- METHODS OF TREATMENT FOR CYSTIC FIBROSIS
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This application describes methods of treating cystic fibrosis or a CFTR mediated disease comprising administering Compound I or a pharmaceutically acceptable salt thereof. (I) The application also describes pharmaceutical compositions comprising Compound I or a pharmaceutically acceptable salt thereof and optionally comprising one or more additional CFTR modulating agents.
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Paragraph 00121
(2020/06/05)
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- METHODS OF TREATMENT FOR CYSTIC FIBROSIS
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This application describes methods of treating cystic fibrosis comprising administering Compound I:, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing.
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Paragraph 00232
(2020/12/11)
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- COMPOSITIONS AND METHODS FOR TREATMENT OF CYSTIC FIBROSIS
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Compositions comprising Compound I of the formula (I) and methods of treating cystic fibrosis comprising administering Compound I. Compositions comprising a pharmaceutically acceptable salt of Compound I and methods of treating cystic fibrosis comprising administering a pharmaceutically acceptable salt of Compound I.
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Paragraph 00324; 00325; 00333; 00340; 00341
(2019/01/22)
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- METHODS OF TREATMENT FOR CYSTIC FIBROSIS
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Methods of treating cystic fibrosis comprising administering at least Compound (I) of the formula. Pharmaceutical compositions containing a pharmaceutically acceptable salt of at least Compound I and methods of treating cystic fibrosis comprising administering a pharmaceutically acceptable salt of at least Compound (I).
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Paragraph 00151
(2019/02/06)
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- METHODS OF TREATMENT FOR CYSTIC FIBROSIS
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Compound I of the formula (I) and/or pharmaceutically acceptable salt(s) of Compound I comprised in a pharmaceutical composition and methods of using the same to treat cystic fibrosis.
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Paragraph 00182
(2019/02/06)
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- Evaluation of 1,2,3-Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX-770 and VX-809
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The 1,2,3-triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogues derived from VX-809 and VX-770, prominent amide-containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX-809, displayed markedly reduced efficacy in F508del-CFTR correction in cellular TECC assays in comparison to VX-809. Surprisingly, triazole analogues derived from potentiator VX-770 displayed no potentiation of F508del, G551D, or WT-CFTR in cellular Ussing chamber assays. However, patch clamp analysis revealed that triazole 60 potentiates WT-CFTR similarly to VX-770. The efficacy of 60 in the cell-free patch clamp experiment suggests that the loss of activity in the cellular assay could be due to the inability of VX-770 triazole derivatives to reach the CFTR binding site. Moreover, in addition to the negative impact on biological activity, triazoles in both structural classes displayed decreased metabolic stability in human microsomes relative to the analogous amides. In contrast to the many studies that demonstrate the advantages of using the 1,2,3-triazole, these findings highlight the negative impacts that can arise from replacement of the amide with the triazole and suggest that caution is warranted when considering use of the 1,2,3-triazole as an amide bioisostere.
- Doiron, Jake E.,Le, Christina A.,Ody, Britton K.,Brace, Jonathon B.,Post, Savannah J.,Thacker, Nathan L.,Hill, Harrison M.,Breton, Gary W.,Mulder, Matthew J.,Chang, Sichen,Bridges, Thomas M.,Tang, Liping,Wang, Wei,Rowe, Steven M.,Aller, Stephen G.,Turlington, Mark
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supporting information
p. 3662 - 3674
(2019/02/19)
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- COMPOSITIONS FOR TREATING CYSTIC FIBROSIS
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A single tablet comprising Compound I:. Methods of treating cystic fibrosis comprising administering one or more of such single tablets to a patient.
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Paragraph 00249
(2019/06/23)
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- CRYSTALLINE FORMS AND COMPOSITIONS OF CFTR MODULATORS
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Crystalline Forms of Compound I: and pharmaceutically acceptable salts thereofare disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.
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Paragraph 0516; 0520
(2019/05/07)
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- CRYSTALLINE FORMS OF MODULATORS OF CFTR
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Crystalline Forms of Compound (I); crystalline Forms of Compound (II) and crystalline forms of pharmaceutically acceptable salts of any of the foregoing are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.
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Paragraph 00430
(2019/10/19)
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- PHARMACEUTICAL COMPOSITIONS FOR TREATING CYSTIC FIBROSIS
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A pharmaceutical composition comprising Compound I: Methods of treating cystic fibrosis comprising administering one or more of such pharmaceutical compositions to a patient.
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Paragraph 0575; 0579
(2019/08/20)
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- MODULATOR OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR, PHARMACEUTICAL COMPOSITIONS, METHODS OF TREATMENT, AND PROCESS FOR MAKING THE MODULATOR
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Compounds of Formula (I), pharmaceutically acceptable salts thereof, deuterated derivatives of any of the foregoing, and metabolites of any of the foregoing are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.
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Paragraph 00217; 00224; 00225
(2018/04/17)
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- MODULATOR OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR, PHARMACEUTICAL COMPOSITIONS, METHODS OF TREATMENT, AND PROCESS FOR MAKING THE MODULATOR
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Compounds of Formula (I) pharmaceutically acceptable salts thereof, deuterated derivatives of any of the foregoing, and metabolites of any of the foregoing are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed. Also disclosed are solid state forms of Compound 1 and salts and solvates thereof.
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Paragraph 00236; 00243; 00244
(2018/06/30)
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- METHODS OF TREATING CYSTIC FIBROSIS IN PATIENTS WITH RESIDUAL FUNCTION MUTATIONS
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Modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), their pharmaceutical compositions, and methods of treating cystic fibrosis in patients with residual function mutations.
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Paragraph 0098; 0102
(2018/10/21)
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- METHODS OF TREATMENT FOR CYSTIC FIBROSIS
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Compound I of the formula (formula) A pharmaceutically acceptable salt of Compound I. Pharmaceutical compositions containing at least Compound I and methods of treating cystic fibrosis comprising administering at least Compound I. Pharmaceutical compositions containing a pharmaceutically acceptable salt of at least Compound I and methods of treating cystic fibrosis comprising administering a pharmaceutically acceptable salt of at least Compound I.
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Paragraph 00208; 00215; 00216
(2019/01/06)
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- Industrial Process for Making an Ivacaftor and its Intermediates
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The present invention relates to an improved process for the preparation of Ivacaftor intermediates. The present invention is also provides industrial applicable, commercially and eco-friendly viable process for the preparation of Ivacaftor
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Paragraph 0087; 0088
(2017/04/23)
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- An Efficient Synthesis of Ivacaftor
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New and practical synthetic route of ivacaftor is described on a grams scale. An electrophilic addition of two t-butyl groups to the aromatic ring is adopted to prepare 5-amino-2,4-di-t-butylphenol in 61% yield over three steps with 98.1% purity (high-performance liquid chromatography). An intramolecular cyclization of ethyl 3-(2-aminophenyl)-3-oxo-propanoate with dimethylformamide-dynamic mechanical analysis is used to prepare 4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 54% yield over four steps. Ivacaftor is obtained by condensation of the two parts in 71% yield with 99.1% purity (high-performance liquid chromatography).
- Zhang, Rui,Han, Guanyu,Jiang, Luobin,Shen, Yao,Yang, Rui,Mao, Yongjun,Wang, Hang
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p. 3169 - 3173
(2017/10/05)
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- 2,4-di-tert-butyl-5-aminophenol method for the preparation of (by machine translation)
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The present invention relates to organic synthesis, and technical field of preparing intermediates of raw materials, in particular to a new medicine for the treatment of cystic fibrosis is a key intermediate (ivacaftor) according to cuts down Catto 2, the 4 [...] di-tert-butyl -5 the method for the preparation of phenol [...], comprising the following steps : (1) acetylation: to (A) aminophenol between, (B) acetic anhydride or acetyl chloride as a raw material, prepared by reaction of N-(the 3 [...] hydroxy-phenyl) acetamide ; (2) tert-butyl substituted: N-(the 3 [...] hydroxy-phenyl) acetamide sulfuric acid catalyzed after thickwith uncle butanol, by preparing N-(2,4 the [...] di-tert-butyl -5 the [...] hydroxy-phenyl-acetamide ; (3) deacetyl: N-(2,4 the [...] di-tert-butyl -5 the [...] hydroxy-phenyl) acetamide using acid or alkali hydrolysis to obtain 2,4 the [...] di-tert-butyl -5 the aminophenol [...]. This synthetic route easy availability of raw materials, mild reaction conditions, post-processing is simple and convenient, suitable for enlarging preparation, and have high yield. (by machine translation)
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Paragraph 0046; 0047; 0048; 0049; 0058-60
(2016/11/24)
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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 0516
(2015/09/22)
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- Discovery of N -(2,4-Di- tert -butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a potent and orally bioavailable CFTR potentiator
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Quinolinone-3-carboxamide 1, a novel CFTR potentiator, was discovered using high-throughput screening in NIH-3T3 cells expressing the F508del-CFTR mutation. Extensive medicinal chemistry and iterative structure-activity relationship (SAR) studies to evaluate potency, selectivity, and pharmacokinetic properties resulted in the identification of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, 48, ivacaftor), an investigational drug candidate approved by the FDA for the treatment of CF patients 6 years of age and older carrying the G551D mutation.
- Hadida, Sabine,Van Goor, Fredrick,Zhou, Jinglan,Arumugam, Vijayalaksmi,McCartney, Jason,Hazlewood, Anna,Decker, Caroline,Negulescu, Paul,Grootenhuis, Peter D. J.
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p. 9776 - 9795
(2015/01/16)
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- PROCESS FOR THE PREPARATION OF IVACAFTOR AND SOLVATES THEREOF
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The present invention provides process for the preparation of ivacaftor and solvates thereof.
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Paragraph 0287
(2014/08/19)
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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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- MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
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The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using such CFTR modulators.
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Page/Page column 72; 73
(2010/07/08)
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- COMPOSITIONS OF N-[2,4-BIS(1,1-DIMETHYLETHYL)-5-HYDROXYPHENYL]-1,4-DIHYDRO-4-OXOQUINOLINE-3-CARBOXAMIDE
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Pharmaceutical compositions including N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) and methods of using such compositions are described herein.
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Page/Page column 8
(2008/06/13)
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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 47-49
(2010/11/28)
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