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Solid Forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

a technology of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl] and n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl], which is applied in the field of solid state forms of n2, 4bis (1, 1dimethylethyl)5hydroxyphenyl1, 4dihydro4oxoquinoline3carboxamide, can solve the debil

Inactive Publication Date: 2013-01-17
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite progress in the treatment of CF, there is no cure.
In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.
In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport.
The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients.
In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death.
This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane.
In addition to impaired trafficking, the mutation results in defective channel gating.
Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport.
As discussed above, it is believed that the deletion of residue 508 in ΔF508-CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to exit the ER, and traffic to the plasma membrane.
As a result, insufficient amounts of the mature protein are present at the plasma membrane and chloride transport within epithelial tissues is significantly reduced.

Method used

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  • Solid Forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
  • Solid Forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
  • Solid Forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

Examples

Experimental program
Comparison scheme
Effect test

example 1

Total Synthesis of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (26)

[0178]

Procedure for the Preparation of ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (25)

[0179]

[0180]Compound 23 (4.77 g, 47.7 mmol) was added dropwise to compound 22 (10 g, 46.3 mmol) with subsurface N2 flow to drive out ethanol below 30° C. for 0.5 hours. The solution was then heated to 100-110° C. and stirred for 2.5 hours. After cooling the mixture to below 60° C., diphenyl ether was added. The resulting solution was added dropwise to diphenyl ether that had been heated to 228-232° C. for 1.5 hours with subsurface N2 flow to drive out ethanol. The mixture was stirred at 228-232° C. for another 2 hours, cooled to below 100° C. and then heptane was added to precipitate the product. The resulting slurry was stirred at 30° C. for 0.5 hours. The solids were then filtrated, and the cake was washed with heptane and dried in vacuo to give compound 25 as brown solid. 1H NMR (DMSO-d6; 400 MHz) δ 12.25 (s), δ 8.49 (d), δ ...

example 2

Total Synthesis of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (1)

[0185]

Procedure for the Preparation of 2,4-di-tert-butylphenyl methyl carbonate (30)

[0186]

Method 1

[0187]To a solution of 2,4-di-tert-butyl phenol, 29, (10 g, 48.5=01) in diethyl ether (100 mL) and triethylamine (10.1 mL, 72.8 mmol), was added methyl chloroformate (7.46 mL, 97 mmol) dropwise at 0° C. The mixture was then allowed to warm to room temperature and stir for an additional 2 hours. An additional 5 mL triethylamine and 3.7 mL methyl chloroformate was then added and the reaction stirred overnight. The reaction was then filtered, the filtrate was cooled to 0° C., and an additional 5 mL triethylamine and 3.7 mL methyl chloroformate was then added and the reaction was allowed to warm to room temperature and then stir for an addition 1 hours. At this stage, the reaction was almost complete and was worked up by filtering, then washing with water (2×), followed by brine. The solutio...

example 3

Procedure for the Recrystallization of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (1)

[0200]

[0201]Compound 1 (1.0 eq) was charged to a reactor. 2-MeTHF (20.0 vol) was added followed by 0.1N HCl (5.0 vol). The biphasic solution was stirred and separated and the top organic phase was washed twice more with 0.1N HCl (5.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 35° C. (jacket temperature) and no more than 8.0° C. (internal reaction temperature) under reduced pressure to 10 vol. Isopropyl acetate (IPAc) (10 vol) was added and the solution concentrated at no more than 35° C. (jacket temperature) and no more than 8.0° C. (internal reaction temperature) to 10 vol. The addition of IPAc and concentration was repeated 2 more times for a total of 3 additions of IPAc and 4 concentrations to 10 vol. After the final concentration, 10 vol of IPA...

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Abstract

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.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims priority to U.S. provisional application Ser. No. 61 / 315,885, filed on Mar. 19, 2010. The entire contents of which is incorporated by reference.TECHNICAL FIELD OF THE INVENTION[0002]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, pharmaceutical compositions thereof, and methods therewith.BACKGROUND OF THE INVENTION[0003]Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.[0004]CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues. Small molecule d...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D215/56A61P11/06A61P11/00A61P29/00A61P1/00A61P1/16A61P1/10A61P3/00A61P3/06A61P3/10A61P7/12A61P27/02A61P19/10A61P19/08A61P25/00A61P25/28A61P25/16A61P25/14A61K31/47
CPCC07D215/56A61P1/00A61P1/10A61P1/16A61P3/00A61P3/06A61P3/10A61P7/12A61P11/00A61P11/06A61P11/08A61P15/00A61P19/08A61P19/10A61P25/00A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P37/08A61P43/00
Inventor AREKAR, SNEHA G.JOHNSTON, STEVEN C.KRAWIEC, MARIUSZMEDEK, ALESMUDUNURI, PRAVEENSULLIVAN, MARK JEFFREY
Owner VERTEX PHARMA INC
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