments and methods combining a HCV protease inhibitor and an AKR competitor

Disclosed are medicaments, pharmaceutical compositions, pharmaceutical kits, and methods based on combinations of a hepatitis C virus (HCV) protease inhibitor and an aldo-keto reductase (AKR) competitor, for concurrent or consecutive administration in treating, preventing, or ameliorating one or more symptoms of HCV, treating disorders associated with HCV, or inhibiting cathepsin activity in a subject.