Solid forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluorormethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihyroquinoline-3-carboxamide

The present invention relates to solid state forms, for example, crystalline forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, pharmaceutical compositions thereof, and methods therewith.

Modulators of cystic fibrosis transmembrane conductance regulator

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator ("CFTR"), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

Pharmaceutical Composition and Administrations Thereof

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention. 1. A method of treating or lessening the severity of Osteoporosis or Osteopenia in a patient comprising administering to said patient Compound 1 or a pharmaceutically acceptable salt thereof.2. The method of claim 1 , wherein Compound 1 is substantially amorphous Compound 1 or a pharmaceutically acceptable salt thereof.3. The method of claim 1 , wherein Compound 1 is amorphous Compound 1 or a pharmaceutically acceptable salt thereof.4. The method of claim 1 , wherein administering Compound 1 to said patient comprises administering a pharmaceutical composition claim 1 , in which the pharmaceutical composition comprises about 34.1 wt % of a solid dispersion by weight of the composition claim 1 , wherein the dispersion comprises about 80 wt % of substantially amorphous or amorphous Compound 1 by weight of the dispersion claim 1 , about 19.5 wt % of HPMCAS by weight of the dispersion claim 1 , and about 0.5 wt % SLS by weight of the dispersion; about 30.5 wt % of microcrystalline cellulose by weight of the composition; about 30.4 wt % of lactose by weight of the composition; about 3 wt % of sodium croscarmellose by weight of the composition; about 0.5 wt % of SLS by weight of the composition; about 0.5 wt % of colloidal silicon dioxide by weight of the composition; and about 1 wt % of magnesium stearate by weight of the composition.5. The method of claim 4 , wherein the pharmaceutical composition contains 150 mg of Compound 1.6. A method of providing bone healing and/or bone repair in a patient comprising administering to said patient Compound 1 or a pharmaceutically acceptable salt thereof.7. The method of claim 6 , wherein ...

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

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.

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (CFTR), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

Biomarkers for Monitoring Impdh Pathway Inhibition

The present invention is directed to methods for ameliorating reproductive disorders. More specifically, the present invention describes methods and compositions for using IL-17 in the treatment of various infertility-related defects.

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

Solid Forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluorormethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihyroquinoline-3-carboxamide

The present invention relates to solid state forms, for example, crystalline forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, pharmaceutical compositions thereof, and methods therewith. 126-. (canceled)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 ...

SOLID FORMS OF N-(4-(7-AZABICYCLO[2.2.1]HEPTAN-7-YL)-2-(TRIFLUORORMETHYL)PHENYL)-4-OXO-5-(TRIFLUOROMETHYL)-1,4-DIHYROQUINOLINE-3-CARBOXAMIDE

The present invention relates to solid state forms, for example, crystalline forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, pharmaceutical compositions thereof, and methods therewith.

Quantification and site-specific profiling of protein phosphorylation

The invention provides methods and compositions for analyzing modification-mediated signaling pathways.

Modulators of ATP-Binding Cassette Transporters

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.

Solid Forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihyroquinoline-3-carboxamide

The present invention relates to solid state forms, for example, crystalline forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, pharmaceutical compositions thereof, and methods therewith. 126-. (canceled)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 ...

Modulators of the cholesterol biosynthetic pathway

The present invention relates to methods for modulating the cholesterol biosynthetic pathway. The level of cholesterol in the body is linked to numerous pathological states. The methods of the present invention alter the transcription levels of genes involved in the cholesterol biosynthesis. The methods of the present invention can used for treating diseases mediated by the cholesterol biosynthetic pathway.

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (CFTR), compositions thereof, and methods therewith. The present invention also relates to pharmaceutical compositions comprising a compound of Formula I with one or both of a Compound of Formula II and/or a Compound of Formula III. Further, the present invention relates to methods of treating CFTR mediated diseases, particularly cystic fibrosis, using modulators of CFTR, and compositions and combinations thereof.

PHARMACEUTICAL COMPOSITION AND ADMINISTRATIONS THEREOF

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention.

Pharmaceutical Composition and Administrations Thereof

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention. 1. A method of treating or lessening the severity of Osteoporosis or Osteopenia in a patient comprising administering to said patient Compound 1 or a pharmaceutically acceptable salt thereof.2. The method of claim 1 , wherein Compound 1 is substantially amorphous Compound 1 or a pharmaceutically acceptable salt thereof.3. The method of claim 1 , wherein Compound 1 is amorphous Compound 1 or a pharmaceutically acceptable salt thereof.4. The method of claim 1 , wherein administering Compound 1 to said patient comprises administering a pharmaceutical composition claim 1 , in which the pharmaceutical composition comprises about 34.1 wt % of a solid dispersion by weight of the composition claim 1 , wherein the dispersion comprises about 80 wt % of substantially amorphous or amorphous Compound 1 by weight of the dispersion claim 1 , about 19.5 wt % of HPMCAS by weight of the dispersion claim 1 , and about 0.5 wt % SLS by weight of the dispersion; about 30.5 wt % of microcrystalline cellulose by weight of the composition; about 30.4 wt % of lactose by weight of the composition; about 3 wt % of sodium croscarmellose by weight of the composition; about 0.5 wt % of SLS by weight of the composition; about 0.5 wt % of colloidal silicon dioxide by weight of the composition; and about 1 wt % of magnesium stearate by weight of the composition.5. The method of claim 4 , wherein the pharmaceutical composition contains 150 mg of Compound 1.6. A method of providing bone healing and/or bone repair in a patient comprising administering to said patient Compound 1 or a pharmaceutically acceptable salt thereof.7. The method of claim 6 , wherein ...

Pharmaceutical composition and administration thereof

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention.

Modulators of cystic fibrosis transmembrane conductance regulator

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (CFTR), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

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. 147-. (canceled)49. A method of treating or lessening the severity of a disease in a patient claim 48 , wherein said disease is selected from cystic fibrosis claim 48 , said method comprising the step of administering to said patient an effective amount of a compound according to .50. The method according to claim 49 , wherein said disease is cystic fibrosis.5155-. (canceled)56. A method of modulating CFTR activity in a biological sample comprising the step of contacting said CFTR with a compound according to .57. A kit for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo claim 48 , comprising:{'claim-ref': {'@idref': 'CLM-00048', 'claim 48'}, '(i) a composition comprising a compound of Formula I according to ;'} a) contacting the composition with the biological sample;', 'b) measuring activity of said CFTR or a fragment thereof., '(ii) instructions for58. The kit of claim 57 , 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, andc) comparing the activity of said CFTR or a fragment thereof in the presence of said additional compound with the activity of said CFTR or a fragment thereof in the presence of a composition of Formula I.5987-. (canceled)88. The kit according to claim 58 , wherein the step of comparing the activity of said CFTR or a fragment thereof provides a measure of the density of said CFTR or a fragment thereof.90. The method according to claim 89 , wherein Ais an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms ...

Pharmaceutical composition and administrations thereof

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention.

Pharmaceutical Composition and Administrations Thereof

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention. 1. A pharmaceutical composition comprising:a. a solid dispersion comprising substantially amorphous Compound 1 and a polymer;b. a filler;c. a disintegrant;d. a surfactant;e. a binder;f. a glidant; andg. a lubricant.2. The pharmaceutical composition of claim 1 , wherein the solid dispersion comprises substantially amorphous Compound 1 and a polymer claim 1 , and the polymer comprises HPMC claim 1 , HPMCAS claim 1 , PVP/VA claim 1 , PVP claim 1 , methacrylic acid/methacrylate copolymer claim 1 , HPC claim 1 , or any combination thereof.3. The pharmaceutical composition of claim 2 , wherein the solid dispersion has a mean particle diameter of greater than about 5 μm.4. The pharmaceutical composition of claim 2 , wherein the solid dispersion has a bulk density of about 0.10 g/cc or greater.5. The pharmaceutical composition of claim 2 , wherein the solid dispersion comprises substantially amorphous Compound 1 claim 2 , and Compound 1 is present in a concentration of at least 20 wt % by weight of the solid dispersion.6. The pharmaceutical composition of claim 5 , wherein the solid dispersion comprises 80 wt % or less of HPMCAS or PVP/VA.7. The pharmaceutical composition of claim 5 , wherein the solid dispersion comprises a surfactant.8. The pharmaceutical composition of claim 7 , wherein the solid dispersion comprises less than 10 wt % of surfactant by weight of solid dispersion.9. The pharmaceutical composition of claim 8 , wherein the solid dispersion comprises a surfactant claim 8 , and the surfactant is SLS.10. The pharmaceutical composition of claim 9 , wherein the solid dispersion comprises amorphous Compound 1.11. The ...

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

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. 158-. (canceled)60. The compound according to claim 59 , wherein Ris halo claim 59 , CN claim 59 , CH claim 59 , CF claim 59 , OCF claim 59 , OCHor SOMe.61. The compound according to claim 59 , wherein Ris hydrogen.62. The compound according to claim 59 , wherein Ris methyl.63. The compound according to claim 59 , wherein Ris hydrogen.64. The compound according to claim 59 , wherein Rand Rare hydrogen.66. The compound according to wherein WRis a C-Cstraight or branched aliphatic claim 65 , or a 3-12 membered cycloaliphatic claim 65 , WRis —OH or OR′ and WRis —C≡CCHN(R′)(R′) claim 65 , —(CH)N(R′)(R′) claim 65 , —(CH)N(R′)(R′) claim 65 , —(CH)N(R′)(R′) or —N(R′)(R′).68. The compound according to wherein WRis a substituted C-Cstraight or branched aliphatic claim 67 , C-Cheterocyclic claim 67 , 3-12 membered cycloaliphatic claim 67 , or 3-12 membered bicyclic and WRis —C≡CCHN(R′)(R′) claim 67 , —(CH)N(R′)(R′) claim 67 , —(CH)N(R′)(R′) claim 67 , —(CH)N(R′)(R′) or —N(R′)(R′).70. The compound according to wherein WRis a substituted C-Cstraight or branched aliphatic claim 69 , C-Cheterocyclic claim 69 , 3-12 membered cycloaliphatic claim 69 , or 3-12 membered bicyclic and WRis —C≡CCHN(R′)(R′) claim 69 , —(CH)N(R′)(R′) claim 69 , —(CH)N(R′)(R′) claim 69 , —(CH)N(R′)(R′) or —N(R′)(R′).71. The compound according to any one of wherein Ris hydrogen.72. The compound according to any one of wherein wherein Ris hydrogen.73. The compound according to any one of wherein wherein Rand Ris hydrogen.75. A pharmaceutical composition comprising a compound of Formula IVD according to and a pharmaceutically acceptable carrier or adjuvant.76. The pharmaceutical composition according ...

Modulators of cystic fibrosis transmembrane conductance regulator

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.

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR. 65. The compound according to any one of - claims 2 , wherein Ris —CF.75. The compound according to any one of - claims 2 , wherein Ris —CN.85. The compound according to any one of - claims 2 , wherein Ris —C≡CCHN(CH).98. The compound according to any one of - claims 6 , wherein Ris hydrogen.108. The compound according to any one of - claims 6 , wherein Ris —CH.118. The compound according to any one of - claims 6 , wherein Ris —CF.128. The compound according to any one of - claims 6 , Ris —OH.138. The compound according to any one of - claims 6 , wherein Ris —CHOH.1413. The compound according to any one of - claims 10 , wherein Ris hydrogen.1513. The compound according to any one of - claims 9 , wherein Ris —CH.1613. The compound according to any one of - claims 9 , wherein Ris —OCH.1713. The compound according to any one of - claims 9 , wherein Ris —CN.1918. A pharmaceutical composition comprising a compound according to any one of - and a pharmaceutically acceptable carrier or adjuvant.20. The pharmaceutical composition according to claim 19 , further comprising an additional agent selected from a mucolytic agent claim 19 , a bronchodialator claim 19 , an antibiotic claim 19 , an anti-infective agent claim 19 , an anti-inflammatory agent claim 19 , a CFTR modulator other than a compound of Formula (I) claim 19 , or a nutritional agent.21. The pharmaceutical composition according to claim 20 , wherein said additional agent is a CFTR modulator other than a compound of Formula (I).2218. A method of treating or lessening the severity of a disease in a patient claims 1 , wherein said disease is selected from cystic fibrosis claims 1 , asthma claims 1 , smoke induced COPD claims 1 , chronic bronchitis claims 1 , rhinosinusitis ...

Modulators of cystic fibrosis transmembrane conductance regulator

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.

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR. 123-. (canceled)25. The method according to claim 24 , wherein said disease is cystic fibrosis.27. The method of claim 26 , wherein disease is cystic fibrosis claim 26 , chronic bronchitis claim 26 , recurrent bronchitis claim 26 , acute bronchitis claim 26 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 26 , female infertility caused by congenital absence of the uterus and vagina (CAUV) claim 26 , idiopathic chronic pancreatitis (ICP) claim 26 , idiopathic recurrent pancreatitis claim 26 , idiopathic acute pancreatitis claim 26 , chronic rhinosinusitis claim 26 , primary sclerosing cholangitis claim 26 , allergic bronchopulmonary aspergillosis claim 26 , diabetes claim 26 , dry eye claim 26 , constipation claim 26 , allergic bronchopulmonary aspergillosis (ABPA) claim 26 , bone diseases claim 26 , and asthma.29. The method of claim 28 , wherein disease is chronic obstructive pulmonary disease (COPD) claim 28 , chronic bronchitis claim 28 , recurrent bronchitis claim 28 , acute bronchitis claim 28 , rhinosinusitis claim 28 , constipation claim 28 , chronic pancreatitis claim 28 , recurrent pancreatitis claim 28 , and acute pancreatitis claim 28 , pancreatic insufficiency claim 28 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 28 , mild pulmonary disease claim 28 , idiopathic pancreatitis claim 28 , liver disease claim 28 , hereditary emphysema claim 28 , gallstones claim 28 , gasgtro-esophageal reflux disease claim 28 , gastrointestinal malignancies claim 28 , inflammatory bowel disease claim 28 , constipation claim 28 , diabetes claim 28 , arthritis claim 28 , osteoporosis claim 28 , and osteopenia.30. The method of claim 28 , wherein ...

Acyclic piperazine and piperidine derivatives

The present invention relates to acyclic piperazine and piperidine derivatives, which are especially useful for treating or preventing neuronal damage, particularly damage associated with neurological diseases. These compounds are also useful for stimulating nerve growth. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage or for stimulating nerve growth.

PHARMACEUTICAL COMPOSITION AND ADMINISTRATIONS THEREOF

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention. 1111-. (canceled)112. A method of treating or lessening the severity of cystic fibrosis in a patient in need thereof , comprising administering to the patient a pharmaceutical composition comprising a solid dispersion , wherein the solid dispersion comprises:a) 80% of amorphous or substantially amorphous N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) by weight of the dispersion, wherein substantially amorphous Compound 1 comprises less than 15% crystalline Compound 1,b) 19.5% of hydroxypropylmethylcellulose acetate succinate (HPMCAS) by weight of the dispersion, andc) 0.5% of sodium lauryl sulfate (SLS) by weight of the dispersion.113. The method of claim 112 , wherein the pharmaceutical composition further comprises 30.5% of microcrystalline cellulose by weight of the composition.114. The method of claim 112 , wherein the pharmaceutical composition further comprises 30.4% of lactose by weight of the composition.115. The method of claim 112 , wherein the pharmaceutical composition further comprises 3% of sodium croscarmellose by weight of the composition.116. The method of claim 112 , wherein the pharmaceutical composition further comprises 0.5% of SLS by weight of the composition.117. The method of claim 112 , wherein the pharmaceutical composition further comprises 0.5% of colloidal silicon dioxide by weight of the composition.118. The method of claim 112 , wherein the pharmaceutical composition further comprises 1.0% of magnesium stearate by weight of the composition.119. The method of claim 112 , wherein the pharmaceutical composition comprises 34.1% of the solid ...

PHARMACEUTICAL COMPOSITION AND ADMINISTRATIONS THEREOF

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention.

Acyclic piperidine derivatives

A compound having the formula (I): wherein: each R¹, R², R³ and R⁴ are independently selected from (C₁-C₁₀)-straight or branched alkyl, Ar-substituted- (C₁-C₁₀)-straight or branched alkyl, (C₂-C₁₀)-straight or branched alkenyl or alkynyl, or Ar-substituted-(C₂-C₁₀)-straight or branched alkenyl or alkynyl; wherein one to two CH₂ groups of said alkyl, alkenyl, or alkynyl chains in each of R¹, R², R³ and R⁴ are optionally and independently replaced with O, S, S(O), S(O), S(O)₂, C(O) or N(R⁵) in a chemically stable arrangement, wherein the CH₂ group of R¹ and R² bound directly to said nitrogen cannot be replaced with C(O); or R¹ and R² taken together form a 4 to 7 membered ring; or R³ and R⁴ taken together form ...

Modulators of cystic fibrosis transmembrane conductance regulator

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator ("CFTR"), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR. 65. The compound according to any one of - claims 2 , wherein Ris —CF.75. The compound according to any one of - claims 2 , wherein Ris —CN.85. The compound according to any one of - claims 2 , wherein Ris —CH.98. The compound according to any one of - claims 6 , wherein Ris hydrogen.108. The compound according to any one of - claims 6 , wherein Ris —CH.118. The compound according to any one of - claims 6 , wherein Ris —CF.128. The compound according to any one of - claims 6 , Ris —OH.138. The compound according to any one of - claims 6 , wherein Ris —CHOH.1413. The compound according to any one of - claims 9 , wherein Ris hydrogen.1513. The compound according to any one of - claims 9 , wherein Ris —CH.1613. The compound according to any one of - claims 9 , wherein Ris —OCH.1712. The compound according to any one of - claims 9 , wherein Ris —CN.1817. The compound according to any one of - wherein X is nitrogen.1917. The compound according to any one of - wherein Y is nitrogen.2120. A pharmaceutical composition comprising a compound according to any one of - and a pharmaceutically acceptable carrier or adjuvant.22. The pharmaceutical composition according to claim 21 , further comprising an additional agent selected from a mucolytic agent claim 21 , a bronchodialator claim 21 , an antibiotic claim 21 , an anti-infective agent claim 21 , an anti-inflammatory agent claim 21 , a CFTR modulator other than a compound of formula (I) claim 21 , or a nutritional agent.23. The pharmaceutical composition according to claim 22 , wherein said additional agent is a CFTR modulator other than a compound of formula (I).2420. A method of treating or lessening the severity of a disease in a patient claims 1 , wherein said disease is selected ...

Modulators of cystic fibrosis transmembrane conductance regulator

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

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. 114-. (canceled)15. A method of treating cystic fibrosis in a patient , wherein said patient is heterozygous for ΔF508 CFTR mutation and heterozygous for R117H CFTR mutation , comprising the step of administering to said patient a pharmaceutical composition comprising:a. a pharmacological agent capable of inducing or augmenting CFTR activity;b. N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide; andc. a pharmaceutically acceptable carrier, adjuvant or vehicle.16. The method according to claim 15 , wherein the pharmacological agent capable of inducing or augmenting CFTR activity increases the amount of CFTR present at the cell surface.17. The method according to claim 15 , wherein the pharmacological agent induces a hitherto absent CFTR activity.18. The method according to claim 15 , wherein the pharmacological agent augments an existing residual CFTR activity.19. The method according to claim 15 , wherein N-(5-hydroxy-2 claim 15 ,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide is administered concurrently with claim 15 , prior to claim 15 , or subsequent to the pharmacological agent capable of inducing or augmenting CFTR activity.20. The method according to claim 19 , wherein N-(5-hydroxy-2 claim 19 ,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide is administered concurrently with the pharmacological agent capable of inducing or augmenting CFTR activity.21. The method according to claim 19 , wherein N-(5-hydroxy-2 claim 19 ,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide is administered prior or subsequent to the pharmacological agent capable of inducing or augmenting CFTR activity.22. A method ...

Modulators of cystic fibrosis transmembrane conductance regulator

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.

Methods for identifying a compound that can bind to membrane-bound receptors

The present invention relates to methods of identifying compounds that can bind to a membrane-bound receptor.

Piperazine and piperidine derivatives

The present invention relates to piperazine and piperidine derivatives, which are especially useful for treating or preventing neuronal damage, particularly damage associated with neurological diseases. These compounds are also useful for stimulating nerve growth. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage or for stimulating nerve growth.

Modulators of ATP-Binding Cassette Transporters

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. 2. A pharmaceutical composition comprising a compound according to and a pharmaceutically acceptable carrier or adjuvant.3. The pharmaceutical composition according to claim 2 , further comprising an additional agent selected from a mucolytic agent claim 2 , a bronchodialator claim 2 , an antibiotic claim 2 , an anti-infective agent claim 2 , an anti-inflammatory agent claim 2 , a CFTR modulator claim 2 , or a nutritional agent.4. The pharmaceutical composition according to claim 2 , wherein said additional agent is a CFTR modulator other than a compound according to .5. A method of treating or lessening the severity of a disease in a patient claim 1 , wherein said disease is selected from cystic fibrosis claim 1 , asthma claim 1 , smoke induced COPD claim 1 , chronic bronchitis claim 1 , rhinosinusitis claim 1 , constipation claim 1 , pancreatitis claim 1 , pancreatic insufficiency claim 1 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 1 , mild pulmonary disease claim 1 , idiopathic pancreatitis claim 1 , allergic bronchopulmonary aspergillosis (ABPA) claim 1 , liver disease claim 1 , hereditary emphysema claim 1 , hereditary hemochromatosis claim 1 , coagulation-fibrinolysis deficiencies claim 1 , such as protein C deficiency claim 1 , Type 1 hereditary angioedema claim 1 , lipid processing deficiencies claim 1 , such as familial hypercholesterolemia claim 1 , Type 1 chylomicronemia claim 1 , abetalipoproteinemia claim 1 , lysosomal storage diseases claim 1 , such as I-cell disease/pseudo-Hurler claim 1 , mucopolysaccharidoses claim 1 , Sandhof/Tay-Sachs claim 1 , Crigler-Najjar type II claim ...

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (CFTR), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

This invention relates to a compound of Formula I: 2. A compound according to claim 1 , wherein R is CHOH.3. A compound according to claim 1 , wherein R is COOH.4. (canceled)5. (canceled)6. A pharmaceutical composition comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'a compound of Formula I, according to ; and'}a pharmaceutically acceptable carrier or adjuvant.9. The pharmaceutical composition of claim 6 , further comprising an additional agent selected from a mucolytic agent claim 6 , a bronchodilator claim 6 , an antibiotic claim 6 , an anti-invective agent claim 6 , an anti-inflammatory agent claim 6 , a CFTR modulator claim 6 , or a nutritional agent.10. A method of modulating CFTR activity in a biological sample comprising the step of contacting said biological sample with a compound of Formula I according to .13. A method of treating or lessening the severity of a disease in a patient comprising administering to said patient an effective amount of a compound of Formula I according to claim 1 , wherein said disease is selected from cystic fibrosis claim 1 , asthma claim 1 , smoke induced COPD claim 1 , chronic bronchitis claim 1 , rhinosinusitis claim 1 , constipation claim 1 , pancreatitis claim 1 , pancreatic insufficiency claim 1 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 1 , mild pulmonary disease claim 1 , idiopathic pancreatitis claim 1 , allergic bronchopulmonary aspergillosis (ABPA) claim 1 , liver disease claim 1 , hereditary emphysema claim 1 , hereditary hemochromatosis claim 1 , coagulation-fibrinolysis deficiencies claim 1 , such as protein C deficiency claim 1 , Type 1 hereditary angioedema claim 1 , lipid processing deficiencies claim 1 , such as familial hypercholesterolemia claim 1 , Type 1 chylomicronemia claim 1 , abetalipoproteinemia claim 1 , lysosomal storage diseases claim 1 , such as I-cell disease/pseudo-Hurler claim 1 , mucopolysaccharidoses claim 1 , Sandhof/Tay-Sachs claim ...

PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

The invention provides a process for the preparation of a compound of Formula 1, 2. The process of claim 1 , wherein Ris independently —OC(O)OR′ claim 1 , —OC(O)NHR′ claim 1 , or{'sub': '2', '—OC(O)N(R), wherein R′ is not hydrogen.'}3. The process of claim 2 , further comprising cleaving the —OC(O)OR′ claim 2 , —OC(O)NHR′ claim 2 , or —OC(O)N(R′)to form —OH.4. The process of claim 3 , wherein the cleavage is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 3 , KOH or sodium methoxide.5. The process of claim 4 , wherein the alcoholic solvent is methanol.6. The process of claim 1 , wherein at least one of Ror Ris independently a Cstraight or branched alkyl which is substituted with —COOR′ or —CON(R′) claim 1 , wherein R′ is not hydrogen.7. The process of claim 6 , further comprising hydrolyzing each —COOR′ claim 6 , or —CON(R′)to form —COOH.8. The process of claim 7 , wherein the hydrolysis is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 7 , KOH or sodium methoxide.9. The process of claim 8 , wherein the alcoholic solvent is methanol.10. The process of claim 6 , wherein Ris independently —OC(O)OR′ claim 6 , —OC(O)NHR′ claim 6 , or —OC(O)N(R′) claim 6 , wherein R′ is not hydrogen.11. The process of claim 10 , further comprising cleaving the —OC(O)OR′ claim 10 , —OC(O)NHR′ claim 10 , or —OC(O)N(R′)to form —OH.12. The process of claim 11 , wherein the cleavage is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 11 , KOH or sodium methoxide.13. The process of claim 12 , wherein the alcoholic solvent is methanol.14. The process of claim 1 , wherein the coupling is performed in the presence of a base.15. The process of claim 14 , wherein the base is KCO claim 14 , EtN claim 14 , NMM claim 14 , pyridine or DIEA.16. The process of claim 1 , wherein the coupling is performed in the presence of a solvent.17. The ...

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

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. 1. A compound selected from:6,7-difluoro-N-(2-fluoro-5-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide;5-hydroxy-N-[5-hydroxy-4-tert-butyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide;4-oxo-N-[3-(1-piperidyl)-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide;N-[4-(3,3-dimethylpyrrolidin-1-yl)-2-(trifluoromethyl)phenyl]-6-methyl-4-oxo-1H-quinoline-3-carboxamide;6-fluoro-N-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide;N-(3-fluoro-4-tert-butyl-phenyl)-5-hydroxy-4-oxo-1H-quinoline-3-carboxamide;methyl 1-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-3-(trifluoromethyl)phenyl]piperidine-2-carboxylate;5-hydroxy-N-[4-[2-hydroxy-1-(hydroxymethyl)-1-methyl-ethyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide;5-hydroxy-4-oxo-N-[5-(trifluoromethyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide;6-fluoro-4-oxo-N-[2-(trifluoromethyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide;N-(5-hydroxy-2,4-ditert-butyl-phenyl)-6-methoxy-4-oxo-1H-quinoline-3-carboxamide;N-[5-hydroxy-4-isopropyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide;N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)-phenyl]-5-methyl-4-oxo-1H-quinoline-3-carboxamide;N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)-phenyl]-7-methyl-4-oxo-1H-quinoline-3-carboxamide;5-hydroxy-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide;N-[2-fluoro-5-hydroxy-4-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide;5-hydroxy-N-[3-methoxy-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide;6-methyl-N-[4-(2-methylpyrrolidin-1-yl)-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide;N-[4-(3,3-dimethylpyrrolidin-1-yl)-2-(trifluoromethyl) ...

Process for Making Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

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.

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATIONS THEREOF

The present invention relates to pharmaceutical compositions comprising a compound of Formulas I and II, optionally in combination with a Compound of Formula III and/or a Compound of Formula IV. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis. 9. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is any of the embodiments listed in Column C of Table I.10. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is any of the embodiments listed in Column D of Table I.1128-. (canceled)29. A pharmaceutical composition comprising:a solid dispersion of Compound 1 or a pharmaceutically acceptable salt thereof; andCompound 3 or a pharmaceutically acceptable salt thereof.30. The pharmaceutical composition of claim 29 , wherein the solid dispersion of Compound 1 comprises about 80 wt % of substantially amorphous Compound 1 by weight of the dispersion claim 29 , about 19.5 wt % of HPMCAS by weight of the dispersion claim 29 , and about 0.5 wt % SLS by weight of the dispersion.31. The pharmaceutical composition of claim 30 , wherein the composition comprises about 34.1 wt % of the solid dispersion by weight of the composition; about 30.5 wt % of microcrystalline cellulose by weight of the composition; about 30.4 wt % of lactose by weight of the composition; about 3 wt % of sodium croscarmellose by weight of the composition; about 0.5 wt % of SLS by weight of the composition; about 0.5 wt % of colloidal silicon dioxide by weight of the composition; and about 1 wt % of magnesium stearate by weight of the composition.32. The pharmaceutical composition according to claim 31 , wherein the composition ...

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATIONS THEREOF

The present invention relates to pharmaceutical compositions comprising a compound of Formula I in combination with one or both of a Compound of Formula II and/or a Compound of Formula III. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis. 2. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and a Compound of Formula II.3. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and a Compound of Formula III.4. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I claim 1 , a Compound of Formula II and a Compound of Formula III.9. A method of treating a CFTR mediated disease in a human comprising administering to the human an effective amount of a pharmaceutical composition according to .10. The method of claim 9 , wherein the CFTR mediated disease is selected from cystic fibrosis claim 9 , asthma claim 9 , smoke induced COPD claim 9 , chronic bronchitis claim 9 , rhinosinusitis claim 9 , constipation claim 9 , pancreatitis claim 9 , pancreatic insufficiency claim 9 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 9 , mild pulmonary disease claim 9 , idiopathic pancreatitis claim 9 , allergic bronchopulmonary aspergillosis (ABPA) claim 9 , liver disease claim 9 , hereditary emphysema claim 9 , hereditary hemochromatosis claim 9 , coagulation-fibrinolysis deficiencies claim 9 , such as protein C deficiency claim 9 , Type 1 hereditary angioedema claim 9 , lipid processing deficiencies claim 9 , such as familial hypercholesterolemia claim 9 , Type 1 chylomicronemia claim 9 , abetalipoproteinemia claim 9 , lysosomal storage diseases claim 9 , such as I-cell disease/pseudo-Hurler claim 9 , mucopolysaccharidoses claim 9 , Sandhof/Tay-Sachs claim 9 , Crigler-Najjar type II claim 9 , polyendocrinopathy/ ...

PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

The invention provides a process for the preparation of a compound of Formula 1, 158-. (canceled)6058. The compound according to claim , wherein the compound is Compound 32.6158. The compound according to claim , wherein the compound is Compound 33. This application claims priority to three U.S. Provisional Applications having Ser. Nos. 61/162,148, filed on Mar. 20, 2009; 61/246,303, filed on Sep. 28, 2009; and 61/248,565, filed on Oct. 5, 2009. Each of the foregoing Provisional Applications are hereby incorporated by reference in their entirety.The present invention relates to a process for making modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”).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.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 drugs, known as potentiators that increase the probability of CFTR channel opening represent one potential therapeutic strategy to treat CF.Specifically, CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are ...

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

This invention relates to a compound of Formula I: 19-. (canceled)16. The method according to claim 13 , wherein said disease is cystic fibrosis.1721-. (canceled)22. The method according to claim 13 , wherein said disease is selected from cystic fibrosis claim 13 , COPD claim 13 , smoke induced COPD claim 13 , hereditary emphysema claim 13 , pancreatitis claim 13 , pancreatic insufficiency claim 13 , and dry-eye disease. This application is a continuation of PCT Application No. PCT/US2010/028062 filed Mar. 19, 2010, which claims the priority of U.S. Application No. 61/162,130 filed Mar. 20, 2009, which is incorporated by reference herein in its entirety.The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.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.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 drugs, known as potentiators that increase the probability of CFTR channel opening represent one potential therapeutic strategy to treat CF.Specifically, CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is ...

Pharmaceutical Compositions and Administrations Thereof

The present invention relates to pharmaceutical compositions comprising a compound of Formula I in combination with one or both of a Compound of Formula II and/or a Compound of Formula III. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis. 2. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and a Compound of Formula II.3. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and a Compound of Formula III.4. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I claim 1 , a Compound of Formula II and a Compound of Formula III.98. A method of treating a CFTR mediated disease in a human comprising administering to the human an effective amount of a pharmaceutical composition according to any one of -.10. The method of claim 9 , wherein the CFTR mediated disease is selected from cystic fibrosis claim 9 , asthma claim 9 , smoke induced COPD claim 9 , chronic bronchitis claim 9 , rhinosinusitis claim 9 , constipation claim 9 , pancreatitis claim 9 , pancreatic insufficiency claim 9 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 9 , mild pulmonary disease claim 9 , idiopathic pancreatitis claim 9 , allergic bronchopulmonary aspergillosis (ABPA) claim 9 , liver disease claim 9 , hereditary emphysema claim 9 , hereditary hemochromatosis claim 9 , coagulation-fibrinolysis deficiencies claim 9 , such as protein C deficiency claim 9 , Type 1 hereditary angioedema claim 9 , lipid processing deficiencies claim 9 , such as familial hypercholesterolemia claim 9 , Type 1 chylomicronemia claim 9 , abetalipoproteinemia claim 9 , lysosomal storage diseases claim 9 , such as I-cell disease/pseudo-Hurler claim 9 , mucopolysaccharidoses claim 9 , Sandhof/Tay-Sachs claim 9 , Crigler-Najjar type II claim 9 , ...

Pharmaceutical Compositions and Administrations Thereof

The present invention relates to pharmaceutical compositions comprising a compound of Formulas I and II, optionally in combination with a Compound of Formula III and/or a Compound of Formula IV. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis. 2. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and Compound of Formula II.5. The pharmaceutical composition of claim 4 , comprising Compound 1 claim 4 , Compound 2 claim 4 , and Compound 3.6. The pharmaceutical composition of claim 1 , comprising Compound 1 claim 1 , Compound 2 claim 1 , and Compound 4.7. The pharmaceutical composition of claim 4 , comprising Compound 1 claim 4 , Compound 2 claim 4 , Compound 3 and Compound 4.9. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is any of the embodiments listed in Column C of Table I.10. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is any of the embodiments listed in Column D of Table I.11. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , the third component is any of the embodiments listed in Column C of Table I claim 8 , and the fourth Component is any of the embodiments listed in Column D of Table I.12. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is Compound 3.13. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component ...

PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

The invention provides a process for the preparation of a compound of Formula 1, 2. The process of claim 1 , wherein Ris independently —OC(O)OR′ claim 1 , —OC(O)NHR′ claim 1 , or —OC(O)N(R′) claim 1 , wherein R′ is not hydrogen.3. The process of claim 2 , further comprising cleaving the —OC(O)OR′ claim 2 , —OC(O)NHR′ claim 2 , or —OC(O)N(R′)to form —OH.4. The process of claim 3 , wherein the cleavage is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 3 , KOH or sodium methoxide.5. The process of claim 4 , wherein the alcoholic solvent is methanol.6. The process of claim 1 , wherein at least one of Ror Ris independently a Cstraight or branched alkyl which is substituted with —COOR′ or —CON(R′) claim 1 , wherein R′ is not hydrogen.7. The process of claim 6 , further comprising hydrolyzing each —COOR′ claim 6 , or —CON(R′)to form —COOH.8. The process of claim 7 , wherein the hydrolysis is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 7 , KOH or sodium methoxide.9. The process of claim 8 , wherein the alcoholic solvent is methanol.10. The process of claim 6 , wherein Ris independently —OC(O)OR′ claim 6 , —OC(O)NHR′ claim 6 , or —OC(O)N(R′) claim 6 , wherein R′ is not hydrogen.11. The process of claim 10 , further comprising cleaving the —OC(O)OR′ claim 10 , —OC(O)NHR′ claim 10 , or —OC(O)N(R′)to form —OH.12. The process of claim 11 , wherein the cleavage is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 11 , KOH or sodium methoxide.13. The process of claim 12 , wherein the alcoholic solvent is methanol.1413. The process of any of - claims 1 , wherein the coupling is performed in the presence of a base.15. The process of claim 14 , wherein the base is KCO claim 14 , EtN claim 14 , NMM claim 14 , pyridine or DIEA.1615. The process of any of - claims 1 , wherein the coupling is performed in the presence of a ...

PHARMACEUTICAL COMPOSITION AND ADMINISTRATIONS THEREOF

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention. 1111-. (canceled)112. A pharmaceutical tablet comprising 34.1% of a solid dispersion by weight of the tablet , wherein the solid dispersion comprises 80% of a mixture of amorphous N-[2 ,4-Bis(1 ,1-dimethylethyl)-5-hydroxyphenyl]-1 ,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) and less than 15% crystalline Compound 1 by weight of the dispersion , 19.5% of HPMCAS by weight of the dispersion , and 0.5% SLS by weight of the dispersion.113. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises 30.5% of microcrystalline cellulose by weight of the tablet.114. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises 30.4% of lactose by weight of the tablet.115. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises 3% of sodium croscarmellose by weight of the tablet.116. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises 0.5% of SLS by weight of the tablet.117. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises 0.5% of colloidal silicon dioxide by weight of the tablet.118. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises 1.0% of magnesium stearate by weight of the tablet.119. The pharmaceutical tablet of claim 112 , wherein the tablet further comprises a coating.120. The pharmaceutical tablet of claim 112 , wherein the tablet has a hardness of 98 N (10 kp)±20 percent.121. The pharmaceutical tablet of claim 112 , wherein the tablet contains 150 mg of Compound 1.122. The pharmaceutical tablet of claim 112 , wherein the tablet contains 100 mg of Compound 1.123. A method of treating ...

PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

The invention provides a process for the preparation of a compound of Formula 1, 158-. (canceled)60. A compound of Formula 3 , or a pharmaceutically acceptable salt thereof.61. A compound of Formula 4 , or a pharmaceutically acceptable salt thereof. This application claims priority to three U.S. Provisional Applications having Ser. No. 61/162,148, filed on Mar. 20, 2009; 61/246,303, filed on Sep. 28, 2009; and 61/248,565, filed on Oct. 5, 2009. Each of the foregoing Provisional applications are hereby incorporated by reference in their entirety.The present invention relates to a process for making modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”).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.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 drugs, known as potentiators that increase the probability of CFTR channel opening represent one potential therapeutic strategy to treat CF.Specifically, CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are ...

Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

This invention relates to a compound of Formula I: 19-. (canceled)16. The method according to claim 13 , wherein said disease is cystic fibrosis.1721-. (canceled)22. The method according to claim 13 , wherein said disease is selected from cystic fibrosis claim 13 , COPD claim 13 , smoke induced COPD claim 13 , hereditary emphysema claim 13 , pancreatitis claim 13 , pancreatic insufficiency claim 13 , and dry-eye disease. This application is a divisional application of U.S. Ser. No. 13/237,303, filed on Sep. 20, 2011, now U.S. Pat. No. 8,614,325, issued Dec. 24, 2013, which is a continuation of PCT Application No. PCT/US2010/028062 filed Mar. 19, 2010, which claims the priority of U.S. Application No. 61/162,130 filed Mar. 20, 2009. The entire contents of each of the aforementioned applications are incorporated herein by reference in their entirety.The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.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.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 drugs, known as potentiators that increase the probability of CFTR channel opening represent one potential therapeutic strategy to treat CF.Specifically, CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion ...

Pharmaceutical Compositions and Administrations Thereof

The present invention relates to pharmaceutical compositions comprising a compound of Formula I in combination with one or both of a Compound of Formula II and/or a Compound of Formula III. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis. 2. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and a Compound of Formula II.3. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and a Compound of Formula III.4. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I claim 1 , a Compound of Formula II and a Compound of Formula III.98. A method of treating a CFTR mediated disease in a human comprising administering to the human an effective amount of a pharmaceutical composition according to any one of -.10. The method of claim 9 , wherein the CFTR mediated disease is selected from cystic fibrosis claim 9 , asthma claim 9 , smoke induced COPD claim 9 , chronic bronchitis claim 9 , rhinosinusitis claim 9 , constipation claim 9 , pancreatitis claim 9 , pancreatic insufficiency claim 9 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 9 , mild pulmonary disease claim 9 , idiopathic pancreatitis claim 9 , allergic bronchopulmonary aspergillosis (ABPA) claim 9 , liver disease claim 9 , hereditary emphysema claim 9 , hereditary hemochromatosis claim 9 , coagulation-fibrinolysis deficiencies claim 9 , such as protein C deficiency claim 9 , Type 1 hereditary angioedema claim 9 , lipid processing deficiencies claim 9 , such as familial hypercholesterolemia claim 9 , Type 1 chylomicronemia claim 9 , abetalipoproteinemia claim 9 , lysosomal storage diseases claim 9 , such as I-cell disease/pseudo-Hurler claim 9 , mucopolysaccharidoses claim 9 , Sandhof/Tay-Sachs claim 9 , Crigler-Najjar type II claim 9 , ...

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATIONS THEREOF

The present invention relates to pharmaceutical compositions comprising a compound of Formulas I and II, optionally in combination with a Compound of Formula III and/or a Compound of Formula IV. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis. 2. The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and Compound of Formula II.5. The pharmaceutical composition of claim 4 , comprising Compound 1 claim 4 , Compound 2 claim 4 , and Compound 3.6. The pharmaceutical composition of claim 1 , comprising Compound 1 claim 1 , Compound 2 claim 1 , and Compound 4.7. The pharmaceutical composition of claim 4 , comprising Compound 1 claim 4 , Compound 2 claim 4 , Compound 3 and Compound 4.9. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is any of the embodiments listed in Column C of Table I.10. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is any of the embodiments listed in Column D of Table I.11. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , the third component is any of the embodiments listed in Column C of Table I claim 8 , and the fourth Component is any of the embodiments listed in Column D of Table I.12. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component is Compound 3.13. The pharmaceutical composition of claim 8 , wherein the Column A component is Compound 1 claim 8 , the Column B Component is Compound 2 claim 8 , and the third Component ...

PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

The invention provides a process for the preparation of a compound of Formula 1,

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

This invention relates to a compound of Formula I: 2. A compound according to claim 1 , wherein R is CHOH.3. A compound according to claim 1 , wherein R is COOH.6. A pharmaceutical composition comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'a compound of Formula I, according to ; and'}a pharmaceutically acceptable carrier or adjuvant.98. The pharmaceutical composition of any of - claims 6 , further comprising an additional agent selected from a mucolytic agent claims 6 , a bronchodilator claims 6 , an antibiotic claims 6 , an anti-invective agent claims 6 , an anti-inflammatory agent claims 6 , a CFTR modulator claims 6 , or a nutritional agent.10. A method of modulating CFTR activity in a biological sample comprising the step of contacting said biological sample with a compound of Formula I according to .13. A method of treating or lessening the severity of a disease in a patient comprising administering to said patient an effective amount of a compound of Formula I according to claim 1 , wherein said disease is selected from cystic fibrosis claim 1 , asthma claim 1 , smoke induced COPD claim 1 , chronic bronchitis claim 1 , rhinosinusitis claim 1 , constipation claim 1 , pancreatitis claim 1 , pancreatic insufficiency claim 1 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 1 , mild pulmonary disease claim 1 , idiopathic pancreatitis claim 1 , allergic bronchopulmonary aspergillosis (ABPA) claim 1 , liver disease claim 1 , hereditary emphysema claim 1 , hereditary hemochromatosis claim 1 , coagulation-fibrinolysis deficiencies claim 1 , such as protein C deficiency claim 1 , Type 1 hereditary angioedema claim 1 , lipid processing deficiencies claim 1 , such as familial hypercholesterolemia claim 1 , Type 1 chylomicronemia claim 1 , abetalipoproteinemia claim 1 , lysosomal storage diseases claim 1 , such as I-cell disease/pseudo-Hurler claim 1 , mucopolysaccharidoses claim 1 , Sandhof/Tay-Sachs claim 1 , ...

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

This invention relates to a compound of Formula I: 2. A compound according to claim 1 , wherein R is CHOH.3. A compound according to claim 1 , wherein R is COOH.4. (canceled)5. (canceled)6. A pharmaceutical composition comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'i. a compound of Formula I according to or a pharmaceutically acceptable salt thereof; and'}ii. a pharmaceutically acceptable carrier or adjuvant.9. The pharmaceutical composition according to claim 6 , further comprising an additional agent selected from a mucolytic agent claim 6 , a bronchodilator claim 6 , an antibiotic claim 6 , an anti-invective agent claim 6 , an anti-inflammatory agent claim 6 , a CFTR modulator claim 6 , or a nutritional agent.10. A method of modulating CFTR activity in a biological sample comprising the step of contacting said biological sample with a compound of Formula I according to or a pharmaceutically acceptable salt thereof.13. A method of treating or lessening the severity of a disease in a patient comprising administering to said patient an effective amount of a compound of Formula I according to or a pharmaceutically acceptable salt thereof claim 1 , wherein said disease is selected from cystic fibrosis claim 1 , asthma claim 1 , smoke induced COPD claim 1 , chronic bronchitis claim 1 , rhinosinusitis claim 1 , constipation claim 1 , pancreatitis claim 1 , pancreatic insufficiency claim 1 , male infertility caused by congenital bilateral absence of the vas deferens (CBAVD) claim 1 , mild pulmonary disease claim 1 , idiopathic pancreatitis claim 1 , allergic bronchopulmonary aspergillosis (ABPA) claim 1 , liver disease claim 1 , hereditary emphysema claim 1 , hereditary hemochromatosis claim 1 , coagulation-fibrinolysis deficiencies claim 1 , such as protein C deficiency claim 1 , Type 1 hereditary angioedema claim 1 , lipid processing deficiencies claim 1 , such as familial hypercholesterolemia claim 1 , Type 1 chylomicronemia claim 1 , ...

PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

The invention provides a process for the preparation of a compound of Formula 1, 158-. (canceled)60. The process of claim 59 , wherein PG is propoxy formyl claim 59 , methanesulfonyl claim 59 , 4-nitro-benzoyl claim 59 , ethoxy formyl claim 59 , butoxy formyl claim 59 , t-butoxy formyl claim 59 , i-propoxy formyl or methoxy formyl.61. The process of claim 60 , wherein PG is methoxy formyl.63. The process of claim 62 , wherein the solvent is diethyl ether claim 62 , or methylene chloride.64. The process of claim 63 , wherein the solvent is methylene chloride.67. The process of claim 66 , wherein the reaction is quenched by adding the reaction mixture to cold water.68. The process of claim 66 , wherein the aqueous layer is extracted with dichloromethane.69. The process of claim 68 , wherein the dichloromethane is further washed with water.70. The process of claim 66 , wherein the product is isolated by crystallization with hexane. This application is a continuation of PCT Application No. PCT/US2010/028069 filed Mar. 19, 2010, which claims the priority of U.S. Application No. 61/162,148 filed Mar. 20, 2009; U.S. Application No. 61/246,303 filed Sep. 28, 2009; and U.S. Application No. 61/248,565 filed Oct. 5, 2009, which are hereby incorporated by reference in their entirety.The present invention relates to a process for making modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”).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.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 drugs, known as potentiators that increase the probability of CFTR channel ...

PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

The invention provides a process for the preparation of a compound of Formula 1, 2. The process of claim 1 , wherein Ris independently —OC(O)OR′ claim 1 , —OC(O)NHR′ claim 1 , or —OC(O)N(R′) claim 1 , wherein R′ is not hydrogen.3. The process of claim 2 , further comprising cleaving the —OC(O)OR′ claim 2 , —OC(O)NHR′ claim 2 , or —OC(O)N(R′)to form —OH.4. The process of claim 3 , wherein the cleavage is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 3 , KOH or sodium methoxide.5. The process of claim 4 , wherein the alcoholic solvent is methanol.6. The process of claim 1 , wherein at least one of Ror Ris independently a Cstraight or branched alkyl which is substituted with —COOR′ or —CON(R′) claim 1 , wherein R′ is not hydrogen.7. The process of claim 6 , further comprising hydrolyzing each —COOR′ claim 6 , or —CON(R′)to form —COOH.8. The process of claim 7 , wherein the hydrolysis is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 7 , KOH or sodium methoxide.9. The process of claim 8 , wherein the alcoholic solvent is methanol.10. The process of claim 6 , wherein Ris independently —OC(O)OR′ claim 6 , —OC(O)NHR′ claim 6 , or —OC(O)N(R′) claim 6 , wherein R′ is not hydrogen.11. The process of claim 10 , further comprising cleaving the —OC(O)OR′ claim 10 , —OC(O)NHR′ claim 10 , or —OC(O)N(R′)to form —OH.12. The process of claim 11 , wherein the cleavage is performed by treating a compound of Formula 1 with an alcoholic solvent in the presence of NaOH claim 11 , KOH or sodium methoxide.13. The process of claim 12 , wherein the alcoholic solvent is methanol.1413. The process of any of - claims 1 , wherein the coupling is performed in the presence of a base.15. The process of claim 14 , wherein the base is KCO claim 14 , EtN claim 14 , NMM claim 14 , pyridine or DIEA.1615. The process of any of - claims 1 , wherein the coupling is performed in the presence of a ...

PROCESS FOR MAKING MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

The invention provides a process for the preparation of a compound of Formula 1,

cystic fibrosis transmembrane conductance regulator modulators

Process for making modulators of cystic fibrosis transmembrane conductance regulator

Pharmaceutical composition and administrations thereof.

La presente invención se relaciona con composiciones farmacéuticas que comprenden una dispersión sólida de N-[2,4-Bis(1,1-dimetiletil)-5-hidroxifenil]-1,4-dihidro-4-oxoquin olina-3-carboxamida, los métodos para elaborar las composiciones farmacéuticas de la presente invención, y los métodos para administrar las composiciones farmacéuticas de la presente invención.

Pharmaceutical compositions and administrations thereof

The present invention relates to pharmaceutical compositions comprising a compound of Formula I in combination with one or both of a Compound of Formula II and/or a Compound of Formula III. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis.(Formula I), (Formula II), (Formula III).

Process for making modulators of cystic fibrosis transmembrane conductance regulator

The invention provides processes for the preparation of compounds of the Formula 2, the Formula 40 and the Formula 43: Compounds of the Formula 2, the Formula 40 and the Formula 43 may be used in a process for the preparation of a compound of Formula 1: (see above formula)

Process for Making Modulators of Cystic Fibrosis Transmembrane Conductance Regulator

The invention provides a process for the preparation of a compound of Formula 1, N H (Rx-X H R2 Formula 1 comprising coupling a carboxylic acid of Formula 2 (Rx-X OH Formula 2 with an aniline of Formula 3 Formula 3 in the presence of a coupling agent.

Modulators of cystic fibrosis transmembrane conductance regulator

N- [2,4-DIS (1,1-DIMETHYLETHYL) -5-HYDROXYPHENYL] -1,4-DIHYDRO-4-OXOKINOLINO-3-CARBOXAMIDE TABLE FOR USE FOR USE

Η παρούσα εφεύρεση αφορά σε φαρμακευτικές συνθέσεις που περιλαμβάνουν διασπορά στερεού του Ν-[2,4-Δις(1,1-διμεθυλαιθυλ)-5-υδροξυφαινυλ]-1,4-διυδρο-4-οξοκινολινο-3 καρβοξαμιδίου, μεθόδους βιομηχανικής κατασκευής φαρμακευτικών συνθέσεων της παρούσας εφεύρεσης και μεθόδους χορήγησης φαρμακευτικών συνθέσεων της παρούσας εφεύρεσης. The present invention relates to pharmaceutical compositions comprising a solid dispersion of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide solid, methods for the manufacture of pharmaceuticals compositions of the present invention and methods of administering pharmaceutical compositions of the present invention.

Modulators of cystic fibrosis transmembrane conductance regulator.

La presente invención se relaciona con moduladores del regulador de conductancia transmembrana de fibrosis quística ("CFTR"), las composiciones de los mismos, y los métodos con los mismos. La presente invención también se relaciona con los métodos para tratar enfermedades utilizando los moduladores del CFTR (1); o las sales farmacéuticamente aceptables de los mismos, en donde: el anillo A se selecciona de:.

Tablet formulation of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide for use in the the treatment of cystic fibrosis

Modulators of cystic fibrosis transmembrane conductance regulator

Pharmaceutical composition and administrations thereof

Pharmaceutical composition and administrations thereof

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention.

Pharmaceutical compositions comprising cftr modulators and administrations thereof

Disclosed is a pharmaceutical composition comprising one of the following combinations: a) Compound 1 and Compound 2 Form I; b) Compound 1 Form A and Compound 2 Form I; c) Compound 1 Form A and Compound 2 Tablet Formulation; d) Compound 1 Form A-HCl and Compound 2 Form I; e) Compound 1 Form B-HCl and Compound 2 Form I; f) Compound 1 Form B, and Compound 2 Form I; g) Compound 1 Form A-HCl and Compound 2 Tablet Formulation; h) Compound 1 Form B-HCl and Compound 2 Tablet Formulation; and i) Compound 1 Form B, and Compound 2 Tablet Formulation, wherein Compound 1 is N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide; Compound 2 is lumacaftor (VX-809 / 3-{ 6-{ [1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino} -3-methylpyridin-2-yl} benzoic acid); Compound 1 Form A is characterized by a peak at about 7.9 degrees and a peak at about 11.9 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation; Compound 1 Form A-HCl is characterized by a peak at about 7.1 degrees, a peak at about 8.2 degrees, a peak at about 14.1 degrees, and a peak at about 21.2 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation; Compound 1 Form B-HCl is characterized by a peak at about 8.3 degrees, a peak at about 9.0 degrees, a peak at about 13.0 degrees, a peak at about 18.0 degrees, and a peak at about 23.0 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation; Compound 1 Form B is characterized by a peak at about 6.7 degrees, a peak at about 10.0 degrees, a peak at about 11.2 degrees, a peak at about 13.4 degrees, a peak at about 24.2 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation; Compound 2 Form I is characterized by the following peaks in an X-ray powder diffraction obtained using Cu K alpha radiation: a peak at 15.4 degrees, a peak at 16.3 degrees, and a peak at 14.5 degrees; and Compound 2 Tablet Formulation ...

Methods and materials for identifying inhibitors of molecular interactions mediated by sh3 domains

This disclosure concerns materials and methods for identifying inhibitors of molecular interactions mediated by SH3 domains, and for compositions and uses relating to such inhibitors.

Pharmaceutical composition comprising a solid dispersion of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N- [2,4-Bis( 1, 1-dimethylethyl)-5 -hydroxyphenyl]- 1,4-dihydro-4-oxoquinoline-3-carboxamide, and a polymer, wherein Compound 1 is present in an amount of about 80% by weight of the solid dispersion.

solid forms of n- (4- (7-azabicyclo [2.2.1] heptan-7-yl) -2- (trifluoromethyl) phenyl) -4-oxo-5- (trifluoromethyl) -1,4-di -hydroquinoline-3-carboxamide

Biomarkers for monitoring inhibition of impdh pathway

The present invention is directed to biomarkers useful for monitoring the effects of inhibition of IMPDH in a patient. Methods and compositions of using the same are described.

Modulators of cystic fibrosis transmembrane conductance regulator

This invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R is COOH or CH 2 OH.

Process for making modulators of cystic fibrosis transmembrane conductance regulator

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.

Solid forms of n-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide

The present invention relates to solid state forms, for example, crystalline forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, pharmaceutical compositions thereof, and methods therewith.

PHARMACEUTICAL COMPOSITION AND SUBMISSIONS THEREOF

Biomarkers for monitoring inhibition of IMPDH pathway

Modulators of cystic fibrosis transmembrane conductance regulator

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

Piperazine and piperidine derivatives for treatment of neurological diseases

The present invention relates to piperazine and piperidine derivatives, which are especially useful for treating or preventing neuronal damage, particularly damage associated with neurological diseases. These compounds are also useful for stimulating nerve growth. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage of for stimulating nerve growth.

Modulators of cystic fibrosis transmembrane conductance regulator

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator ("CFTR"), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR. (1); or pharmaceutically acceptable salts thereof, wherein: ring A is selected from:

Pharmaceutical composition of n-(2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide and administration thereof

The present invention relates to pharmaceutical compositions comprising a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, methods of manufacturing pharmaceutical compositions of the present invention, and methods of administering pharmaceutical compositions of the present invention.

Modulators of the cholesterol biosynthetic pathway

The present invention relates to methods for modulating the cholesterol biosynthetic pathway. The level of cholesterol in the body is linked to numerous pathological states. The methods fo the present invention alter the transcription levels of genes involved in the cholesterol biosynthesis. The methods of the present invention can used for treating diseases mediated by the cholesterol biosynthetic pathway.

PROCEDURE FOR MANUFACTURING MODULATORS OF CFTR REGULATOR

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.

Piperazine and piperidine derivatives for treatment of neurological diseases

Solid forms of n- (4- (7-azabicyclo [2.2.1] heptan-7-yl) -2- (trifluoromethyl) phenyl) -3-oxo-5- (trifluoromethyl) -1,4-dihydroquinoline-3 carboxamide

Hepatitis c virus infection biomarkers

A signature set of genes associated with hepatitis C virus infection is described. Figure 1 depicts a line graph demonstrating median HCV RNA levels (y axis) over time (x axis) in HCV infected patients after treatment with VX-950 or a placebo control.

Process for making modulators of cystic fibrosis transmembrane conductance regulator

Process for making modulators of cystic fibrosis transmembrane conductance regulator

Process for making modulators of cystic fibrosis transmembrane conductance regulator

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.

Piperazine and piperidine derivatives for treatment of neurological diseases

Hepatitis c virus infection biomarkers

A signature set of genes associated with hepatitis C virus infection is described. Figure 1 depicts a line graph demonstrating median HCV RNA levels (y axis) over time (x axis) in HCV infected patients after treatment with VX-950 or a placebo control.

Modulators of cystic fibrosis transmembrane conductance regulator

Piperazin und piperadin-derivate fur die behandlung von neurologischen krankheiten

Quantification and site-specific profiling of protein phosphorylation

The invention provides methods and compositions for analyzing modification-mediated signaling pathways.

Φαρμακευτικη συνθεση και χορηγησεις αυτης

Η παρούσα εφεύρεση αφορά σε φαρμακευτικές συνθέσεις που περιλαμβάνουν στερεά διασπορά Ν-[2,4-δις(1,1-διμεθυλαιθυλ)-5-υδροξυφαινυλ]-1,4-διυδρο-4- οξοκινολίνο-3-καρβοξαμιδίου, μεθόδους παραγωγής φαρμακευτικών συνθέσεων της παρούσας εφεύρεσης και μεθόδους χορήγησης φαρμακευτικών συνθέσεων της παρούσας εφεύρεσης.

Quantification and site-specific profiling of protein phosphorylation

The invention provides methods and compositions for analyzing modification-mediated signaling pathways.

Tablet formulation of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide for use in the treatment of cystic fibrosis

N-[2,4-bis(1,1-dimetyylietyyli)-5-hydroksifenyyli]-1,4-dihydro-4-oksokinoliini-3-karboksamidin tablettiformulaatio käytettäväksi kystisen fibroosin hoitamisessa

Tabletformulering af N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinolin-3-carboxamid til anvendelse til behandling af cystisk fibrose

Process for making modulators of cystic fibrosis transmembrane conductance regulator

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.

Formulacija tablete N-(2,4-bis(1,1-dimetiletil)-5-hidroksifenil)-1,4-dihidro-4-oksokinolin -3-karboksamida za uporabo v zdravljenju cistične fibroze