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

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.

1 . Crystalline N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) characterized as Form C. 
     
     
         2 . Form C according to  claim 1 , characterized by a peak having a 2-Theta value from about 6.0 to about 6.4 degrees in an XRPD spectrum. 
     
     
         3 . Form C according to  claim 1  or  2 , characterized by a peak having a 2-Theta value from about 7.3 to about 7.7 degrees in an XRPD spectrum. 
     
     
         4 . Form C according to any of  claims 1 - 3 , characterized by a peak having a 2-Theta value from about 8.1 to about 8.5 degrees in an XRPD spectrum. 
     
     
         5 . Form C according to any of  claims 1 - 4 , characterized by a peak having a 2-Theta value from about 12.2 to about 12.6 degrees in an XRPD spectrum. 
     
     
         6 . Form C according to any of  claims 1 - 5 , characterized by a peak having a 2-Theta value from about 14.4 to about 14.8 degrees in an XRPD spectrum. 
     
     
         7 . Form C according to any of  claims 1 - 6 , characterized by a peak having a 2-Theta value from about 17.7 to about 18.1 degrees in an XRPD spectrum. 
     
     
         8 . Form C according to any of  claims 1 - 7 , characterized by a peak having a 2-Theta value from about 20.3 to about 20.7 degrees in an XRPD spectrum. 
     
     
         9 . Form C according to any of  claims 1 - 8 , characterized by a peak having a 2-Theta value from about 20.7 to about 21.1 degrees in an XRPD spectrum. 
     
     
         10 . Form C according to  claim 1 , characterized by one or more peaks in an XRPD spectrum selected from about 6.2, about 7.5, about 8.3, about 12.4, about 14.6, about 17.9, about 20.5 and about 20.9 degrees as measured on a 2-Theta scale. 
     
     
         11 . Form C according to  claim 10 , characterized by all of the following peaks in an XRPD spectrum: about 6.2, about 7.5, about 8.3, about 12.4, about 14.6, about 17.9, about 20.5 and about 20.9 degrees as measured on a 2-Theta scale. 
     
     
         12 . Form C according to any of  claims 1 - 11 , characterized by a peak at about 152.0 ppm in a  13 C SSNMR spectrum. 
     
     
         13 . Form C according to any of  claims 1 - 12 , characterized by a peak at about 135.4 ppm in a  13 C SSNMR spectrum. 
     
     
         14 . Form C according to any of  claims 1 - 13 , characterized by a peak at about 131.8 ppm in a  13 C SSNMR spectrum. 
     
     
         15 . Form C according to any of  claims 1 - 14 , characterized by a peak at about 117.0 ppm in a  13 C SSNMR spectrum. 
     
     
         16 . Form C according to any of  claims 1 - 15 , characterized by a peak at about 130.2 ppm in a  13 C SSNMR spectrum. 
     
     
         17 . Form C according to any of  claims 1 - 16 , characterized by a peak at about 124.8 ppm in a  13 C SSNMR spectrum. 
     
     
         18 . Form C according to any of  claims 1 - 17 , characterized by a peak at about 34.5 ppm in a  13 C SSNMR spectrum. 
     
     
         19 . Form C according to  claim 1 , characterized by one or more peaks in a  13 C SSNMR spectrum selected from about 152.0 ppm, about 135.4 ppm, about 131.8 ppm, about 130.2, about 124.8 ppm, about 117.0 ppm and about 34.5 ppm. 
     
     
         20 . Form C according to  claim 1 , characterized by a peak at about 152.0 ppm, a peak at about 135.4 ppm, a peak at about 131.8 ppm and a peak at about 117.0 ppm in a  13 C SSNMR spectrum. 
     
     
         21 . Form C according to  claim 20 , further characterized by a peak at about 130.2 ppm, a peak at about 124.8 ppm and a peak at about 34.5 ppm in a  13 C SSNMR spectrum. 
     
     
         22 . Form C of  claim 1 , characterized by a Solid State NMR spectral pattern substantially similar  FIG. 6 . 
     
     
         23 . Form C according to any of  claims 1 - 22 , characterized by a single crystal which is determined to possess a monoclinic crystal system, a P2 1 /c space group, and the following unit cell dimensions:
 a=12.211 Angstroms   b=5.961 Angstroms   c=32.662 Angstroms   α=90.00°   β=119.62°   γ=90.00°   
     
     
         24 . A pharmaceutical composition comprising Form C of any of  claims 1 - 23 , and a pharmaceutically acceptable adjuvant or carrier. 
     
     
         25 . A pharmaceutical composition according to  claim 24 , further comprising an additional agent selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Form C, or a nutritional agent. 
     
     
         26 . A pharmaceutical composition according to  claim 25 , wherein the additional agent is a CFTR modulator other than Form C. 
     
     
         27 . A method of treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders such as Huntington's, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease, Osteoporosis, Osteopenia, bone healing and bone growth (including bone repair, bone regeneration, reducing bone resorption and increasing bone deposition), Gorham's Syndrome, chloride channelopathies such as myotonia congenita (Thomson and Becker forms), Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, and Primary Ciliary Dyskinesia (PCD), a term for inherited disorders of the structure and/or function of cilia, including PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia, said method comprising the step of administering to said patient an effective amount of Form C according to any of  claims 1 - 23 . 
     
     
         28 . The method according to  claim 27 , wherein said disease is cystic fibrosis. 
     
     
         29 . The method according to  claim 27  or  28 , wherein the patient possesses one or more of the following mutations of human CFTR: ΔF508, R117H, and G551D. 
     
     
         30 . The method according to  claim 29 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the ΔF508 mutation of human CFTR. 
     
     
         31 . The method according to  claim 29 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR. 
     
     
         32 . The method according to  claim 30 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the ΔF508 mutation of human CFTR on at least one allele. 
     
     
         33 . The method according to  claim 30 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the ΔF508 mutation of human CFTR on both alleles. 
     
     
         34 . The method according to  claim 31  wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR on at least one allele. 
     
     
         35 . The method according to  claim 31 , wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR on both alleles. 
     
     
         36 . A kit for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo, comprising:
 (i) a composition comprising Form C according to any of  claims 1 - 23 ;   (ii) instructions for:
 a) contacting the composition with the biological sample; and 
 b) measuring activity of said CFTR or a fragment thereof. 
   
     
     
         37 . The kit according to  claim 36 , further comprising instructions for:
 a) contacting an additional compound with the biological sample;   b) measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound; and   c) comparing the activity of said CFTR or fragment thereof in the presence of said additional compound with the activity of the CFTR or fragment thereof in the presence of the composition comprising Form C according to any of  claims 1 - 23 .   
     
     
         38 . The kit of  claim 37 , wherein the step of comparing the activity of said CFTR or fragment thereof provides a measure of the density of said CFTR or fragment thereof.