- Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
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The present invention features compositions comprising a plurality of therapeutic agents wherein the presence of one therapeutic agent enhances the properties of at least one other therapeutic agent. In one embodiment, the therapeutic agents are cystic fibrosis transmembrane conductance regulators (CFTR) such as a CFTR corrector or CFTR potentiator for the treatment of CFTR mediated diseases such as cystic fibrosis. Methods and kits thereof are also disclosed.
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Page/Page column 120-122
(2021/04/21)
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- Utilizing o-Quinone Methide Chemistry: Synthesis of d9-Ivacaftor
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Lead time and cost are important factors for any pharmaceutical API. However, these issues become even more important when the drug substance contains an isotope such as deuterium, which has a natural abundance of only ~0.016% of all hydrogen. Fewer suppliers and logistical barriers both play a role in driving up the cost. These factors can challenge the supply route used to manufacture d9-ivacaftor (17), requiring investigation into alternative routes. By adapting the work from Pettus et al., a synthetic approach utilizing a transient o-quinone methide allowed access to the deuterium-labeled o-tert-butylphenol moiety. This was developed and proven on pilot scale to significantly reduce the number of deuterated reagents used, leading to an overall reduction in cost by a factor of 10, while also providing the substantial benefit of applying prior process knowledge from the parent, nonisotopically enriched API ivacaftor (7).
- Lewandowski, Bérénice L.,Looker, Adam R.,Roeper, Stefanie,Ryan, Michael P.,Wilde, Nathan,Ye, Zhifeng
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- AN IMPROVED PROCESS FOR THE SYNTHESIS OF IVACAFTOR
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The present disclosed an improved process for the synthesis of ivacaftor starting from indole acetic acid ester which can be performed in batch as well as continuous flow synthesis. The present invention further disclosed to a continuous process for the synthesis of compound of formula (II) or formula (III) from compound of formula (I) in continuous flow reactor.
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- PROCESS FOR THE SYNTHESIS OF IVACAFTOR AND RELATED COMPOUNDS
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The present patent discloses a novel one pot two-step process for the synthesis of ivacaftor and related compounds of [Formula (I)], wherein R1, R2, R3, R4, R5, R6, R7 and Ar1 are as described above; its tautomers or pharmaceutically acceptable salts thereof starting from indole acetic acid amides.
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Paragraph 062-064
(2016/12/01)
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- CO-CRYSTALS OF MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
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The present disclosure relates to co-crystals comprising N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) and a co-former and methods for their preparation. The present disclosure further relates to pharmaceutical compositions comprising the co-crystal forms, as well as methods of treatment therewith and kits.
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Paragraph 0444-0445
(2016/05/02)
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- CO-CRYSTALS OF MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
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The present disclosure relates to co-crystals comprising N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) and a co-former and methods for their preparation. The present disclosure further relates to pharmaceutical compositions comprising the co-crystal forms, as well as methods of treatment therewith and kits.
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Paragraph 00392; 00393
(2016/05/02)
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- PROCESS OF PREPARING PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF CFTR MEDIATED DISEASES
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Processes of preparing pharmaceutical compositions comprising 3-(6-(1-(2,2- difluorobenzo[d][1,3] dioxol-5 -yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) in Form I and a solid dispersion comprising substantially amorphous N-(5- hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide (Compound 2), methods of treating, lessening the severity of, or symptomatically treating CFTR mediated diseases, such as cystic fibrosis, methods of administering, and kits thereof are disclosed.
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Paragraph 00353-00354
(2015/06/03)
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- Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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Paragraph 0904
(2015/09/22)
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- Breaking and Making of Rings: A Method for the Preparation of 4-Quinolone-3-carboxylic Acid Amides and the Expensive Drug Ivacaftor
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A simple and convenient method to access 4-quinolone-3-carboxylic acid amides from indole-3-acetic acid amides through one-pot oxidative cleavage of the indole ring followed by condensation (Witkop-Winterfeldt type oxidation) was explored. The scope of the method was confirmed with more than 20 examples and was successfully applied to the synthesis of the drug Ivacaftor, the most expensive drug on the market.
- Vasudevan,Jachak, Gorakhnath R.,Reddy, D. Srinivasa
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p. 7433 - 7437
(2016/01/25)
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- PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF CFTR MEDIATED DISEASES
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Pharmaceutical compositions comprising 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5- yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) in Form I and a solid dispersion comprising substantially amorphous N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4- oxo-1H-quinoline-3-carboxamide (Compound 2), methods of treating, lessening the severity of, or symptomatically treating CFTR mediated diseases, such as cystic fibrosis, methods of manufacturing, methods of administering, and kits thereof are disclosed.
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Paragraph 00156; 00328; 00338; 00339
(2014/05/24)
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- Solid form of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione having specified X-ray diffraction pattern
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The invention relates to a packaging comprising one or more administration units comprising a solid form of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione.
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Paragraph 0239; 0240
(2015/01/18)
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- Expeditious synthesis of ivacaftor
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An expeditious synthesis for Ivacaftor featuring modified Leimgruber-Batcho procedure was described. The overall yield is 39% over six steps from commercially available 2-nitrobenzoyl chloride.
- He, Yang,Xu, Qien,Ma, Wenpeng,Zhang, Jian,Sun, Hongbing,Shen, Jingshan
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p. 1035 - 1040
(2014/04/17)
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- SOLID FORMS OF N-[2,4-BIS(1,1-DIMETHYLETHYL)-5-HYDROXYPHENYL]-1,4-DIHYDRO-4-OXOQUINOLINE-3-CARBOXAMIDE
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The present invention relates to crystalline solvate forms of N-[2,4-bis(1,1- dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) and methods for their preparation. The present invention further relates to pharmaceutical compositions comprising the crystalline solvate forms, as well as methods of treatment therewith.
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Page/Page column 53; 54
(2013/11/05)
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- USE OF (N- [2, 4 -BIS (1, 1 -DIMETHYLETHYL) - 5 - HYDROXYPHENYL] - 1, 4 - DIHYDRO - 4 - OXOQUINOLINE - 3 - CA RBOXAMIDE) FOR TREATING CFTR MEDIATED DISEASES
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The present invention relates to the use of N-[2,4-bis(l,l-dimethylethyl)-5- hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide, solids forms, and pharmaceutical compositions thereof for the treatment of CFTR mediated diseases, particularly cystic fibrosis, in patients possessing specific genetic mutations.
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Paragraph 0096
(2013/05/22)
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- Solid Forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
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The present invention relates to crystalline solvate forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) and methods for their preparation. The present invention further relates to pharmaceutical compositions comprising the crystalline solvate forms, as well as methods of treatment therewith.
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Paragraph 00581; 00582
(2013/11/05)
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- SOLID FORMS OF N-[2,4-BIS(1,1-DIMETHYLETHYL)-5-HYDROXYPHENYL]-1,4-DIHYDRO-4-OXOQUINOLINE-3-CARBOXAMIDE
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The present invention relates to solid state forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1), pharmaceutical compositions thereof and methods therewith.
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Page/Page column 19
(2011/10/10)
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- PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
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The invention provides a process for the preparation of a compound of Formula 1; comprising coupling a carboxylic acid of Formula 2; with an aniline of Formula 3; in the presence of a coupling agent.
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Page/Page column 86; 89-90
(2010/10/03)
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