US20110064811A1 - Solid forms of N-[2,4-BIS(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide - Google Patents

Solid forms of N-[2,4-BIS(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide Download PDF

Info

Publication number
US20110064811A1
US20110064811A1 US11/647,505 US64750506A US2011064811A1 US 20110064811 A1 US20110064811 A1 US 20110064811A1 US 64750506 A US64750506 A US 64750506A US 2011064811 A1 US2011064811 A1 US 2011064811A1
Authority
US
United States
Prior art keywords
oxoquinoline
dimethylethyl
hydroxyphenyl
dihydro
bis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/647,505
Other languages
English (en)
Inventor
Patricia Hurter
William Rowe
Christopher R. Young
Adriana Costache
Patrick R. Connelly
Mariusz Krawiec
Yuchuan Gong
Yushi Feng
Martin Trudeau
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vertex Pharmaceuticals Inc
Original Assignee
Vertex Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=38228833&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20110064811(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to US11/647,505 priority Critical patent/US20110064811A1/en
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Assigned to VERTEX PHARMACEUTICALS INCORPORATED reassignment VERTEX PHARMACEUTICALS INCORPORATED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GONG, YUCHUAN, CONNELLY, PATRICK R., COSTACHE, ADRIANA, FENG, YUSHI, KRAWIEC, MARIUSZ, YOUNG, CHRISTOPHER R., HURTER, PATRICIA, ROWE, WILLIAM, TRUDEAU, MARTIN
Publication of US20110064811A1 publication Critical patent/US20110064811A1/en
Priority to US13/358,778 priority patent/US8410274B2/en
Priority to US13/785,692 priority patent/US8754224B2/en
Priority to US14/272,692 priority patent/US9139530B2/en
Priority to US14/852,892 priority patent/US9670163B2/en
Assigned to VERTEX PHARMACEUTICALS INCORPORATED reassignment VERTEX PHARMACEUTICALS INCORPORATED ASSIGNEE CHANGE OF ADDRESS Assignors: VERTEX PHARMACEUTICALS INCORPORATED
Priority to US15/584,324 priority patent/US9931334B2/en
Priority to US15/900,147 priority patent/US10537565B2/en
Priority to US16/704,713 priority patent/US11291662B2/en
Priority to US17/953,412 priority patent/US20230263794A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]

Definitions

  • the present invention relates to solid state forms, for example, crystalline and amorphous forms, of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, pharmaceutical compositions thereof, and methods therewith.
  • 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 linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
  • CFTR cystic fibrosis
  • a defect in this gene causes mutations in CFTR resulting in cystic fibrosis (“CF”), the most common fatal genetic disease in humans. Cystic fibrosis affects approximately one in every 2,500 infants in the United States. Within the general United States population, up to 10 million people carry a single copy of the defective gene without apparent ill effects. In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.
  • CF cystic fibrosis
  • CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport.
  • anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients.
  • CF patients In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death.
  • the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis.
  • individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea—perhaps explaining the relatively high frequency of the CF gene within the population.
  • the most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as ⁇ F508-CFTR. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease.
  • deletion of residue 508 in ⁇ F508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727).
  • CFTR transports a variety of molecules in addition to anions
  • this role represents one element in an important mechanism of transporting ions and water across the epithelium.
  • the other elements include the epithelial Na + channel, ENaC, Na + /2CL ⁇ /K + co-transporter, Na + —K + -ATPase pump and the basolateral membrane K + channels, that are responsible for the uptake of chloride into the cell.
  • Chloride absorption takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na + —K + -ATPase pump and Cl-channels expressed on the basolateral surface of the cell.
  • Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl ⁇ channels, resulting in a vectorial transport.
  • COPD chronic obstructive pulmonary disease
  • COPD dry eye disease
  • Sjögren's Syndrome a chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • CFTR dry eye disease
  • Sjögren's Syndrome a chronic obstructive pulmonary disease
  • COPD is characterized by airflow limitation that is progressive and not fully reversible. The airflow limitation is due to mucus hypersecretion, emphysema, and bronchiolitis.
  • Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD.
  • CFTR Dry eye disease
  • tear aqueous production and abnormal tear film lipid, protein and mucin profiles There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies, and diseases, such as cystic fibrosis and Sjögrens's syndrome.
  • Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration.
  • Sjögrens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis. Defective protein trafficking is believed to cause the disease, for which treatment options are limited. Modulators of CFTR activity may hydrate the various organs afflicted by the disease and help to elevate the associated symptoms.
  • the diseases associated with the first class of ER malfunction are cystic fibrosis (due to misfolded ⁇ F508-CFTR as discussed above), hereditary emphysema (due to a1-antitrypsin; non Piz variants), hereditary hemochromatosis, hoagulation-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 (due to lysosomal processing enzymes), Sandhof/Tay-Sachs (due to ⁇ -hexosaminidase), Crigler-Najjar type II (due to UDP-glucuronyl-sialyc-transferase),
  • Glycanosis CDG type 1 hereditary emphysema (due to ⁇ 1-Antitrypsin (PiZ variant), congenital hyperthyroidism, osteogenesis imperfecta (due to Type I, II, IV procollagen), hereditary hypofibrinogenemia (due to fibrinogen), ACT deficiency (due to ⁇ 1-antichymotrypsin), Diabetes insipidus (DI), neurophyseal DI (due to vasopvessin hormone/V2-receptor), neprogenic DI (due to aquaporin II), Charcot-Marie Tooth syndrome (due to peripheral myelin protein 22), Perlizaeus-Meabacher disease, neurodegenerative diseases such as Alzheimer's disease (due to ⁇ APP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's
  • CFTR modulators may be beneficial for the treatment of secretory diarrheas, in which epithelial water transport is dramatically increased as a result of secretagogue activated chloride transport.
  • the mechanism involves elevation of cAMP and stimulation of CFTR.
  • Diarrhea is both a significant factor in malnutrition and the leading cause of death (5,000,000 deaths/year) in children less than five years old.
  • Diarrhea in barn animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs, also known as scours, is a major cause of death in these animals. Diarrhea can result from any major transition, such as weaning or physical movement, as well as in response to a variety of bacterial or viral infections and generally occurs within the first few hours of the animal's life.
  • ETEC enterotoxogenic E. coli
  • Common viral causes of diarrhea include rotavirus and coronavirus.
  • Other infectious agents include cryptosporidium, giardia lamblia , and salmonella , among others.
  • Symptoms of rotaviral infection include excretion of watery feces, dehydration and weakness. Coronavirus causes a more severe illness in the newborn animals, and has a higher mortality rate than rotaviral infection. Often, however, a young animal may be infected with more than one virus or with a combination of viral and bacterial microorganisms at one time. This dramatically increases the severity of the disease.
  • Compound 1 N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (hereinafter “Compound 1”) which has the structure below:
  • Compound 1 is known as both N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
  • the invention features solid amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
  • the solid amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide comprises less than about 15% crystalline N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
  • the invention features a preparation of amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide substantially free of crystalline N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
  • the preparation comprises a solid dispersion, a mixture or a liquid dispersion.
  • the preparation comprises solid particles.
  • the amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide has a particle size distribution of DI 0, less than 5 ⁇ m.
  • the amporphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide have a particle size distribution of D50, less than 17 ⁇ m.
  • the amporphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide have a particle size distribution of D90, less than 100 ⁇ m.
  • the solid dispersion further comprises a surfactant, polymer, or inert pharmaceutically acceptable substance.
  • the solid dispersion comprises a polymer, and the polymer is one or more than one water-soluble polymer or partially water-soluble polymer.
  • the solid dispersion has a higher glass transition temperature than the glass transition temperature of neat amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
  • the polymer is hydroxypropylmethylcellulose (HPMC). In some embodiments, the polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS). In some embodiments, the polymer is vinylpyrrolidone/vinyl acetate copolymer (PVP/VA). In some embodiments, the polymer is present in an amount of from about 10% by weight to about 80% by weight, for example, the polymer is present in an amount of less than about 70% by weight, the polymer is present in an amount of about 50% by weight, or the polymer is present in an amount of about 49.5% by weight.
  • HPMC hydroxypropylmethylcellulose
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • PVP/VA vinylpyrrolidone/vinyl acetate copolymer
  • the polymer is present in an amount of from about 10% by weight to about 80% by weight, for example, the polymer is present in an amount of less than about 70% by weight, the polymer is present in an amount of about 50% by
  • the N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is present in an amount of from about 10% by weight to about 80% by weight, for example, the N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is present in an amount of less than about 70% by weight or the N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is present in an amount of about 50% by weight.
  • At least about 80% by weight of the N N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is in an amorphous form. In some embodiments, substantially all the N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is in an amorphous form.
  • the solid dispersion is obtained by spray drying.
  • the invention features a pharmaceutical composition comprising amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
  • the amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is substantially free of crystalline N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
  • the invention features, a pharmaceutical composition
  • a pharmaceutical composition comprising an amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide as a solid dispersion and one or more of a surfactant, polymer, inert pharmaceutically acceptable substance, or pharmaceutically acceptable carrier.
  • the solid dispersion comprises a polymer and wherein the polymer is one or more than one water-soluble polymer or partially water-soluble polymer.
  • the solid dispersion has a higher glass transition temperature than the glass transition temperature of neat amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
  • the polymer is HPMC. In some embodiments, the polymer is HPMCAS. In some embodiments, the polymer is PVP/VA.
  • the invention features a pharmaceutical composition
  • a pharmaceutical composition comprising: an amorphous solid dispersion of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide wherein said N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide comprises about 30-75% wt/wt of the pharmaceutical composition, one or more polymer selected from the group of HPMC and HPMCAS, wherein said polymer is comprises about 30-75% wt/wt of the pharmaceutical composition, and a surfactant, wherein said surfactant comprises about 0.25-1% wt/wt of the pharmaceutical composition.
  • the polymer is HPMCAS. In some embodiments, the polymer is HPMC.
  • the surfactant is sodium laurel sulfate.
  • said N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide comprises about 50% wt/wt of the pharmaceutical composition
  • said polymer is HPMCAS and comprises about 49.5% wt/wt of the pharmaceutical composition
  • a said surfactant is sodium laurel sulfate and comprises about 0.5% wt/wt of the pharmaceutical composition.
  • the invention features a pharmaceutical composition comprising;
  • an aqueous suspension comprising amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide particles and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is a polymer in solution selected from the group of HPMC and HPMCAS. In some embodiments, the pharmaceutically acceptable carrier is a polymer in solution is PVP/VA.
  • the amorphous compound is in the form of a solid dispersion.
  • the pharmaceutical composition further comprises a surfactant, either in the solution or as a component of the solid dispersion, for example, SLS.
  • the polymer is either in the solution or as a component of the solid dispersion particles or both.
  • the aqueous suspension comprises from about 0.1% to about 20% by weight of the surfactant. In some embodiments, the aqueous suspension comprises from about 0.1% to about 2.0% by weight of polymer, for example, about 1% by weight of polymer.
  • the invention features a process for preparing an amorphous form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide comprising spray-drying N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide to provide an amorphous form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
  • the method comprises combining N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and a suitable solvent to form a mixture and then spray-drying the mixture to obtain the amorphous form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
  • the mixture is a solution N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and the suitable solvent.
  • the suitable solvent comprises acetone or MEK.
  • the suitable solvent comprises a mixture of solvents, for example, a mixture of acetone and water or a mixture of MEK and water.
  • the water in the solvent mixture is present at about 10% wt.
  • the method comprises a) forming a mixture comprising N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, a polymer, and a solvent; and b) spray-drying the mixture to form a solid dispersion comprising N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
  • the mixture comprises a solution of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, the polymer, and the solvent.
  • the polymer is selected from HPMC and HPMCAS.
  • the polymer is PVP/VA.
  • the polymer is present in an amount of from about 30% to about 70% by weight in the solid dispersion.
  • the mixture further comprises a surfactant, for example, SLS.
  • the solvent comprises acetone, for example, a mixture of acetone and water. In some embodiments, the solvent comprises from about 0% to about 20% water and from about 70% to about 100% acetone.
  • the invention features a solid dispersion prepared according a process described herein.
  • the invention features a method for treating a CFTR-mediated disease in a mammal comprising administering amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
  • the method comprises administering an amorphous solid dispersion of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
  • the method comprises administering an additional therapeutic agent.
  • the invention features a pharmaceutical pack or kit comprising amorphous N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and a pharmaceutically acceptable carrier.
  • the invention features a crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, characterized by one or more peaks at from about 4.8 to about 5.2 degrees, for example, about 5.0 degrees, and from about 15.4 to about 15.8 degrees, for example, about 15.6 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak at from about 7.6 to about 8.0, e.g., 7.8.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak at from about 8.3 to about 8.7, for example, about 8.5.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak at from about 9.0 to about 9.4, for example, about 9.2.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak at from about 9.7 to about 10.1, for example about 9.9.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak at from about 11.7 to about 12.1, for example, about 11.9.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak at from about 12.4 to about 12.8, for example, about 12.6.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak at from about 13.7 to about 14.1, for example about 13.9.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak at from about 14.7 to about 15.1, for example, about 14.9.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 16.3 to about 16.7, for example about 16.5.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 17.9 to about 18.3, for example, about 18.1.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 18.3 to about 18.7, for example, about 18.5.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 20.5 to about 20.9, for example, about 20.7.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 21.8 to about 22.2, for example, about 22.0.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 23.1 to about 23.7, for example, about 23.5.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 25.1 to about 25.5, for example, about 25.3.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 27.8 to about 28.2, for example, about 28.0.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is characterized by an X-ray powder diffraction pattern obtained using Cu K alpha radiation substantially similar to FIG. 4 .
  • the invention features a pharmaceutical composition
  • a pharmaceutical composition comprising the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide having the characteristics of Form A, for example as described above, and a pharmaceutically acceptable adjuvant or carrier.
  • the invention features a process for preparing a crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide of Form A, for example as characterized above, wherein said process comprises the step of heating N N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide to about 250° C. and cooling to room temperature.
  • the invention features a method for treating a CFTR mediated disease in a mammal comprising administering N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide of Form A, for example as characterized above.
  • the N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is a component of a pharmaceutical composition.
  • the method comprises administering an additional therapeutic agent.
  • the invention features a pharmaceutical pack or kit comprising crystalline N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide of Form A, for example as characterized above and a pharmaceutically acceptable carrier.
  • the invention features a crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, characterized by one or more peaks at from about 6.2 to about 6.6, for example, about 6.4, from about 7.5 to about 7.9, for example, about 7.7, from about 12.5 to about 12.9, for example, about 12.7, and from about 17.9 to about 18.3, for example, about 18.1 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 8.2 to about 8.6, for example, about 8.4.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 10.8 to about 11.2, for example, about 11.0.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 14.6 to about 15.0, for example, about 14.8.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 15.9 to about 16.3, for example, about 16.1.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 16.9 to about 17.3, for example, about 17.1.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 18.4 to about 18.8, for example, about 18.6.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 19.2 to about 19.6, for example, about 19.4.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 20.9 to about 21.3, for example, about 21.1.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 22.4 to about 22.8, for example, about 22.6.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 23.2 to about 23.6, for example, about 23.4.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 23.7 to about 24.1, for example, about 23.9.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 24.7 to about 25.1, for example, about 24.9.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 25.3 to about 25.7, for example, about 25.5.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 26.5 to about 26.9, for example, about 26.7.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 27.3 to about 27.7, for example, about 27.5.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 29.4 to about 29.8, for example, about 29.6.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro 4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 33.3 to about 33.7, for example, about 33.5.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro 4-oxoquinoline-3-carboxamide is further characterized by the following peak from about 36.6 to about 37.0, for example, about 36.8.
  • the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide is characterized by an X-ray powder diffraction pattern obtained using Cu K alpha radiation substantially similar to FIG. 7 .
  • the invention features a pharmaceutical composition
  • a pharmaceutical composition comprising the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to Form B; for example, as characterized above, and a pharmaceutically acceptable adjuvant or carrier.
  • the invention features a process for preparing the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to Form B, for example, as characterized above, wherein said process comprises the steps of alternatively heating and cooling a slurry of Compound 1 and acetonitrile.
  • the process comprises heating said slurry at about 50 C. for about 12 hours.
  • said cooling step comprises placing said slurry at room temperature for about 12 hours, followed by cooling at about 0° C. overnight.
  • the invention features a method of treating a CFTR mediated disease in a patient comprising the step of administering to said patient a crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutical composition comprising a crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to Form B, for example, as characterized above.
  • Processes described herein can be used to prepare the compositions of this invention.
  • the amounts and the features of the components used in the processes would be as described herein.
  • amorphous refers to a solid material having no long range order in the position of its molecules
  • Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long range order.
  • Amorphous solids are generally isotropic, i.e. exhibit similar properties in all directions and do not have definite melting points.
  • an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD).
  • XRPD X-ray power diffraction
  • one or several broad peaks appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid. See, US 2004/0006237 for a comparison of XRPDs of an amorphous material and crystalline material.
  • substantially amorphous Compound 1 is used interchangeably with the phrase “amorphous Compound 1 substantially free of crystalline Compound 1.”
  • substantially amorphous Compound 1 has less than about 30% crystalline Compound 1, for example, less than about 30% of crystalline Compound 1, e.g., less than about 25% crystalline Compound 1, less than about 20% crystalline Compound 1, less than about 15% crystalline Compound 1, less than about 10% crystalline Compound 1, less than about 5% crystalline Compound 1, less than about 2% crystalline Compound 1.
  • Compound 1 has less than about 15% crystalline compound 1.
  • Some embodiments include a preparation of substantially amorphous Compound 1, for example having the degree of crystalline Compound 1 as described above.
  • crystalline solids refers to compounds or compositions where the structural units are arranged in fixed geometric patterns or lattices, so that crystalline solids have rigid long range order.
  • the structural units that constitute the crystal structure can be atoms, molecules, or ions. Crystalline solids show definite melting points.
  • a “dispersion” refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle).
  • the size of the dispersed phase can vary considerably (e.g. colloidal particles of nanometer dimension, to multiple microns in size).
  • the dispersed phases can be solids, liquids, or gases.
  • the dispersed and continuous phases are both solids.
  • a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase), or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase).
  • an amorphous solid dispersion includes the polymer constituting the dispersed phase, and the drug constitute the continuous phase.
  • the dispersion includes amorphous. Compound 1 or substantially amorphous Compound 1.
  • solid amorphous dispersion generally refers to a solid dispersion of two or more components, usually a drug and polymer, but possibly containing other components such as surfactants or other pharmaceutical excipients, where Compound 1 is amorphous or substantially amorphous (e.g., substantially free of crystalline Compound 1), and the physical stability and/or dissolution and/or solubility of the amorphous drug is enhanced by the other components.
  • a solid dispersion as provided herein is a particularly favorable embodiment of this invention.
  • Solid dispersions typically include a compound dispersed in an appropriate carrier medium, such as a solid state carrier.
  • a carrier according to this invention comprises a polymer, preferably, a water-soluble polymer or a partially water-soluble polymer. It would be understood that one or more than one water-soluble polymer could be used in a solid dispersion of this invention.
  • An exemplary solid dispersion is a co-precipitate or a co-melt of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]1,4-dihydro-4-oxoquinoline-3-carboxamide with at least one polymer.
  • a “Co-precipitate” is a product after dissolving a drug and a polymer in a solvent or solvent mixture followed by the removal of the solvent or solvent mixture. Sometimes the polymer can be suspended in the solvent or solvent mixture.
  • the solvent or solvent mixture includes organic solvents and supercritical fluids.
  • a “co-melt” is a product after heating a drug and a polymer to melt, optionally in the presence of a solvent or solvent mixture, followed by mixing, removal of at least a portion of the solvent if applicable, and cooling to room temperature at a selected rate.
  • the solid dispersions are prepared by adding a solution of a drug and a solid polymer followed by mixing and removal of the solvent. To remove the solvent, vacuum drying, spray drying, tray drying, lyophilization, and other drying procedures may be applied.
  • FIG. 1 is an X-Ray powder diffraction pattern of Compound 1.
  • FIG. 3 is the DSC trace of Compound 1.
  • FIG. 4 is the X-Ray powder diffraction pattern of Form A.
  • FIG. 5 is the DSC trace of Form A.
  • FIG. 6 is the TGA trace of Form A.
  • FIG. 7 is the X-Ray powder diffraction pattern of Form B.
  • FIG. 8 is the DSC trace of Form B.
  • FIG. 9 is the TGA trace of Form B.
  • FIG. 10 is a conformational picture of Form B, based on single crystal X-Ray analysis.
  • FIG. 11 is the X-Ray powder diffraction pattern of the Amorphous Form.
  • FIG. 12 is the TGA trace of the Amorphous Form.
  • FIG. 13 is the DSC trace of the Amorphous Form.
  • Form A of Compound 1 is characterized by one or more peaks at from about 4.8 to about 5.2, for example, about 5.0, e.g., 4.99, and from about 15.4 to about 15.8, for example, about 15.6 e.g., 15.58 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation (2 ⁇ ). Other peaks (2 ⁇ ), which can be characteristic of Form.
  • A include the following: from about 7.6 to about 8.0, for example, about 7.8, e.g., 7.75; from about 8.3 to about 8.7, for example, about 8.5, e.g., 8.46; from about 9.0 to about 9.4, for example, about 9.2, e.g., 9.21; from about 9.7 to about 10.1, for example, about 9.9, e.g., 9.92; from about 11.7 to about 12.1, for example, about 11.9, e.g., 11.93; from about 12.4 to about 12.8, for example, about 12.6, e.g., 12.64; from about 13.7 to about 14.1, for example, about 13.9, e.g., 13.88; from about 14.7 to about 15.1, for example, about 14.9, e.g., 14.91; from about 16.3 to about 16.7, for example, about 16.5, e.g., 16.46; from about 17.9 to about 18.3, for example, about 18.1, e.g., 18.09; from about 18.3 to about 18.7, for
  • compositions including Form A and a pharmaceutically acceptable adjuvant or carrier, such as a polymer or surfactant are also described.
  • Form A can be formulated in a pharmaceutical composition, in some instances; with another therapeutic agent, for example another therapeutic agent for treating cystic fibrosis or a symptom thereof.
  • Methods of treating a CFTR mediated disease, such as cystic fibrosis, in a patient include administering to said patient Form A or a pharmaceutical composition comprising Form A.
  • the solid state crystal Form B of Compound 1 is characterized by one or more peaks at from about 6.0 to about 6.4 for example, about 6.2, e.g., 6.17, from about 7.4 to about 7.8 for example, about 7.6, e.g., 7.61, from about 12.1 to about 12.5 for example, about 12.3, e.g., 12.33, and from about 17.8 to about 18.2 for example, about 18.0, e.g., 17.96 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation (2 ⁇ ).
  • peaks (2 ⁇ ), which can be characteristic of Form B include the following: from about 8.2 to about 8.6 for example, about 8.4, e.g., 8.40; from about 10.8 to about 11.2 for example, about 11.0, e.g., 11.02; from about 14.6 to about 15.0 for example, about 14.8, e.g., 14.83; from about 15.9 to about 16.3 for example, about 16.1, e.g., 16.14; from about 16.9 to about 17.3 for example, about 17.1, e.g., 17.11; from about 18.4 to about 18.8 for example, about 18.6, e.g., 18.55; from about 19.2 to about 19.6 for example, about 19.4, e.g., 19.43; from about 20.9 to about 21.3 for example, about 21.1, e.g., 21.05; from about 22.4 to about 22.8 for example, about 22.6, e.g., 22.56; from about 23.2 to about 216 for example, about 23.4, e.g., 23.37;
  • Form B has determined crystal structure dimensions of Form B by analysis of single crystal data.
  • compositions including Form B and a pharmaceutically acceptable adjuvant or carrier, such as a polymer or surfactant are also described.
  • Form B can be formulated in a pharmaceutical composition, in some instances, with another therapeutic agent, for example another therapeutic agent for treating cystic fibrosis or a symptom thereof.
  • Methods of treating a CFTR mediated disease, such as cystic fibrosis, in a patient include administering to said patient Form B or a pharmaceutical composition comprising Form B.
  • Compound 1 can be present as an amorphous solid, for example amorphous Compound 1 as a substantially neat preparation, or amorphous compound 1 as a component as a dispersion such as a solid amorphous dispersion.
  • an amorphous form of Compound 1 is substantially free of crystalline Compound 1 (e.g., Form A, Form B or any crystalline form of Compound 1), for example Compound 1 has less than about 30% of crystalline Compound 1, e.g., less than about 25% crystalline Compound 1, less than about 20% crystalline Compound 1, less than about 15% crystalline Compound 1, less than about 10% crystalline Compound 1, less than about 5% crystalline Compound 1, less than about 2% crystalline. Compound 1, preferably less than about 15% crystalline compound 1.
  • Compound 1 can be characterized by an X-ray powder diffraction pattern obtained using Cu K alpha radiation substantially similar to FIG. 11 .
  • the substantially amorphous form of Compound 1 can be characterized as having an XRPD having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern.
  • XRPD X-ray power diffraction
  • Solid dispersions including amorphous Compound 1 and a polymer (or solid state carrier) also are included herein.
  • Compound 1 is present as an amorphous compound as a component of a solid amorphous dispersion.
  • the solid amorphous dispersion generally includes Compound 1 and a polymer.
  • Exemplary polymers include cellulosic polymers such as HPMC or HPMCAS and pyrrolidone containing polymers such as PVP/VA.
  • the solid amporphous dispersion includes one or more additional exipients, such as a surfactant.
  • a polymer is able to dissolve in aqueous media.
  • the solubility of the polymers may be pH-independent or pH-dependent.
  • the latter include one or more enteric polymers.
  • enteric polymer refers to a polymer that is preferentially soluble in the less acidic environment of the intestine relative to the more acid environment of the stomach, for example, a polymer that is insoluble in acidic aqueous media but soluble when the pH is above 5-6.
  • An appropriate polymer should be chemically and biologically inert.
  • the glass transition temperature (T g ) of the polymer should be as high as possible.
  • preferred polymers have a glass transition temperature at least equal to or greater than the glass transition temperature of the drug (e.g., Compound 1).
  • Other preferred polymers have a glass transition temperature that is within about 10 to about 15° C. of the drug (e.g., Compound 1).
  • suitable glass transition temperatures of the polymers include at least about 90° C., at least about 95° C., at least about 100° C., at least about 105° C., at least about 110° C., at least about 115° C., at least about 120° C., at least about 125° C., at least about 130° C., at least about 135° C., at least about 140° C., at least about 145° C., at least about 150° C., at least about 155° C., at least about 160° C., at least about 165° C., at least about 170° C., or at least about 175° C. (as measured under dry conditions).
  • a polymer with a higher T g generally has lower molecular mobility at room temperature, which can be a crucial factor in stabilizing the physical stability of the amorphous solid dispersion.
  • the hygroscopicity of the polymers should be as low, e.g., less than about 10%.
  • the hygroscopicity of a polymer or composition is characterized at about 60% relative humidity.
  • the polymer has less than about 10% water absorption, for example less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, or less than about 2% water absorption.
  • the hygroscopicity can also affect the physical stability of the solid dispersions. Generally, moisture adsorbed in the polymers can greatly reduce the T g of the polymers as well as the resulting solid dispersions, which will further reduce the physical stability of the solid dispersions as described above.
  • the polymer is one or more water-soluble polymer(s) or partially water-soluble polymer(s).
  • Water-soluble or partially water-soluble polymers include but are not limited to, cellulose derivatives (e.g., hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC)) or ethylcellulose; polyvinylpyrrolidones (PVP); polyethylene glycols (PEG); polyvinyl alcohols (PVA); acrylates, such as polymethacrylate (e.g., Eudragit® E); cyclodextrins (e.g., ⁇ -cyclodextrin) and copolymers and derivatives thereof, including for example PVP-VA (polyvinylpyrollidone-vinyl acetate).
  • HPMC hydroxypropylmethylcellulose
  • HPC hydroxypropylcellulose
  • PVP polyvinylpyrrolidones
  • PEG polyethylene glycols
  • PVA polyvinyl alcohols
  • the polymer is hydroxypropylmethylcellulose (HPMC), such as HPMC E50, HPMCE15, or HPMC60SH50).
  • HPMC hydroxypropylmethylcellulose
  • the polymer can be a pH-dependent enteric polymer.
  • pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., cellulose acetate phthalate (CAP)), hydroxypropyl methyl cellulose phthalates (HPMCP), hydroxypropyl methyl cellulose acetate succinate.
  • HPMCAS carboxymethylcellulose
  • CMC carboxymethylcellulose
  • a salt thereof e.g., a sodium salt such as (CMC-Na)
  • CAT cellulose acetate trimellitate
  • HPCAP hydroxypropylcellulose acetate phthalate
  • HPCAP hydroxypropylmethyl-cellulose acetate phthalate
  • MCAP methylcellulose acetate phthalate
  • polymethacrylates e.g., Eudragit® S.
  • the polymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS).
  • the amount of polymer relative to the total weight of the solid dispersion ranges from about 0.1% to 99% by weight. Unless otherwise specified, percentages of drug, polymer and other excipients as described within a dispersion are given in weight percentages.
  • the amount of polymer is typically at least about 20%, and preferably at least about 30%, for example, at least about 35%, at least about 40%, at least about 45%, or about 50% (e.g., 49.5%).
  • the amount is typically about 99% or less, and preferably about 80% or less, for example about 75% or less, about 70% or less, about 65% or less, about 60% or less, or about 55% or less.
  • the polymer is in an amount of up to about 50% of the total weight of the dispersion (and even more specifically, between about 40% and 50%, such as about 49%, about 49.5%, or about 50%).
  • HPMC and HPMCAS are available in a variety of grades from ShinEtsu, for example, HPMCAS is available in a number of varieties, including AS-LF, AS-MF, AS-HF, AS-LG, AS-MG, AS-HG. Each of these grades vary with the percent substitution of acetate and succinate.
  • the dispersion further includes other minor ingredients, such as a surfactant (e.g., SLS).
  • a surfactant e.g., SLS
  • the surfactant is present in less than about 10% of the dispersion, for example less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, about 1%, or about 0.5%.
  • Suitable polymers for use in combination with Compound 1, for example to form a solid dispersion such as an amorphous solid dispersion should have one or more of the following properties:
  • the glass transition temperature of the polymer should have a temperature of no less than about 10-15° C. lower than the glass transition temperature of Compound 1.
  • the glass transition temperature of the polymer is greater than the glass transition temperature of Compound 1, and in general at least 50° C. higher than the desired storage temperature of the drug product.
  • the polymer should be relatively non-hygroscopic.
  • the polymer should, when stored under standard conditions, absorb less than about 10% water, for example, less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5%, less than about 4%, or less than about 3% water.
  • the polymer will, when stored under standard conditions, be substantially free of absorbed water.
  • the polymer should have similar or better solubility in solvents suitable for spray drying processes relative to that of Compound 1.
  • the polymer will dissolve in one or more of the same solvents or solvent systems as Compound 1. It is preferred that the polymer is soluble in at least one non-hydroxy containing solvent such as methylene chloride, acetone, or a combination thereof.
  • the polymer when combined with Compound 1, for example in a solid dispersion or in a liquid suspension, should increase the solubility of Compound 1 in aqueous and physiologically relative media either relative to the solubility of Compound 1 in the absence of polymer or relative to the solubility of Compound 1 when combined with a reference polymer.
  • the polymer could increase the solubility of amorphous Compound 1 by reducing the amount of amorphous Compound 1 that converts to crystalline Compound 1, either from a solid amorphous dispersion or from a liquid suspension.
  • the polymer should decrease the relaxation rate of the amorphous substance.
  • the polymer should increase the physical and/or chemical stability of Compound 1.
  • the polymer should improve the manufacturability of Compound 1.
  • the polymer should improve one or more of the handling, administration or storage properties of Compound 1.
  • the polymer should not interact unfavorably with other pharmaceutical components, for example excipients.
  • the suitability of a candidate polymer (or other component) can be tested using the spray drying methods (or other methods) described herein to form an amorphous composition.
  • the candidate composition can be compared in terms of stability, resistance to the formation of crystals, or other properties, and compared to a reference preparation, e.g., a preparation of neat amorphous Compound 1 or crystalline Compound 1.
  • a reference preparation e.g., a preparation of neat amorphous Compound 1 or crystalline Compound 1.
  • a candidate composition could be tested to determine whether it inhibits the time to onset of solvent mediated crystallization, or the percent conversion at a given time under controlled conditions, by at least 50%, 75%, 100%, or 110% as well as the reference preparation, or a candidate composition could be tested to determine if it has improved bioavailability or solubility relative to crystalline Compound 1.
  • a solid dispersion or other composition may include a surfactant.
  • a surfactant or surfactant mixture would generally decrease the interfacial tension between the solid dispersion and an aqueous medium.
  • An appropriate surfactant or surfactant mixture may also enhance aqueous solubility and bioavailability of Compound 1 from a solid dispersion.
  • the surfactants for use in connection with the present invention include, but are not limited to, sorbitan fatty acid esters (e.g., Spans®), polyoxyethylene sorbitan fatty acid esters (e.g., Tweens®), sodium lauryl sulfate (SLS), sodium dodecylbenzene sulfonate (SDBS) dioctyl sodium sulfosuccinate (Docusate), dioxycholic acid sodium salt (DOSS), Sorbitan Monostearate, Sorbitan Tristearate, hexadecyltrimethyl ammonium bromide (HTAB), Sodium N-lauroylsarcosine, Sodium Oleate, Sodium Myristate, Sodium Stearate, Sodium Palmitate, Gelucire 44/14, ethylenediamine tetraacetic acid (EDTA), Vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate (TAGS), Lecithin,
  • the amount of the surfactant (e.g., SLS) relative to the total weight of the solid dispersion may be between 0.1-15%. Preferably, it is from about 0.5% to about 10%, more preferably from about 05 to about 5%, e.g., about 1%, about 2%, about 3%, about 4%, or about 5%.
  • the amount of the surfactant relative to the total weight of the solid dispersion is at least about 0.1, preferably about 0.5%.
  • the surfactant would be present in an amount of no more than about 15%, and preferably no more than about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2% or about 1%.
  • An embodiment wherein the surfactant is in an amount of about 0.5% by weight is preferred.
  • Candidate surfactants can be tested for suitability for use in the invention in a manner similar to that described for testing polymers.
  • the solid form of Compound 1 can vary depending on the method used to prepare Compound 1.
  • Compound 1 can be prepared using a method to provide crystalline Compound 1, such as Form A or Form B, or Compound 1 can be prepared using a method to provide amorphous Compound 1, for example as a neat preparation or where Compound 1 is a component in a dispersion such as a solid amorphous dispersion (e.g., a dispersion of Compound 1 and a polymer such as a cellulosic polymer e.g., HPMC or HPMCAS or a pyrrolidone polymer such as PVP/VA).
  • a dispersion such as a solid amorphous dispersion (e.g., a dispersion of Compound 1 and a polymer such as a cellulosic polymer e.g., HPMC or HPMCAS or a pyrrolidone polymer such as PVP/VA).
  • a dispersion such as a solid
  • Form A of Compound 1 can be prepared, for example, by heating Compound 1 to at or above its melting point, for example to about 250° C. and then cooling the compound, thereby providing Compound 1 having a solid state of Form A.
  • Form A can be characterized by one or more characteristic peaks as determined using XRPD.
  • Compound 1 as Form A can be identified by the presence of one or peaks at 2 ⁇ , including one or more of the following peaks at or about: about 5.0 e.g.
  • Form B of Compound 1 can be prepared, for example, by subjecting a slurry of compound 1 in a solvent to heating and cooling cycles.
  • the solvent is a solvent where Compound 1 has limited solubility at room temperature, for example, acetone.
  • the slurry is subject to a plurality of heat/cool cycles, where the slurry is generally warmed to a temperature above room temperature but below the boiling point of the solvent, for example about 40° C. to about 60° C., e.g., about 50° C.
  • the slurry is generally subjected to at least 2 heat/cool cycles, for example, 2, 3, 4, 5, or 6, preferably 5 cycles.
  • Each cycle was timed to last at least about 8 hours (e.g., 4 hours of heating followed by 4 hours at room temperature, 6 hours of heating followed by 6 hours at room temperature, 8 hours of heating followed by 8 hours at room temperature, preferably 12 hours of heating followed by 12 hours at room temperature).
  • crude Compound 1 can be refluxed in as a slurry in acetonitrile (e.g., 27 volumes of acetonitrile) for 24 hours.
  • acetonitrile e.g., 27 volumes of acetonitrile
  • the mixture is then cooled, e.g., to about room temperature, e.g., about 20° C.
  • Form B is then isolated, for example, by filtration as a white to off-white.
  • the resulting wet cake is rinsed with acetonitrile (e.g., 5 volumes) and dried under vacuum at 50° C. until a constant weight is attained.
  • Form B can be characterized by one or more characteristic peaks as determined using XRPD.
  • Compound 1 as Form B can be identified by the presence of one or peaks at 2 ⁇ , including one or more of the following peaks at or about: about 6.2, e.g., 6.17; about 7.6, e.g., 7.61; about 8.4, e.g., 8.40; about 11.0, e.g., 11.02; about 12.3, e.g., 1233; about 14.8, e.g., 14.83; about 16.1, e.g., 16.14; about 17.1, e.g., 17.11; about 18.0, e.g., 17.96; about 18.6, e.g., 18.55; about 19.4, e.g., 19.43; about 21.1, e.g., 21.05; about 22.6, e.g., 22:56; about 23.4, e.g., 23.37; about 23.9, e.g., 23.94; about 24.9, e
  • Amporphous compound 1 can be made using a variety of techniques, including, for example spray drying a solution of Compound 1 to provide amorphous Compound 1, e.g., as a neat solid or as a component of a solid dispersion, said method utilizing spray-drying means to effect said conversion.
  • Amorphous Compound 1 can be made by converting a form of Compound 1, e.g., a crystalline form of Compound 1, such as Form A or Form B, into a substantially amorphous form of Compound 1 by dissolving Compound into a solution and spray drying the solution of Compound 1, thereby converting a form of Compound 1, such as crystalline Compound 1, into amorphous Compound 1.
  • An exemplary process for making amorphous Compound 1 by converting Form B into a substantially amorphous form of Compound 1 is recited in the examples.
  • any method for obtaining amorphous forms of Compound 1, including neat amorphous Compound 1 and solid amorphous dispersions of Compound 1, can be used including, for example, those described in US 2003/0186952 (see the documents cited therein at paragraph 1092) and US 2003/0185891).
  • methods that could be used include those that involve rapid removal of solvent from a mixture or cooling a molten sample. Such methods include, but are not limited to, rotational evaporation, freeze-drying (i.e., lyophilization), vacuum drying, melt congealing, and melt extrusion.
  • a preferred embodiment includes amorphous.
  • Preparations disclosed herein can be obtained by spray-drying a mixture comprising Compound 1, a suitable polymer, and an appropriate solvent.
  • Spray drying is a method that involves atomization of a liquid mixture containing, e.g., a solid and a solvent, and removal of the solvent. Atomization can be done, for example, through a nozzle or on a rotating disk.
  • Spray drying is a process that converts a liquid feed to a dried particulate form.
  • a secondary drying process such as fluidized bed drying or vacuum drying, may be used to reduce residual solvents to pharmaceutically acceptable levels.
  • spray-drying involves contacting a highly dispersed liquid suspension or solution, and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets.
  • the preparation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that may be atomized using the selected spray-drying apparatus.
  • the preparation is sprayed into a current of warm filtered air that evaporates the solvent and conveys the dried product to a collector (e.g., a cyclone).
  • the spent air is then exhausted with the solvent, or alternatively the spent air is sent to a condenser to capture and potentially recycle the solvent.
  • Commercially available types of apparatus may be used to conduct the spray-drying.
  • commercial spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray driers manufactured by Niro) (see, US 2004/0105820; US 2003/0144257).
  • Spray-drying typically employs solids loads of material from about 3% to about 30% by weight, (i.e., drug plus and excipients), for example about 4% to about 20% by weight, preferably at least about 10%.
  • the upper limit of solids loads is governed by the viscosity of (e.g., the ability to pump) the resulting solution and the solubility of the components in the solution.
  • the viscosity of the solution can determine the size of the particle in the resulting powder product.
  • the spray-drying is conducted with an inlet temperature of from about 60° C. to about 200° C., for example, from about 95° C. to about 185° C., from about 110 C. to about 182° C., from about 96° C. to about 108° C., e.g., about 175° C.
  • the spray-drying is generally conducted with an outlet temperature of from about 30° C. to about 80° C., for example from about 31° C. to about 72° C., about 37° C. to about 41° C. e.g., about 60° C.
  • the atomization flow rate is generally from about 4 kg/h to about 12 kg/h, for example, from about 4.3 kg/h to about 10.5 kg/h, e.g., about 6 kg/h or about 10.5 kg/h.
  • the feed flow rate is generally from about 3 kg/h to about 10 kg/h, for example, from about 3.5 kg/h to about 9.0 kg/h, e.g., about 8 kg/h or about 7.1 kg/h.
  • the atomization ratio is generally from about 0.3 to 1.7, e.g., from about 0.5 to 1.5, e.g., about 0.8 or about 1.5.
  • Removal of the solvent may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., from about room temperature to about 100° C.), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200° C.).
  • a subsequent drying step such as tray drying, fluid bed drying (e.g., from about room temperature to about 100° C.), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200° C.).
  • the solid dispersion is fluid-bed dried.
  • the solvent includes a volatile solvent, for example a solvent having a boiling point of less than about 100° C.
  • the solvent includes a mixture of solvents, for example a mixture of volatile solvents or a mixture of volatile and non-volatile solvents.
  • the mixture can include one or more non-volatile solvents, for example, where the non-volatile solvent is present in the mixture at less than about 15%, e.g., less than about 12%, less than about 10%, less than about 8%, less than about 5%, less than about 3%, or less than about 2%.
  • Preferred solvents are those solvents where Compound 1 has a solubility of at least about 10 mg/ml (e.g., at least about 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml, 50 mg/ml, or greater). More preferred solvents include those where Compound 1 has a solubility of at least about 50 mg/ml.
  • Exemplary solvents that could be tested include acetone, cyclohexane, dichloromethane, N,N-Dimethylacetamide (DMA), N,N-Dimethylformamide (DMF), 1,3 Dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), dioxane, ethyl acetate, ethyl ether, glacial acetic acid (HAc), methyl ethyl ketone (MEK), N-methyl-2-pyrrolidinone (NMP), methyl tert-butyl ether, tetrahydrofuran (THF) and pentane.
  • DMA N,N-Dimethylacetamide
  • DMF N,N-Dimethylformamide
  • DI 1,3 Dimethyl-2-imidazolidinone
  • DMSO dimethyl sulfoxide
  • DMSO dioxane
  • ethyl acetate ethyl ether
  • co-solvents include acetone/DMSO, acetone/DMF, acetone/water, MEK/water, THF/water, dioxane/water.
  • the solvents can be present in of from about 0.1% to about 99.9%.
  • water is a co-solvent with acetone where water is present from about 0.1% to about 15%, for example about 9% to about 11%, e.g., about 10%.
  • water is a co-solvent with MEK where water is present from about 0.1% to about 15%, for example about 9% to about 11%, e.g., about 10%.
  • the solvent solution include three solvents.
  • acetone and water can be mixed with a third solvent such as DMA, DMF, DMI, DMSO, or HAc.
  • a third solvent such as DMA, DMF, DMI, DMSO, or HAc.
  • preferred solvents dissolve both Compound 1 and the polymer. Suitable solvents include those described above, for example, MEK, acetone, water, and mixtures thereof.
  • the particle size and the temperature drying range may be modified to prepare an optimal solid dispersion.
  • a small particle size would lead to improved solvent removal.
  • Applicants have found however, that smaller particles can lead to fluffy particles that, under some circumstances do not provide optimal solid dispersions for downstream processing such as tabletting.
  • crystallization or chemical degradation of Compound 1 may occur.
  • a sufficient amount of the solvent may not be removed.
  • the methods herein provide an optimal particle size and an optimal drying temperature.
  • particle size is such that D10 ( ⁇ m) is less than about 5, e.g., less than about 4.5, less than about 4.0, or less than about 3.5, D50 ( ⁇ m) is generally less than about 17, e.g., less than about 16, less than about 15, less than about 14, less than about 13, and D90 ( ⁇ m) is generally less than about 175, e.g., less than about 170, less than about 170, less than about 150, less than about 125, less than about 100, less than about 90, less than about 80, less than about 70, less than about 60, or less than about less than about 50.
  • bulk density of the spray dried particles is from about 0.08 g/cc to about 0.20 g/cc, e.g., from about 0.10 to about 0.15 g/cc, e.g., about 0.11 g/cc or about 0.14 g/cc.
  • Tap density of the spray dried particles generally ranges from about 0.08 g/cc to about 0.20 g/cc, e.g., from about 0.10 to about 0.15 g/cc, e.g., about 0.11 g/cc or about 0.14 g/cc, for 10 taps; 0.10 g/cc to about 0.25 g/cc; e.g., from about 0.11 to about 0.21 g/cc, e.g., about 0.15 g/cc, about 0.19 g/cc, or about 0.21 g/cc for 500 taps; 0.15 g/cc to about 0.27 g/cc, e.g., from about 0.18 to about 0.24 g/cc, e.g., about 0.18 g/cc, about 0.19 g/cc, about 0.20 g/cc, or about 0.24 g/cc for 1250 taps; and 0.15 g/cc to about 0.27 g/c
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. All tautomeric forms of the Compound 1 are included herein. E.g., Compound 1 may exist as tautomers, both of which are included herein:
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds of formula (I) wherein one or more hydrogen atoms are replaced deuterium or tritium, or one or more carbon atoms are replaced by a 13C- or 14C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, probes in biological assays, or compounds with improved therapeutic profile.
  • compositions comprising any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.
  • a pharmaceutically acceptable derivative or a prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc
  • the present invention provides a method of treating a condition, disease, or disorder implicated by CFTR.
  • the present invention provides a method of treating a condition, disease, or disorder implicated by a deficiency of CFTR activity, the method comprising administering a composition comprising a solid state form of Compound 1 described herein (e.g., Form A, Form B, or amorphous Compound 1, e.g., neat or as a component in a dispersion) to a subject, preferably a mammal, in need thereof.
  • a “CFTR-mediated disease” as used herein is a disease selected from cystic fibrosis, 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, Hereditary emphysema, Congenital hyperthyroidism, Oste
  • the present invention provides a method of treating cystic fibrosis, 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
  • the present invention provides a method of treating cystic fibrosis comprising the step of administering to said mammal a composition comprising a solid state form of Compound 1 described herein (e.g., Form A, or Form B, or amorphous Compound 1, e.g., neat or as a component in a dispersion).
  • a composition comprising a solid state form of Compound 1 described herein (e.g., Form A, or Form B, or amorphous Compound 1, e.g., neat or as a component in a dispersion).
  • an “effective amount” of a solid state form of Compound 1 e.g., Form A, or Form B, or amorphous Compound 1, e.g., neat or as a component in a dispersion
  • a pharmaceutically acceptable composition thereof is that amount effective for treating or lessening the severity of any of the diseases recited above.
  • a solid state form of Compound 1 described herein e.g., Form A, or Form B, or amorphous Compound 1, e.g., neat or as a component in a dispersion
  • a pharmaceutically acceptable composition thereof is useful for treating or lessening the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia.
  • the presence of residual CFTR activity at the epithelial surface can be readily detected using methods known in the art, e.g., standard electrophysiological, biochemical, or histochemical techniques.
  • Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of sweat or salivary CF concentrations, or ex vivo biochemical or histochemical techniques to monitor cell surface density. Using such methods, residual CFTR activity can be readily detected in patients heterozygous or homozygous for a variety of different mutations, including patients homozygous or heterozygous for the most common mutation, ⁇ F508.
  • a solid state form of Compound 1 described herein e.g., Form A, or Form B, or amorphous Compound 1, e.g., neat or as a component in a dispersion
  • a pharmaceutically acceptable composition thereof is useful for treating or lessening the severity of cystic fibrosis in patients within certain clinical phenotypes, e.g., a moderate to mild clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of epithelia.
  • Such phenotypes include patients exhibiting pancreatic insufficiency or patients diagnosed with idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as, for example, water or other solvents, solubil
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets; dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Solid state form of Compound 1 described herein e.g., Form A, or Form B, or amorphous Compound 1, e.g., neat or as a component in a dispersion
  • a pharmaceutically acceptable composition thereof can be employed in combination therapies, that is, Form A or Form B or a pharmaceutically acceptable composition thereof can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the additional agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than a compound of the present invention, or a nutritional agent.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • a solid state form of Compound 1 described herein e.g., Form A, or Form B, or amorphous Compound 1, e.g., neat or as a component in a dispersion
  • a pharmaceutically acceptable composition thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • the present invention in another aspect, includes a composition for coating an implantable device comprising a solid state form of Compound 1 described herein (e.g., Form A, or Form B, or amorphous Compound 1, e.g., neat or as a component in a dispersion) or a pharmaceutically acceptable composition thereof, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • a solid state form of Compound 1 described herein e.g., Form A, or Form B, or amorphous Compound 1, e.g., neat or as a component in a dispersion
  • a carrier suitable for coating said implantable device e.g., a carrier suitable for coating said implantable device.
  • the present invention includes an implantable device coated with a composition comprising a solid state form of Compound 1 described herein (e.g., Form A, or Form B, or amorphous Compound 1, e.g., neat or as a component in a dispersion) or a pharmaceutically acceptable composition thereof, and a carrier suitable for coating said implantable device.
  • a composition comprising a solid state form of Compound 1 described herein (e.g., Form A, or Form B, or amorphous Compound 1, e.g., neat or as a component in a dispersion) or a pharmaceutically acceptable composition thereof, and a carrier suitable for coating said implantable device.
  • Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol
  • DSC Differential scanning calorimetry
  • TGA Thermal gravimetric analysis
  • TGA Q500 V6.3 Build 189 (TA Instruments, New Castle, Del.) was used for TGA measurement. Temperature was equilibrated by Curie point with nickel. Samples of 10-20 mg were scanned from 25° C. to 350° C. at a heating rate of 10° C./min. A nitrogen gas balance purge of 10 ml/min and a sample purge of 90 ml/min were used. Data were collected by Thermal Advantage Q SeriesTM software version 2.2.0.248 and analyzed by Universal Analysis software version 4.1 D (TA Instruments, New Castle, Del.). The reported numbers represent single analyses.
  • XRD data of Form A, Form B, and amorphous Compound 1 were collected on a Bruker D8 DISCOVER with GADDS powder diffractometer with HI-STAR 2-dimensional detector and a flat graphite monochromator. Cu sealed tube with K ⁇ radiation was used at 40 kV, 35 mA. The samples were placed on zero-background silicon wafers at 25° C. For each sample, two data frames were collected at 120 seconds each at 2 different 2 ⁇ angles: 8° and 26°. The frames data were integrated with GADDS software and merged with DIFFRACT plus EVA software.
  • Methyl chloroformate (58 mL, 750 mmol) was added dropwise to a solution of 2,4-di-tert-butyl-phenol (103.2 g, 500 mmol), Et 3 N (139 mL, 1000 mmol) and DMAP (3.05 g, 25 mmol) in dichloromethane (400 mL) cooled in an ice-water bath to 0° C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered through silica gel (approx. 1 L) using 10% ethyl acetate-hexanes ( ⁇ 4 L) as the eluent.
  • the ether layer was dried (MgSO 4 ), concentrated and purified by column chromatography (0-10% ethyl acetate-hexanes) to yield a mixture of carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester as a pale yellow solid (4.28 g), which was used directly in the next step.
  • the DSC trace of Compound 1 is shown in FIG. 3 .
  • Form A was obtained by heating Compound 1 as a solid to 250° C. and cooling to room temperature.
  • the DSC thermogram on Compound 1 shows that the compound undergoes a melt with an onset temperature of 195° C., followed by a re-crystallisation with onset at 220° C.
  • the DSC data for Form A is shown in FIG. 5 .
  • the TGA trace for Form A is shown in FIG. 6 .
  • Crude Compound 1 was a slurry in refluxing acetonitrile (27 volumes) for 24 hours. After 24 hours, the mixture was allowed to cool to 20° C. Form B was isolated by filtration as a white to off-white. The wet cake was rinsed with acetonitrile (5 volumes) and dried under vacuum at 50° C. until a constant weight is attained, thereby providing Form B.
  • the DSC trace of Form B is shown in FIG. 8 .
  • the TGA trace for Form B is shown in FIG. 9 .
  • FIG. 10 A conformational picture of Form B is provided in FIG. 10 , which is in color.
  • the anisotropic displacement factor exponent takes the form: ⁇ 2 ⁇ 2 [h 2 a * 2 U 11 + . . . + 2 h k a * b * U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 N(1) 42(1) 41(2) 14(2) 5(1) 4(1) 3(1) C(3) 34(2) 40(2) 16(2) ⁇ 1(1) 4(1) ⁇ 4(1) C(4) 34(2) 38(2) 17(2) 0(1) 4(1) ⁇ 1(1) C(5) 34(2) 42(2) 17(2) ⁇ 2(1) 6(1) ⁇ 6(1) C(2) 37(2) 42(2) 16(2) 1(1) 5(1) 1(2) C(8) 44(2) 41(2) 30(2) ⁇ 4(2) 10(1) 5(2) C(7) 46(2) 44(2) 22(2) ⁇ 4(1) 9(1) ⁇ 5(2) C(6) 41(2) 40(2) 23(2) 1(2) 9(1) ⁇ 1(2) C(9) 41(2) 40(2) 24(2) 5(1) 4(1) 3(2) C(11) 35(2) 41(2) 18(2) 1(1) 4(1) ⁇ 4(2) C(15) 37(2) 37(2) 37
  • Form B 4 g was dissolved in 86.4 g of acetone and 9.6 g water under the above conditions. The run time was 15 min. The product was dried under vacuum at 25° C. for over 24 hrs to produce the Amorphous Form.
  • the XRPD spectrum of the Amorphous Form is shown in FIG. 11 .
  • the TGA trace for Amorphous Form is shown in FIG. 12 .
  • the DSC trace for Amorphous Form is shown in FIG. 13 .
  • Bioavailability of crystalline Form B, 85% amorphous Compound 1 and HPMCAS solid dispersion of Compound 1 were evaluated in rat, the results of which are provided in Table 4 below. These forms of the compound were dosed in an oral suspension with a vehicle containing 0.5% methyl cellulose/0.5% SLS/99% water. Bioavailability of various solid forms was evaluated as compared to a multicomponent IV solution of Compound 1. Bioavailability of crystalline polymorph B was 3-6%, compared to 61-95% for amorphous material and 109-111% for solid dispersion.
  • crystalline polymorph B has a measured solubility of 1.0 ⁇ g/ml, while the 85% amorphous material has a solubility of 67.4 ⁇ g/ml.
  • the crystalline material showed 67-74% bioavailability when dosed as a PEG solution, indicating that absorption was solubility limited.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Hematology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Endocrinology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Immunology (AREA)
  • Obesity (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Pulmonology (AREA)
  • Psychiatry (AREA)
  • Dermatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Rheumatology (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Medicinal Preparation (AREA)
US11/647,505 2005-12-28 2006-12-28 Solid forms of N-[2,4-BIS(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide Abandoned US20110064811A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US11/647,505 US20110064811A1 (en) 2005-12-28 2006-12-28 Solid forms of N-[2,4-BIS(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US13/358,778 US8410274B2 (en) 2005-12-28 2012-01-26 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US13/785,692 US8754224B2 (en) 2005-12-28 2013-03-05 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US14/272,692 US9139530B2 (en) 2005-12-28 2014-05-08 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US14/852,892 US9670163B2 (en) 2005-12-28 2015-09-14 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US15/584,324 US9931334B2 (en) 2005-12-28 2017-05-02 Solid forms of N[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US15/900,147 US10537565B2 (en) 2005-12-28 2018-02-20 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US16/704,713 US11291662B2 (en) 2005-12-28 2019-12-05 Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US17/953,412 US20230263794A1 (en) 2005-12-28 2022-09-27 Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US75438105P 2005-12-28 2005-12-28
US11/647,505 US20110064811A1 (en) 2005-12-28 2006-12-28 Solid forms of N-[2,4-BIS(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/358,778 Continuation US8410274B2 (en) 2005-12-28 2012-01-26 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

Publications (1)

Publication Number Publication Date
US20110064811A1 true US20110064811A1 (en) 2011-03-17

Family

ID=38228833

Family Applications (9)

Application Number Title Priority Date Filing Date
US11/647,505 Abandoned US20110064811A1 (en) 2005-12-28 2006-12-28 Solid forms of N-[2,4-BIS(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US13/358,778 Active US8410274B2 (en) 2005-12-28 2012-01-26 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US13/785,692 Active US8754224B2 (en) 2005-12-28 2013-03-05 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US14/272,692 Active US9139530B2 (en) 2005-12-28 2014-05-08 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US14/852,892 Active US9670163B2 (en) 2005-12-28 2015-09-14 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US15/584,324 Active US9931334B2 (en) 2005-12-28 2017-05-02 Solid forms of N[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US15/900,147 Active US10537565B2 (en) 2005-12-28 2018-02-20 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US16/704,713 Active US11291662B2 (en) 2005-12-28 2019-12-05 Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US17/953,412 Pending US20230263794A1 (en) 2005-12-28 2022-09-27 Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

Family Applications After (8)

Application Number Title Priority Date Filing Date
US13/358,778 Active US8410274B2 (en) 2005-12-28 2012-01-26 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US13/785,692 Active US8754224B2 (en) 2005-12-28 2013-03-05 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US14/272,692 Active US9139530B2 (en) 2005-12-28 2014-05-08 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US14/852,892 Active US9670163B2 (en) 2005-12-28 2015-09-14 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US15/584,324 Active US9931334B2 (en) 2005-12-28 2017-05-02 Solid forms of N[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US15/900,147 Active US10537565B2 (en) 2005-12-28 2018-02-20 Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US16/704,713 Active US11291662B2 (en) 2005-12-28 2019-12-05 Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US17/953,412 Pending US20230263794A1 (en) 2005-12-28 2022-09-27 Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

Country Status (20)

Country Link
US (9) US20110064811A1 (sr)
EP (3) EP3708564B1 (sr)
JP (3) JP5409010B2 (sr)
CN (1) CN101384172B (sr)
AU (1) AU2006332726B2 (sr)
BR (1) BRPI0620960A2 (sr)
CA (1) CA2635581C (sr)
CY (2) CY1118980T1 (sr)
DK (2) DK3219705T3 (sr)
ES (2) ES2790700T3 (sr)
HK (1) HK1125540A1 (sr)
HR (2) HRP20170682T1 (sr)
HU (2) HUE049976T2 (sr)
LT (2) LT3219705T (sr)
ME (1) ME03786B (sr)
PL (2) PL3219705T3 (sr)
PT (2) PT3219705T (sr)
RS (2) RS60205B1 (sr)
SI (1) SI3219705T1 (sr)
WO (1) WO2007079139A2 (sr)

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080306062A1 (en) * 2005-11-08 2008-12-11 Hadida Ruah Sara S Modulators of atp-binding cassette transporters
US20090143381A1 (en) * 2007-11-16 2009-06-04 Hadida Ruah Sara S Modulators of atp-binding cassette-transporters
US20090170905A1 (en) * 2007-12-07 2009-07-02 Ali Keshavarz-Shokri Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US20090176839A1 (en) * 2007-12-07 2009-07-09 Ali Keshavarz-Shokri Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US20090176989A1 (en) * 2007-12-07 2009-07-09 David Siesel Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US20090221597A1 (en) * 2008-02-28 2009-09-03 Sara Hadida Ruah Heteroaryl derivatives as cftr modulators
US20090246137A1 (en) * 2008-03-31 2009-10-01 Vertex Pharmaceuticals Incorporated Pyridyl derivatives as cftr modulators
US20090253736A1 (en) * 2007-11-02 2009-10-08 Vertex Pharmaceuticals Incorporated Azaindole derivatives as cftr modulators
US20100036130A1 (en) * 2007-12-07 2010-02-11 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US20100087490A1 (en) * 2008-09-29 2010-04-08 Vertex Pharmaceuticals Incorporated Dosage Units of 3-(6-(1-(2,2-Difluorobenzo[D] [1,3] Dioxol-5-YL) Cyclopropanecarboxamido)-3-Methylpyridin-2-YL)Benzoic Acid
US20100113555A1 (en) * 2006-04-07 2010-05-06 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette Transporters
US20100113508A1 (en) * 2008-10-23 2010-05-06 Vertex Pharmaceuticals, Incorporated Modulators of Cystic Fibrosis Transmembrane Conductance Regulator
US20100249113A1 (en) * 2005-12-28 2010-09-30 Vertex Pharmaceuticals Incorporated Modulators of atp binding cassette transporters
US20100331344A1 (en) * 2006-04-07 2010-12-30 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette Transporters
US20110144123A1 (en) * 2003-11-14 2011-06-16 Vertex Pharmaceuticals Incorporated Thiazoles and Oxazoles Useful as Modulators of ATP-Binding Cassette Transporters
US20110230519A1 (en) * 2010-03-19 2011-09-22 Vertex Pharmaceuticals Incorporated Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
WO2011133953A1 (en) 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
WO2011133951A1 (en) 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
US8076357B2 (en) 2006-05-12 2011-12-13 Vertex Pharmaceuticals Incorporated Compositions of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US20120220625A1 (en) * 2008-08-13 2012-08-30 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US8431605B2 (en) 2003-09-06 2013-04-30 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
US8507687B2 (en) 2010-04-07 2013-08-13 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
WO2013130669A1 (en) 2012-02-27 2013-09-06 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administration thereof
US8541453B2 (en) 2004-08-20 2013-09-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8552034B2 (en) 2010-04-07 2013-10-08 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and administration thereof
US8563593B2 (en) 2010-06-08 2013-10-22 Vertex Pharmaceuticals Incorporated Formulations of (R)-1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US8586615B2 (en) 2005-08-11 2013-11-19 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US8674108B2 (en) 2012-04-20 2014-03-18 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethy)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US8802868B2 (en) 2010-03-25 2014-08-12 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide
WO2014125506A2 (en) * 2013-02-15 2014-08-21 Laurus Labs Private Limited A process for the preparation of ivacaftor and its intermediates
US8969386B2 (en) 2007-05-09 2015-03-03 Vertex Pharmaceuticals Incorporated Modulators of CFTR
US9012496B2 (en) 2012-07-16 2015-04-21 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of (R)-1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide and administration thereof
US9254291B2 (en) 2011-11-08 2016-02-09 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9371287B2 (en) 2009-03-20 2016-06-21 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
US9399648B2 (en) 2007-08-24 2016-07-26 Vertex Pharmaceuticals Incorporated Isothiazolopyridinones useful for the treatment of (inter alia) cystic fibrosis
WO2016181414A1 (en) 2015-05-12 2016-11-17 Council Of Scientific & Industrial Research Process for the synthesis of ivacaftor and related compounds
US9670163B2 (en) 2005-12-28 2017-06-06 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
WO2017208253A2 (en) 2016-05-30 2017-12-07 Council Of Scientific & Industrial Research An improved process for the synthesis of ivacaftor
US10022352B2 (en) 2006-04-07 2018-07-17 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10047053B2 (en) 2011-05-18 2018-08-14 Vertex Pharmaceuticals (Europe) Limited Deuterated CFTR potentiators
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10231932B2 (en) 2013-11-12 2019-03-19 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
US10302602B2 (en) 2014-11-18 2019-05-28 Vertex Pharmaceuticals Incorporated Process of conducting high throughput testing high performance liquid chromatography
US10646481B2 (en) 2008-08-13 2020-05-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US10662192B2 (en) 2004-06-24 2020-05-26 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10759721B2 (en) 2015-09-25 2020-09-01 Vertex Pharmaceuticals (Europe) Limited Deuterated CFTR potentiators
US11179469B2 (en) 2017-04-28 2021-11-23 Nitto Denko Corporation Transdermal absorption preparation
WO2022013360A1 (en) * 2020-07-17 2022-01-20 Synthon B.V. Pharmaceutical composition comprising ivacaftor
US11708331B2 (en) 2017-12-01 2023-07-25 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator

Families Citing this family (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW201414469A (zh) * 2006-03-20 2014-04-16 Vertex Pharma 對包括ｖｘ-９５０之藥物實施噴霧乾燥之方法及由此方法製備之產物
CA2699292A1 (en) * 2007-09-14 2009-03-26 Vertex Pharmaceuticals Incorporated Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
CN101959856A (zh) * 2008-03-11 2011-01-26 雷迪博士实验室有限公司 来那度胺的制备
EP2263671B1 (en) * 2008-04-02 2016-07-20 Astellas Pharma Inc. Amide derivative-containing pharmaceutical composition
US20100256184A1 (en) * 2008-08-13 2010-10-07 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
MX2011004374A (es) * 2008-10-23 2011-05-23 Vertex Pharma Formas solidas de n-(4-(7-azabiciclo[2.2.1]heptan-7-il)-2-(trifluo rometil)fenil)-4-oxo-5-(trifluorometil)-1,4-dihidroquinolin-3-car boxamida.
NZ592687A (en) * 2008-10-23 2013-04-26 Vertex Pharma Modulators of cystic fibrosis transmembrane conductance regulator
CA2755969C (en) 2009-03-20 2018-05-08 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
JP5877157B2 (ja) 2009-10-23 2016-03-02 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ Ｎ−（４−（７−アザビシクロ［２．２．１］ヘプタン−７−イル）−２−（トリフルオロメチル）フェニル）−４−オキソ−５−（トリフルオロメチル）−１，４−ジヒドロキノリン−３−カルボキサミドの固体形態
NZ603386A (en) * 2010-05-20 2015-02-27 Vertex Pharma Pharmaceutical compositions and administrations thereof
JP2013536231A (ja) * 2010-08-23 2013-09-19 バーテックス ファーマシューティカルズ インコーポレイテッド （ｒ）−１−（２，２−ジフルオロベンゾ［ｄ］［１，３］ジオキソール−５−イル）−ｎ−（１−（２，３−ジヒドロキシプロピル）−６−フルオロ−２−（１−ヒドロキシ−２−メチルプロパン−２−イル）−１ｈ−インドール−５−イル）シクロプロパンカルボキサミドを含む医薬組成物およびその投与
JP2013536251A (ja) 2010-08-27 2013-09-19 バーテックス ファーマシューティカルズ インコーポレイテッド 薬学的組成物およびその投与
PL2709986T3 (pl) 2011-05-18 2017-09-29 Concert Pharmaceuticals Inc. Deuterowane pochodne iwakaftoru
EP2838882A1 (en) * 2012-04-20 2015-02-25 Vertex Pharmaceuticals Incorporated Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
MY183582A (en) 2012-11-19 2021-02-26 Vertex Pharmaceuticals Europe Ltd Deuterated cftr potentiators
CN103044263A (zh) * 2013-01-14 2013-04-17 中国药科大学 一种治疗囊性纤维化药物的中间体的制备方法
ES2730474T3 (es) * 2013-01-31 2019-11-11 Glenmark Pharmaceuticals Ltd Proceso para la preparación de ivacaftor y solvatos de este
CA2906008C (en) 2013-03-13 2019-07-09 Flatley Discovery Lab, Llc Pyridazinone compounds and methods for the treatment of cystic fibrosis
CA2927661A1 (en) 2013-11-13 2015-05-21 Apotex Inc. Solid forms of ivacaftor and processes for the preparation thereof
CN104644557B (zh) * 2013-11-22 2017-10-31 上海宣泰医药科技有限公司 卟啉铁固体分散体及其制备方法
WO2015128882A2 (en) * 2014-02-27 2015-09-03 Msn Laboratories Private Limited Crystalline forms of n-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide and process for the preparation thereof
CN112250627B (zh) 2014-10-06 2024-02-02 弗特克斯药品有限公司 囊性纤维化跨膜转导调节因子调节剂
EP3229791A4 (en) * 2014-12-09 2018-09-26 Laurus Labs Limited Novel polymorphs of ivacaftor, process for its preparation and pharmaceutical composition thereof
CN104725314A (zh) * 2015-03-23 2015-06-24 上海皓元化学科技有限公司 一种Ivacaftor的新晶型及其制备方法
PT108370B (pt) * 2015-03-30 2018-10-25 Hovione Farm S A Processo de preparação de brometo de aclidínio
WO2016160945A1 (en) 2015-03-31 2016-10-06 Concert Pharmaceuticals, Inc. Deuterated vx-661
ES2839299T3 (es) 2015-09-02 2021-07-05 Laurus Labs Ltd Procedimientos para la preparación de ivacaftor
US20180353500A1 (en) 2015-09-21 2018-12-13 Vertex Pharmaceuticals (Europe) Limited Administration of deuterated cftr potentiators
HUP1600271A2 (hu) 2016-04-25 2017-10-30 Druggability Tech Ip Holdco Ltd Ivacaftor és Lumacaftor sóinak és származékainak komplexei, eljárás azok elõállítására és azok gyógyszerészetileg elfogadható készítményei
HUP1600270A2 (hu) * 2016-04-25 2017-10-30 Druggability Tech Ip Holdco Ltd Ivacaftornak, sóinak és származékainak komplexei, eljárás azok elõállítására és azok gyógyszerészetileg elfogadott készítményei
US10383865B2 (en) 2016-04-25 2019-08-20 Druggability Technologies Ip Holdco Limited Pharmaceutical combination composition comprising complex formulations of Ivacaftor and Lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them
US10206915B2 (en) * 2016-04-25 2019-02-19 Druggability Technologies Ip Holdco Limited Complexes of Ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
CA3022519A1 (en) 2016-05-04 2017-11-09 Concert Pharmaceuticals, Inc. Treatment of hair loss disorders with deuterated jak inhibitors
RS62670B1 (sr) 2016-09-30 2021-12-31 Vertex Pharma Modulator transmembranskog regulatora provodnosti cistične fibroze, farmaceutske kompozicije, metode lečenja i proces izrade modulatora
MX2019006637A (es) 2016-12-09 2019-08-21 Vertex Pharma Modulador del regulador de conductancia transmembrana de fibrosis quistica composiciones farmaceuticas metodos de tratamiento y proceso para producir el modulador.
AU2018279646B2 (en) 2017-06-08 2023-04-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
MA49631A (fr) 2017-07-17 2020-05-27 Vertex Pharma Méthodes de traitement de la fibrose kystique
CA3071278A1 (en) 2017-08-02 2019-02-07 Vertex Pharmaceuticals Incorporated Processes for preparing pyrrolidine compounds
CA3078893A1 (en) 2017-10-19 2019-04-25 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of cftr modulators
MX2020005753A (es) 2017-12-08 2020-08-20 Vertex Pharma Procesos para producir moduladores de regulador de conductancia transmembranal de fibrosis quistica.
WO2019136314A1 (en) 2018-01-05 2019-07-11 The Curators Of The University Of Missouri Compounds and methods for treatment of cystic fibrosis
WO2019148195A2 (en) 2018-01-29 2019-08-01 Ohio State Innovation Foundation Cyclic peptidyl inhibitors of cal-pdz binding domain
TWI810243B (zh) 2018-02-05 2023-08-01 美商維泰克斯製藥公司 用於治療囊腫纖化症之醫藥組合物
US11066417B2 (en) 2018-02-15 2021-07-20 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulators
WO2019200246A1 (en) 2018-04-13 2019-10-17 Alexander Russell Abela Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
WO2020214921A1 (en) 2019-04-17 2020-10-22 Vertex Pharmaceuticals Incorporated Solid forms of modulators of cftr
TW202115092A (zh) 2019-08-14 2021-04-16 美商維泰克斯製藥公司 囊腫纖維化跨膜傳導調節蛋白之調節劑
MX2022001828A (es) 2019-08-14 2022-06-08 Vertex Pharma Formas cristalinas de moduladores del regulador de conductancia transmembrana de la fibrosis quistica (cftr).
TW202120517A (zh) 2019-08-14 2021-06-01 美商維泰克斯製藥公司 製備cftr調節劑之方法
CA3150738A1 (en) 2019-08-14 2021-02-18 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2021236139A1 (en) 2020-05-21 2021-11-25 Concert Pharmaceuticals, Inc. Novel deuterated jak inhibitor and uses thereof
CR20230120A (es) 2020-08-07 2023-09-01 Vertex Pharma Moduladores del regulador de la conductancia transmembrana de la fibrosis quística
MX2023001744A (es) 2020-08-13 2023-04-19 Vertex Pharma Formas cristalinas de moduladores de regulador de conductancia transmembrana de la fibrosis quística (cftr).
MX2023001993A (es) 2020-08-20 2023-02-27 Univ Leland Stanford Junior Metodos para tratar enfermedades respiratorias caracterizados por hipersecrecion de mucosidad.
JP2023545081A (ja) 2020-10-07 2023-10-26 バーテックス ファーマシューティカルズ インコーポレイテッド 嚢胞性線維症膜コンダクタンス制御因子モジュレーター
WO2022076621A1 (en) 2020-10-07 2022-04-14 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US20230365587A1 (en) 2020-10-07 2023-11-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
EP4225763A1 (en) 2020-10-07 2023-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
CR20230198A (es) 2020-10-07 2023-07-03 Vertex Pharma Moduladores del regulador de la conductancia transmembrana de la fibrosis quística
WO2022076627A1 (en) 2020-10-07 2022-04-14 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US20230374038A1 (en) 2020-10-07 2023-11-23 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
KR20230104619A (ko) 2020-10-07 2023-07-10 버텍스 파마슈티칼스 인코포레이티드 낭성 섬유증 막관통 전도도 조절자의 조절제
WO2022076628A1 (en) 2020-10-07 2022-04-14 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
EP4225750A1 (en) 2020-10-07 2023-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11384054B2 (en) * 2020-10-22 2022-07-12 Scinopharm Taiwan, Ltd. Crystalline form of ivacaftor and a process for preparing the same
AU2021372512A1 (en) 2020-10-28 2023-06-22 Sun Pharmaceutical Industries, Inc. Regimens for the treatment of hair loss disorders with deuterated jak inhibitors
WO2022098644A1 (en) 2020-11-03 2022-05-12 Landos Biopharma, Inc. Crystalline forms of piperazine-1,4-diylbis((6-(1h-benzoi[d]imidazo-2-yl)pyridin-2yl)methanone) as lancl2 modulators
CA3204725A1 (en) 2020-12-10 2022-06-16 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
WO2022190126A1 (en) * 2021-03-09 2022-09-15 Laurus Labs Limited Oral film of cftr modulator(s)
EP4329815A1 (en) 2021-04-29 2024-03-06 Novartis AG Deubiquitinase-targeting chimeras and related methods
CN118159272A (zh) 2021-08-11 2024-06-07 太阳医药工业公司 用氘化的jak抑制剂来治疗脱发病症
CA3228509A1 (en) 2021-08-12 2023-02-16 Sun Pharmaceutical Industries, Inc. Treatment of jak-inhibition-responsive disorders with prodrugs of jak inhibitors
AU2023215372A1 (en) 2022-02-03 2024-08-22 Vertex Pharmaceuticals Incorporated Methods of preparing and crystalline forms of (6a,12a)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[ 12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol
TW202333699A (zh) 2022-02-03 2023-09-01 美商維泰克斯製藥公司 囊腫纖維化之治療方法
AU2023218262A1 (en) 2022-02-08 2024-08-22 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
AU2023249173A1 (en) 2022-04-06 2024-10-03 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2023215520A1 (en) 2022-05-04 2023-11-09 Sun Pharmaceutical Industries, Inc. Dosage regimens for treatment with deuterated jak inhibitors
WO2023224931A1 (en) 2022-05-16 2023-11-23 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
WO2023224924A1 (en) 2022-05-16 2023-11-23 Vertex Pharmaceuticals Incorporated Solid forms of a macrocyclic compounds as cftr modulators and their preparation
WO2024031081A1 (en) 2022-08-04 2024-02-08 Vertex Pharmaceuticals Incorporated Compositions for the treatment of cftr-mediated diseases
EP4335434A1 (en) 2022-08-17 2024-03-13 Sanovel Ilac Sanayi Ve Ticaret A.S. Pharmaceutical compositions comprising ivacaftor
WO2024056798A1 (en) 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Macrocyclic cftr modulators
TW202421102A (zh) 2022-09-15 2024-06-01 瑞士商愛杜西亞製藥有限公司 巨環cftr調節劑與cftr校正子及/或cftr增效劑之組合

Citations (82)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3524858A (en) * 1967-05-18 1970-08-18 Warner Lambert Pharmaceutical 1,4 - dihydro-1-substituted alkyl-6,7-methylenedioxy - 4 - oxoquinoline-3-carboxylic acid
US3992540A (en) * 1974-08-13 1976-11-16 Roussel-Uclaf 3-Quinoline-substituted 4-oxy-carboxamides
US4107310A (en) * 1976-02-11 1978-08-15 Roussel Uclaf Quinoline-3-carboxamides
US4221779A (en) * 1977-06-28 1980-09-09 Graham Neil B Pharmaceutical composition for treating tropical diseases
US4312870A (en) * 1979-06-21 1982-01-26 Ciba-Geigy Corporation Pyrazoloquinolines
US4450166A (en) * 1981-06-12 1984-05-22 Roussel Uclaf N-(4,5-Dihydro-thiazol-2-yl)-3-quinoline-carboxamides having anxiolytic activity
US4450167A (en) * 1981-07-17 1984-05-22 Roussel Uclaf 3-Quinoline carboxamides having anxiolytic activity
US4777252A (en) * 1987-08-13 1988-10-11 E. R. Squibb & Sons, Inc. 2-oxo-1-[[(substituted sulfonyl)amino]-carbonyl]azetidines
US4786644A (en) * 1987-11-27 1988-11-22 Hoechst-Roussel Pharmaceuticals Inc. 1-aryl-3-quinolinecarboxamide
US4845105A (en) * 1984-10-30 1989-07-04 Roussel Uclaf 4-OH-quinoline carboxylic acid amides having analgesic and anti-inflammatory activity
US4908366A (en) * 1987-01-28 1990-03-13 Bayer Aktiengesellschaft Antibacterial 8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids
US4956465A (en) * 1987-10-09 1990-09-11 Bayer Aktiengesellschaft Quinolone- and 1,8-naphthyridin-4-one-carboxylic acids which are C-bonded in the 7-position
US5026711A (en) * 1988-06-06 1991-06-25 Sanofi 4-amino quinolines and naphthyridines and their use as medicines
US5175151A (en) * 1990-09-07 1992-12-29 Schering Corporation Antiviral compounds and antihypertensive compounds
US5180400A (en) * 1990-05-29 1993-01-19 L'oreal Method for dyeing keratinous fibres using an aminoindole in combination with a quinone derivative
US5322847A (en) * 1992-11-05 1994-06-21 Pfizer Inc. Azabenzimidazoles in the treatment of asthma, arthritis and related diseases
US5352690A (en) * 1992-07-01 1994-10-04 Eli Lilly And Company 1,2,4-trioxygenated benzene derivatives useful as leukotriene antagonists
US5364414A (en) * 1989-10-20 1994-11-15 L'oreal Tinctorial composition for keratinous fibres containing oxidation dye precursors and aminoindole couplers, methods for dyeing using these compositions and new compounds
US5378694A (en) * 1990-09-07 1995-01-03 Schering Corporation Acyl and alkoxy substituted quinolines
US5380713A (en) * 1991-08-06 1995-01-10 Bristol-Myers Squibb Company Peptide aldehydes as antithrombotic agents
US5412104A (en) * 1990-09-07 1995-05-02 Schering Corporation Ester and alkoxy substituted benzopyrans
US5491139A (en) * 1988-10-24 1996-02-13 The Procter & Gamble Company Antimicrobial quinolonyl lactams
US5527763A (en) * 1991-12-24 1996-06-18 Kumiai Chemical Industry Co., Ltd. Pyrimidine or triazine derivatives and herbicides
US5536727A (en) * 1992-05-20 1996-07-16 Merck & Co., Inc. 17-Ethers and thioethers of 4-aza-steroids
US5573868A (en) * 1993-04-22 1996-11-12 Daikin Industries, Ltd. Material for generating electric energy
US5610162A (en) * 1992-05-20 1997-03-11 Merck & Co., Inc. Ester derivatives of 4-aza-steroids
US5663179A (en) * 1992-07-10 1997-09-02 Laboratoires Glaxo Sa Certain isoquinoline derivatives having anti-tumor properties
US5708000A (en) * 1994-05-24 1998-01-13 Laboratoire Laphal N4-substituted cytosinyl 1,3-oxathiolane nucleoside analogues, and their antiviral activity
US5728691A (en) * 1994-02-25 1998-03-17 Laboratorios Aranda S.A. De C.V. Quinolonylcarboxamidocephalosporin derivatives and pharmaceutical compositions containing them
US5744471A (en) * 1993-10-22 1998-04-28 Zeneca Limited Pyridazion quinoline compounds
US5750754A (en) * 1993-03-29 1998-05-12 Zeneca Limited Heterocyclic compounds
US5753666A (en) * 1995-08-02 1998-05-19 Chiroscience Limited Quinolones and their therapeutic use
US5804588A (en) * 1996-05-20 1998-09-08 Chiroscience Limited Quinoline carboxanides and their therapeutic use
US5807869A (en) * 1995-10-19 1998-09-15 Takeda Chemical Industries, Ltd. Quinoline derivatives, their production and use
US5811553A (en) * 1994-05-27 1998-09-22 Smithkline Beecham Farmaceutici S.P.A. Quinoline derivatives(2)
US5834485A (en) * 1996-05-20 1998-11-10 Chiroscience Limited Quinoline sulfonamides and their therapeutic use
US5840745A (en) * 1995-01-26 1998-11-24 Pharmacia S. P. A. Hydrosoluble 3-arylidene-2-oxindole derivatives as tyrosine kinase inhibitors
US5874424A (en) * 1995-12-20 1999-02-23 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US5891878A (en) * 1995-08-02 1999-04-06 Chiroscience Limited Quinolones and their therapeutic use
US5892114A (en) * 1996-04-18 1999-04-06 Bayer Aktiengesellschaft Hetero-linked phenylglycinolamides
US6069151A (en) * 1996-11-06 2000-05-30 Darwin Discovery, Ltd. Quinolines and their therapeutic use
US6133265A (en) * 1996-07-23 2000-10-17 Neurogen Corporation Certain amido- and amino- substituted benzylamine derivatives; a new class of neuropeptide Y1 specific ligands
US6215016B1 (en) * 1996-03-27 2001-04-10 Toray Industries, Inc. Ketone derivatives and medical application thereof
US6218393B1 (en) * 1996-10-18 2001-04-17 Xenova Limited Anthranilic acid derivatives as multi drug resistance modulators
US6258822B1 (en) * 1997-08-06 2001-07-10 Abbott Laboratories Urokinase inhibitors
US6362340B1 (en) * 1998-12-01 2002-03-26 Rhodia Chimie Method for preparing 4-hydroquinolines and/or tautomeric compounds
US6395750B1 (en) * 1999-10-25 2002-05-28 Active Biotech Ab Drugs for the treatment of malignant tumors
US6413956B1 (en) * 1999-05-06 2002-07-02 Neurogen Corporation Substituted 4-oxo-quinoline-3-carboxamides
US6429207B1 (en) * 1997-11-21 2002-08-06 Nps Pharmaceuticals, Inc. Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases
US6444617B1 (en) * 1998-07-28 2002-09-03 Nihon Nohyaku Co., Ltd. Fused-heterocycle dicarboxylic acid diamide derivatives or salts thereof, herbicide and usage thereof
US6448254B1 (en) * 1998-04-20 2002-09-10 Abbott Laboratories Substituted amides, their production and their use
US20020173520A1 (en) * 1998-07-15 2002-11-21 Active Biotech Ab Quinoline derivatives
US6515001B2 (en) * 2001-03-05 2003-02-04 Chemokine Therapeutic Corporation IL-8 receptor ligands-drugs for inflammatory and autoimmune diseases
US6544987B2 (en) * 1999-12-01 2003-04-08 Pfizer Inc. Compounds, compositions, and methods for stimulating neuronal growth and elongation
US20030195201A1 (en) * 2001-12-10 2003-10-16 Bo Yunxin Y. Vanilloid receptor ligands and their use in treatments
US20030195191A1 (en) * 2000-05-11 2003-10-16 Gordon Burton N-sulfonyl hydroxamic acid derivatives as inhibitors of cd23
US20040033959A1 (en) * 2002-07-19 2004-02-19 Boehringer Ingelheim Pharmaceuticals, Inc. Pharmaceutical compositions for hepatitis C viral protease inhibitors
US20040043983A1 (en) * 2002-08-13 2004-03-04 Li Jie Jack Naphthalene derivatives as matrix metalloproteinase inhibitors
US6720344B2 (en) * 1996-06-20 2004-04-13 The Board Of Regents Of The University Of Texas System Methods and compositions for stimulating osteoblast proliferation or treating malignant cell proliferation and methods for selecting osteoblast proliferation stimulants
US6723850B1 (en) * 1998-08-03 2004-04-20 Applied Research Systems Ars Holding N.V. Process for the synthesis of (1-H)-benzo[c]quinolizin-3-ones derivatives
US20040082798A1 (en) * 2001-03-07 2004-04-29 Cristina Alonso-Alija Novel amino dicarboxylic acid derivatives with pharmaceutical properties
US20040121005A1 (en) * 2000-06-15 2004-06-24 Acusphere, Inc. Porous COX-2 inhibitor matrices and methods of manufacture thereof
US6790858B2 (en) * 2001-02-21 2004-09-14 Zentaris Ag Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormone
US6849648B2 (en) * 2001-10-12 2005-02-01 Warner-Lambert Company Phenylene alkyne matrix metalloproteinase inhibitors
US6878713B2 (en) * 2001-04-25 2005-04-12 Wockhardt Limited Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments
US20050176741A1 (en) * 2002-04-26 2005-08-11 Masahiko Okano Quinazoline derivative and medicine
US6930131B2 (en) * 2002-04-10 2005-08-16 Wyeth Aryl substituted 3-ethoxy phenyl trifluoromethane sulfonamides for the treatment of non-insulin dependent diabetes mellitus (NIDDM)
US20050186261A1 (en) * 2004-01-30 2005-08-25 Angiotech International Ag Compositions and methods for treating contracture
US20050187300A1 (en) * 2002-07-15 2005-08-25 Myriad Genetics, Incorporated Compounds, compositions, and methods employing same
US20050192315A1 (en) * 2004-02-06 2005-09-01 Active Biotech Ab New compositions containing quinoline compounds
US20050208095A1 (en) * 2003-11-20 2005-09-22 Angiotech International Ag Polymer compositions and methods for their use
US20050222199A1 (en) * 2002-05-14 2005-10-06 Xenova Limited Process for the preparation of a hydrate of an antranilic acid derivative
US6974806B2 (en) * 2000-07-13 2005-12-13 Takeda Pharmaceutical Company Limited Lipid-rich plaque inhibitors
US6977001B2 (en) * 2002-03-15 2005-12-20 Wella Ag Dye compositions containing quinolinium salts
US7037913B2 (en) * 2002-05-01 2006-05-02 Bristol-Myers Squibb Company Bicyclo 4.4.0 antiviral derivatives
US20060148806A1 (en) * 2003-07-24 2006-07-06 Susumu Watanuki Quinolone derivative or salt thereof
US7084156B2 (en) * 2001-11-27 2006-08-01 Merck & Co., Inc. 2-Aminoquinoline compounds
US20060178516A1 (en) * 2002-05-14 2006-08-10 Johnstone Timothy B Substituted quinolone carboxylic acids, their derivatives, site of action, and uses thereof
US7105535B2 (en) * 2001-02-02 2006-09-12 Pfizer Italia S.R.L. Oxazolyl-pyrazole derivatives as kinase inhibitors
US7112594B2 (en) * 2000-08-09 2006-09-26 Mitsubishi Pharma Corporation Fused bicyclic amide compounds and medicinal use thereof
US7179839B2 (en) * 2001-02-13 2007-02-20 Sanofi-Aventis Deutschland Gmbh Acylated indanyl amines and their use as pharmaceuticals
US7495103B2 (en) * 2004-06-24 2009-02-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters

Family Cites Families (413)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE279887C (sr)
FR960299A (sr) 1950-04-15
US3830797A (en) 1964-11-05 1974-08-20 Pennwalt Corp Tertiary-aliphatic-alpha-(peracyl)azo compounds
US3751406A (en) 1967-07-24 1973-08-07 Polaroid Corp Azo compounds useful in photographic processes
DE1908548A1 (de) 1968-02-29 1970-11-05 Warner Lambert Co Chinolinderivate
BE757639A (fr) 1969-10-17 1971-04-16 Roussel Uclaf Nouveaux derives de la cephalosporine et procede de preparation
AT308173B (de) 1970-02-03 1973-06-25 Maurer Friedrich Soehne Überbrückungsvorrichtung für Dehnungsfugen in Brücken od. dgl.
US4110355A (en) 1972-12-26 1978-08-29 Polaroid Corporation Anthraquinone compounds useful in photographic processes
US3931145A (en) 1972-12-27 1976-01-06 Gaf Corporation Keto-amido containing phenylazophenyl dyestuffs
GB1433774A (en) 1973-02-26 1976-04-28 Allen & Hanburys Ltd Heterocyclic compounds apparatus for conveying articles
GB1433151A (en) 1973-04-05 1976-04-22 Allen & Hanburys Ltd Benzo-ij-quinolizines
FR2324304A2 (fr) 1975-09-22 1977-04-15 Roussel Uclaf Nouveaux derives de l'acide 3-quinoleine carboxylique, leur procede de preparation et leur application comme medicament
FR2340092A2 (fr) 1976-02-09 1977-09-02 Roussel Uclaf Nouveaux derives de l'acide 3-quinoleine carboxylique, leur procede de preparation et leur application comme medicament
DE2808070A1 (de) 1978-02-24 1979-08-30 Bayer Ag Verfahren zur herstellung von 4-pyridon-3-carbonsaeuren und/oder deren derivaten
FR2443467A1 (fr) 1978-12-08 1980-07-04 Roussel Uclaf Nouveaux derives de l'acide 3-quinoleine carboxylique, leur procede de preparation et leur application comme medicament
JPS56110612A (en) * 1980-02-08 1981-09-01 Yamanouchi Pharmaceut Co Ltd Readily disintegrable and absorbable compression molded article of slightly soluble drug
US4390541A (en) 1980-12-19 1983-06-28 Lilly Industries Limited Quinolone derivatives and their use in a method of controlling an immediate hypersensitivity disease
US4638067A (en) 1982-09-09 1987-01-20 Warner-Lambert Co. Antibacterial agents
US5281612A (en) 1982-09-09 1994-01-25 Warner-Lambert Company Naphthyridine antibacterial agents
FR2537140B1 (fr) 1982-12-07 1986-07-18 Roussel Uclaf Nouveaux derives de la 4-hydroxy-3-quinoleine carboxamide, leur sels, procede de preparation, application a titre de medicaments, et compositions les renfermant
SU1360584A3 (ru) 1983-08-12 1987-12-15 Варнер-Ламберт Компани (Фирма) Способ получени нафтиридинхинолин-или бензоксазинкарбоновых кислот или их фармацевтически допустимых солей присоединени кислоты
EP0180548B1 (de) 1984-11-01 1989-06-28 Ciba-Geigy Ag Gegen Lichteinwirkung stabilisierte Ueberzugsmittel
US4687539A (en) 1986-10-29 1987-08-18 International Business Machines Corp. End point detection and control of laser induced dry chemical etching
DD279887A1 (de) 1987-07-03 1990-06-20 Inst Pharmakologische Forschun Verfahren zur herstellung von d-alpha-(4(1h)-1,5-naphthyridon-3-carboxamido)-benzylpenicillin und anderen beta-lactamantibiotika
DE3827253A1 (de) 1987-08-20 1989-03-02 Sandoz Ag Ester und amide von cyclischen carbonsaeuren und cyclischen alkoholen und aminen sowie verfahren zu deren herstellung und sie enthaltende therapeutische zusammensetzungen
PL153722B1 (en) 1987-08-27 1991-05-31 Suitomo Chemical Co Ltdjp Method for manufacturing 3-fluoro-4-aminephenol
DE3731516A1 (de) 1987-09-18 1989-03-30 Bayer Ag N-aryl-stickstoffheterocyclen
DE3808117A1 (de) 1988-03-11 1989-09-21 Bayer Ag N-cyclopropylaniline und deren verwendung in verfahren zur herstellung von 1-cyclopropyl-chinoloncarbonsaeuren und deren derivaten
DE3808118A1 (de) 1988-03-11 1989-09-21 Bayer Ag Verfahren zur herstellung von 1-cyclopropyl-chinoloncarbonsaeuren und deren derivaten
DE3816119A1 (de) 1988-05-11 1989-11-23 Bayer Ag 7-substituierte chinolon- und naphthyridoncarbonsaeure-derivate
JPH01287066A (ja) 1988-05-13 1989-11-17 Fujimoto Seiyaku Kk 新規なアントラニル酸誘導体
JPH01168920U (sr) 1988-05-18 1989-11-29
DE3827221A1 (de) 1988-08-11 1990-02-15 Bayer Ag Substituierte n-phenyl-stickstoff- bzw. stickstoff-schwefel-heterocyclen, verfahren sowie entsprechende heterocyclische phenolderivate, phenyliso(thio)cyanate und -carbamate als zwischenprodukte zu ihrer herstellung, ihre verwendung in herbiziden und pflanzenwuchsregulierenden mitteln
DE3903799A1 (de) 1989-02-09 1990-08-16 Bayer Ag N-aryl-stickstoffheterocyclen
JPH0334977A (ja) 1989-06-29 1991-02-14 Yoshitomi Pharmaceut Ind Ltd イミダゾリルベンゾラクタム化合物
DE3924052A1 (de) 1989-07-21 1991-01-24 Bayer Ag N- (indol-6-yl)-heterocyclen
EP0418596A3 (en) 1989-09-21 1991-10-23 American Cyanamid Company Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form
GB2236751B (en) 1989-10-14 1993-04-28 Wyeth John & Brother Ltd Heterocyclic compounds
US5254135A (en) 1989-10-20 1993-10-19 L'oreal Methods for dyeing keratinous fibres with aminoindoles, compositions and devices for use
FR2659552B2 (fr) 1989-10-20 1994-11-04 Oreal Procede de teinture des fibres keratiniques avec des aminoindoles, composition et dispositif de mise en óoeuvre.
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5409503A (en) 1990-05-31 1995-04-25 Wella Aktiengesellschaft Oxidation hair dye with a content of 5-aminophenyl derivatives, process for oxidative dyeing of hair and new 5-aminophenol derivatives
DE4017516A1 (de) 1990-05-31 1991-12-05 Wella Ag Oxidationshaarfaerbemittel mit einem gehalt an 3-aminophenol-derivaten, verfahren zum oxidativen faerben von haaren sowie neue 3-aminophenol-derivate
DE4026530A1 (de) 1990-08-22 1992-02-27 Basf Ag Synergistische mittel zur regulierung des pflanzenwachstums
JPH04171521A (ja) 1990-11-05 1992-06-18 Fujitsu Ltd タッチパネル
IL100917A0 (en) 1991-02-16 1992-11-15 Fisons Plc Pyridinone and pyrimidinone derivatives,their preparation and pharmaceutical compositions containing them
RU1796623C (ru) 1991-03-11 1993-02-23 Институт химии Башкирского научного центра Уральского отделения АН СССР Способ получени этилового эфира 6,7-дифтор-1,4-дигидро-4-оксо-3-хинолинкарбоновой кислоты
CA2065106A1 (en) 1991-04-04 1992-10-05 Junichi Fukawa Silver halide photographic light-sensitive material and photographic product for film-making process
FR2675380A1 (fr) 1991-04-18 1992-10-23 Oreal Procede de teinture des fibres keratiniques avec des aminoindoles, a ph basique, compositions mises en óoeuvre et nouveaux composes.
US5938792A (en) 1991-04-18 1999-08-17 L'oreal Process for dyeing keratinous fibers with aminoindoles and oxidation dye precursors at basic Ph's and dyeing agents
GB9108547D0 (en) 1991-04-22 1991-06-05 Fujisawa Pharmaceutical Co Quinoline derivatives
SK117793A3 (en) 1991-04-29 1994-05-11 Merck & Co Inc Optimized tablet formulation
JPH05184185A (ja) 1991-12-27 1993-07-23 Copal Electron Co Ltd Ｄｃブラシレスモータ速度制御方法
JPH05231760A (ja) 1992-02-24 1993-09-07 Sanyo Electric Co Ltd 冷蔵庫の温度制御装置
JPH0672979A (ja) 1992-06-08 1994-03-15 Hiroyoshi Hidaka アミノベンジル誘導体
RU2047614C1 (ru) 1992-06-15 1995-11-10 Джон Вайс энд Бразер Лимитед Гетероциклические соединения, или их фармацевтически приемлемые аддитивные соли кислоты, или n-оксид гетероциклического соединения, или его аддитивная соль кислоты
WO1994014797A1 (en) 1992-12-23 1994-07-07 Smithkline Beecham Corporation Quinoline compounds and the treatment of leucotriene related diseases therewith
JPH06278180A (ja) 1993-03-26 1994-10-04 Mitsubishi Heavy Ind Ltd 型盤開限度ストッパ装置
US5994341A (en) 1993-07-19 1999-11-30 Angiogenesis Technologies, Inc. Anti-angiogenic Compositions and methods for the treatment of arthritis
JPH0733729A (ja) 1993-07-26 1995-02-03 Kirin Brewery Co Ltd Ｎ−シアノ−ｎ′−置換−アリールカルボキシイミダミド化合物の製造法
JPH0782498A (ja) 1993-09-17 1995-03-28 Fuji Photo Film Co Ltd ビスアゾ化合物
JP3319838B2 (ja) 1993-11-12 2002-09-03 本田技研工業株式会社 車両のトラクション制御装置
JPH07179407A (ja) 1993-11-12 1995-07-18 Green Cross Corp:The 新規縮合環系化合物またはその塩、およびその医薬用途
ITMI941099A1 (it) 1994-05-27 1995-11-27 Smithkline Beecham Farma Derivati chinolinici
EP0705835A1 (de) 1994-09-01 1996-04-10 Ciba-Geigy Ag Oxa- oder thiaaliphatisch überbrückte Chinoxalin-2,3-dione
AU1106195A (en) 1994-11-09 1996-06-06 Novo Nordisk A/S Heterocyclic compounds, their preparation and use
JP3556982B2 (ja) 1994-12-15 2004-08-25 小島プレス工業株式会社 ラゲ−ジトレイ
WO1996019239A1 (fr) * 1994-12-21 1996-06-27 Yamanouchi Pharmaceutical Co., Ltd. Composition solide a solubilite et absorbabilite ameliorees
JPH08208824A (ja) 1995-01-31 1996-08-13 Idemitsu Kosan Co Ltd ポリカーボネートの製造方法
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
JPH08301849A (ja) 1995-05-01 1996-11-19 Takeda Chem Ind Ltd ヘテロ環化合物およびその製造法
JPH0971534A (ja) 1995-06-26 1997-03-18 Tanabe Seiyaku Co Ltd 医薬組成物
DE19601142A1 (de) 1995-07-13 1997-01-16 Agfa Gevaert Ag Verfahren zur Erzeugung eines farbigen Bildes
DE19532235A1 (de) 1995-08-31 1997-03-06 Keppler Bernhard K Priv Doz Dr An Phosphonsäuren gekoppelte antibakteriell wirksame Verbindungen zur Therapie von Infektionen im Bereich des Knochens
GB9526546D0 (en) 1995-12-23 1996-02-28 Pfizer Ltd Compounds useful in therapy
EP0882046A1 (en) 1996-02-21 1998-12-09 Darwin Discovery Limited Quinolones and their therapeutic use
DE19651099A1 (de) 1996-12-09 1998-06-10 Consortium Elektrochem Ind Mehrkomponentensystem zum Verändern, Abbau oder Bleichen von Lignin, ligninhaltigen Materialien oder ähnlichen Stoffen sowie Verfahren zu seiner Anwendung
AU6209098A (en) 1997-01-15 1998-08-07 Novartis Ag Herbicidal agent
US5948814A (en) 1997-02-20 1999-09-07 The Curators Of The University Of Missouri Genistein for the treatment of cystic fibrosis
ZA986594B (en) 1997-07-25 1999-01-27 Abbott Lab Urokinase inhibitors
ATE364374T1 (de) * 1997-08-11 2007-07-15 Pfizer Prod Inc Feste pharmazeutische dispersionen mit erhöhter bioverfügbarkeit
EE04294B1 (et) 1997-08-26 2004-06-15 Hoechst Marion Roussel, Inc. Farmatseutiline kompositsioon piperidinoalkanooldekongestandi kombineerimiseks
US20020017295A1 (en) 2000-07-07 2002-02-14 Weers Jeffry G. Phospholipid-based powders for inhalation
SK286564B6 (sk) 1997-12-22 2009-01-07 Bayer Corporation Substituované arylmočoviny ako inhibítory rafkinázy a farmaceutický prípravok s ich obsahom
WO1999046267A1 (en) 1998-03-12 1999-09-16 Novo Nordisk A/S Modulators of protein tyrosine phosphatases (ptpases)
HUP0102612A2 (hu) 1998-03-12 2001-11-28 Novo Nordisk A/S Fehérje-tirozinfoszfatázokat moduláló vegyületek és ezeket tartalmazó gyógyászati készítmények
JP2000016982A (ja) 1998-06-30 2000-01-18 Kumiai Chem Ind Co Ltd キノリン誘導体及びこれを有効成分とする除草剤
US7001770B1 (en) 1998-10-15 2006-02-21 Canji, Inc. Calpain inhibitors and their applications
WO2000026197A1 (en) 1998-10-29 2000-05-11 Bristol-Myers Squibb Company Novel inhibitors of impdh enzyme
US6248739B1 (en) 1999-01-08 2001-06-19 Pharmacia & Upjohn Company Quinolinecarboxamides as antiviral agents
US6248736B1 (en) 1999-01-08 2001-06-19 Pharmacia & Upjohn Company 4-oxo-1,4-dihydro-3-quinolinecarboxamides as antiviral agents
PT1033364E (pt) 1999-03-01 2005-07-29 Pfizer Prod Inc Ciano com acidos oxamicos e derivados como ligandos de receptores de tiroide
JP2000256358A (ja) 1999-03-10 2000-09-19 Yamanouchi Pharmaceut Co Ltd ピラゾール誘導体
CO5200844A1 (es) 1999-09-17 2002-09-27 Novartis Ag Una combinacion que comprende nateglinida y cuando por menos otro compuesto antidiabetico usada para el tratamiento de desordenes metabolicos, especialmente diabetes, o de una enfermedad o condicion asociada con dibetes
SE0002320D0 (sv) 1999-10-25 2000-06-21 Active Biotech Ab Malignant tumors
EP1227084B1 (en) 1999-10-28 2005-12-14 Trine Pharmaceuticals, Inc. Drug discharge pump inhibitors
AU1302301A (en) 1999-11-08 2001-06-06 Sankyo Company Limited Nitrogenous heterocycle derivatives
JP2001199965A (ja) 1999-11-08 2001-07-24 Sankyo Co Ltd 含窒素複素環誘導体
UA75055C2 (uk) 1999-11-30 2006-03-15 Пфайзер Продактс Інк. Похідні бензоімідазолу, що використовуються як антипроліферативний засіб, фармацевтична композиція на їх основі
EP1244660B1 (en) 1999-12-23 2006-03-22 AstraZeneca AB Methods and compositions for the treatment of pain
JP2001233859A (ja) 2000-02-23 2001-08-28 Yamanouchi Pharmaceut Co Ltd 抗ヘリコバクター・ヒ゜ロリ化合物の新規製造法及びその中間体
US20010053791A1 (en) 2000-03-16 2001-12-20 Babcock Walter C. Glycogen phosphorylase inhibitor
AU2001267442B2 (en) 2000-05-17 2004-07-01 Syngenta Participations Ag Process for the preparation of aniline compounds
WO2002003938A1 (en) 2000-06-29 2002-01-17 Clairol Incorporated Iodo-containing organic couplers for use in oxidative hair dyeing
US6777400B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
WO2002038126A2 (en) 2000-11-08 2002-05-16 Aeromatic-Fielder Ag A process for production of particles for pharmaceutical compositions having increased bioavailability
JP2002212179A (ja) 2001-01-15 2002-07-31 Wakunaga Pharmaceut Co Ltd 新規アニリド誘導体又はその塩及びこれを含有する医薬
GB2372986A (en) 2001-01-17 2002-09-11 Xenova Ltd 2-oxo, 4-hydroxy pyrroles and quinolines
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
ES2566056T3 (es) 2001-03-29 2016-04-08 Eli Lilly And Company N-(2-ariletil)bencilaminas como antagonistas del receptor 5-HT6
JP2002296731A (ja) 2001-03-30 2002-10-09 Fuji Photo Film Co Ltd 熱現像カラー画像記録材料
JP2002322054A (ja) 2001-04-26 2002-11-08 Dai Ichi Seiyaku Co Ltd 薬剤排出ポンプ阻害薬
JP2002322154A (ja) 2001-04-27 2002-11-08 Dai Ichi Seiyaku Co Ltd 抗真菌化合物
JP2002326935A (ja) 2001-05-07 2002-11-15 Sankyo Co Ltd 含窒素複素環誘導体を含有する医薬
JPWO2002094809A1 (ja) 2001-05-24 2004-09-09 山之内製薬株式会社 ３−キノリン−２（１ｈ）−イリデンインドリン−２−オン誘導体
JP2003012667A (ja) 2001-06-26 2003-01-15 Rrf Kenkyusho:Kk キノリンカルボキサミド骨格を有する抗菌剤
WO2003024409A2 (en) 2001-09-21 2003-03-27 Case Western Reserve University Q4n2neg2 enhances cftr activity
JP3748222B2 (ja) 2001-11-07 2006-02-22 株式会社リコー 可逆性感熱発色組成物及びそれを用いた可逆性記録媒体
HUP0501067A2 (en) 2001-11-14 2006-02-28 Teva Pharma Amorphous and crystalline forms of losartan potassium and process for their preparation
TW200300349A (en) 2001-11-19 2003-06-01 Sankyo Co A 4-oxoqinoline derivative
US20030187026A1 (en) 2001-12-13 2003-10-02 Qun Li Kinase inhibitors
CA2474958A1 (en) 2002-02-01 2003-08-07 Pfizer Products Inc. Method for making homogeneous spray-dried solid amorphous drug dispersions using pressure nozzles
AR038375A1 (es) 2002-02-01 2005-01-12 Pfizer Prod Inc Composiciones farmaceuticas de inhibidores de la proteina de transferencia de esteres de colesterilo
JP2003238413A (ja) 2002-02-14 2003-08-27 Kyowa Hakko Kogyo Co Ltd ステロイドスルファターゼ阻害剤
SE0201669D0 (sv) 2002-06-03 2002-06-03 Pharmacia Ab New formulation and use thereof
TWI314041B (en) 2002-10-21 2009-09-01 Sankyo Agro Co Ltd Quinolyl-3-carboxamide compound
AR042206A1 (es) 2002-11-26 2005-06-15 Novartis Ag Acidos fenilaceticos y derivados
JP2004189738A (ja) 2002-11-29 2004-07-08 Nippon Nohyaku Co Ltd 置換アニリド誘導体、その中間体及び農園芸用薬剤並びにその使用方法
US20050113423A1 (en) 2003-03-12 2005-05-26 Vangoor Frederick F. Modulators of ATP-binding cassette transporters
WO2004105779A2 (en) 2003-05-27 2004-12-09 Cesare Montecucco Green tea and oplyphenol inhibitors of bacterial proteases
DE602004022819D1 (de) 2003-06-06 2009-10-08 Vertex Pharma Von atp-bindende kassette transportern
CN1191252C (zh) 2003-08-11 2005-03-02 中国药科大学 3－位取代的喹诺酮衍生物及其在药学上的应用
MXPA06002567A (es) 2003-09-06 2006-09-04 Vertex Pharma Moduladores de transportadores con casete de union de atp.
US20050059035A1 (en) 2003-09-09 2005-03-17 Quest Diagnostics Incorporated Methods and compositions for the amplification of mutations in the diagnosis of cystic fibrosis
TR201910177T4 (tr) 2003-09-12 2019-08-21 Amgen Inc Bir sinakalset HCl içeren hızlı çözünme formülasyonu.
US7223759B2 (en) 2003-09-15 2007-05-29 Anadys Pharmaceuticals, Inc. Antibacterial 3,5-diaminopiperidine-substituted aromatic and heteroaromatic compounds
KR20060121909A (ko) 2003-10-08 2006-11-29 버텍스 파마슈티칼스 인코포레이티드 사이클로알킬 또는 피라닐 그룹을 포함하는 ａｔｐ-결합카세트 수송자의 조절자
DK1683524T3 (da) 2003-11-14 2011-03-14 Ajinomoto Kk Dispergering på fast form eller medicinsk præparat på fast form af phenyalaninderivat
ES2328824T3 (es) 2003-11-14 2009-11-18 Vertex Pharmaceuticals Incorporated Tiazoles y oxazoles utiles como moduladores de transportadores de tipo casete de union a atp.
EP1727520A2 (en) 2003-12-09 2006-12-06 Medcrystalforms, Llc Method of preparation of mixed phase co-crystals with active agents
AU2003297904A1 (en) 2003-12-12 2005-07-14 University Of Maryland, Baltimore Immunomodulatory compounds that target and inhibit the py+3 binding site of tyrosene kinase p56 lck sh2 domain
WO2005075435A1 (en) 2004-01-30 2005-08-18 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
US7977322B2 (en) 2004-08-20 2011-07-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
WO2005094805A1 (ja) 2004-04-01 2005-10-13 Institute Of Medicinal Molecular Design. Inc. イミン誘導体及びアミド誘導体
JP2006206612A (ja) 2004-05-27 2006-08-10 Ono Pharmaceut Co Ltd 固形製剤用組成物
CA2569402A1 (en) 2004-06-04 2005-12-22 The Regents Of The University Of California Compounds having activity in increasing ion transport by mutant-cftr and uses thereof
US20140343098A1 (en) 2004-06-24 2014-11-20 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
US8354427B2 (en) 2004-06-24 2013-01-15 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
JP2008505124A (ja) 2004-07-02 2008-02-21 アドバンシス ファーマスーティカル コーポレイション パルス送達用錠剤
US20060035890A1 (en) 2004-08-10 2006-02-16 Amit Banerjee Compounds and methods for the treatment of ubiquitin conjugating disorders
CN101076344B (zh) 2004-09-21 2011-07-13 T·J·拉利 多用途生物材料组合物
US8143257B2 (en) 2004-11-23 2012-03-27 Ptc Therapeutics, Inc. Substituted phenols as active agents inhibiting VEGF production
US8242149B2 (en) 2005-03-11 2012-08-14 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
WO2006101740A2 (en) 2005-03-18 2006-09-28 The Regents Of The University Of California Compounds having activity in correcting mutant-cftr processing and uses thereof
EP1875911A4 (en) 2005-04-28 2010-03-03 Eisai R&D Man Co Ltd STABILIZED COMPOSITION
EP1891018B1 (en) 2005-05-24 2011-11-16 Vertex Pharmaceuticals, Inc. Modulators of atp-binding cassette transporters
KR20080053297A (ko) 2005-08-11 2008-06-12 버텍스 파마슈티칼스 인코포레이티드 낭포성 섬유종 트랜스막 전도도 조정자의 조절자
CN101287732A (zh) 2005-08-11 2008-10-15 沃泰克斯药物股份有限公司 囊性纤维化跨膜电导调节剂的调控剂
US8314256B2 (en) 2005-10-06 2012-11-20 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US20120232059A1 (en) 2005-11-08 2012-09-13 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette Transporters
EP1945632B1 (en) 2005-11-08 2013-09-18 Vertex Pharmaceuticals Incorporated Heterocyclic modulators of atp-binding cassette transporters
US20080057047A1 (en) 2005-11-29 2008-03-06 Benedikt Sas Use of bacillus amyloliquefaciens PB6 for the prophylaxis or treatment of gastrointestinal and immuno-related diseases
US7989430B2 (en) 2005-12-06 2011-08-02 Regents Of The University Of Minnesota Antibacterial agents
WO2007075901A2 (en) 2005-12-24 2007-07-05 Vertex Pharmaceuticals Incorporated Quinolin- 4 - one derivatives as modulators of abc transporters
CA2635214A1 (en) 2005-12-27 2007-07-05 Vertex Pharmaceuticals Incorporated Compounds useful in cftr assays and methods therewith
WO2007074472A2 (en) 2005-12-27 2007-07-05 Jubilant Organosys Limited Mouth dissolving pharmaceutical composition and process for preparing the same using a high amount of silicon dioxide
US7671221B2 (en) 2005-12-28 2010-03-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
EP2016065B1 (en) 2005-12-28 2012-09-19 Vertex Pharmaceuticals Incorporated 1-(benzo[d][1,3]dioxol-5-yl)-n-(phenyl)cyclopropane-carboxamide derivatives and related compounds as modulators of atp-binding cassette transporters for the treatment of cystic fibrosis
DK3219705T3 (da) 2005-12-28 2020-04-14 Vertex Pharma Farmaceutiske sammensætninger af den amorfe form af n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinolin-3-carboxamid
UY30118A1 (es) 2006-01-31 2007-06-29 Tanabe Seiyaku Co Compueto amina trisustituido
AU2007225088B2 (en) 2006-03-13 2012-09-13 Kyorin Pharmaceutical Co., Ltd Aminoquinolones as GSK-3 inhibitors
WO2007106957A1 (en) 2006-03-21 2007-09-27 Laboratoires Smb S.A. Multiple units controlled-release floating dosage forms
US10022352B2 (en) 2006-04-07 2018-07-17 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
CA2869945C (en) 2006-04-07 2018-01-23 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
US7645789B2 (en) 2006-04-07 2010-01-12 Vertex Pharmaceuticals Incorporated Indole derivatives as CFTR modulators
AU2007240439B2 (en) 2006-04-20 2012-10-11 Janssen Pharmaceutica N.V. Inhibitors of c-fms kinase
ES2377840T3 (es) * 2006-05-12 2012-04-02 Vertex Pharmaceuticals, Inc. Composiciones de N-[2,4-bis(1,1-dimetiletil)-5-hidroxifenil]-1,4-dihidro-4-oxoquinolina-3-carboxamida
PE20080661A1 (es) 2006-09-12 2008-06-12 Glaxo Group Ltd COMPOSICION FARMACEUTICA QUE COMPRENDE UN INHIBIDOR DEL FACTOR Xa
US8563573B2 (en) 2007-11-02 2013-10-22 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
ES2646175T3 (es) 2006-11-03 2017-12-12 Vertex Pharmaceuticals Incorporated Derivados de azaindol como moduladores de CFTR
US7754739B2 (en) 2007-05-09 2010-07-13 Vertex Pharmaceuticals Incorporated Modulators of CFTR
MX2009006806A (es) 2006-12-22 2009-08-27 Vertex Pharma Secado por rocio fluidizado.
WO2008083130A2 (en) 2006-12-26 2008-07-10 Dr. Reddy's Laboratories Limited Amorphous and crystalline form a of carvedilol phosphate
BRPI0810660A2 (pt) * 2007-04-18 2014-10-07 Cornerstone Pharmaceuticals Inc Derivados do ácido lipóico
EP2789606B1 (en) 2007-05-09 2017-11-15 Vertex Pharmaceuticals Incorporated Modulators of CFTR
EP2170901B1 (en) 2007-05-25 2015-07-01 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
JP4834699B2 (ja) 2007-07-30 2011-12-14 田辺三菱製薬株式会社 医薬組成物
JP4846769B2 (ja) 2007-07-30 2011-12-28 田辺三菱製薬株式会社 医薬組成物
US20110177999A1 (en) 2007-08-09 2011-07-21 Vertex Pharmaceuticals Incorporated Therapeutic Combinations Useful in Treating CFTR Related Diseases
CA2696298C (en) 2007-08-24 2016-09-06 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
CA2699292A1 (en) 2007-09-14 2009-03-26 Vertex Pharmaceuticals Incorporated Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
NZ583878A (en) 2007-09-14 2012-10-26 Vertex Pharma Modulators of ABC transporter and cystic fibrosis transmembrane conductance regulator (CFTR)
EP3012250B1 (en) 2007-11-16 2017-11-08 Vertex Pharmaceuticals Incorporated Isoquinoline modulators of atp-binding cassette transporters
US20100036130A1 (en) 2007-12-07 2010-02-11 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
EP3683218B1 (en) 2007-12-07 2024-09-18 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
JP2011506331A (ja) 2007-12-07 2011-03-03 バーテックス ファーマシューティカルズ インコーポレイテッド ３−（６−（１−（２，２−ジフルオロベンゾ［ｄ］［１，３］ジオキソール−５−イル）シクロプロパンカルボキサミド）−３−メチルピリジン−２−イル）安息香酸の処方物
NZ612635A (en) 2007-12-07 2015-06-26 Vertex Pharma Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
AU2008335031B2 (en) 2007-12-13 2013-11-28 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
CA2931134C (en) 2008-02-28 2019-07-30 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as cftr modulators
SI2615085T1 (sl) 2008-03-31 2015-11-30 Vertex Pharmaceuticals Incorporated Piridilni derivati kot cftr-modulatorji
ME03019B (me) 2008-08-13 2018-10-20 Vertex Pharma Farmaceutska kompozicija n-[2,4-bis(1,1- dimeтileтil)-5-hidroksifenil]- 1,4-dihidro-4-oksohinolin-3-karboksamida i njeno ordiniranje
US20100256184A1 (en) 2008-08-13 2010-10-07 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
EP2328609A1 (en) 2008-08-26 2011-06-08 Cystic Fibrosis Foundation Therapeutics, Inc. Rapidly disintegrating tablets comprising lipase, amylase, and protease
JP2012504143A (ja) 2008-09-29 2012-02-16 バーテックス ファーマシューティカルズ インコーポレイテッド ３−（６−（１−（２，２−ジフルオロベンゾ［ｄ］［１，３］ジオキソール−５−イル）シクロプロパンカルボキサミド）−３−メチルピリジン−２−イル）安息香酸の用量単位
WO2010042549A1 (en) 2008-10-07 2010-04-15 Mpex Pharmaceuticals, Inc. Inhalation of levofloxacin for reducing lung inflammation
HUE038428T2 (hu) 2008-10-07 2018-10-29 Horizon Orphan Llc Aeroszol fluorokinolon készítmények javított farmakokinetika érdekében
US9333235B2 (en) 2008-10-22 2016-05-10 Trustees Of Dartmouth College Combination therapy and kit for the prevention and treatment of cystic fibrosis
US20110257223A1 (en) 2008-10-23 2011-10-20 Vertex Pharmaceuticals Incorporated Modulators of Cystic Fibrosis Transmembrane Conductance Regulator
NZ592687A (en) 2008-10-23 2013-04-26 Vertex Pharma Modulators of cystic fibrosis transmembrane conductance regulator
MX2011004374A (es) 2008-10-23 2011-05-23 Vertex Pharma Formas solidas de n-(4-(7-azabiciclo[2.2.1]heptan-7-il)-2-(trifluo rometil)fenil)-4-oxo-5-(trifluorometil)-1,4-dihidroquinolin-3-car boxamida.
BRPI0919930A2 (pt) 2008-10-23 2016-02-16 Vertex Pharma moduladores de regulador de condutância transmembrana de fibrose cística
UA104876C2 (uk) 2008-11-06 2014-03-25 Вертекс Фармасьютікалз Інкорпорейтед Модулятори atф-зв'язувальних касетних транспортерів
NZ592694A (en) 2008-11-06 2013-05-31 Vertex Pharma ATP-Binding Cassette (ABC) transporters as modulators of CFTR activity
US8367660B2 (en) 2008-12-30 2013-02-05 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
GB201111244D0 (en) 2011-06-30 2011-08-17 Konink Nl Akademie Van Wetenschappen Knaw Culture media for stem cells
JP2012520683A (ja) 2009-03-19 2012-09-10 メルク・シャープ・エンド・ドーム・コーポレイション 低分子干渉核酸（ｓｉＮＡ）を用いた結合組織増殖因子（ＣＴＧＦ）遺伝子発現のＲＮＡ干渉媒介性阻害
JP2012520684A (ja) 2009-03-19 2012-09-10 メルク・シャープ・エンド・ドーム・コーポレイション 低分子干渉核酸（ｓｉＮＡ）を用いたＢＴＢａｎｄＣＮＣＨｏｍｏｌｏｇｙ１（塩基性ロイシンジッパー転写因子１）（Ｂａｃｈ１）遺伝子発現のＲＮＡ干渉媒介性阻害
EP2408915A2 (en) 2009-03-19 2012-01-25 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF GATA BINDING PROTEIN 3 (GATA3) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
WO2010107958A1 (en) 2009-03-19 2010-09-23 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 (STAT6) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
CA2755969C (en) 2009-03-20 2018-05-08 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
EP3330255B1 (en) 2009-03-20 2020-12-09 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
EP2411516A1 (en) 2009-03-27 2012-02-01 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF APOPTOSIS SIGNAL-REGULATING KINASE 1 (ASK1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
CA2756069A1 (en) 2009-03-27 2010-09-30 Merck Sharp & Dohme Corp. Rna interference mediated inhibition of the intercellular adhesion molecule 1 (icam-1)gene expression using short interfering nucleic acid (sina)
WO2010111471A2 (en) 2009-03-27 2010-09-30 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1 (STAT1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
US20120004281A1 (en) 2009-03-27 2012-01-05 Merck Sharp & Dohme Corp RNA Interference Mediated Inhibition of the Nerve Growth Factor Beta Chain (NGFB) Gene Expression Using Short Interfering Nucleic Acid (siNA)
EP2411518A2 (en) 2009-03-27 2012-02-01 Merck Sharp&Dohme Corp. Rna interference mediated inhibition of the high affinity ige receptor alpha chain (fcerla) gene expression using short interfering nucleic acid (sina)
US20120022143A1 (en) 2009-03-27 2012-01-26 Merck Sharp & Dohme Corp RNA Interference Mediated Inhibition of the Thymic Stromal Lymphopoietin (TSLP) Gene Expression Using Short Interfering Nucliec Acid (siNA)
RU2543622C2 (ru) 2009-09-17 2015-03-10 Вертекс Фармасьютикалз Инкорпорейтед Способ получения азабициклических соединений
CA2777245A1 (en) 2009-10-22 2011-04-28 Vertex Pharmaceuticals Incorporated Compositions for treatment of cystic fibrosis and other chronic diseases
JP5789611B2 (ja) 2009-10-23 2015-10-07 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ 嚢胞性線維症膜コンダクタンス制御因子のモジュレーターを調製するためのプロセス
JP5877157B2 (ja) 2009-10-23 2016-03-02 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ Ｎ−（４−（７−アザビシクロ［２．２．１］ヘプタン−７−イル）−２−（トリフルオロメチル）フェニル）−４−オキソ−５−（トリフルオロメチル）−１，４−ジヒドロキノリン−３−カルボキサミドの固体形態
WO2011056477A2 (en) 2009-10-26 2011-05-12 Zhe Lu Methods for treating inflammation and oxidative stress related diseases
CA2781888C (en) 2009-12-11 2019-06-18 Nono Inc. Agents and methods for treating ischemic and other diseases
WO2011088404A1 (en) 2010-01-15 2011-07-21 Infinity Pharmaceuticals , Inc Treatment of fibrotic conditions using hedgehog inhibitors
US20150152348A1 (en) 2010-02-26 2015-06-04 Sharps Compliance, Inc. Systems and methods for collecting, transporting and repurposing or destroying unused pharmaceuticals
WO2011116397A1 (en) 2010-03-19 2011-09-22 Vertex Pharmaceuticals Incorporated Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US8802868B2 (en) 2010-03-25 2014-08-12 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide
HUE062892T2 (hu) 2010-03-25 2023-12-28 Vertex Pharma (R)-1(2,2-difluorbenzo[d][1,3]dioxol-5-il)-N-(1-(2,3-dihidroxipropil)-6-fluor-2-(1-hidroxi- 2-metilpropán-2-il)-1H-indol-5-il)ciklopropánkarboxamid elõállítása és köztitermékei
MX2012011655A (es) 2010-04-07 2012-11-23 Vertex Pharma Formas solidas de acido 3-(6-(1-(2,2-difluorobenzo [d][1-3]dioxol-5-il]ciclopropanocarboxamido)-3-metilpiridin-2-il) benzoico.
HRP20211752T1 (hr) 2010-04-07 2022-02-18 Vertex Pharmaceuticals Incorporated Farmaceutski pripravci 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioksol-5-il)ciklopropankarboksamido)-3-metilpiridin-2-il)benzojeve kiseline i njihova primjena
NZ603043A (en) 2010-04-22 2015-02-27 Vertex Pharma Pharmaceutical compositions comprising cftr modulators and administrations thereof
ES2858351T3 (es) 2010-04-22 2021-09-30 Vertex Pharma Compuesto intermedio para proceso de producción de compuestos de cicloalquilcaraboxamido-indol
WO2011133956A1 (en) 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
AU2011242452A1 (en) 2010-04-22 2012-11-08 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
TW201202250A (en) 2010-05-20 2012-01-16 Vertex Pharma Processes for producing modulators of cystic fibrosis transmembrane conductance regulator
NZ603386A (en) 2010-05-20 2015-02-27 Vertex Pharma Pharmaceutical compositions and administrations thereof
US8563593B2 (en) 2010-06-08 2013-10-22 Vertex Pharmaceuticals Incorporated Formulations of (R)-1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
EP3970726A1 (en) 2010-06-24 2022-03-23 ViroPharma Biologics LLC Methods of treatment for esophageal inflammation
JP2013536231A (ja) 2010-08-23 2013-09-19 バーテックス ファーマシューティカルズ インコーポレイテッド （ｒ）−１−（２，２−ジフルオロベンゾ［ｄ］［１，３］ジオキソール−５−イル）−ｎ−（１−（２，３−ジヒドロキシプロピル）−６−フルオロ−２−（１−ヒドロキシ−２−メチルプロパン−２−イル）−１ｈ−インドール−５−イル）シクロプロパンカルボキサミドを含む医薬組成物およびその投与
JP2013536251A (ja) 2010-08-27 2013-09-19 バーテックス ファーマシューティカルズ インコーポレイテッド 薬学的組成物およびその投与
EP2464346A1 (en) 2010-08-30 2012-06-20 Pulmatrix, Inc. Treatment of cystic fibrosis using calcium lactate, leucine and sodium chloride in a respiraple dry powder
AU2011296343B2 (en) 2010-08-30 2015-12-10 Pulmatrix Operating Company, Inc. Dry powder formulations and methods for treating pulmonary diseases
US8372845B2 (en) 2010-09-17 2013-02-12 Novartis Ag Pyrazine derivatives as enac blockers
US9050339B2 (en) 2010-09-17 2015-06-09 Novartis Ag Pyrazine derivatives as ENaC blockers
US8802700B2 (en) 2010-12-10 2014-08-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
ES2650744T3 (es) 2010-12-14 2018-01-22 Electrophoretics Limited Inhibidores de la caseína quinasa 1 delta (CK1delta)
EP2670733B1 (en) 2011-02-01 2019-04-10 The Board of Trustees of the University of Illionis N-hydroxybenzamide derivatives as hdac inhibitors and therapeutic methods using the same
WO2012148953A1 (en) 2011-04-25 2012-11-01 Stc.Unm Solid compositions for pharmaceutical use
WO2012154888A1 (en) 2011-05-09 2012-11-15 Proteostasis Therapeutics, Inc. Compounds for treating protein folding disorders
PL2709986T3 (pl) 2011-05-18 2017-09-29 Concert Pharmaceuticals Inc. Deuterowane pochodne iwakaftoru
US8945605B2 (en) 2011-06-07 2015-02-03 Parion Sciences, Inc. Aerosol delivery systems, compositions and methods
ITMI20111068A1 (it) 2011-06-14 2012-12-15 Azienda Ospedaliera Universitaria I Ntegrata Di Ve Trimetilangelicina come correttore di cftr in cellule dell'epitelio bronchiale
AR086745A1 (es) 2011-06-27 2014-01-22 Parion Sciences Inc 3,5-diamino-6-cloro-n-(n-(4-(4-(2-(hexil(2,3,4,5,6-pentahidroxihexil)amino)etoxi)fenil)butil)carbamimidoil)pirazina-2-carboxamida
KR101317656B1 (ko) 2011-06-30 2013-10-15 연세대학교 산학협력단 복제효소 인산화를 조절하는 신규 ｃ형 간염 예방 또는 치료용 조성물
CN103930422A (zh) 2011-07-19 2014-07-16 无限药品股份有限公司 杂环化合物及其用途
TWI565709B (zh) 2011-07-19 2017-01-11 英菲尼提製藥股份有限公司 雜環化合物及其用途
WO2013032591A1 (en) 2011-08-29 2013-03-07 Infinity Pharmaceuticals Inc. Heterocyclic compounds and uses thereof
WO2013052844A1 (en) 2011-10-07 2013-04-11 Pulmatrix, Inc. Methods for treating and diagnosing respiratory tract infections
UA115868C2 (uk) 2011-11-02 2018-01-10 Бьорінгер Інгельхайм Інтернаціональ Гмбх Гетероциклічні сполуки, лікарські засоби, які містять зазначені сполуки, їх застосування і способи їх одержання
WO2013067410A1 (en) 2011-11-02 2013-05-10 Vertex Pharmaceuticals Incorporated Use of (n- [2, 4 -bis (1, 1 -dimethylethyl) - 5 - hydroxyphenyl] - 1, 4 - dihydro - 4 - oxoquinoline - 3 - ca rboxamide) for treating cftr mediated diseases
US9580409B2 (en) 2011-11-07 2017-02-28 Sunovion Pharmaceuticals, Inc. Modulators of opioid receptors and methods of use thereof
US20140127901A1 (en) 2012-11-08 2014-05-08 Taiwan Semiconductor Manufacturing Company, Ltd. Low-k damage free integration scheme for copper interconnects
CA2852991C (en) 2011-11-08 2019-12-31 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
JP2015504870A (ja) 2011-12-16 2015-02-16 タリックス ファーマシューティカルズ リミテッド 線維症を処置するためのアンジオテンシン
DK2795322T3 (en) 2011-12-19 2016-01-25 Umc Utrecht Holding Bv Quantitative rapid test for measuring cftr function in primary intestinal culture model
US8859559B2 (en) 2011-12-20 2014-10-14 Boehringer Ingelheim International Gmbh Substituted pyrazines and their use in the treatment of disease
SG10201606135TA (en) 2012-01-25 2016-09-29 Vertex Pharma Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
AU2013226076B2 (en) 2012-02-27 2017-11-16 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administration thereof
CN104487075A (zh) 2012-02-29 2015-04-01 普马特里克斯公司 可吸入干粉剂
US8809340B2 (en) 2012-03-19 2014-08-19 Novartis Ag Crystalline form
CN104619321A (zh) 2012-04-06 2015-05-13 Uab研究基金会 用于增加cftr活性的方法
US8940742B2 (en) 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2013157018A1 (en) 2012-04-18 2013-10-24 Indian Institute Of Technology Madras A process for the preparation of the core structure in quinolone and napthyridone class of antibiotics
US8674108B2 (en) 2012-04-20 2014-03-18 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethy)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
EP2659890A1 (en) 2012-04-30 2013-11-06 Orphan Synergy Europe - Pharma Methods and compositions for the treatment of fibrosis
PT2664326T (pt) 2012-05-17 2018-01-19 I E R F C European Institute For Cystic Fibrosis Res Terapia combinada para a fibrose quística
FR2990859B1 (fr) 2012-05-24 2014-05-23 Gaetan Terrasse Utilisation d'une molecule h4 agoniste pour le traitement de la mucoviscidose
WO2013174757A1 (en) 2012-05-25 2013-11-28 Boehringer Ingelheim International Gmbh Tertiary amines, medicaments containing said amines, use thereof and processes for the preparation thereof
WO2013181530A1 (en) 2012-06-01 2013-12-05 Icahn School Of Medicine At Mount Sinai Ceramide levels in the treatment and prevention of infections
DE102012209520A1 (de) 2012-06-06 2013-12-12 Osram Opto Semiconductors Gmbh Metallkomplexe als p-Dotanden für organische elektronische Matrixmaterialien
DE102012209523A1 (de) 2012-06-06 2013-12-12 Osram Opto Semiconductors Gmbh Hauptgruppenmetallkomplexe als p-Dotanden für organische elektronische Matrixmaterialien
AU2013270681A1 (en) 2012-06-08 2014-12-18 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of CFTR -mediated disorders
US8828998B2 (en) 2012-06-25 2014-09-09 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
EP3103872B1 (en) 2012-07-12 2018-08-29 ProQR Therapeutics II B.V. Oligonucleotides for making a change in the sequence of a target rna molecule present in a living cell
US20150209448A1 (en) 2012-07-12 2015-07-30 Proqr Therapeutics N.V. Exon replacement with stabilized artificial rnas
EP2872122A1 (en) 2012-07-16 2015-05-20 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of (r)-1-(2,2-diflurorbenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide and administration thereof
EP2875001B1 (en) 2012-07-18 2019-01-09 Sunshine Lake Pharma Co., Ltd. Nitrogenous heterocyclic derivatives and their application in drugs
WO2014012935A1 (de) 2012-07-20 2014-01-23 Bayer Pharma Aktiengesellschaft Substituierte aminoindan- und aminotetralin-carbonsäuren und ihre verwendung
EP2875003B1 (de) 2012-07-20 2016-11-16 Bayer Pharma Aktiengesellschaft Neue 5-aminotetrahydrochinolin-2-carbonsäuren und ihre verwendung
BR112015001838B1 (pt) 2012-07-27 2022-10-25 Izumi Technology, Llc Composição de inibidor de efluxo
WO2014026959A1 (en) 2012-08-13 2014-02-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for treatment of cystic fibrosis
US9566310B2 (en) 2012-09-10 2017-02-14 Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Reno Methods of treating muscular dystrophy
JP6072920B2 (ja) 2012-09-24 2017-02-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 複素環化合物、前記化合物を含む薬物、これらの使用及びこれらの調製方法
AU2013319788B2 (en) 2012-09-24 2019-04-11 Yissum Reasearch Development Company of the Hebrew University Of Jerusalem Ltd. Restoration of the CFTR function by splicing modulation
WO2014058974A1 (en) 2012-10-10 2014-04-17 Emory University Methods of managing inflammation using glycolysis pathway inhibitors
EP2906570A4 (en) 2012-10-15 2016-06-08 Yeda Res & Dev USE OF LONG-TERM SPHINGOID BASES AND THEIR ANALOGUE IN THE TREATMENT AND PREVENTION OF BACTERIAL INFECTIONS
US20140120060A1 (en) 2012-11-01 2014-05-01 Infinity Pharmaceuticals, Inc. Treatment of rheumatoid arthritis and asthma using pi3 kinase inhibitors
SI2914248T2 (sl) 2012-11-02 2023-12-29 Vertex Pharmaceuticals Incorporated, Farmacevtski sestavki za zdravljenje bolezni, pri katerih posreduje CFTR
JP6146990B2 (ja) 2012-11-16 2017-06-14 コンサート ファーマシューティカルズ インコーポレイテッド 重水素化されたｃｆｔｒ増強物質
MY183582A (en) 2012-11-19 2021-02-26 Vertex Pharmaceuticals Europe Ltd Deuterated cftr potentiators
WO2014081820A1 (en) 2012-11-20 2014-05-30 Discoverybiomed, Inc. Small molecule cftr correctors
US9546176B2 (en) 2012-11-20 2017-01-17 Discoverybiomed, Inc. Small molecule bicyclic and tricyclic CFTR correctors
US10034988B2 (en) 2012-11-28 2018-07-31 Fontem Holdings I B.V. Methods and devices for compound delivery
EP2929346A1 (en) 2012-12-05 2015-10-14 Institut National de la Santé et de la Recherche Médicale (INSERM) Diagnosis of cystic fibrosis
CA2894279A1 (en) 2012-12-07 2014-06-12 Paul Boucher Nasal cannula for delivery of aerosolized medicaments
KR20150095870A (ko) 2012-12-17 2015-08-21 패리온 사이언스 인코퍼레이티드 3,5-디아미노-6-클로로-n-(n-(4-페닐부틸)카르밤이미도일)피라진-2-카르복스아미드 화합물
AR094263A1 (es) 2012-12-21 2015-07-22 Plexxikon Inc Compuestos moduladores selectivos de proteinquinasas
CN103044263A (zh) 2013-01-14 2013-04-17 中国药科大学 一种治疗囊性纤维化药物的中间体的制备方法
US20140221424A1 (en) 2013-01-30 2014-08-07 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for use in the treatment of cystic fibrosis
ES2730474T3 (es) 2013-01-31 2019-11-11 Glenmark Pharmaceuticals Ltd Proceso para la preparación de ivacaftor y solvatos de este
WO2014125506A2 (en) 2013-02-15 2014-08-21 Laurus Labs Private Limited A process for the preparation of ivacaftor and its intermediates
CN105121632B (zh) 2013-02-18 2021-08-10 大学健康网络 由多能干细胞生成肝细胞和胆管细胞的方法
CN104030981A (zh) 2013-03-06 2014-09-10 上海特化医药科技有限公司 Ivacaftor的制备方法及其中间体
EP2968285A4 (en) 2013-03-13 2016-12-21 Flatley Discovery Lab COMPOUNDS AND METHODS FOR THE TREATMENT OF CYSTIC FIBROSIS
CA2906008C (en) 2013-03-13 2019-07-09 Flatley Discovery Lab, Llc Pyridazinone compounds and methods for the treatment of cystic fibrosis
US9452139B2 (en) 2013-03-14 2016-09-27 Novartis Ag Respirable agglomerates of porous carrier particles and micronized drug
EP2970194A1 (en) 2013-03-15 2016-01-20 Infinity Pharmaceuticals, Inc. Salts and solid forms of isoquinolinones and composition comprising and methods of using the same
WO2014145735A2 (en) 2013-03-15 2014-09-18 Orpro Therapeutics, Inc. Product and process for mucus viscosity normalization
US20140296164A1 (en) 2013-03-29 2014-10-02 Calista Therapeutics, Inc. Compositions and methods of use for cell targeted inhibitors of the Cystic Fibrosis transmembrane regulator associated ligand
CN103224466A (zh) 2013-04-15 2013-07-31 北京大学 具有β-分泌酶抑制功能的化合物及其制备方法与应用
WO2014186608A1 (en) 2013-05-15 2014-11-20 Adverse Events, Inc. System and method for surveillance and evaluation of safety risks associated with medical interventions
WO2014186704A2 (en) 2013-05-17 2014-11-20 N30 Pharmaceuticals, Inc. Novel compounds for the treatment of cystic fibrosis
EP2815749A1 (en) 2013-06-20 2014-12-24 IP Gesellschaft für Management mbH Solid form of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione having specified X-ray diffraction pattern
US20160151335A1 (en) 2013-06-26 2016-06-02 Proteostasis Therapeutics, Inc. Methods of modulating cftr activity
WO2015007516A1 (en) 2013-07-15 2015-01-22 Boehringer Ingelheim International Gmbh Novel 5-substituted benzimidazolium compounds
EP3022196B1 (en) 2013-07-15 2017-09-06 Boehringer Ingelheim International GmbH Novel benzimidazolium compounds
EP3022197B1 (en) 2013-07-15 2017-09-06 Boehringer Ingelheim International GmbH Novel tetra- and pentasubstituted benzimidazolium compounds
US10265314B2 (en) 2013-07-25 2019-04-23 Bayer Pharma Aktiengesellschaft SGC stimulators in combination with additional treatment for the therapy of cystic fibrosis
EP2835423A1 (en) 2013-08-09 2015-02-11 Commissariat à l'Énergie Atomique et aux Énergies Alternatives Ligase E3 RNF185 inhibitors and uses thereof
JP6472807B2 (ja) 2013-09-12 2019-02-20 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル 嚢胞性線維症の処置のための方法及び医薬組成物
WO2015051241A1 (en) 2013-10-04 2015-04-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
ES2900806T3 (es) 2013-10-04 2022-03-18 Infinity Pharmaceuticals Inc Compuestos heterocíclicos y usos de los mismos
US20150099270A1 (en) 2013-10-04 2015-04-09 Thomas C. DOWLING Method of screening pharmaceuticals for drug interactions and nephrotoxicity
FR3011467B1 (fr) 2013-10-08 2016-02-12 Centre Nat Rech Scient Composes et compositions comprenant de tels composes pour la prevention ou le traitement des dyslipidemies
US20160244452A1 (en) 2013-10-21 2016-08-25 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US20160229778A1 (en) 2013-11-08 2016-08-11 Board Of Regents, The University Of Texas System Direct b-arylation of carbonyl compounds
US10231932B2 (en) 2013-11-12 2019-03-19 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
CA2927661A1 (en) 2013-11-13 2015-05-21 Apotex Inc. Solid forms of ivacaftor and processes for the preparation thereof
CA2932477C (en) 2013-12-06 2023-10-10 Baikang (Suzhou) Co., Ltd Bioreversable promoieties for nitrogen-containing and hydroxyl-containing drugs
AU2014366049B2 (en) 2013-12-19 2018-04-05 Sunshine Lake Pharma Co., Ltd. Nitrogenous heterocyclic derivatives and their application in drugs
US20160271056A1 (en) 2013-12-23 2016-09-22 Nitric Solutions Inc. Cystic fibrosis treatment comprising nitric oxide
CN106455705A (zh) 2014-01-22 2017-02-22 方特慕控股第私人有限公司 用于吸烟欲望救济的方法和装置
KR20160117596A (ko) 2014-02-07 2016-10-10 오스펙스 파마슈티칼스, 인코포레이티드 신규 제약 제제
CN103787968B (zh) 2014-02-27 2016-04-13 上海湖发化学技术有限公司 化合物的制备方法
WO2015128882A2 (en) 2014-02-27 2015-09-03 Msn Laboratories Private Limited Crystalline forms of n-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide and process for the preparation thereof
AU2015229117A1 (en) 2014-03-13 2016-09-29 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
EP3116501A1 (en) 2014-03-13 2017-01-18 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing cftr activity
JP6701088B2 (ja) 2014-03-19 2020-05-27 インフィニティー ファーマシューティカルズ， インコーポレイテッド Ｐｉ３ｋ−ガンマ媒介障害の治療で使用するための複素環式化合物
RU2744460C2 (ru) 2014-04-15 2021-03-09 Вертекс Фармасьютикалз Инкорпорейтед Фармацевтические композиции для лечения заболеваний, опосредованных муковисцидозным трансмембранным регулятором проводимости
WO2015168079A1 (en) 2014-04-29 2015-11-05 Infinity Pharmaceuticals, Inc. Pyrimidine or pyridine derivatives useful as pi3k inhibitors
US11052132B2 (en) 2014-05-08 2021-07-06 Phasebio Pharmaceuticals, Inc. Methods and compositions for treating cystic fibrosis
EP3142701B1 (en) 2014-05-12 2018-06-27 Verona Pharma PLC New treatment
EP3142748B1 (en) 2014-05-15 2019-09-11 Celgene Corporation Use of pde4 inhibitors and combinations thereof for the treatment of cystic fibrosis
EP3142663A1 (en) 2014-05-16 2017-03-22 Celgene Corporation Compositions and methods for the treatment of atherosclerotic cardiovascular diseases with pde4 modulators
WO2015179369A1 (en) 2014-05-20 2015-11-26 Infinity Pharmaceuticals, Inc. Treatment of pulmonary or respiratory diseases by inhalation administration of pi3 kinase inhibitors
CA2952862A1 (en) 2014-06-19 2015-12-23 Proteostasis Therapeutics, Inc. Compounds, compositions and methods of increasing cftr activity
EP3177272A1 (en) 2014-08-04 2017-06-14 Sandoz AG Aqueous granulation process for amorphous poorly water soluble drugs
AU2015304851A1 (en) 2014-08-21 2017-02-23 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as RIP1 kinase inhibitors as medicaments
GB201415381D0 (en) 2014-08-29 2014-10-15 Algipharma As Inhalable powder formulations of alginate oligomers
CN104530415B (zh) 2014-10-01 2017-09-01 厦门赛诺邦格生物科技股份有限公司 一种异官能化y型聚乙二醇衍生物、制备方法及其生物相关物质
CN104530413B (zh) 2014-10-01 2017-08-25 厦门赛诺邦格生物科技股份有限公司 一种多官能化h型聚乙二醇衍生物修饰的生物相关物质
CN104530417B (zh) 2014-10-01 2017-09-08 厦门赛诺邦格生物科技股份有限公司 一种多官能化h型聚乙二醇衍生物及其制备方法
CN104725628B (zh) 2014-10-01 2018-04-17 厦门赛诺邦格生物科技股份有限公司 一种含可降解基团的单一官能化支化聚乙二醇、制备方法及其生物相关物质
US9855249B2 (en) 2014-10-02 2018-01-02 Flatley Discovery Lab, Llc Isoxazole compounds and methods for the treatment of cystic fibrosis
US9708348B2 (en) 2014-10-03 2017-07-18 Infinity Pharmaceuticals, Inc. Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof
ES2971157T3 (es) 2014-10-06 2024-06-03 Apm Therapeutics 1 Inc Compuestos de triazolopiridina y métodos para el tratamiento de la fibrosis quística
CN112250627B (zh) 2014-10-06 2024-02-02 弗特克斯药品有限公司 囊性纤维化跨膜转导调节因子调节剂
JP6746569B2 (ja) 2014-10-07 2020-08-26 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ 嚢胞性線維症膜貫通コンダクタンス制御因子のモジュレーターの共結晶
US20170281612A1 (en) 2014-10-08 2017-10-05 Nivalis Therapeutics, Inc. Methods for the Treatment of Cystic Fibrosis
US20160108406A1 (en) 2014-10-08 2016-04-21 University Of Iowa Research Foundation Method of regulating cftr expression and processing
GB201418892D0 (en) 2014-10-23 2014-12-10 Proqr Therapeutics B V DNA editing
TW201615221A (zh) 2014-10-24 2016-05-01 朗齊生物醫學股份有限公司 炎症用藥臨床新應用
CA2966023A1 (en) 2014-10-31 2016-05-06 Abbvie S.A.R.L. Substituted tetrahydropyrans and method of use
ES2830279T3 (es) 2014-10-31 2021-06-03 Abbvie Overseas Sarl Cromanos sustituidos y método de uso
EP3217997A4 (en) 2014-11-12 2018-08-15 Trustees of Dartmouth College Dab2 inhibitors for the prevention and treatment of cystic fibrosis
WO2016075703A2 (en) 2014-11-13 2016-05-19 Laurus Labs Private Limited An improved process for preparation of 5-amino-2,4-di-tert- butylphenol or an acid addition salt thereof
SG11201703963QA (en) 2014-11-18 2017-06-29 Vertex Pharma Process of conducting high throughput testing high performance liquid chromatography
WO2016086136A1 (en) 2014-11-26 2016-06-02 Catabasis Pharmaceuticals, Inc. Fatty acid cysteamine conjugates of cftr modulators and their use in treating medical disorders
MA41031A (fr) 2014-11-26 2017-10-03 Catabasis Pharmaceuticals Inc Conjugués cystéamine-acide gras et leur utilisation comme activateurs de l'autophagie
EP3226861A2 (en) 2014-12-05 2017-10-11 Centre National de la Recherche Scientifique (CNRS) Compounds for treating cystic fibrosis
EP3229791A4 (en) 2014-12-09 2018-09-26 Laurus Labs Limited Novel polymorphs of ivacaftor, process for its preparation and pharmaceutical composition thereof
DK3230736T3 (da) 2014-12-12 2020-06-08 Celcuity Inc Fremgangsmåder til måling af ErbB-signaleringsvejsaktivitet til at diagnosticere og behandle cancerpatienter
US10738011B2 (en) 2014-12-23 2020-08-11 Proteostasis Therapeutics, Inc. Derivatives of 5-(hetero)arylpyrazol-3-carboxylic amide or 1-(hetero)aryltriazol-4-carboxylic amide useful for the treatment of inter alia cystic fibrosis
MA41253A (fr) 2014-12-23 2017-10-31 Proteostasis Therapeutics Inc Composés, compositions et procédés pour augmenter l'activité du cftr
CA2971850A1 (en) 2014-12-23 2016-06-30 Proteostasis Therapeutics, Inc. Derivatives of 5-phenyl- or 5-heteroarylthiazol-2-carboxylic amide useful for the treatment of inter alia cystic fibrosis
CA2971835A1 (en) 2014-12-23 2016-06-30 Proteostasis Therapeutics, Inc. Derivatives of 3-heteroarylisoxazol-5-carboxylic amide useful for the treatment of inter alia cystic fibrosis
AU2015370463B2 (en) 2014-12-24 2020-12-24 Kither Biotech S.R.L. Novel PI3K gamma inhibitor peptide for treatment of respiratory system diseases
EA201892625A1 (ru) 2015-01-09 2019-07-31 Джилид Аполло, Ллс КОМБИНИРОВАННАЯ ТЕРАПИЯ С ПРИМЕНЕНИЕМ ИНГИБИТОРА АЦЕТИЛ-КоА-КАРБОКСИЛАЗЫ (ACC) ДЛЯ ЛЕЧЕНИЯ НЕАЛКОГОЛЬНОЙ ЖИРОВОЙ БОЛЕЗНИ ПЕЧЕНИ
US20180147187A1 (en) 2015-01-12 2018-05-31 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing cftr activity
BR112017016205A2 (pt) 2015-02-09 2018-03-27 Romani Luigina thymosin alpha 1 para uso no tratamento de fibrose cística
DE102015002820A1 (de) 2015-03-02 2016-09-08 Marco Schmidt Verfahren zur Speicherung genetischer Daten der personalisierten Medizin
CN104725314A (zh) 2015-03-23 2015-06-24 上海皓元化学科技有限公司 一种Ivacaftor的新晶型及其制备方法
WO2016160945A1 (en) 2015-03-31 2016-10-06 Concert Pharmaceuticals, Inc. Deuterated vx-661
GB201507926D0 (en) 2015-05-08 2015-06-24 Proqr Therapeutics N V Improved treatments using oligonucleotides
WO2016181414A1 (en) 2015-05-12 2016-11-17 Council Of Scientific & Industrial Research Process for the synthesis of ivacaftor and related compounds
UY36680A (es) 2015-05-19 2016-12-30 Glaxosmithkline Ip Dev Ltd Amidas heterocíclicas como inhibidores de quinasa
CA3021752A1 (en) 2015-06-11 2016-12-15 Aizant Drug Research Solutions Private Limited Nanoparticulate ivacaftor formulations
CN108383784B (zh) 2015-08-05 2020-07-17 上海皓元医药股份有限公司 一种Ivacaftor的合成方法及其中间体
CN105153105B (zh) 2015-08-15 2018-01-19 浙江永宁药业股份有限公司 1‑(2,2‑二氟苯并[d][1,3]二氧杂环戊烯‑5‑基)环丙烷甲酸的合成方法及其中间体
CN105237414B (zh) 2015-09-30 2017-03-22 浙江永宁药业股份有限公司 ivacaftor中间体及其制备方法和用途
CN105457038A (zh) 2015-11-09 2016-04-06 东南大学 一种速释型药物磷脂化合物及其药物组合物
CN105884628B (zh) 2016-06-06 2018-06-29 上海工程技术大学 2,4-二叔丁基-5-氨基酚的制备方法
US20180280349A1 (en) 2017-03-28 2018-10-04 Vertex Pharmaceuticals Incorporated Methods of treating cystic fibrosis in patients with residual function mutations

Patent Citations (82)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3524858A (en) * 1967-05-18 1970-08-18 Warner Lambert Pharmaceutical 1,4 - dihydro-1-substituted alkyl-6,7-methylenedioxy - 4 - oxoquinoline-3-carboxylic acid
US3992540A (en) * 1974-08-13 1976-11-16 Roussel-Uclaf 3-Quinoline-substituted 4-oxy-carboxamides
US4107310A (en) * 1976-02-11 1978-08-15 Roussel Uclaf Quinoline-3-carboxamides
US4221779A (en) * 1977-06-28 1980-09-09 Graham Neil B Pharmaceutical composition for treating tropical diseases
US4312870A (en) * 1979-06-21 1982-01-26 Ciba-Geigy Corporation Pyrazoloquinolines
US4450166A (en) * 1981-06-12 1984-05-22 Roussel Uclaf N-(4,5-Dihydro-thiazol-2-yl)-3-quinoline-carboxamides having anxiolytic activity
US4450167A (en) * 1981-07-17 1984-05-22 Roussel Uclaf 3-Quinoline carboxamides having anxiolytic activity
US4845105A (en) * 1984-10-30 1989-07-04 Roussel Uclaf 4-OH-quinoline carboxylic acid amides having analgesic and anti-inflammatory activity
US4908366A (en) * 1987-01-28 1990-03-13 Bayer Aktiengesellschaft Antibacterial 8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids
US4777252A (en) * 1987-08-13 1988-10-11 E. R. Squibb & Sons, Inc. 2-oxo-1-[[(substituted sulfonyl)amino]-carbonyl]azetidines
US4956465A (en) * 1987-10-09 1990-09-11 Bayer Aktiengesellschaft Quinolone- and 1,8-naphthyridin-4-one-carboxylic acids which are C-bonded in the 7-position
US4786644A (en) * 1987-11-27 1988-11-22 Hoechst-Roussel Pharmaceuticals Inc. 1-aryl-3-quinolinecarboxamide
US5026711A (en) * 1988-06-06 1991-06-25 Sanofi 4-amino quinolines and naphthyridines and their use as medicines
US5491139A (en) * 1988-10-24 1996-02-13 The Procter & Gamble Company Antimicrobial quinolonyl lactams
US5364414A (en) * 1989-10-20 1994-11-15 L'oreal Tinctorial composition for keratinous fibres containing oxidation dye precursors and aminoindole couplers, methods for dyeing using these compositions and new compounds
US5180400A (en) * 1990-05-29 1993-01-19 L'oreal Method for dyeing keratinous fibres using an aminoindole in combination with a quinone derivative
US5412104A (en) * 1990-09-07 1995-05-02 Schering Corporation Ester and alkoxy substituted benzopyrans
US5378694A (en) * 1990-09-07 1995-01-03 Schering Corporation Acyl and alkoxy substituted quinolines
US5175151A (en) * 1990-09-07 1992-12-29 Schering Corporation Antiviral compounds and antihypertensive compounds
US5380713A (en) * 1991-08-06 1995-01-10 Bristol-Myers Squibb Company Peptide aldehydes as antithrombotic agents
US5527763A (en) * 1991-12-24 1996-06-18 Kumiai Chemical Industry Co., Ltd. Pyrimidine or triazine derivatives and herbicides
US5536727A (en) * 1992-05-20 1996-07-16 Merck & Co., Inc. 17-Ethers and thioethers of 4-aza-steroids
US5610162A (en) * 1992-05-20 1997-03-11 Merck & Co., Inc. Ester derivatives of 4-aza-steroids
US5352690A (en) * 1992-07-01 1994-10-04 Eli Lilly And Company 1,2,4-trioxygenated benzene derivatives useful as leukotriene antagonists
US5663179A (en) * 1992-07-10 1997-09-02 Laboratoires Glaxo Sa Certain isoquinoline derivatives having anti-tumor properties
US5322847A (en) * 1992-11-05 1994-06-21 Pfizer Inc. Azabenzimidazoles in the treatment of asthma, arthritis and related diseases
US5750754A (en) * 1993-03-29 1998-05-12 Zeneca Limited Heterocyclic compounds
US5573868A (en) * 1993-04-22 1996-11-12 Daikin Industries, Ltd. Material for generating electric energy
US5744471A (en) * 1993-10-22 1998-04-28 Zeneca Limited Pyridazion quinoline compounds
US5728691A (en) * 1994-02-25 1998-03-17 Laboratorios Aranda S.A. De C.V. Quinolonylcarboxamidocephalosporin derivatives and pharmaceutical compositions containing them
US5708000A (en) * 1994-05-24 1998-01-13 Laboratoire Laphal N4-substituted cytosinyl 1,3-oxathiolane nucleoside analogues, and their antiviral activity
US5811553A (en) * 1994-05-27 1998-09-22 Smithkline Beecham Farmaceutici S.P.A. Quinoline derivatives(2)
US5840745A (en) * 1995-01-26 1998-11-24 Pharmacia S. P. A. Hydrosoluble 3-arylidene-2-oxindole derivatives as tyrosine kinase inhibitors
US5753666A (en) * 1995-08-02 1998-05-19 Chiroscience Limited Quinolones and their therapeutic use
US5891878A (en) * 1995-08-02 1999-04-06 Chiroscience Limited Quinolones and their therapeutic use
US5807869A (en) * 1995-10-19 1998-09-15 Takeda Chemical Industries, Ltd. Quinoline derivatives, their production and use
US5874424A (en) * 1995-12-20 1999-02-23 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US6215016B1 (en) * 1996-03-27 2001-04-10 Toray Industries, Inc. Ketone derivatives and medical application thereof
US5892114A (en) * 1996-04-18 1999-04-06 Bayer Aktiengesellschaft Hetero-linked phenylglycinolamides
US5804588A (en) * 1996-05-20 1998-09-08 Chiroscience Limited Quinoline carboxanides and their therapeutic use
US5834485A (en) * 1996-05-20 1998-11-10 Chiroscience Limited Quinoline sulfonamides and their therapeutic use
US6720344B2 (en) * 1996-06-20 2004-04-13 The Board Of Regents Of The University Of Texas System Methods and compositions for stimulating osteoblast proliferation or treating malignant cell proliferation and methods for selecting osteoblast proliferation stimulants
US6133265A (en) * 1996-07-23 2000-10-17 Neurogen Corporation Certain amido- and amino- substituted benzylamine derivatives; a new class of neuropeptide Y1 specific ligands
US6218393B1 (en) * 1996-10-18 2001-04-17 Xenova Limited Anthranilic acid derivatives as multi drug resistance modulators
US6069151A (en) * 1996-11-06 2000-05-30 Darwin Discovery, Ltd. Quinolines and their therapeutic use
US6258822B1 (en) * 1997-08-06 2001-07-10 Abbott Laboratories Urokinase inhibitors
US6429207B1 (en) * 1997-11-21 2002-08-06 Nps Pharmaceuticals, Inc. Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases
US6448254B1 (en) * 1998-04-20 2002-09-10 Abbott Laboratories Substituted amides, their production and their use
US20020173520A1 (en) * 1998-07-15 2002-11-21 Active Biotech Ab Quinoline derivatives
US6444617B1 (en) * 1998-07-28 2002-09-03 Nihon Nohyaku Co., Ltd. Fused-heterocycle dicarboxylic acid diamide derivatives or salts thereof, herbicide and usage thereof
US6723850B1 (en) * 1998-08-03 2004-04-20 Applied Research Systems Ars Holding N.V. Process for the synthesis of (1-H)-benzo[c]quinolizin-3-ones derivatives
US6362340B1 (en) * 1998-12-01 2002-03-26 Rhodia Chimie Method for preparing 4-hydroquinolines and/or tautomeric compounds
US6413956B1 (en) * 1999-05-06 2002-07-02 Neurogen Corporation Substituted 4-oxo-quinoline-3-carboxamides
US6395750B1 (en) * 1999-10-25 2002-05-28 Active Biotech Ab Drugs for the treatment of malignant tumors
US6544987B2 (en) * 1999-12-01 2003-04-08 Pfizer Inc. Compounds, compositions, and methods for stimulating neuronal growth and elongation
US20030195191A1 (en) * 2000-05-11 2003-10-16 Gordon Burton N-sulfonyl hydroxamic acid derivatives as inhibitors of cd23
US20040121005A1 (en) * 2000-06-15 2004-06-24 Acusphere, Inc. Porous COX-2 inhibitor matrices and methods of manufacture thereof
US6974806B2 (en) * 2000-07-13 2005-12-13 Takeda Pharmaceutical Company Limited Lipid-rich plaque inhibitors
US7112594B2 (en) * 2000-08-09 2006-09-26 Mitsubishi Pharma Corporation Fused bicyclic amide compounds and medicinal use thereof
US7105535B2 (en) * 2001-02-02 2006-09-12 Pfizer Italia S.R.L. Oxazolyl-pyrazole derivatives as kinase inhibitors
US7179839B2 (en) * 2001-02-13 2007-02-20 Sanofi-Aventis Deutschland Gmbh Acylated indanyl amines and their use as pharmaceuticals
US6790858B2 (en) * 2001-02-21 2004-09-14 Zentaris Ag Quinoline, isoquinoline and phthalazine derivatives as antagonists of the gonadotropin-releasing hormone
US6515001B2 (en) * 2001-03-05 2003-02-04 Chemokine Therapeutic Corporation IL-8 receptor ligands-drugs for inflammatory and autoimmune diseases
US20040082798A1 (en) * 2001-03-07 2004-04-29 Cristina Alonso-Alija Novel amino dicarboxylic acid derivatives with pharmaceutical properties
US6878713B2 (en) * 2001-04-25 2005-04-12 Wockhardt Limited Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments
US6849648B2 (en) * 2001-10-12 2005-02-01 Warner-Lambert Company Phenylene alkyne matrix metalloproteinase inhibitors
US7084156B2 (en) * 2001-11-27 2006-08-01 Merck & Co., Inc. 2-Aminoquinoline compounds
US20030195201A1 (en) * 2001-12-10 2003-10-16 Bo Yunxin Y. Vanilloid receptor ligands and their use in treatments
US6977001B2 (en) * 2002-03-15 2005-12-20 Wella Ag Dye compositions containing quinolinium salts
US6930131B2 (en) * 2002-04-10 2005-08-16 Wyeth Aryl substituted 3-ethoxy phenyl trifluoromethane sulfonamides for the treatment of non-insulin dependent diabetes mellitus (NIDDM)
US20050176741A1 (en) * 2002-04-26 2005-08-11 Masahiko Okano Quinazoline derivative and medicine
US7037913B2 (en) * 2002-05-01 2006-05-02 Bristol-Myers Squibb Company Bicyclo 4.4.0 antiviral derivatives
US20050222199A1 (en) * 2002-05-14 2005-10-06 Xenova Limited Process for the preparation of a hydrate of an antranilic acid derivative
US20060178516A1 (en) * 2002-05-14 2006-08-10 Johnstone Timothy B Substituted quinolone carboxylic acids, their derivatives, site of action, and uses thereof
US20050187300A1 (en) * 2002-07-15 2005-08-25 Myriad Genetics, Incorporated Compounds, compositions, and methods employing same
US20040033959A1 (en) * 2002-07-19 2004-02-19 Boehringer Ingelheim Pharmaceuticals, Inc. Pharmaceutical compositions for hepatitis C viral protease inhibitors
US20040043983A1 (en) * 2002-08-13 2004-03-04 Li Jie Jack Naphthalene derivatives as matrix metalloproteinase inhibitors
US20060148806A1 (en) * 2003-07-24 2006-07-06 Susumu Watanuki Quinolone derivative or salt thereof
US20050208095A1 (en) * 2003-11-20 2005-09-22 Angiotech International Ag Polymer compositions and methods for their use
US20050186261A1 (en) * 2004-01-30 2005-08-25 Angiotech International Ag Compositions and methods for treating contracture
US20050192315A1 (en) * 2004-02-06 2005-09-01 Active Biotech Ab New compositions containing quinoline compounds
US7495103B2 (en) * 2004-06-24 2009-02-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters

Cited By (151)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8741939B2 (en) 2003-09-06 2014-06-03 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8853415B2 (en) 2003-09-06 2014-10-07 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9249131B2 (en) 2003-09-06 2016-02-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8431605B2 (en) 2003-09-06 2013-04-30 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
US20110144123A1 (en) * 2003-11-14 2011-06-16 Vertex Pharmaceuticals Incorporated Thiazoles and Oxazoles Useful as Modulators of ATP-Binding Cassette Transporters
US8232302B2 (en) 2003-11-14 2012-07-31 Vertex Pharmaceuticals Incorporated Thiazoles and oxazoles useful as modulators of ATP-binding cassette transporters
US9550761B2 (en) 2004-01-30 2017-01-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10626111B2 (en) 2004-01-30 2020-04-21 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10662192B2 (en) 2004-06-24 2020-05-26 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8541453B2 (en) 2004-08-20 2013-09-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8586615B2 (en) 2005-08-11 2013-11-19 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US9351962B2 (en) 2005-08-11 2016-05-31 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US8962856B2 (en) 2005-08-11 2015-02-24 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US9856248B2 (en) 2005-08-11 2018-01-02 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US20080306062A1 (en) * 2005-11-08 2008-12-11 Hadida Ruah Sara S Modulators of atp-binding cassette transporters
US8741933B2 (en) 2005-11-08 2014-06-03 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US20110172229A1 (en) * 2005-11-08 2011-07-14 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
US11084804B2 (en) 2005-11-08 2021-08-10 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9216969B2 (en) 2005-11-08 2015-12-22 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8461156B2 (en) 2005-11-08 2013-06-11 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8324207B2 (en) 2005-11-08 2012-12-04 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8318733B2 (en) 2005-11-08 2012-11-27 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9670163B2 (en) 2005-12-28 2017-06-06 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US20100249113A1 (en) * 2005-12-28 2010-09-30 Vertex Pharmaceuticals Incorporated Modulators of atp binding cassette transporters
US8524767B2 (en) 2005-12-28 2013-09-03 Vertex Pharmaceuticals Incorporated Modulators of ATP binding cassette transporters
US11291662B2 (en) 2005-12-28 2022-04-05 Vertex Pharmaceuticals Incorporated Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US10537565B2 (en) 2005-12-28 2020-01-21 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US8846753B2 (en) 2005-12-28 2014-09-30 Vertex Pharamaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9931334B2 (en) 2005-12-28 2018-04-03 Vertex Pharmaceuticals Incorporated Solid forms of N[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US8415387B2 (en) 2006-04-07 2013-04-09 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US20110071206A1 (en) * 2006-04-07 2011-03-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette Transporters
US9758510B2 (en) 2006-04-07 2017-09-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US20100113555A1 (en) * 2006-04-07 2010-05-06 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette Transporters
US8952050B2 (en) 2006-04-07 2015-02-10 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US20100331344A1 (en) * 2006-04-07 2010-12-30 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette Transporters
US11639347B2 (en) 2006-04-07 2023-05-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9974781B2 (en) 2006-04-07 2018-05-22 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8912199B2 (en) 2006-04-07 2014-12-16 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10239867B2 (en) 2006-04-07 2019-03-26 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8952049B2 (en) 2006-04-07 2015-02-10 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10975061B2 (en) 2006-04-07 2021-04-13 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8623905B2 (en) 2006-04-07 2014-01-07 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10987348B2 (en) 2006-04-07 2021-04-27 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8598181B2 (en) 2006-04-07 2013-12-03 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8575209B2 (en) 2006-04-07 2013-11-05 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10022352B2 (en) 2006-04-07 2018-07-17 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8076357B2 (en) 2006-05-12 2011-12-13 Vertex Pharmaceuticals Incorporated Compositions of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US9732080B2 (en) 2006-11-03 2017-08-15 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US9102672B2 (en) 2006-11-03 2015-08-11 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US8969386B2 (en) 2007-05-09 2015-03-03 Vertex Pharmaceuticals Incorporated Modulators of CFTR
US9725440B2 (en) 2007-05-09 2017-08-08 Vertex Pharmaceuticals Incorporated Modulators of CFTR
US9399648B2 (en) 2007-08-24 2016-07-26 Vertex Pharmaceuticals Incorporated Isothiazolopyridinones useful for the treatment of (inter alia) cystic fibrosis
US8563573B2 (en) 2007-11-02 2013-10-22 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US20090253736A1 (en) * 2007-11-02 2009-10-08 Vertex Pharmaceuticals Incorporated Azaindole derivatives as cftr modulators
US9012473B2 (en) 2007-11-16 2015-04-21 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8722704B2 (en) 2007-11-16 2014-05-13 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette-transporters
US8507524B2 (en) 2007-11-16 2013-08-13 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette-transporters
US20090143381A1 (en) * 2007-11-16 2009-06-04 Hadida Ruah Sara S Modulators of atp-binding cassette-transporters
US9522145B2 (en) 2007-11-16 2016-12-20 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9840499B2 (en) 2007-12-07 2017-12-12 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US8653103B2 (en) 2007-12-07 2014-02-18 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US20090176989A1 (en) * 2007-12-07 2009-07-09 David Siesel Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US8816093B2 (en) 2007-12-07 2014-08-26 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US12065432B2 (en) 2007-12-07 2024-08-20 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US8846718B2 (en) 2007-12-07 2014-09-30 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US20100036130A1 (en) * 2007-12-07 2010-02-11 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US10597384B2 (en) 2007-12-07 2020-03-24 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US8124781B2 (en) 2007-12-07 2012-02-28 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9150552B2 (en) 2007-12-07 2015-10-06 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US9321725B2 (en) 2007-12-07 2016-04-26 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9776968B2 (en) 2007-12-07 2017-10-03 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US8592602B2 (en) 2007-12-07 2013-11-26 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US20090176839A1 (en) * 2007-12-07 2009-07-09 Ali Keshavarz-Shokri Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US8507534B2 (en) 2007-12-07 2013-08-13 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US9434717B2 (en) 2007-12-07 2016-09-06 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US8461342B2 (en) 2007-12-07 2013-06-11 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9012652B2 (en) 2007-12-07 2015-04-21 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US20090170905A1 (en) * 2007-12-07 2009-07-02 Ali Keshavarz-Shokri Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US8796312B2 (en) 2008-02-28 2014-08-05 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
US9504683B2 (en) 2008-02-28 2016-11-29 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
US9079916B2 (en) 2008-02-28 2015-07-14 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
US8299099B2 (en) 2008-02-28 2012-10-30 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
US9751890B2 (en) 2008-02-28 2017-09-05 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
US20090221597A1 (en) * 2008-02-28 2009-09-03 Sara Hadida Ruah Heteroaryl derivatives as cftr modulators
US8227615B2 (en) 2008-03-31 2012-07-24 Vertex Pharmaceutical Incorporated Pyridyl derivatives as CFTR modulators
US8889875B2 (en) 2008-03-31 2014-11-18 Vertex Pharmaceuticals Incorporated Pyridyl derivatives as CFTR modulators
US20090246137A1 (en) * 2008-03-31 2009-10-01 Vertex Pharmaceuticals Incorporated Pyridyl derivatives as cftr modulators
US8524910B2 (en) 2008-03-31 2013-09-03 Vertex Pharmaceuticals Incorporated Pyridyl derivatives as CFTR modulators
US20120220625A1 (en) * 2008-08-13 2012-08-30 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US11564916B2 (en) 2008-08-13 2023-01-31 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US10646481B2 (en) 2008-08-13 2020-05-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US8716338B2 (en) 2008-09-29 2014-05-06 Vertex Pharmaceuticals Incorporated Dosage units of 3-(6-(1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US20100087490A1 (en) * 2008-09-29 2010-04-08 Vertex Pharmaceuticals Incorporated Dosage Units of 3-(6-(1-(2,2-Difluorobenzo[D] [1,3] Dioxol-5-YL) Cyclopropanecarboxamido)-3-Methylpyridin-2-YL)Benzoic Acid
US9192606B2 (en) 2008-09-29 2015-11-24 Vertex Pharmaceuticals Incorporated Dosage units of 3-(6-(1-(2,2-difluorobenzo[d] [1,3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US8513282B2 (en) 2008-10-23 2013-08-20 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US8785640B2 (en) 2008-10-23 2014-07-22 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US20100113508A1 (en) * 2008-10-23 2010-05-06 Vertex Pharmaceuticals, Incorporated Modulators of Cystic Fibrosis Transmembrane Conductance Regulator
US8598205B2 (en) 2008-10-23 2013-12-03 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US9371287B2 (en) 2009-03-20 2016-06-21 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
US9751839B2 (en) 2009-03-20 2017-09-05 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
US8471029B2 (en) * 2010-03-19 2013-06-25 Vertex Pharmaceutical Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US8785476B2 (en) 2010-03-19 2014-07-22 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US20110230519A1 (en) * 2010-03-19 2011-09-22 Vertex Pharmaceuticals Incorporated Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US10906891B2 (en) 2010-03-25 2021-02-02 Vertex Pharmaceuticals Incoporated Solid forms of (R)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US8802868B2 (en) 2010-03-25 2014-08-12 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide
US11578062B2 (en) 2010-03-25 2023-02-14 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US8552034B2 (en) 2010-04-07 2013-10-08 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and administration thereof
US10076513B2 (en) 2010-04-07 2018-09-18 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and administration thereof
US11052075B2 (en) 2010-04-07 2021-07-06 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and administration thereof
US9314455B2 (en) 2010-04-07 2016-04-19 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US8507687B2 (en) 2010-04-07 2013-08-13 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US9241934B2 (en) 2010-04-07 2016-01-26 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and administration thereof
US8742122B2 (en) 2010-04-07 2014-06-03 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
EP3138563A1 (en) 2010-04-22 2017-03-08 Vertex Pharmaceuticals Inc. Pharmaceutical compositions and administrations thereof
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
WO2011133953A1 (en) 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
WO2011133951A1 (en) 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
US8563593B2 (en) 2010-06-08 2013-10-22 Vertex Pharmaceuticals Incorporated Formulations of (R)-1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10894773B2 (en) 2011-05-18 2021-01-19 Vertex Pharmaceuticals (Europe) Limited Deuterated CFTR potentiators
US10047053B2 (en) 2011-05-18 2018-08-14 Vertex Pharmaceuticals (Europe) Limited Deuterated CFTR potentiators
US10479766B2 (en) 2011-05-18 2019-11-19 Verex Pharmaceuticals (Europe) Limited Deuterated CFTR potentiators
US9254291B2 (en) 2011-11-08 2016-02-09 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US11752106B2 (en) 2012-02-27 2023-09-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US10272046B2 (en) 2012-02-27 2019-04-30 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US8883206B2 (en) 2012-02-27 2014-11-11 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US11147770B2 (en) 2012-02-27 2021-10-19 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
WO2013130669A1 (en) 2012-02-27 2013-09-06 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administration thereof
US8674108B2 (en) 2012-04-20 2014-03-18 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethy)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US9045425B2 (en) 2012-04-20 2015-06-02 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US10058546B2 (en) 2012-07-16 2018-08-28 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of (R)-1-(2,2-difluorobenzo[D][1,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1) cyclopropanecarbox-amide and administration thereof
US9012496B2 (en) 2012-07-16 2015-04-21 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of (R)-1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide and administration thereof
WO2014125506A2 (en) * 2013-02-15 2014-08-21 Laurus Labs Private Limited A process for the preparation of ivacaftor and its intermediates
US9573902B2 (en) 2013-02-15 2017-02-21 Laurus Labs Private Ltd. Process for the preparation of Ivacaftor and its intermediates
WO2014125506A3 (en) * 2013-02-15 2014-12-24 Laurus Labs Private Limited A process for the preparation of ivacaftor and its intermediates
US10231932B2 (en) 2013-11-12 2019-03-19 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US11951212B2 (en) 2014-04-15 2024-04-09 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10980746B2 (en) 2014-04-15 2021-04-20 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
US10302602B2 (en) 2014-11-18 2019-05-28 Vertex Pharmaceuticals Incorporated Process of conducting high throughput testing high performance liquid chromatography
WO2016181414A1 (en) 2015-05-12 2016-11-17 Council Of Scientific & Industrial Research Process for the synthesis of ivacaftor and related compounds
US10336703B2 (en) 2015-05-12 2019-07-02 Council Of Scientific And Industrial Research Process for the synthesis of ivacaftor and related compounds
US10759721B2 (en) 2015-09-25 2020-09-01 Vertex Pharmaceuticals (Europe) Limited Deuterated CFTR potentiators
US11274081B2 (en) 2016-05-30 2022-03-15 Council Of Scientific & Industrial Research Process for the synthesis of ivacaftor
WO2017208253A2 (en) 2016-05-30 2017-12-07 Council Of Scientific & Industrial Research An improved process for the synthesis of ivacaftor
EP4043439A1 (en) 2016-05-30 2022-08-17 Council of Scientific and Industrial Research An improved process for the synthesis of ivacaftor [
US11179469B2 (en) 2017-04-28 2021-11-23 Nitto Denko Corporation Transdermal absorption preparation
US11708331B2 (en) 2017-12-01 2023-07-25 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US12024491B2 (en) 2017-12-01 2024-07-02 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
WO2022013360A1 (en) * 2020-07-17 2022-01-20 Synthon B.V. Pharmaceutical composition comprising ivacaftor

Also Published As

Publication number Publication date
CN101384172A (zh) 2009-03-11
US9931334B2 (en) 2018-04-03
EP1993360A2 (en) 2008-11-26
BRPI0620960A2 (pt) 2011-11-29
PL1993360T3 (pl) 2017-08-31
HUE032813T2 (en) 2017-11-28
US20230263794A1 (en) 2023-08-24
PL3219705T3 (pl) 2020-08-10
HUE049976T2 (hu) 2020-11-30
US20130317060A1 (en) 2013-11-28
HRP20170682T1 (hr) 2017-07-14
LT1993360T (lt) 2017-06-12
CY1118980T1 (el) 2018-01-10
RS55940B1 (sr) 2017-09-29
JP2009522278A (ja) 2009-06-11
US20120214841A1 (en) 2012-08-23
US20200352930A1 (en) 2020-11-12
EP1993360A4 (en) 2010-12-01
CN101384172B (zh) 2014-05-07
RS60205B1 (sr) 2020-06-30
SI3219705T1 (sl) 2020-08-31
HRP20200708T1 (hr) 2020-07-24
JP5409010B2 (ja) 2014-02-05
US9139530B2 (en) 2015-09-22
JP5734369B2 (ja) 2015-06-17
US9670163B2 (en) 2017-06-06
WO2007079139A3 (en) 2008-01-17
CA2635581A1 (en) 2007-07-12
DK3219705T3 (da) 2020-04-14
EP3708564B1 (en) 2024-10-09
EP3219705A1 (en) 2017-09-20
EP3219705B1 (en) 2020-03-11
EP3708564A1 (en) 2020-09-16
US10537565B2 (en) 2020-01-21
JP2015096539A (ja) 2015-05-21
US20170231970A1 (en) 2017-08-17
US8410274B2 (en) 2013-04-02
JP2014012701A (ja) 2014-01-23
LT3219705T (lt) 2020-04-27
DK1993360T3 (en) 2017-05-22
CY1122861T1 (el) 2021-05-05
US20190070162A1 (en) 2019-03-07
ES2790700T3 (es) 2020-10-28
PT1993360T (pt) 2017-05-25
HK1125540A1 (en) 2009-08-14
ME03786B (me) 2021-04-20
PT3219705T (pt) 2020-05-20
WO2007079139A9 (en) 2007-11-29
ES2624554T3 (es) 2017-07-14
US20140242172A1 (en) 2014-08-28
EP1993360B1 (en) 2017-02-08
AU2006332726B2 (en) 2012-12-13
AU2006332726A1 (en) 2007-07-12
US8754224B2 (en) 2014-06-17
CA2635581C (en) 2017-02-28
WO2007079139A2 (en) 2007-07-12
US20210251978A9 (en) 2021-08-19
US11291662B2 (en) 2022-04-05
US20160229806A1 (en) 2016-08-11

Similar Documents

Publication Publication Date Title
US11291662B2 (en) Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US8076357B2 (en) Compositions of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
AU2018204203B2 (en) Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
AU2020201314B2 (en) Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

Legal Events

Date Code Title Description
AS Assignment

Owner name: VERTEX PHARMACEUTICALS INCORPORATED, MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HURTER, PATRICIA;ROWE, WILLIAM;YOUNG, CHRISTOPHER R.;AND OTHERS;SIGNING DATES FROM 20070925 TO 20071001;REEL/FRAME:020041/0336

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE

AS Assignment

Owner name: VERTEX PHARMACEUTICALS INCORPORATED, MASSACHUSETTS

Free format text: ASSIGNEE CHANGE OF ADDRESS;ASSIGNOR:VERTEX PHARMACEUTICALS INCORPORATED;REEL/FRAME:037841/0274

Effective date: 20160126