CRYSTALLINE FORMS OF A MACROCYCLIC HCV NS3 INHIBITING TRIPEPTIDE

SYNTHESIS OF AN ANTIVIRAL COMPOUND AND INTERMEDIATES THEREOF

Síntesis de un compuesto antiviral e intermediarios de la misma. Reivindicación 1: Un proceso para la preparación de un compuesto de fórmula (5) o un cocristal, o una sal del mismo; caracterizado porque comprende poner en contacto un compuesto de fórmula (3) o un cocristal, o una sal del mismo, con un compuesto de fórmula (4) bajo condiciones de O-arilación para dar el compuesto de fórmula (5) o un cocristal, o una sal del mismo, donde R es C₁₋₆ alquilo, PG es un grupo protector, y R¹ es un grupo saliente. Reivindicación 5: Un proceso para la preparación de un compuesto de fórmula (1) o un cocristal, o una sal farmacéuticamente aceptable del mismo, caracterizado porque comprende: a) poner en contacto un compuesto de fórmula (3) o un cocristal, o una sal del mismo, con un compuesto de fórmula (4) bajo condiciones de O-arilación para dar un compuesto de fórmula (5) o un cocristal, o una sal del mismo; b) someter el compuesto de fórmula (5) o un cocristal, o una sal del mismo a condiciones ...

CRYSTALLINE FORMS OF AN ANTIVIRAL COMPOUND BACKGROUND

Se prepararon formas cristalinas del compuesto anti-HCV (1aR,5S,8S,9S,10R,22aR)-5-terc-butil-N-[(1R,2R)-2-(difluorometil)-1-{[(1-metilciclopropil)sulfonil]carbamoil}ciclopropil]-9-etil-18,18-difluoro-14-metoxi-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahidro-8H-7,10-metanociclopropa[18,19][1,10,3,6]dioxadiazaciclononadecino[11,12-b]quinoxalina-8-carboxamida compuesto de fórmula (1) y se caracterizaron en estado sólido. También se proporcionan procesos de fabricación y métodos para usar las formas cristalinas.

SYNTHESIS OF A MACROCYCLIC HCV NS3 INHIBITING TRIPEPTIDE

SYNTHESIS OF A MACROCYCLIC HCV NS3 INHIBITING TRIPEPTIDE

PROCESS AND INTERMEDIATES FOR PREPARING INTEGRASE INHIBITORS

PROCESS AND INTERMEDIATES FOR PREPARING INTEGRASE INHIBITORS

The invention provides synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties. 6. The method of wherein the compound of formula 5 is acylated with an acetyl halide.7. The method of wherein the acylation is carried out in the presence of a Lewis acid.8. The method of wherein the Lewis acid is aluminum trichloride.10. The method of wherein R is ethyl.11. The method of wherein the compound of formula 8 is acylated with diethyl carbonate.12. The method of wherein the acylation utilizes a base.13. The method of wherein the base is a metal alkoxide.16. The method of wherein Rand Rare each methyl.20. The method of wherein converting the compound of formula 8 to the compound of formula 13 or the salt thereof comprises the method described in .21. The method of wherein converting the compound of formula 8 to the compound of formula 13 or the salt thereof comprises the method described in . This application claims priority to and the benefit under 35 U.S.C. 119(e) of U.S. Provisional Application No. 61/679,475, filed on Aug. 3, 2012, the disclosure of which is hereby incorporated by reference in its entirety.International Patent Application Publication Number WO 2004/046115 provides certain 4-oxoquinolone compounds that are useful as HIV integrase inhibitors. The compounds are reported to be useful as anti-HIV agents.International Patent Application Publication Number WO 2005/113508 provides certain specific crystalline forms of one of these 4-oxoquinolone compounds (i.e. 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinolone-3-carboxylic acid). The specific crystalline forms are reported to have superior physical and chemical stability compared to other physical forms of the compound.International Patent Application WO2009/036161 and International Patent Application WO2008/033836 describe methods for preparing the 4-oxoquinolone ...

CRYSTALLINE FORMS OF AN ANTIVIRAL COMPOUND

Crystalline forms of the anti-HCV compound (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide (Compound I) were prepared and characterized in the solid state: 2. Compound I Form I according to claim 1 , further comprising:i) a peak at 12.9 °2θ±0.2°,{'figref': {'@idref': 'DRAWINGS', 'FIG. 1'}, 'ii) the diffractogram substantially as shown in ;'}{'figref': {'@idref': 'DRAWINGS', 'FIG. 2'}, 'iii) a differential scanning calorimetry (DSC) curve substantially as shown in ;'}{'figref': {'@idref': 'DRAWINGS', 'FIG. 3'}, 'iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in ;'}{'figref': {'@idref': 'DRAWINGS', 'FIG. 4'}, 'v) a dynamic vapor sorption (DVS) curve substantially as shown in ;'}{'sup': '1', 'figref': {'@idref': 'DRAWINGS', 'FIG. 5'}, 'vi) a nuclear magnetic resonance spectrum (H NMR) substantially as shown in ; or'}vii) about 1.7 mole equivalents of ethanol.34-. (canceled)5. Compound I Form II according to claim 1 , further comprising:i) a peak at 15.4 °2θ±0.2°;{'figref': {'@idref': 'DRAWINGS', 'FIG. 6'}, 'ii) a diffractogram substantially as shown in ;'}{'figref': {'@idref': 'DRAWINGS', 'FIG. 7'}, 'iii) a differential scanning calorimetry (DSC) curve substantially as shown in ;'}{'figref': {'@idref': 'DRAWINGS', 'FIG. 8'}, 'iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in ;'}{'sup': '1', 'figref': {'@idref': 'DRAWINGS', 'FIG. 9'}, 'v) a nuclear magnetic resonance spectrum (H NMR) substantially as shown in ; or'}{'figref': {'@idref': 'DRAWINGS', 'FIG. 10'}, 'vi) a dynamic vapor sorption (DVS) curve substantially as shown in ; or'}vii) about 1 mole equivalents of ethyl acetate.67-. (canceled)8. Compound I Form III according to ...

SYNTHESIS OF AN ANTIVIRAL COMPOUND

The present disclosure provides processes for the preparation of a compound of formula I: 24-. (canceled)68-. (canceled)1113-. (canceled)1632-. (canceled) This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Ser. No. 61/920,446 filed on Dec. 23, 2013, the entirety of which is incorporated herein by reference.The present disclosure relates generally to the field of organic synthetic methodology for the preparation of Flaviviridae virus inhibitor compounds and their synthetic intermediates.The hepatitis C virus (HCV), a member of the hepacivirus genera within the Flaviviridae family, is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 2000, 32, 98-112). Consequently, a significant focus of current antiviral research is directed toward the development of improved methods for the treatment of chronic HCV infections in humans (Ciesek, S., von Hahn T., and Manns, M P., Clin. Liver Dis., 2011, 15, 597-609; Soriano, V. et al, J. Antimicrob. Chemother., 2011, 66, 1573-1686; Brody, H., Nature Outlook, 2011, 474, S1-S7; Gordon, C. P., et al., J. Med. Chem. 2005, 48, 1-20; Maradpour, D., et al., Nat. Rev. Micro. 2007, 5, 453-463).Virologic cures of patients with chronic HCV infection are difficult to achieve because of the prodigious amount of daily virus production in chronically infected patients and the high spontaneous mutability of HCV (Neumann, et al., Science 1998, 282, 103-7; Fukimoto, et al., Hepatology, 1996, 24, 1351-4; Domingo, et al., Gene 1985, 40, 1-8; Martell, et al., J. Virol. 1992, 66, 3225-9). HCV treatment is further complicated by the fact that HCV is genetically diverse and expressed as several different genotypes and numerous subtypes. For example, HCV is currently classified into six major genotypes (designated 1-6), many subtypes (designated a, b, c, and so on), and about 100 different strains (numbered 1, 2, 3, and so on).HCV is distributed worldwide with genotypes 1, 2, and 3 ...

SYNTHESIS OF AN ANTIVIRAL COMPOUND

The present disclosure provides processes for the preparation of a compound of formula I: 115-. (canceled) This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Ser. No. 61/920,446 filed on Dec. 23, 2013, the entirety of which is incorporated herein by reference.The present disclosure relates generally to the field of organic synthetic methodology for the preparation of Flaviviridae virus inhibitor compounds and their synthetic intermediates.The hepatitis C virus (HCV), a member of the hepacivirus genera within the Flaviviridae family, is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 2000, 32, 98-112). Consequently, a significant focus of current antiviral research is directed toward the development of improved methods for the treatment of chronic HCV infections in humans (Ciesek, S., von Hahn T., and Manns, M P., Clin. Liver Dis., 2011, 15, 597-609; Soriano, V. et al, J. Antimicrob. Chemother., 2011, 66, 1573-1686; Brody, H., Nature Outlook, 2011, 474, S1-S7; Gordon, C. P., et al., J. Med. Chem. 2005, 48, 1-20; Maradpour, D., et al., Nat. Rev. Micro. 2007, 5, 453-463).Virologic cures of patients with chronic HCV infection are difficult to achieve because of the prodigious amount of daily virus production in chronically infected patients and the high spontaneous mutability of HCV (Neumann, et al., Science 1998, 282, 103-7; Fukimoto, et al., Hepatology, 1996, 24, 1351-4; Domingo, et al., Gene 1985, 40, 1-8; Martell, et al., J. Virol. 1992, 66, 3225-9). HCV treatment is further complicated by the fact that HCV is genetically diverse and expressed as several different genotypes and numerous subtypes. For example, HCV is currently classified into six major genotypes (designated 1-6), many subtypes (designated a, b, c, and so on), and about 100 different strains (numbered 1, 2, 3, and so on).HCV is distributed worldwide with genotypes 1, 2, and 3 predominate within the United States, Europe, Australia ...

CRYSTALLINE FORMS OF AN ANTIVIRAL COMPOUND

Crystalline forms of the anti-HCV compound (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide (Compound I) were prepared and characterized in the solid state:

Process and intermediates for preparing integrase inhibitors

The invention provides synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.

Process and intermediates for preparing integrase inhibitors

The invention provides synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.

Process and intermediates for preparing integrase inhibitors

Synthesis of a macrocyclic HCV NS3 inhibiting tripeptide

The present disclosure provides processes for the preparation of a compound of formula I: which is useful as an antiviral agent. The disclosure also provides compounds and processes for the preparation of the compounds that are synthetic intermediates to the compound of formula I.

Synthesis of a macrocyclic hcv ns3 inhibiting tripeptide

The present disclosure provides processes for the preparation of a compound of formula I: which is useful as an antiviral agent. The disclosure also provides compounds and processes for the preparation of the compounds that are synthetic intermediates to the compound of formula I.

Crystalline forms of an NS3 NS3 inhibitor macrocyclic tripeptide

Una forma cristalina del compuesto I:**Fórmula** en donde, la forma cristalina es un solvato de etanol (Forma I del Compuesto I), caracterizado por un difractograma de rayos X de polvo que comprende picos (± 0,2 º) a 8,6, 11,1, 12,9 y 15,5 º 2θ como se determina en un difractómetro usando radiación Cu-α. A crystalline form of compound I: ** Formula ** wherein, the crystalline form is an ethanol solvate (Form I of Compound I), characterized by a powder X-ray diffractogram comprising peaks (± 0.2 °) at 8.6, 11.1, 12.9 and 15.5 º 2θ as determined on a diffractometer using Cu-α radiation.

Crystalline forms of a macrocyclic hcv ns3 inhibiting tripeptide

Crystalline forms of the anti-HCV compound (1R,5S,8S,9S,10R,22aR )-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6] dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide (Compound I) were prepared and characterized in the solid state. Also provided are processes of manufacture and methods of using the crystalline forms.

Synthesis of an antiviral compound

The present disclosure provides processes for the preparation of a compound of formula I: which is useful as an antiviral agent. The disclosure also provides compounds and processes for the preparation of the compounds that are synthetic intermediates to the compound of formula I.

Synthesis of a macrocyclic hcv ns3 inhibiting tripeptide.

La presente descripción provee procedimientos para la preparación de un compuesto de la fórmula I: el cual es útil como un agente antiviral. La descripción también provee compuestos y procedimientos para la preparación de los compuestos que son intermediarios de síntesis para el compuesto de la fórmula I.

Crystalline forms and salt forms of a kinase inhibitor

The present invention relates to crystalline free base of the tyrosine kinase inhibitor, Compound 1. The invention also relates to crystalline salts of Compound 1. The invention also relates to pharmaceutical compositions comprising the solid polymorphs of the free base and salts of Compound 1. The invention further relates to methods of treating a disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of a protein kinase.

Process and intermediates for preparing integrase inhibitors

The invention provides synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.

Crystalline forms of an antiviral compound

Crystalline forms of the anti-HCV compound (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide (Compound I) were prepared and characterized in the solid state: Also provided are processes of manufacture and methods of using the crystalline forms.

Crystalline forms and salt forms of a kinase inhibitor

The present invention relates to crystalline free base of the tyrosine kinase inhibitor, Compound 1. The invention also relates to crystalline salts of Compound 1. The invention also relates to pharmaceutical compositions comprising the solid polymorphs of the free base and salts of Compound 1. The invention further relates to methods of treating a disease, disorder, or syndrome mediated at least in part by modulating

Crystalline forms and salt forms of a kinase inhibitor

The present invention relates to crystalline free base of the tyrosine kinase inhibitor, Compound 1. The invention also relates to crystalline salts of Compound 1. The invention also relates to pharmaceutical compositions comprising the solid polymorphs of the free base and salts of Compound 1. The invention further relates to methods of treating a disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of a protein kinase.

Crystalline forms of an antiviral compound

Crystalline forms of the anti-HCV compound (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide (Compound I) were prepared and characterized in the solid state: Also provided are processes of manufacture and methods of using the crystalline forms.

Synthesis of an antiviral compound

The present disclosure provides processes for the preparation of a compound of formula I: which is useful as an antiviral agent. The disclosure also provides compounds and processes for the preparation of the compounds that are synthetic intermediates to the compound of formula I.