- Synthesis and Process Optimization of Boceprevir: A Protease Inhibitor Drug
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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.
- Bhalerao, Dinesh S.,Arkala, Anil Kumar Reddy,Madhavi,Nagaraju,Gade, Srinivas Reddy,Kumar, U. K. Syam,Bandichhor, Rakeshwar,Dahanukar, Vilas H.
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- PROCESS FOR PREPARATION OF BOCEPREVIR AND INTERMEDIATES THEREOF
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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
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- PROCESS AND INTERMEDIATES FOR THE PREPARATION OF 3-AMINO-4-CYCLOBUTYL-2-HYDROXYBUTANAMIDE AND SALTS THEREOF
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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.
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- BISULFITE PURIFICATION OF AN ALPHA-KETO AMIDE
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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.
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Page/Page column 27
(2008/12/06)
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- 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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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.
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Page/Page column 6-7
(2008/06/13)
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- Pharmaceutical formulations and methods of treatment using the same
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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.
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Page/Page column 453
(2010/11/25)
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- Liver/plasma concentration ratio for dosing hepatitis C virus protease inhibitor
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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.
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Page/Page column 516
(2010/11/25)
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- 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
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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.
- 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
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p. 6074 - 6086
(2007/10/03)
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- Methods of treating hepatitis C virus
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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.
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Page/Page column 469
(2008/06/13)
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- Controlled-release formulation
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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.
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Page/Page column 449
(2010/11/25)
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- Methods for treating hepatitis C
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Methods of treating hepatitis C are provided comprising using a therapeutically effective amount of at least one novel hepatitis C (“HCV”) protease inhibitor or, alternatively, at least one antiviral or immuno-modulating HCV agent, which is not an HCV protease inhibitor, for a first treatment period. Subsequently, a combination of the at least one novel hepatitis C (“HCV”) protease inhibitor and the at least one antiviral or immuno-modulating HCV agent are administered in a therapeutically effective amount for a second treatment period. The methods are provided for treating a wide variety of diseases, disorders and symptoms associated with hepatitis C virus by modulating the activity of HCV protease (for example HCV NS3/NS4a serine protease) in a subject.
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Page/Page column 554
(2010/11/25)
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- Methods of treating hepatitis C virus
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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, or inhibiting cathepsin activity in a subject using the same, in which the mean volume of distribution/bioavailability (Vd/F) of the compound as measured in the plasma of the subject is greater than about 1000 L.
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Page/Page column 413-414
(2010/11/25)
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- Medicaments and methods combining a HCV protease inhibitor and an AKR competitor
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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.
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Page/Page column 77-78
(2010/11/25)
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- Administration of HCV protease inhibitors in combination with food to improve bioavailability
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Methods of treating, preventing or ameliorating one or more symptoms of hepatitis C in a subject comprising the step of administering at least one HCV protease inhibitor in combination with food are provided. Also provided are methods of increasing bioavailability of an HCV protease inhibitor and methods of increasing serum levels of an HCV protease inhibitor in a subject. All methods comprise adminstering at least one HCV protease inhibitor in combination with food, the at least one HCV protease inhibitor selected from the group consisting of compounds of Formulae I-XXVI, described herein. Administration of compounds of the present invention in combination with food provides improved bioavailability and increased peak serum levels of the compounds as compared to administration without food.
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Page/Page column 626
(2010/11/25)
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- METHOD FOR MODULATING ACTIVITY OF HCV PROTEASE THROUGH USE OF A NOVEL HCV PROTEASE INHIBITOR TO REDUCE DURATION OF TREATMENT PERIOD
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Methods are provided for using at least one novel hepatitis C ("HCV") protease inhibitor in combination with at least one antiviral and/or immunomodulatory agent, which is different from the at least one HCV protease inhibitor, for treating a wide variety of diseases or disorders associated with hepatitis C virus by modulating the activity of HCV protease (for example HCV NS3/NS4a serine protease) and reducing HCV viral load in a subject in a reduced treatment period. With the present invention, a hepatitis C viral load is reduced in a subject to a concentration of less than 6?10-5 HCV virions per milliliter of plasma in a time period of less than or equal to about 24 weeks. With the present invention, a hepatitis C viral production is suppressed with an effectiveness in a range of 0.7 to 0.997. "
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Page/Page column 531
(2010/11/25)
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- METHOD OF TREATING INTERFERON NON-RESPONDERS USING HCV PROTEASE INHIBITOR
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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.
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Page/Page column 403-404
(2010/11/25)
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- ASYMMETRIC DOSING METHODS
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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.
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Page/Page column 440
(2010/11/25)
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- (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 as inhibitor of hepatitis C virus NS3/NS4a serine protease
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The present invention discloses the compound of Formula 3 as an inhibitor of HCV protease, as well as methods for preparing the compound. In another embodiment, the invention discloses pharmaceutical compositions comprising the compound as well as methods of using them to treat disorders associated with the HCV protease.
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Page/Page column 10-11
(2010/02/14)
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- PROCESS AND INTERMEDIATES FOR THE PREPARATION OF (1R, 2S, 5S)-3-AZABICYCLO[3, 1, 0]HEXANE-2-CARBOXAMIDE, N-[3-AMINO-1-(CYCLOBUTYLMETHYL)-2, 3-DIOXOPROPYL] ]-3-[(2S)-2-[[[1, 1-DIMETHYLETHYL]AMINO]CARBONYLAMINO]-3, 3-DIMETHYL-1-OXOBUTYL]-6, 6-DIMETHYL
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In one embodiment, the present application relates to a process of making a compound of formula (I): and to certain intermediate compounds that are made within the process of making the compound of formula (I).
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Page/Page column 22-23
(2008/06/13)
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