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Solid forms of (r)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihyderoxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide

A kind of technology of dioxole, cyclopropane carboxamide is applied in (R)-1(2,2-difluorobenzo[D][1,3]dioxole-5- yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl) Solid form domain of cyclopropanecarboxamide, which can address issues such as preventing proper folding of nascent proteins, defective channel gating, and reduced transport of anions across epithelial cells

Active Publication Date: 2013-01-23
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition to impaired flux, mutations lead to defective channel gating
Reduced number of channels on the membrane and defective gating together result in reduced transport of anions across epithelial cells, resulting in defective ion and fluid transport
[0010] As discussed above, it is believed that the deletion of residue 508 of ΔF508-CFTR prevents proper folding of the nascent protein, resulting in the inability of this mutant protein to leave the ER and pass through the plasma membrane

Method used

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  • Solid forms of (r)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihyderoxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide
  • Solid forms of (r)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihyderoxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide
  • Solid forms of (r)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihyderoxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide

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Embodiment

[0192] Methods and materials

[0193] Modulated Differential Scanning Calorimetry (MDSC) and Differential Scanning Calorimetry (DSC)

[0194] Modulated Differential Scanning Calorimetry (MDSC) was used to test the glass transition temperature of the amorphous form of the compound and the spray-dried dispersion. Differential scanning calorimetry (DSC) was used to determine the melting point of crystalline material and to discriminate between different polymorphs. Data were collected using a TA DSC Q2000 Differential Scanning Calorimeter (TA Instruments, New Castle, DE). This instrument is calibrated with indium. Approximately 1-5 mg of the sample was weighed into a pot sealed with a crimped aluminum lid with a hole. Samples were scanned from -20°C - 220°C for MDSC at a heating rate of 2°C / min with + / - 1°C adjustment every 60 seconds. Samples were scanned from 25°C to 220°C for DSC at a heating rate of 10°C / min. Data via Thermal Advantage Q Series TM Software (version: 2.7...

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Abstract

The present invention relates to solid forms of (R)-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 1) in substantially crystalline form (Form A) or amorphous form, pharmaceutical compositions thereof, and methods of treatment therewith.

Description

[0001] Technical Field of the Invention [0002] The present invention relates to ( R )-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)- Solid state forms, e.g. crystalline and amorphous forms, of 6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, pharmaceutically acceptable combinations thereof substances and their methods of use. Background of the invention [0003] CFTR is a cAMP / ATP-mediated anion channel expressed in a variety of cell types, including absorptive and secretory epithelial cells, where the channel regulates anion flux across membranes and the activity of other ion channels and proteins. In epithelial cells, proper functioning of CFTR is critical for maintaining transport of electrolytes throughout the body, including in respiratory and digestive tissues. Consisting of approximately 1480 amino acids, CFTR encodes a protein consisting of tandem repeats of transmembrane domains, each containing six transmemb...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61K31/404A61P11/00
CPCC07D405/12C07B2200/13A61P1/10A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P13/02A61P13/12A61P15/00A61P15/08A61P15/10A61P19/00A61P19/08A61P19/10A61P21/00A61P21/02A61P21/04A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P27/02A61P27/04A61P29/00A61P3/00A61P31/00A61P31/04A61P35/00A61P3/06A61P3/08A61P37/06A61P37/08A61P43/00A61P5/02A61P5/10A61P5/14A61P5/16A61P5/18A61P5/20A61P7/00A61P7/02A61P7/04A61P7/10A61P7/12A61P3/10C07D209/04C07D209/40
Inventor A.克沙瓦什霍克里B.张T.E.阿尔卡焦E.C.李Y.张M.克拉维奇
Owner VERTEX PHARMA INC