- 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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- 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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- 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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- 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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- 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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- 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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- 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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- 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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- 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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- 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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- 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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- A Ivacaftor synthetic method and intermediate
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The present invention relates to an ivacaftor synthesis method and an intermediate thereof, wherein the ivacaftor synthesis method is achieved through the following scheme. The synthesis method has characteristics of novel synthesis route, easy operation, high yield and good safety, and is suitable for industrial production. The invention further provides the novel intermediate represented by a formula 7 or 8, wherein X is chlorine or bromine, and R is hydrogen or C1-C5 alkyl, preferably hydrogen, methyl or ethyl. The formula 7 or 8 is defined in the specification.
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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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- 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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- 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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- 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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- 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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- 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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- PROCESSES FOR THE PREPARATION OF IVACAFTOR
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The present invention provides processes for the preparation of ivacaftor using novel intermediates and a process for its preparation.
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Page/Page column 48; 49
(2017/03/21)
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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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- Method for the preparation of compounds (by machine translation)
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The present invention provides the method for preparing the compound of formula I shows, the method comprises : (1) a compound of the formula 1 compound as shown in the nitration reaction, in order to obtains the type 2 illustrated compound ; (2) using phenmethyl chlorine to type 2 to a compound represented by the hydroxyl protection processing, in order to obtains the type 3 illustrated compound ; (3) a compound of the formula 3 is subjected to a reducing reaction of the compound, in order to obtains the type 4 illustrated compound ; (4) a compound of the formula 5 compound is contacted with aniline is shown, in order to obtains the type 6 illustrated compound ; (5) a compound of the formula 4 with a compound represented by the formula 6 compound shown in contact, in order to obtains the type 7 illustrated compound ; (6) a compound of the formula 7 is shown of the deprotection reaction of hydroxy compound, so that compound I showsobtains the type. The synthetic method of this invention the route is short, the operation is simple, easy availability of raw materials, high yield, high purity final product, is suitable for industrial production. (by machine translation)
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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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- 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 066
(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 003692; 00393
(2016/05/02)
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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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- 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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- SOLID FORMS OF IVACAFTOR AND PROCESSES FOR THE PREPARATION THEREOF
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Provided herein is a polymorphic form of Ivacaftor, namely APO-I, as well as processes for the preparation and pharmaceutical compositions of the same. Also, provided is a new solvate of Ivacaftor, processes for its preparation and use in the preparation of pure Ivacaftor.
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Page/Page column 20; 21
(2015/06/03)
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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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- PHARMACEUTICAL COMPOSITIONS FOR USE IN THE TREATMENT OF CYSTIC FIBROSIS
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The present invention relates to the use of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and pharmaceutical compositions thereof for the treatment of cystic fibrosis, in patients, including kits and/or products thereof.
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- A PROCESS FOR THE PREPARATION OF IVACAFTOR AND ITS INTERMEDIATES
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The present invention provides novel intermediates of ivacaftor and process for its preparation. The present invention also provides process for the preparation of ivacaftor and pharmaceutically acceptable salt thereof using novel intermediates.
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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 0273
(2014/08/19)
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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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- 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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- 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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- PHARMACEUTICL COMPOSITIONS FOR THE TREATMENT OF CFTR -MEDIATED DISORDERS
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The present invention relates to the use of N-[2,4-bis(1,1-dimethylethyl)-5- hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxaraide (Compound 1), solids forms, and pharmaceutical compositions thereof for the treatment of CFTR-mediated diseases, particularly cystic fibrosis, in patients possessing specific genetic mutations. The present invention also relates to the use of Compound ? in combination with 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxoI- 5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 2), and Compound 1 in combination with (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3- dihydroxypropyl)~6~fluoro-2-( 1 -hydroxy-2-methylpropan-2-yl)- 1H-indol-5- yl)cyclopropanecarboxamide (Compound 3), for the treatment of CFTR-mediated diseases, particularly cystic fibrosis, in patients possessing specific genetic mutations. The present invention also relates to solid forms and formulations of Compound 2 or Compound 3 in combination with Compound 1, 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 00545; 00546
(2014/01/08)
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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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- 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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- 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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- 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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- 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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- 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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- 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; 9
(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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- MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS
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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 ABC transporter mediated diseases using such modulators.
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Page/Page column 240
(2008/06/13)
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