WO2017151725A1 - Formularions d'un inhibiteur de la s-nitrosoglutathione réductase - Google Patents

Formularions d'un inhibiteur de la s-nitrosoglutathione réductase Download PDF

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WO2017151725A1
WO2017151725A1 PCT/US2017/020129 US2017020129W WO2017151725A1 WO 2017151725 A1 WO2017151725 A1 WO 2017151725A1 US 2017020129 W US2017020129 W US 2017020129W WO 2017151725 A1 WO2017151725 A1 WO 2017151725A1
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hydroxyquinolin
benzoic acid
fluoro
chloro
group
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PCT/US2017/020129
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English (en)
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Chris DELANY
Rajendrakumar Dasharath KALE
Sherif GABRIEL
Peter Bove
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Nivalis Therapeutics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to pharmaceutical compositions comprising 3- chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid (Compound 1).
  • the invention also provides pharmaceutically acceptable compositions comprising solid forms of Compound 1 and methods of using the compositions in the treatment of various disorders.
  • the present invention is also directed to a method of treating or lessening the severity of cystic fibrosis in a patient, comprising the step of stabilizing the CFTR protein both in the cell and at the cell membrane by administering to said patient an effective amount of an inhibitor of S- nitrosoglutathione reductase (GSNOR).
  • GSNOR S- nitrosoglutathione reductase
  • Nitric oxide is one of the few gaseous signaling molecules known in biological systems, and plays an important role in controlling various biological events.
  • the endothelium uses NO to signal surrounding smooth muscle in the walls of arterioles to relax, resulting in vasodilation and increased blood flow to hypoxic tissues.
  • NO is also involved in regulating smooth muscle proliferation, platelet function, and
  • NO neurotransmission
  • NO plays a role in host defense.
  • NO is highly reactive and has a lifetime of a few seconds, it can both diffuse freely across membranes and bind to many molecular targets. These attributes make NO an ideal signaling molecule capable of controlling biological events between adjacent cells and within cells.
  • NO is a free radical gas, which makes it reactive and unstable, thus NO is short lived in vivo, having a half-life of 3-5 seconds under physiologic conditions.
  • NO can combine with thiols to generate a biologically important class of stable NO adducts called S-nitrosothiols (SNO's).
  • SNO's S-nitrosothiols
  • GSNO S-nitrosoglutathione
  • S-nitrosoglutathione is a key regulator of nitric oxide (NO) homeostasis and cellular S-nitrosothiol (SNO) levels, and studies have focused on examining endogenous production of GSNO and SNO proteins, which occurs downstream from the production of the NO radical by the nitric oxide synthetase (NOS) enzymes. More recently there has been an increasing understanding of enzymatic catabolism of GSNO which has an important role in governing available concentrations of GSNO and consequently available NO and SNO's.
  • GSNOR S-nitrosoglutathione reductase
  • GSNOR shows greater activity toward GSNO than other substrates (Jensen et al., (1998); Liu et al., (2001)) and appears to mediate important protein and peptide denitrosating activity in bacteria, plants, and animals.
  • GSNOR appears to be the major GSNO-metabolizing enzyme in eukaryotes (Liu et al., (2001)).
  • GSNO can accumulate in biological compartments where GSNOR activity is low or absent (e.g., airway lining fluid) (Gaston et al., (1993)).
  • GSNO specifically has been implicated in physiologic processes ranging from the drive to breathe (Lipton et al., Nature, 413: 171-174 (2001)) to regulation of the cystic fibrosis transmembrane regulator (Zaman et al., Biochem Biophys Res Commun, 284:65-70 (2001)), to regulation of vascular tone, thrombosis, and platelet function (de Belder et al., Cardiovasc Res.; 28(5):691-4 (1994)), Z. Kaposzta, et al., Circulation; 106(24): 3057 - 3062, (2002)) as well as host defense (de Jesus-Berrios et al., Curr.
  • GSNO S-nitrosoglutathione reductase
  • NO and GSNO maintain normal lung physiology and function via their modulatory effects on the cystic fibrosis transmembrane regulator (CFTR), antiinflammatory and bronchodilatory actions.
  • CTR cystic fibrosis transmembrane regulator
  • COPD chronic obstructive pulmonary disease
  • S-nitrosoglutathione has been shown to promote repair and/or
  • GSNOR S-nitrosoglutathione reductase
  • IBD Inflammatory bowel diseases
  • GI gastrointestinal
  • NO, GSNO, and GSNOR can exert influences.
  • NO and GSNO function to maintain normal intestinal physiology via anti-inflammatory actions and maintenance of the intestinal epithelial cell barrier.
  • reduced levels of GSNO and NO are evident and likely occur via up-regulation of GSNOR activity.
  • the lowered levels of these mediators contribute to the pathophysiology of IBD via disruption of the epithelial barrier via dysregulation of proteins involved in maintaining epithelial tight junctions.
  • This epithelial barrier dysfunction with the ensuing entry of micro-organisms from the lumen, and the overall lowered anti-inflammatory capabilities in the presence of lowered NO and GSNO, are key events in IBD progression that can be potentially influenced by targeting GSNOR.
  • Cystic fibrosis is one of the most common lethal genetic diseases in
  • CF is an autosomal recessive hereditary disease caused by a mutation in the gene for the cystic fibrosis transmembrane regulator (CFTR) protein.
  • the CFTR protein is located on the apical membrane and is responsible for chloride transport across epithelial cells on mucosal surfaces.
  • CF is diagnosed by the level of chloride in sweat because patients with CF have elevated sweat chloride due to the primary defect in CFTR. More than 1,000 disease-associated mutations have been discovered in the CFTR gene with the most common mutation being a deletion of the amino acid phenylalanine at position 508 (F508del). The F508del mutation is present in approximately 86% of CF patients. Approximately 47% of CF patients are homozygous and have two copies of the F508del mutation, and
  • lung disease is the most critical manifestation, characterized by airway obstruction, infection and inflammation that allow bacteria to grow unfettered and impair the lung's immune system. More than 90% of all CF patients die of respiratory failure. In the pancreas, damage caused by CF leads to diabetes, while the build-up of mucus prevents the release of digestive enzymes leading to poor nutrient absorption.
  • GSNO S- nitrosoglutathione
  • GSNOR S-nitrosoglutathione reductase
  • GSNO has been identified as a positive modulator of CFTR.
  • GSNOR is the primary catabolizing enzyme of GSNO. Inhibition of GSNOR may improve F508del-CFTR function via nitrosation of chaperone proteins, prevention of CFTR proteosomal degradation, promotion of CFTR maturation, and maintenance of epithelial tight junctions.
  • NO, GSNO, and GSNOR can also exert influences on disorders of the
  • GI gastrointestinal
  • IBD inflammatory bowel disease
  • cystic fibrosis gastrointestinal disease GI
  • NO and GSNO function to maintain normal intestinal physiology via antiinflammatory actions and maintenance of the intestinal epithelial cell barrier.
  • Acetaminophen overdoses are the leading cause of acute liver failure (ALF) in the United States, Great Britain and most of Europe. More than 100,000 calls to the U.S. Poison Control Centers, 56,000 emergency room visits, 2,600 hospitalizations, nearly 500 deaths are attributed to acetaminophen in this country annually. Approximately, 60% recover without needing a liver transplant, 9% are transplanted and 30% of patients succumb to the illness. The acetaminophen-related death rate exceeds by at least three-fold the number of deaths due to all other idiosyncratic drug reactions combined (Lee, Hepatol Res 2008; 38 (Suppl. 1):S3- S8).
  • liver transplantation has become the primary treatment for patients with fulminant hepatic failure and end- stage chronic liver disease, as well as certain metabolic liver diseases.
  • the demand for transplantation now greatly exceeds the availability of donor organs. It has been estimated that more than 18,000 patients are currently registered with the United Network for Organ Sharing (UNOS) and that an additional 9,000 patients are added to the liver transplant waiting list each year, yet less than 5,000 cadaveric donors are available for transplantation.
  • UNOS United Network for Organ Sharing
  • the invention includes pharmaceutical compositions and pharmaceutical preparations comprising 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid (Compound 1) which has the structure below:
  • Compound 1 is active in a variety of assays and therapeutic models demonstrating selective and reversible inhibition of the s-nitrosoglutathione reductase enzyme. Notably, Compound 1 demonstrates efficacy in asthma, COPD, cystic fibrosis, and IBD models (described in the ' 181 application and international application PCT/US2015/054728). Accordingly, Compound 1 is useful for treating one or more disorders associated with activity of GSNOR.
  • the invention provides a pharmaceutical composition comprising:
  • the composition includes two or more types of fillers.
  • the invention provides a pharmaceutical composition comprising:
  • the composition includes two or more types of fillers. In another embodiment, the composition includes two or more types of glidants.
  • Compound 1 is in substantially one of its crystalline solid forms, as described in U.S. Provisional Application No. 62/216,765, entitled “SOLID FORMS OF AN S -NITROS OGLUTATHIONE REDUCTASE INHIBITOR", filed on September 10, 2015 by Jian Qiu, and PCT application PCT/US2016/050974 filed September 9, 2016.
  • Compound 1 is in substantially crystalline hemi-hydrate Form A (Compound 1 Form A).
  • Compound 1 is in substantially crystalline anhydrous Form B (Compound 1 Form B).
  • Compound 1 includes, amongst other forms, including non-crystalline forms, the following solid state forms: Compound 1 Form A and Compound 1 Form B.
  • amounts of Compound 1 it is intended to mean amount of active Compound 1.
  • a formulation containing Compound 1, if in anhydrous form B is about 100% active.
  • a formulation containing Compound 1, if in semi-hydrate form A is about 97% active, and about 3% water (i.e. if 100 mg of Compound 1 semi- hydrate Form A is weighed out, once the water is taken into account, it contains about 97 mg of active Compound 1.)
  • the dosage form of the pharmaceutical composition comprises about 95 mg to about 100 mg of Compound 1.
  • the pharmaceutical compositions described herein are useful for treating or lessening the severity of a variety of diseases or disorders as described in detail herein.
  • the diseases or disorders are selected from pulmonary disorders and inflammatory disorders.
  • the diseases or disorders are selected from cystic fibrosis, asthma, chronic obstructive pulmonary disorder, and inflammatory bowel disease.
  • the invention provides a pharmaceutical composition comprising the following components: Compound 1, Lactose monohydrate (Fast- Flow), HPC
  • the composition additionally contains Microcrystalline Cellulose, and / or Dibasic calcium phosphate, and / or Croscarmellose sodium.
  • the invention provides a pharmaceutical composition comprising the following components: Compound 1, Lactose monohydrate (Fast- Flow), Dibasic calcium phosphate (anhydrous), Pregelatinized starch, Colloidal silicon dioxide, and Magnesium Stearate.
  • Compound 1 Lactose monohydrate (Fast- Flow), Dibasic calcium phosphate (anhydrous), Pregelatinized starch, Colloidal silicon dioxide, and Magnesium Stearate.
  • the invention provides a pharmaceutical composition in the form of a capsule (containing about 95 - 100 mg of Compound 1) that comprises Compound 1 and one or more pharmaceutically acceptable excipients, for example, a filler, a
  • disintegrant a binder, a glidant, and a lubricant and any combination thereof, where the capsule has a dissolution of at least about 60% in about 30 minutes.
  • the dissolution rate is at least about 75% in about 30 minutes.
  • the dissolution rate is at least about 80% in about 30 minutes.
  • compositions of the invention can be processed into a tablet form, capsule form, pouch form, lozenge form, or other solid form that is suited for oral administration.
  • the pharmaceutical compositions are in capsule form.
  • the present invention also relates to methods for treating patients with cystic fibrosis, an autosomal recessive hereditary disease caused by a mutation in the gene CFTR.
  • Mutations in the CFTR protein result in loss of CFTR activity at the surface of epithelial cells leading to abnormal ion transport, dehydration of the airway surface, mucosal obstruction of exocrine glands, and an altered inflammatory response, especially in the lungs.
  • Multiple organ systems are involved, most notably the respiratory and gastrointestinal (GI) systems.
  • Pulmonary problems are characterized by airway obstruction, impaired mucociliary clearance, inflammation, and infection.
  • CF is diagnosed by the levels of chloride in sweat and people with CF have elevated sweat chloride levels.
  • CFTR modulator therapy uses sweat chloride as a clinical biomarker of effect. Reduction in sweat chloride levels indicates direct modulation of CFTR. Therefore, the ultimate goal of CFTR modulator therapy is to maximize and maintain CFTR function, thereby restoring chloride transport.
  • GSNO S-nitrosoglutathione
  • GSNOR S-nitrosoglutathione reductase
  • the present invention provides methods for treating or lessening the severity of CF by stabilizing the CFTR protein at the cell membrane for a prolonged period of time, comprising the step of administering to a patient in need an effective amount of an S- nitrosoglutathione reductase ("GSNOR") inhibitor.
  • GSNOR S- nitrosoglutathione reductase
  • the GSNOR inhibitor is a compound of Formula 1 as shown in the detailed description.
  • the GSNOR inhibitor is Compound 1, or 3-chloro-4-(6-hydroxyquinolin-2- yl)benzoic acid.
  • the GSNOR inhibitor is administered concurrently with, prior to, or subsequent to, one or more secondary active agents.
  • the secondary active agent(s) of the invention are selected from CFTR correctors and CFTR potentiators.
  • the secondary active agent is the CFTR corrector VX-809.
  • the secondary active agent is the CFTR corrector VX-661.
  • the secondary active agent is the CFTR potentiator VX-770.
  • the GSNOR inhibitor is administered with VX-809 and VX-770.
  • the GSNOR inhibitor is administered with VX-661 and VX-770.
  • the GSNOR inhibitor 3-chloro-4-(6-hydroxyquinolin-2- yl)benzoic acid is administered with VX-809 and VX-770.
  • the GSNOR inhibitor 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid is administered with VX- 661 and VX-770.
  • the invention encompasses pharmaceutically acceptable salts, stereoisomers, prodrugs, metabolites, and N-oxides of the described compounds.
  • compositions of the present invention can be prepared in any suitable pharmaceutically acceptable dosage form.
  • FIG. 1 CFBE41o- cells stably expressing HRP-tagged F508del-CFTR were treated with a CFTR corrector (VX-809 or VX-661, 3 ⁇ , 24 h) alone or in the presence of a GSNORi (100 ⁇ , 24 h). Relative fluorescent units (RFU) was plotted for each treatment.
  • Figure 2A and 2B CFBE41o- cells stably expressing HRP-tagged F508del-CFTR were treated with a CFTR corrector (VX-809 or VX-661, 3 ⁇ , 24 h) alone or in the presence of a GSNORi (100 ⁇ , 24 h):
  • Figures 2A and 2B show the % of CFTR remaining at the plasma membrane for VX-809 treated ( Figure 2A), or VX-661 treated cells ( Figure 2B)
  • FIG. 3 CFBE41o- cells were treated with a CFTR corrector (VX-809 or VX- 661) + potentiator (VX-770) in addition to the GSNOR inhibitor 3-chloro-4-(6- hydroxyquinolin-2-yl)benzoic acid. Relative fluorescent units (RFU) was plotted for each treatment.
  • Figure 4A and 4B CFBE41o- cells were treated with a CFTR corrector (VX-809 or VX-661) + potentiator (VX-770) in addition to the GSNOR inhibitor 3-chloro-4-(6- hydroxyquinolin-2-yl)benzoic acid.
  • Figures 4A and 4B show the % of CFTR remaining at the plasma membrane for the VX-809 + VX-770 treatment groups ( Figure 4A), and for the VX-661 + VX-770 treatment groups ( Figure 4B).
  • GSNOR has been shown to function in vivo and in vitro to metabolize GSNO. Based on this, it follows that inhibition of this enzyme potentiates bioactivity of GSNO in diseases in which activity of this enzyme is increased and GSNO levels are depleted, such as CF. Dysregulation of this enzyme and depleted GSNO levels in CF contribute to the instability of CFTR, its degradation, and lack of function.
  • CF is a lethal genetic disease affecting 70,000 people worldwide, including approximately 30,000 in the U.S. (Ramsey et al. 2011, Cystic Fibrosis Foundation Patient Registry Report 2013). Due to advancements in the management of CF and the development of novel drugs that target the defective CFTR protein, the predicted median age of death has risen to approximately 41 years of age, however, the actual median age at death still remains at approximately 27 years (Cystic Fibrosis Foundation Patient Registry Report 2013).
  • CF is an autosomal recessive hereditary disease caused by a mutation in the gene for the cystic fibrosis transmembrane regulator (CFTR) protein. Mutations in the CFTR protein result in loss of CFTR activity at the surface of epithelial cells leading to abnormal ion transport, dehydration of secretions, mucosal obstruction of exocrine glands, and an altered inflammatory response, especially in the lungs. Instability of the mutant CFTR protein contributes to its lack of function and is increasingly recognized as a novel target for new drug therapies targeted toward CF (Arora et al., Biochemistry. 2014; 53(25): 4169-79, Clancy, Sci Transl Med. 2014. 6(246): 246fs27).
  • CFTR cystic fibrosis transmembrane regulator
  • CFTR aids the regulation of epithelial salt and water transport in multiple organs, including the lung, pancreas, liver, and intestinal tract.
  • Clinical manifestations of CF include abnormal sweat electrolytes, chronic and progressive respiratory disease, exocrine pancreatic dysfunction, and infertility; however, it is lung disease that is the primary cause of morbidity and mortality.
  • the loss of CFTR mediated CI " secretion is believed to cause airway surface dehydration due to both a decrease in CFTR-mediated CI " and fluid secretion and a secondary increase in epithelial Na + channel (ENaC)-mediated Na + and fluid absorption. This imbalance results in dehydration of the airway surface, and likely contributes to the deleterious cascade of mucus accumulation, infection, inflammation, and destruction that characterizes CF lung disease.
  • ENaC epithelial Na + channel
  • the G551D mutation is the most common mutation found on the second allele, a Class III mutation present in approximately 4% of heterozygous patients (Cystic Fibrosis Foundation Patient Registry, 2013 Annual Data Report. Bethesda, Maryland. ⁇ 2014 Cystic Fibrosis
  • glycosylation steps as it moves from the endoplasmic reticulum (ER) to the Golgi complex and is eventually transported to the cell surface. Once at the cell surface, the channel must be able to properly activate and open, allowing anion transport to occur.
  • ER endoplasmic reticulum
  • the cell's quality control mechanisms ER-associated degradation (ERAD), rapidly degrade and remove any misfolded proteins.
  • the F508del mutation causes protein misfolding, resulting in efficient (i.e., rapid) ERAD and minimal protein expression at the plasma membrane. Further decreases in function are caused by abnormal activation of the small amount of protein that reaches the membrane and reduced residence time in the apical membrane (Boinot et al., J Pharmacol Exp Ther. 2014. 350:624-634, Odolczyk et al., EMBO Molecular Medicine. 2013. 5: 1484-1501).
  • the complexity of restoring the function of F508-del CFTR will require multiple approaches. Since the median predicted survival age is currently about 37 years, there is a large medical need for more efficacious therapies that address the underlying defect of CF.
  • CFTR modulators include CFTR activators, potentiators, correctors, and antagonists.
  • CFTR activators act on their own to stimulate CFTR-mediated ion transport and include agents that increase cAMP levels, such as b-adrenergic agonists, adenylate cyclase activators, and phosphodiesterase inhibitors.
  • CFTR potentiators act in the presence of endogenous or pharmacological CFTR activators to increase the channel gating activity of cell-surface localized CFTR, resulting in enhanced ion transport.
  • CFTR correctors act by increasing the delivery and amount of functional CFTR protein to the cell surface, resulting in enhanced ion transport.
  • compounds with a new mechanism of action, GSNOR inhibitors have been identified that have been shown to modulate CFTR activity (PCT/US2015/054728).
  • CFTR stabilizers such as the GSNOR inhibitors of the present invention
  • amplifiers, activators, potentiators, and correctors may be coadministered to maximize clinical efficacy or therapeutic window, if needed.
  • CFTR modulation therapy in CF patients is to maximize and maintain CFTR function, thereby restoring fluid transport across epithelial cells.
  • ivacaftor VX-770
  • CFTR "potentiator" that initially targeted the F508del/G551D heterozygous population.
  • Ivacaftor has demonstrated significant clinical benefit in a specific group of heterozygous CF patients. Despite the significant improvements in lung function achieved with ivacaftor in these patients, current strategies are aimed at providing even greater improvements to target the F508del-CFTR allele.
  • Inhibitors of S-nitrosoglutathione reductase may provide a novel therapeutic strategy in cystic fibrosis (CF).
  • GSNO has been identified as a potential modulator of CFTR (Zaman et al., 2001); however, attempts to deliver GSNO exogenously are fraught with difficulties related to formulation, intracellular delivery, and inconsistency of results.
  • GSNOR inhibitors on the other hand are distinguished by their ability to consistently demonstrate preservation of intracellular GSNO and potent bronchodilatory and anti-inflammatory effects in animal models of COPD and asthma.
  • GSNOR inhibition can increase CFTR mediated chloride transport.
  • Mechanisms by which GSNOR inhibitors may improve F508del-CFTR function include nitrosation of chaperone proteins potentially improving the stability of the misfolded protein allowing it to move beyond a stalled folding intermediate(s) (Coppinger et al., PLoS One. 2012;7(5):e37682), prevention of CFTR proteosomal degradation, promotion of CFTR maturation, and maintenance of epithelial tight junctions.
  • GSNOR inhibitors in CF extend beyond their potential to affect chloride and water transport and to increase the airway surface fluid level. They may also affect what appears to be a primary defect in local mucosal immunity. Cohen and Prince have noted that even in the absence of clinically apparent viral or bacterial infection, there is often evidence of inflammation in CF airways, as evidenced by polymorphonuclear neutrophil (PMN) accumulation and excessive concentrations of interleukin-8 (IL-8) and free proteases, accompanied by over-activated nuclear factor kappa B (NFKB) and ineffective antioxidant transport (Cohen and Prince (Nat Med. 2012; 18(4): 509-19)).
  • PMN polymorphonuclear neutrophil
  • IL-8 interleukin-8
  • NFKB nuclear factor kappa B
  • GSNOR inhibition has been demonstrated in several in vitro and in vivo models. Of particular relevance to cystic fibrosis are the mouse models of COPD (cigarette smoke and elastase/papain) in which cellular influx was prevented or reversed, and epithelial cell damage was minimized. The relevance of these models to CF lung disease lies in their common inflammatory manifestations of NFKB activation, neutrophilic infiltration, and elastase-mediated lung injury. GSNOR inhibition has been shown to down regulate the activity of transcription factor NFKB by nitrosation of NFKB regulatory proteins. GSNOR inhibition, therefore, offers a novel mechanism for targeting inflammatory pathways in CF.
  • COPD cigarette smoke and elastase/papain
  • CFTR function through stabilizing the protein both in the cell and at the cell membrane and anti-inflammatory effects arising from GSNOR inhibition may lead to clinical improvement in CF patients, which may be preceded by measurable changes in FEVi, sweat chloride, NPD, and inflammatory biomarkers in serum and airway secretions, sputum and/or bronchoalveolar lavage fluid (BALF).
  • Other measurements of clinical improvement may be intestinal current measurements and weight gain.
  • n is selected from the group consisting of 0, 1, 2, or 3;
  • Ri is independently selected from the group consisting of chloro, fluoro, bromo, cyano, and methoxy;
  • R 2 b and R 2c are independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, fluorinated C1-C3 alkyl, cyano, C1-C3 alkoxy, and N(CH 3 ) 2 ;
  • X is selected from the group consisting of
  • n is selected from the group consisting of 0, 1, and 2;
  • R 3 is independently selected from the group consisting of halogen, Ci-C 3 alkyl, fluorinated Ci-C 3 alkyl, cyano, hydroxy, Ci-C 3 alkoxy, and NR 4 R 4 ' where R 4 and R 4 ' are independently selected from the group consisting of Ci-C 3 alkyl, or R 4 when taken together with R 4 ' form a ring with 3 to 6 members; and
  • A is selected from the group consisting of O
  • Ri is independently selected from the group consisting of chloro, fluoro, and bromo;
  • R 3 is independently selected from the group consisting of halogen, Ci-C 3 alkyl, fluorinated Ci-C 3 alkyl, cyano, Ci-C 3 alkoxy, and NR 4 R 4 ' where R 4 and R 4 ' are independently selected from the group consisting of Ci-C 3 alkyl, or R 4 when taken together with R 4 ' form a ring with 3 to 6 members; and
  • X is selected from the group consisting of
  • R 3 is independently selected from the group consisting of halogen, Ci-C 3 alkyl, fluorinated Ci-C 3 alkyl, cyano, Ci-C 3 alkoxy, and NR 4 R 4 ' where R 4 and R 4 ' are methyl, or alternatively together with the said N form the ring aziridin- 1-yl or morpholino.
  • m is selected from the group consisting of 0 and 1 ;
  • R 2 b and R 2c are independently selected from the group consisting of hydrogen, chloro, fluoro, methyl, trifluoromethyl, cyano, methoxy, and N(CH 3 ) 2 ;
  • n is selected from the group consisting of 0 and 1 ; and
  • R 3 is independently selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, cyano, hydroxy, methoxy, and N(CH 3 ) 2 .
  • A is COOH
  • suitable compounds of Formula I include, but are not limited to:
  • the GSNOR inhibitor is selected from the group consisting of 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid, 3-fluoro-4-(6-hydroxyquinolin-2- yl)benzoic acid, and 4-(6-hydroxyquinolin-2-yl)-3-methylbenzoic acid.
  • the GSNOR inhibitor is 3-chloro-4-(6-hydroxyquinolin-2- yl)benzoic acid, or Compound 1 :
  • Compound 1 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid, is designated as compound number 8 in the '181 application and the synthesis of Compound 1 is described in detail at Example 8 of the ' 181 application.
  • Compound 1 is active in a variety of assays and therapeutic models demonstrating selective and reversible inhibition of s-nitrosoglutathione reductase (GSNOR). Notably, Compound 1 demonstrates efficacy in asthma, COPD, cystic fibrosis, and IBD models (described in international PCT Publication WO2012/048181 and PCT application
  • Compound 1 is useful for treating one or more disorders associated with activity of GSNOR.
  • the present invention provides methods and pharmaceutical compositions that are useful in treating or lessening the severity of cystic fibrosis in a patient by increasing the amount of the CFTR protein at the plasma membrane for a prolonged time by administering to said patient an effective amount of a GSNOR inhibitor, administered alone or with one or more secondary active agents.
  • the GSNOR inhibitor of the pharmaceutical composition can be administered concurrently with, prior to, or subsequent to, one or more secondary active agents.
  • the GSNOR inhibitor is a compound of Formula 1.
  • the GSNOR inhibitor is Compound 1.
  • the present invention provides methods of treating or lessening the severity of cystic fibrosis in a patient by increasing the amount of CFTR protein at the plasma membrane for a prolonged period of time by administering to said patient a therapeutically effective amount of a GSNOR inhibitor with the corrector VX-809, either with our without the potentiator VX-770.
  • the present invention provides methods of treating or lessening the severity of cystic fibrosis in a patient by increasing the amount of CFTR protein at the plasma membrane for a prolonged period of time by administering to said patient a therapeutically effective amount of a GSNOR inhibitor with the corrector VX-661, either with our without the potentiator VX-770.
  • Compound 1 is administered with VX-809, with or without the potentiator VX- 770.
  • Compound 1 is administered with VX-661, with or without the potentiator VX-770.
  • the increase of the amount of CFTR protein at the plasma membrane versus control is for at least 1.5 hours. In some embodiments, the increase of the amount of the CFTR protein at the plasma membrane versus control is for at least 3 hours. In some embodiments the amount of CFTR protein at the plasma membrane at 1.5 hours after treatment with GSNOR inhibitor is increased by at least 10% (i.e. at least 20%, at least 30%, at least 40%, at least 50%) versus control. In some embodiments the amount of CFTR protein at the plasma membrane at 3 hours after treatment with GSNOR inhibitor is increased by at least 10% (i.e. greater than 10%, greater than 20%, greater than 30%, greater than 40%, or greater than 50%) versus control. In some embodiments the GSNOR inhibitor is a compound of Formula 1. In some embodiments, the GSNOR inhibitor is Compound 1.
  • the method includes a therapeutically effective amount of GSNOR inhibitor administered with VX-809 whereby the amount of CFTR at the plasma membrane at 3 hours post treatment is increased by at least 20 % (i.e. greater than 20%, or greater than 30%) versus treatment with VX-809 alone.
  • the method includes a therapeutically effective amount of GSNOR inhibitor administered with VX-661 whereby the amount of CFTR at the plasma membrane at 3 hours post treatment is increased by at least 30 % (i.e. greater than 40%, or greater than 50%) versus treatment with VX-661 alone.
  • the GSNOR inhibitor is a compound of Formula 1.
  • the GSNOR inhibitor is Compound 1.
  • the method includes a therapeutically effective amount of GSNOR inhibitor administered with VX-809 and VX-770 whereby the amount of CFTR at the plasma membrane at 3 hours post treatment is increased by at least 20% (i.e. greater than 20%, greater than 30%, greater than 40%, or greater than 50%) versus treatment with VX- 809 and VX-770.
  • the method includes a therapeutically effective amount of GSNOR inhibitor administered with VX-661 and VX-770 whereby the amount of CFTR at the plasma membrane at 3 hours post treatment is increased by at least 20% (i.e. greater than 20%, greater than 30%, greater than 40%, or greater than 50%) versus treatment with VX-661 and VX-770.
  • the GSNOR inhibitor is a compound of Formula 1.
  • the GSNOR inhibitor is Compound 1.
  • the invention also provides pharmaceutical compositions, pharmaceutical formulations, and solid dosage forms comprising Compound 1, which may be in substantially crystalline form.
  • Compound 1 is in crystalline Form A (Compound 1 Form A), disclosed in U.S. Provisional Application US 62/216,765, entitled “SOLID FORMS OF AN S -NITROS OGLUTATHIONE REDUCTASE INHIBITOR", filed on September 10, 2015 by Jian Qiu, and in PCT application PCT/US2016/050974, filed September 9, 2016 with same name and inventor.
  • Compound 1 is in crystalline Form B (Compound 1 Form B), also disclosed in US 62/216,765 and PCT/US2016/050974.
  • the amount of Compound 1 that is present in the dosage form of the pharmaceutical composition is about 95 to about 100 mg. In some embodiments of this aspect, weight/weight relative percent of Compound 1 that is present in the pharmaceutical composition is from about 23 wt % to about 37 wt %. In some embodiments of this aspect, weight/weight relative percent of Compound 1 that is present in the pharmaceutical composition is from about 24 percent to about 35 percent. In some embodiments of this aspect, weight/weight relative percent of Compound 1 that is present in the pharmaceutical composition is from about 25 percent to about 27 percent. In some embodiments of this aspect, weight/weight relative percent of Compound 1 that is present in the pharmaceutical composition is from about 32 percent to about 34 percent.
  • Compound 1 is present as substantially pure Compound 1.
  • substantially pure means greater than ninety percent pure; preferably greater than 95 percent pure; more preferably greater than 99 percent pure (i.e., not mixed with other crystalline forms of Compound 1).
  • the invention provides a pharmaceutical composition comprising:
  • the invention provides a pharmaceutical composition comprising:
  • the dosage form of the pharmaceutical composition comprises about 95 to about 100 mg of Compound 1. In one embodiment, the composition comprises from about 23 wt % to about 37 wt % of Compound 1 by weight of the composition.
  • the pharmaceutical composition comprises Compound 1, a disintegrant, at least one filler, a lubricant, and a dry binder.
  • the composition comprises from about 23 wt % to about 29 wt % of Compound 1 by weight of the composition. In another embodiment, this composition comprises from about 25 wt % to about 27 wt % of Compound 1 by weight of the composition.
  • the pharmaceutical composition comprises Compound 1, a disintegrant, at least one filler, a lubricant, and a glidant.
  • the composition comprises from about 30 wt % to about 37 wt % of Compound 1 by weight of the composition. In another embodiment, this composition comprises about 31 wt % to about 35 wt % of Compound 1 by weight of the composition. In another embodiment, this
  • composition comprises about 32 wt % to about 34 wt % of Compound 1 by weight of the composition.
  • the concentration of Compound 1 in the composition depends on several factors such as the amount of pharmaceutical composition needed to provide a desired amount of Compound 1, the desired dissolution profile of the pharmaceutical composition, and the bulk density of compound 1.
  • Fillers suitable for the invention are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition.
  • the term diluent is often used interchangeably with fillers.
  • Exemplary fillers include: celluloses, modified celluloses, (e.g. sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, powdered cellulose), cellulose acetate, microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate (DCP, or dicalcium phosphate), starches (e.g.
  • sugars infectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, sucrose, lactose, mannitol, sorbitol, or the like), or any combination thereof.
  • the pharmaceutical composition comprises a total weight percent of filler in an amount of at least at least 40 wt % (e.g., at least about 45 wt %, at least about 50 wt %, or at least about 60 wt %) by weight of the composition.
  • the pharmaceutical composition can contain one, two or three different fillers.
  • the pharmaceutical composition comprises from about 40 wt % to about 70 wt % of total amount of filler (e.g., about 45 wt % to about 70 wt %, or about 45 wt % to about 57 wt %), by weight of the composition.
  • the pharmaceutical composition comprises from about 40 wt % to about 70 wt % of total amount of filler (e.g., about 45 wt % to about 70 wt %, or about 45 wt % to about 57 wt %), by weight of the composition.
  • the pharmaceutical composition comprises from about 40 wt % to about 70 wt %
  • composition comprises one or more fillers in an amount each of at least 8 wt % (e.g., at least about 10 wt %, at least about 20 wt %,at least about 30 wt %, or at least about 40 wt %) by weight of the composition.
  • the pharmaceutical composition comprises about 15 wt % to about 70 wt % (e.g. about 25 wt % to about 50 wt %, or about 30 wt % to about 45 wt %, or about 33 wt % to about 44 wt %) of lactose by weight of the composition.
  • the pharmaceutical composition comprises from about 5 wt % to about 35 wt % (e.g., from about 8 wt % to about 30 wt %, from about 8 wt % to about 20 wt%) of DCP (dibasic calcium phosphate), by weight of the composition.
  • the pharmaceutical composition comprises about 15 wt % to about 50 wt % (e.g., about 18 wt to about 48 wt %) of Microcrystalline Cellulose, PH102, by weight of the composition.
  • Disintegrants suitable for the invention enhance the dispersal of the
  • compositions are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition.
  • Exemplary disintegrants include croscarmellose sodium, pregelatinized starch, sodium starch glycolate, or a combination thereof.
  • the pharmaceutical composition comprises disintegrant in an amount of about 20 wt % or less (e.g., about 15 wt % or less,) by weight of the composition.
  • the pharmaceutical composition comprises from about 0.5 wt % to about 16 wt % (e.g., from about 1 wt % to about 15 wt %, or from about 8 wt % to about 16 wt %, or from about 9 wt % to about 15 wt %) of disintegrant, by weight of the composition.
  • the pharmaceutical composition comprises about 15 wt % or less (e.g., about 15 wt %, or about 13 wt %, or about 11 wt %, or about 10 wt %, or about 9 wt %) of pregelatinized starch, by weight of the composition.
  • the pharmaceutical composition comprises about 5 wt % or less (e.g., about 2 wt %, or about 1 wt %) of croscarmellose sodium, by weight of the composition.
  • Binders suitable for the invention enhance the tablet strength of the
  • binders include polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn (maize) starch, modified cellulose (e.g., hydroxymethyl cellulose, hydroxypropyl cellulose), or any combination thereof.
  • the pharmaceutical composition comprises a binder in an amount of about 10 wt % or less (e.g., about 8 wt % or less, about 6 wt % or less) by weight of the composition.
  • the pharmaceutical composition comprises about 10 wt % or less (e.g., about 8 wt %, or about 6 wt %) of hydroxypropyl cellulose (HPC), by weight of the composition.
  • HPC hydroxypropyl cellulose
  • Glidants suitable for the invention enhance the flow properties of the
  • glidants include colloidal silicon dioxide, talc, or a combination thereof.
  • the pharmaceutical composition comprises a glidant in an amount of 2 wt % or less (e.g., 1.75 wt % or less, 1.25 wt % or less, 1.0 wt % or less) by weight of the composition.
  • the pharmaceutical composition comprises from about 0.05 wt % to about 2 wt % (e.g., from about 0.07 wt % to about 1.5 wt % or from about 1.0 wt % to about 1.2 wt %) of glidant, by weight of the composition.
  • the pharmaceutical composition comprises about 2 wt % or less (e.g., about 1.75 wt % or less, about 1.5 wt % or less, or about 1.25 wt % or less) of colloidal silicon dioxide, by weight of the composition.
  • the pharmaceutical composition comprises from about 0.05 wt % to about 2 wt % (e.g., from about 0.7 wt % to about 1.5 wt % or from about 1.0 wt % to about 1.2 wt %) of colloidal silicon dioxide, by weight of the composition.
  • the pharmaceutical composition can include an oral solid pharmaceutical dosage form which can comprise a lubricant that can prevent adhesion of a powder blend to a surface (e.g., a surface of a mixing bowl, a compression die, punch or tamping pin).
  • a lubricant can also reduce interparticle friction within the granulate and improve the compression and ejection of compressed pharmaceutical compositions from a die press.
  • the lubricant is also compatible with the ingredients of the pharmaceutical
  • lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof.
  • the pharmaceutical composition comprises a lubricant in an amount of 5 wt % or less (e.g., 4.0 wt % or less, or 3.00 wt % or less, or 2.0 wt % or less, or 1.0 wt % or less) by weight of the composition.
  • the pharmaceutical composition comprises from about 5 wt % to about 0.10 wt % (e.g., from about 3 wt % to about 0.5 wt % or from about 2 wt % to about 1 wt %) of lubricant, by weight of the composition.
  • the pharmaceutical composition comprises 5 wt % or less (e.g., 4.0 wt % or less, 3.0 wt % or less, or 2.0 wt % or less, or 1.0 wt % or less) of magnesium stearate, by weight of the composition.
  • the pharmaceutical composition comprises from about 5 wt % to about 0.10 wt % (e.g., from about 3 wt % to about 0.5 wt % or from about 2.0 wt % to about 1.0 wt %) of magnesium stearate, by weight of the composition.
  • compositions of the invention can optionally comprise one or more colorants, flavors, and/or fragrances to enhance the visual appeal, taste, and/or scent of the composition.
  • Suitable colorants, flavors, or fragrances are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition.
  • the pharmaceutical composition comprises a colorant, a flavor, and/or a fragrance.
  • N91115 (3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid) is disclosed in International PCT Publication WO2012/048181 ("the ' 181 application") as an inhibitor of GSNOR and thus as a useful treatment for NO related diseases such as cystic fibrosis, asthma, COPD, IBD, etc.
  • Form A of 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid which is a substantially crystalline hemi-hydrate form known as N91115 Form A, is disclosed in PCT application Serial No. PCT/US2016/050974, filed on September 9, 2016. All applications are incorporated in their entirety by reference herein.
  • N91115 can exist in a variety of solid forms. Such forms include polymorphs and amorphous forms.
  • the solid forms can be solvates, hydrates and unsolvated forms of N91115. All such forms are contemplated by the present invention.
  • the present invention provides N91115 as a mixture of one or more solid forms of N91115.
  • polymorph refers to the different crystal structures (of solvated or unsolvated forms) in which a compound can crystallize.
  • solvate refers to a solid form with either a stoichiometric or non-stoichiometric amount of solvent (e.g., a channel solvate).
  • solvent e.g., a channel solvate
  • hydrate refers to a solid form with either a stoichiometric or non-stoichiometric amount of water.
  • hemi-hydrate refers to a solid form with about 1 equivalent of water relative to 2 equivalents of anhydrous N91115 in the crystal structure. For polymorphs, the water is incorporated into the crystal structure.
  • the term "about”, when used in reference to a degree 2-theta value refers to the stated value + 0.3 degree 2-theta. In certain embodiments, “about” refers to + 0.2 degree 2-theta or + 0.1 degree 2-theta. In certain embodiments, “about” refers to + 0.2 degree 2-theta.
  • N91115 is a crystalline solid. In other embodiments, N91115 is a crystalline solid substantially free of amorphous N91115. As used herein, the term "substantially free of amorphous N91115" means that the compound contains no significant amount of amorphous N91115. In certain embodiments, at least about 90% by weight of crystalline N91115 is present, or at least about 95% by weight of crystalline N91115 is present. In still other embodiments of the invention, at least about 97%, 98% or 99% by weight of crystalline N91115 is present.
  • N91115 is a hydrate polymorphic form.
  • the present invention provides a hemi-hydrate polymorphic form of N91115 referred to herein as Form A.
  • Form A of N91115 is also known as Form III of N91115.
  • Form A of N91115 is characterized by one or more peaks in its powder X-ray diffraction pattern selected from those at about 12.92, about 18.01, about 18.86, about 22.63, about 23.00, about 23.72, and about 24.88 degrees 2-theta (°2 ⁇ ).
  • Form A of N91115 is characterized by two or more peaks in its powder X-ray diffraction pattern selected from those at about 12.92, about 18.01, about 18.86, about 22.63, about 23.00, about 23.72, and about 24.88 degrees 2-theta.
  • Form A of N91115 is characterized by three or more peaks in its powder X-ray diffraction pattern selected from those at about 12.92, about 18.01, about 18.86, about 22.63, about 23.00, about 23.72, and about 24.88 degrees 2-theta.
  • Form A of N91115 is characterized by a peak in its powder X-ray diffraction pattern at about 12.92.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.92 and one or more additional peaks selected from those at about 18.01, about 18.86, about 22.63, about 23.00, about 23.72, and about 24.88 degrees 2-theta.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.92 and two or more additional peaks selected from those at about 18.01, about 18.86, about 22.63, about 23.00, about 23.72, and about 24.88 degrees 2-theta.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.92 and three or more additional peaks selected from those at about 18.01, about 18.86, about 22.63, about 23.00, about 23.72, and about 24.88 degrees 2-theta.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.92 and four or more additional peaks selected from those at about 18.01, about 18.86, about 22.63, about 23.00, about 23.72, and about 24.88 degrees 2-theta.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.92 and about 18.01, and optionally one or more additional peaks selected from about 18.86, about 22.63, about 23.00, about 23.72, and about 24.88 degrees 2-theta.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.92, about 18.01, and about 22.63, and optionally one or more additional peaks selected from about 18.86, about 23.00, about 23.72, and about 24.88 degrees 2-theta.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.92, about 18.01, about 22.63, and about 24.88, and optionally one or more additional peaks selected from about 18.86, about 23.00, and about 23.72.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.92, about 18.01, about 18.86, about 22.63, about 23.00, about 23.72, and about 24.88 degrees 2-theta.
  • Form A of N91115 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from the group consisting of at about 8.32, 8.97, 12.92, 14.56, 15.14, 18.01, 18.86, 22.63, 23.00, 23.72 and 24.88 degrees 2- theta.
  • Form A of N91115 is characterized by all or substantially all of the peaks in its X-ray powder diffraction pattern selected from those at about 8.32, 8.97, 12.92, 14.56, 15.14, 18.01, 18.86, 22.63, 23.00, 23.72 and 24.88 degrees 2-theta.
  • Form A of N91115 is characterized by all or substantially all of the peaks in its X-ray powder diffraction pattern selected from those at about:
  • Form A of N91115 is characterized by one or more peaks in its powder X-ray diffraction pattern selected from those at about 12.9, about 18.0, about 18.9, about 22.6, about 23.0, about 23.7, and about 24.9 degrees 2-theta. In some embodiments, Form A of N91115 is characterized by two or more peaks in its powder X-ray diffraction pattern selected from those at about 12.9, about 18.0, about 18.9, about 22.6, about 23.0, about 23.7, and about 24.9 degrees 2-theta.
  • Form A of N91115 is characterized by three or more peaks in its powder X-ray diffraction pattern selected from those at about 12.9, about 18.0, about 18.9, about 22.6, about 23.0, about 23.7, and about 24.9 degrees 2-theta.
  • Form A of N91115 is characterized by a peak in its powder X-ray diffraction pattern at about 12.9.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.9 and one or more additional peaks selected from those at about 18.0, about 18.9, about 22.6, about 23.0, about 23.7, and about 24.9 degrees 2-theta.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.9 and two or more additional peaks in its powder X-ray diffraction pattern selected from those at about 18.0, about 18.9, about 22.6, about 23.0, about 23.7, and about 24.9 degrees 2-theta.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.9 and three or more additional peaks in its powder X-ray diffraction pattern selected from those at about 18.0, about 18.9, about 22.6, about 23.0, about 23.7, and about 24.9 degrees 2- theta.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.9 and four or more additional peaks in its powder X-ray diffraction pattern selected from those at about 18.0, about 18.9, about 22.6, about 23.0, about 23.7, and about 24.9 degrees 2-theta.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.9 and about 18.0, and optionally one or more additional peaks selected from about 18.9, about 22.6, about 23.0, about 23.7, and about 24.9 degrees 2-theta.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.9, about 18.0, and about 22.6, and optionally one or more additional peaks selected from about 18.9, about 23.0, about 23.7, and about 24.9 degrees 2-theta.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.9, about 18.0, about 22.6, and about 24.9, and optionally one or more additional peaks selected from about 18.9, about 23.0, and about 23.7.
  • Form A of N91115 is characterized by peaks in its powder X-ray diffraction pattern at about 12.9, about 18.0, about 18.9, about 22.6, about 23.0, about 23.7, and about 24.9 degrees 2-theta.
  • Form A of N91115 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from the group consisting of at about 8.3, 9.0, 12.9, 14.6, 15.1, 18.0, 18.9, 22.6, 23.0, 23.7 and 24.9 degrees 2-theta.
  • Form A of N91115 is characterized by all or substantially all of the peaks in its X-ray powder diffraction pattern selected from those at about 8.3, 9.0, 12.9, 14.6, 15.1, 18.0, 18.9, 22.6, 23.0, 23.7 and 24.9 degrees 2-theta.
  • Form A of N91115 is characterized by all or substantially all of the peaks in its X-ray powder diffraction pattern selected from those at about:
  • the pharmaceutical composition includes or can be made into a capsule.
  • the pharmaceutical composition includes or can be made into tablets and the tablets can be coated with a colorant and optionally labeled with a logo, other image and/or text using a suitable ink.
  • the pharmaceutical composition includes or can be made into tablets and the tablets can be coated with a colorant, waxed, and optionally labeled with a logo, other image and/or text using a suitable ink.
  • Suitable colorants and inks are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition.
  • the suitable colorants and inks can be any color and are water based or solvent based.
  • tablets made from the pharmaceutical composition can be coated with a colorant and then labeled with a logo, other image, and/or text using a suitable ink.
  • compositions of the invention can be processed into a tablet form, capsule form, pouch form, lozenge form, or other solid form that is suited for oral administration.
  • the pharmaceutical compositions are in capsule form.
  • Capsule formulations can be obtained by filling the powder blend or granulated pharmaceutical formulations mentioned hereinbefore in conventional capsules, for instance, hard or soft capsules.
  • compositions of the invention include a GSNOR inhibitor of Formula 1 and at least one pharmaceutically acceptable carrier.
  • the GSNOR inhibitor pharmaceutical composition can be administered as a monotherapy.
  • the pharmaceutical composition of the invention includes a GSNOR inhibitor in combination with one or more secondary active agents.
  • the pharmaceutical composition of the invention includes a GSNOR inhibitor in combination with one or more palliative care agents.
  • the GSNOR inhibitor of the pharmaceutical composition can be administered concurrently with, prior to, or subsequent to, one or more secondary active agents and/or palliative care agents.
  • compositions comprising the compositions described herein and at least one pharmaceutically acceptable carrier. Suitable carriers are described in "Remington: The Science and Practice, Twentieth Edition,” published by Lippincott Williams & Wilkins, which is incorporated herein by reference. Pharmaceutical compositions according to the invention may also comprise one or more non- inventive compound active agents.
  • the compounds of the pharmaceutical compositions of Formula 1 can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired secondary active agents or medical procedures.
  • the particular combination of therapies (secondary agents or procedures) to employ in a combination regimen will take into account compatibility of the desired agents and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder (for example, a pharmaceutical composition may be administered concurrently with one or more secondary agents used to treat the same disorder), or they may achieve different effects (such as control adverse effects).
  • the secondary active agent of the pharmaceutical combination is selected from a compound or therapy that modulates CFTR function.
  • the secondary active agent(s) are selected from CFTR correctors and/or CFTR potentiators.
  • the secondary active agents include a CFTR potentiator and a CFTR corrector.
  • the secondary active agent is selected from one or more CFTR amplifiers.
  • the pharmaceutical composition may be used with any single or combination of palliative agents including mucolytic agents, bronchodilators, antibiotics, anti-infective agents, anti-inflammatory agents, nutritional agents, or other palliative agents known to manage CF.
  • palliative agents including mucolytic agents, bronchodilators, antibiotics, anti-infective agents, anti-inflammatory agents, nutritional agents, or other palliative agents known to manage CF.
  • the compounds of the pharmaceutical combination of the invention can be utilized in any pharmaceutically acceptable dosage form, including, but not limited to injectable dosage forms, liquid dispersions, gels, aerosols, ointments, creams, lyophilized formulations, dry powders, tablets, capsules, controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsatile release formulations, mixed immediate release and controlled release formulations, etc.
  • the compounds of the invention described herein can be formulated: (a) for administration selected from the group consisting of oral, pulmonary, intravenous, intra-arterial, intrathecal, intra- articular, rectal, ophthalmic, colonic, parenteral, intracisternal, intravaginal,
  • formulations delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or (d) any combination thereof.
  • the pharmaceutically acceptable dosage form is administered orally.
  • Compound 1 has been formulated and delivered orally via capsule (US provisional application 62/216,771, US provisional application 62/303,218, and PCT application
  • an inhalation formulation can be used to achieve high local concentrations.
  • Formulations suitable for inhalation include dry power or aerosolized or vaporized solutions, dispersions, or suspensions capable of being dispensed by an inhaler or nebulizer into the endobronchial or nasal cavity of infected patients to treat upper and lower respiratory bacterial infections.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can comprise one or more of the following components: (1) a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol, or other synthetic solvents; (2) antibacterial agents such as benzyl alcohol or methyl parabens; (3) antioxidants such as ascorbic acid or sodium bisulfite; (4) chelating agents such as ethylenediaminetetraacetic acid; (5) buffers such as acetates, citrates, or phosphates; and (5) agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • a parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use may comprise sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, N.J.), or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists.
  • the pharmaceutical composition should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium comprising, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol or sorbitol, and inorganic salts such as sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the
  • composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active reagent in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating at least one compound of the invention into a sterile vehicle that contains a basic dispersion medium and any other required ingredients.
  • exemplary methods of preparation include vacuum drying and freeze-drying, both of which yield a powder of a compound of the invention plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed, for example, in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compound of the invention can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser that contains a suitable propellant, e.g. , a gas such as carbon dioxide, a nebulized liquid, or a dry powder from a suitable device.
  • a suitable propellant e.g. , a gas such as carbon dioxide, a nebulized liquid, or a dry powder from a suitable device.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active reagents are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the reagents can also be prepared in the form of suppositories (e.g. , with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • the compounds of the invention are prepared with carriers that will protect against rapid elimination from the body.
  • a controlled release formulation can be used, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
  • suspensions of the compounds of the invention may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate, triglycerides, or liposomes.
  • Non-lipid polycationic amino polymers may also be used for delivery.
  • the suspension may also include suitable stabilizers or agents to increase the solubility of the compounds and allow for the preparation of highly concentrated solutions.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of the compound of the invention calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the compound of the invention and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active agent for the treatment of individuals.
  • compositions of compounds of Formula 1 can comprise one or more pharmaceutical excipients.
  • excipients include, but are not limited to binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients.
  • excipients are known in the art.
  • Exemplary excipients include: (1) binding agents which include various celluloses and cross-linked polyvinylpyrrolidone,
  • microcrystalline cellulose such as Avicel ® PH101 and Avicel ® PH102, silicified
  • microcrystalline cellulose ProSolv SMCCTM
  • gum tragacanth and gelatin
  • filling agents such as various starches, lactose, lactose monohydrate, and lactose anhydrous
  • filling agents such as various starches, lactose, lactose monohydrate, and lactose anhydrous
  • disintegrating agents such as alginic acid, Primogel, corn starch, lightly crosslinked polyvinyl pyrrolidone, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof;
  • lubricants including agents that act on the flowability of a powder to be compressed, include magnesium stearate, colloidal silicon dioxide, such as Aerosil ® 200, talc, stearic acid, calcium stearate, and silica gel; (5) glidants such as colloidal silicon dioxide; (6) preservatives, such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of
  • parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride; (7) diluents such as pharmaceutically acceptable inert fillers, such as
  • microcrystalline cellulose lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing; examples of diluents include microcrystalline cellulose, such as Avicel ® PH101 and Avicel ® PH102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose ® DCL21 ; dibasic calcium phosphate such as Emcompress ® ; mannitol; starch; sorbitol; sucrose; and glucose; (8) sweetening agents, including any natural or artificial sweetener, such as sucrose, saccharin sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame; (9) flavoring agents, such as peppermint, methyl salicylate, orange flavoring, Magnasweet ® (trademark of MAFCO), bubble gum flavor, fruit flavors, and the like; and (10) effervescent agents, including effer
  • Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts.
  • Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
  • sodium bicarbonate component of the effervescent couple may be present.
  • bioactivity indicates an effect on one or more cellular or extracellular process (e.g., via binding, signaling, etc.) which can impact physiological or pathophysiological processes.
  • N-oxide or amine oxide
  • amine oxide refers to a compound derived from a tertiary amine by the attachment of one oxygen atom to the nitrogen atom, R 3 N + -0 ⁇ .
  • the term includes the analogous derivatives of primary and secondary amines.
  • the term "pharmaceutically acceptable” means approved by a regulatory agency of a federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and, more particularly, in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered and includes, but is not limited to such sterile liquids as water and oils.
  • a "pharmaceutically acceptable salt” or “salt” of a compound of the invention is a product of the disclosed compound that contains an ionic bond, and is typically produced by reacting the disclosed compound with either an acid or a base, suitable for administering to a subject.
  • a pharmaceutically acceptable salt can include, but is not limited to, acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, arylalkylsulfonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates, and tartrates; alkali metal cations such as Li, Na, and K, alkali earth metal salts such as Mg or Ca, or organic amine salts.
  • acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, arylalkylsulfonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates, and tartrates; alkali metal cations such as Li, Na, and K
  • a "pharmaceutical composition” is a formulation comprising the disclosed combination in a form suitable for administration to a subject.
  • a pharmaceutical composition of the invention is preferably formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, oral and parenteral, e.g. , intravenous, intradermal, subcutaneous, inhalation, topical, transdermal, transmucosal, and rectal administration.
  • a "secondary active agent” is a compound or therapy that increases CFTR function.
  • a secondary active agent is selected from the group consisting of CFTR correctors and CFTR potentiators.
  • a secondary active agent is selected from the group consisting of CFTR correctors, potentiators, or amplifiers as well as gene therapy directed toward CF.
  • CFTR corrector is a compound that promotes maturation and delivery of CFTR proteins to the apical surface.
  • CFTR correctors include but are not limited to VX-809 (3- ⁇ 6- ⁇ [l-(2,2- difluoro- l,3-benzodioxol-5- yl)cyclopropanecarbonyl]amino ⁇ -3-methylpyridin-2-yl ⁇ benzoic acid), VX-661 (l-(2,2- difluoro-l,3-benzodioxol-5-yl)-N-[l-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy- l, l- dimethylethyl)-lH-indol-5-yl]-cyclopropanecarboxamide), compounds of
  • PCT/US2014/038385 and compounds of PCT/US2015/021841.
  • VX-809 has also recently been classified as a "CFTR conformational stabilizer" by the FDA in a Summary Review of Regulatory Action dated June 25, 2015, but continues to be known in the art and literature as a CFTR corrector, and is treated as such herein.
  • a "CFTR potentiator” is a compound that activates apical CFTR by increasing the open time of the channel.
  • An example of a CFTR potentiator includes but is not limited to VX-770 (N-(2,4-Di-ieri-butyl-5-hydroxyphenyl)-4-oxo-l,4- dihydroquinoline-3-carboxamide).
  • gene therapy is any therapy directed toward the genetic defect in CF.
  • CFTR amplifier is any compound that increases CFTR activity.
  • a "palliative care agent” is an agent for the management of CF other than a secondary active agent that may include a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a nutritional agent, or other agent known to manage the symptoms of CF, collectively termed herein as palliative care.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the term "therapeutically effective amount” generally means the amount necessary to ameliorate at least one symptom of a disorder to be prevented, reduced, or treated as described herein.
  • the phrase "therapeutically effective amount” as it relates to the GSNOR inhibitors of the present invention shall mean the GSNOR inhibitor dosage that provides the specific pharmacological response for which the GSNOR inhibitor is
  • a therapeutically effective amount of a GSNOR inhibitor that is administered to a particular subject in a particular instance will not always be effective in treating the conditions/diseases described herein, even though such dosage is deemed to be a
  • the phrase "therapeutically effective amount” as it relates to the secondary active agent of the present invention shall mean the dosage that provides the specific
  • GSNOR inhibitor or "s-nitrosoglutathione reductase inhibitor” or “GSNORi” means a compound which inhibits the enzyme S-nitrosoglutathione reductase and demonstrates activity in the enzyme assay described in WO2012/048181 (the '181 application) (e.g., GSNOR Assays as described in detail in Example 58 of the ' 181 application).
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • kits comprising the compositions of the invention.
  • kits can comprise, for example, (1) at least one compound of the invention; and (2) at least one pharmaceutically acceptable carrier, such as a solvent or solution.
  • Additional kit components can optionally include, for example: (1) any of the
  • compositions identified herein such as stabilizers, buffers, etc.
  • delivery apparatus such as an inhaler, nebulizer, syringe, etc.
  • the invention encompasses methods of preventing the progression of or treating cystic fibrosis through the use of one or more of the disclosed pharmaceutical compositions.
  • the methods comprise administering a therapeutically effective amount of a GSNOR inhibitor in combination with one or more secondary agent(s) to a patient in need.
  • the GSNOR inhibitor can be administered concurrently with, prior to, or subsequent to, one or more secondary active agents.
  • the method is a method of treating or lessening the severity of cystic fibrosis in a patient by stabilizing the CFTR protein at the cell membrane, comprising the step of administering to said patient an effective amount of the pharmaceutical composition described herein.
  • the method is a method of treating or lessening the severity of cystic fibrosis in a patient by increasing the amount of the CFTR protein at the plasma membrane for a prolonged period of time comprising the step of administering to said patient an effective amount of a GSNOR inhibitor pharmaceutical composition administered alone or with one or more secondary active agents.
  • the GSNOR inhibitor of the pharmaceutical composition can be administered concurrently with, prior to, or subsequent to, one or more secondary active agents.
  • the GSNOR inhibitor is a compound of Formula 1.
  • the GSNOR inhibitor is Compound 1.
  • the GSNOR inhibitor of the pharmaceutical composition of the invention used in the methods of treatment according to the invention can be a pharmaceutically acceptable salt, a stereoisomer, a prodrug, a metabolite, or an N-oxide thereof.
  • the methods of the present invention can be pharmaceutical compositions of the invention employed in combination therapies, that is, the pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired secondary active agents or medical procedures.
  • the particular combination of therapies (secondary agents or procedures) to employ in a combination regimen will take into account compatibility of the desired agents and/or procedures and the desired therapeutic effect to be achieved.
  • the patient can be a human patient with any disease causing mutation of CF.
  • the patient has at least one copy of the F508del mutation.
  • the patient is a F508del-CFTR homozygous patient.
  • the patient is a F508del-CFTR homozygous patient.
  • the terms patient and subject may be used interchangeably.
  • treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder. More specifically, “treating” includes reversing, attenuating, alleviating, minimizing, suppressing, or halting at least one deleterious symptom or effect of a disease (disorder) state, disease progression, disease causative agent (e.g., bacteria or viruses), or other abnormal condition. Treatment is continued as long as symptoms and/or pathology ameliorate.
  • a disease disorder
  • disease causative agent e.g., bacteria or viruses
  • GSNOR inhibitors and compositions described herein are generally useful for the treatment of diseases wherein there is a need for increased NO bioactivity.
  • GSNOR inhibitors of the invention are active in a variety of assays and therapeutic models demonstrating selective and reversible inhibition of s-nitrosoglutathione reductase.
  • GSNOR inhibitors of Formula 1 demonstrate efficacy in asthma, COPD, cystic fibrosis, and IBD models (disclosed in the international PCT Publication WO2012/048181 and PCT application PCT/US2015/054728). Accordingly, GSNOR inhibitors of Formula 1 are useful for treating one or more disorders associated with activity of GSNOR.
  • modulation of GSNOR may be achieved, for example, by administering one or more of the GSNOR inhibitors of the disclosed compositions that disrupts or down-regulates GSNOR function, or decreases GSNOR levels.
  • the present invention provides a method for treating or lessening the severity of a subject with cystic fibrosis.
  • the method of the invention is a method of treating a subject afflicted with any mutation of CF in any age group. Such a method comprises administering to a subject a therapeutically effective amount of a GSNOR inhibitor as a monotherapy or in combination with one or more secondary active agents.
  • the subject of the invention is afflicted with at least one copy of the F508del mutation.
  • the subject of the invention is afflicted with two copies of the F508del mutation.
  • compositions of the invention are capable of treating and/or slowing the progression of cystic fibrosis. For approximately 90% of patients with CF, death results from progressive respiratory failure associated with impaired mucus clearance and excessive overgrowth of bacteria and fungi in the airways (Gibson et al., 2003, Proesmans et al., 2008).
  • GSNOR inhibitors are capable of preserving endogenous s-nitrosothiol (SNO) pools via inhibiting GSNO catabolism and therefore positively modulate CFTR.
  • GSNOR inhibitors are also distinguished by their ability to demonstrate preservation of GSNO, potent bronchodilatory and anti-inflammatory effects in animal models of COPD (porcine pancreatic elastase) (Blonder et al., ATS 2011 abstract reference) and asthma.
  • Pharmaceutical compositions of the invention are capable of treating and/or slowing the progression of CF.
  • appropriate amounts of compounds of the pharmaceutical compositions are an amount sufficient to treat and/or slow the progression of CF and can be determined without undue experimentation by preclinical and/or clinical trials.
  • the therapeutically effective amount for the treatment of a subject is the amount that causes amelioration of the disorder being treated or protects against a risk associated with the disorder.
  • a therapeutically effective amount is an amount effective in reducing sweat chloride, improving or preventing the decline in lung function, decreasing the frequency of infective pulmonary exacerbations, improving nutritional status and body weight or improving overall symptoms.
  • the therapeutically effective amount or dosing schedule of the GSNOR inhibitor and / or secondary active agents may be favorably altered to maximize any one or more of the positive effects listed above.
  • GSNOR inhibitors and compositions thereof, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder or disease.
  • the exact amount required may vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular mutation of the disease, the particular agent, its mode of administration, and the like.
  • GSNOR inhibitors 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.
  • 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.
  • compositions of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer, prodrug, metabolite, or N-oxide thereof can be applied to various apparatus in circumstances when the presence of such compounds would be beneficial.
  • apparatus can be any device or container, for example, implantable devices in which a compound of the invention can be used to coat a surgical mesh or cardiovascular stent prior to implantation in a patient.
  • the compounds of the invention can also be applied to various apparatus for in vitro assay purposes or for culturing cells.
  • pharmaceutically acceptable salt thereof, or a stereoisomer, a prodrug, a metabolite, or an N- oxide thereof can also be used as an agent for the development, isolation or purification of binding partners to compounds of the invention, such as antibodies, natural ligands, and the like. Those skilled in the art can readily determine related uses for the compounds of the present invention.
  • Compound 1 is used as the starting point for the other solid state forms and can be prepared as was described in WO 2012/048181.
  • solid forms including powders comprising the active agent Compound 1 and the included pharmaceutically acceptable excipients (e.g. filler,
  • disintegrant, glidant, lubricant, or any combination thereof can be subjected to direct blending, meaning mixing followed by encapsulation occurs without compression, compaction, or liquid addition and is often used synonymously with dry blending.
  • the blend comprising the active agent Compound 1 and the included pharmaceutically acceptable excipients e.g. filler, disintegrant, glidant, lubricant, or any combination thereof
  • Formulations as described herein may be produced using one or more mixing and/or dry granulations steps. Dry granulation can be carried out by a mechanical process, which transfers energy to the mixture without any use of any liquid substances (neither in the form of aqueous solutions, solutions based on organic solutes, or mixtures thereof) in contrast to wet granulation processes, also contemplated herein.
  • the mechanical process requires compaction such as the one provided by roller compaction.
  • An example of an alternative method for dry granulation is slugging.
  • the method for producing a pharmaceutical composition comprises providing an admixture of a solid forms, e.g. an admixture of powdered and/or liquid ingredients, the admixture comprising Compound 1 and one or more excipients selected from for example, a glidant, a lubricant, a disintegrant, and a filler; mixing the admixture until the admixture is substantially homogenous.
  • the admixture can then be compressed or compacted into a granular form. Then the granular composition comprising Compound 1 can be compressed into tablets or formulated into capsules as described above or in the Examples below.
  • Pharmaceutical formulations, for example a capsule as described herein, can be made using the granules prepared
  • the admixture is mixed by stirring, blending, shaking, or the like using hand mixing, a mixer, a blender, any combination thereof, or the like.
  • mixing can occur between successive additions, continuously throughout the ingredient addition, after the addition of all of the ingredients or combinations of ingredients, or any combination thereof.
  • the admixture is mixed until it has a substantially homogenous composition.
  • the manufacturing of Compound 1 capsules involves three major unit operations: blending, roller compaction, and encapsulation.
  • the manufacturing of Compound 1 capsules involves two major unit operations: direct blending and encapsulation.
  • roller compactors such as the Freund Vector TF-Labo may be used.
  • the blend may be roller compacted in ribbons and milled into granules using a Freund Vector TF-Labo (for example, Roller Pressure: 6 MPa, Roller Speed: 2 rpm, Feed Screw Speed: 40 rpm, Screen: 18 Mesh).
  • the roller compacted granules may be blended with extra- granular excipients such as fillers and lubricant using a V-shell blender.
  • the blending time may be up to 5 minutes, for example 5, 3 or 1 minute(s).
  • Compound 1 and excipients may be screened prior to or after weigh-out.
  • Compound 1 may be pre-blended with one or more of the excipients to simplify screening.
  • Blending Compound 1 and excipients may be added to the blender in different order. The blending may be performed in a Turbula blender, bin blender or v-shell blender. The components may be blended for up to 52 minutes without lubricant followed by additional blending with lubricant for up to up to 5 minutes, for example 4, 2, or 1 minute(s).
  • the powder blend may be encapsulated using either semi- automated or fully automated capsule filling machines.
  • semi- automated or fully automated capsule filling machines For example, the T.M.P. Millan MS3/6N, the Bosch GFK-705, or the Bosch GKF-1500.
  • Screening/Weighing Compound 1 and excipients may be screened prior to or after weigh-out. Possible screen sizes are mesh 14, mesh 20, mesh 30, or mesh 35.
  • Compound 1 may be pre-blended with one or more of the excipients to simplify screening.
  • Dosage forms prepared as above can be subjected to in vitro dissolution evaluations according to Test 711 "Dissolution" in United States Pharmacopeia, United States Pharmacopeial Convention, Inc., Rockville, Md., (“USP"), to determine the rate at which the active substance is released from the dosage forms.
  • the content of active substance and the impurity levels are typically measured by techniques such as high performance liquid chromatography (HPLC).
  • the invention includes use of packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, glassine foil, aluminum pouches, and blisters or strips composed of aluminum or high-density polyvinyl chloride (PVC), optionally including a desiccant, polyethylene (PE), polyvinylidene dichloride (PVDC), PVC/PE/PVDC, PVC/Aclar and the like.
  • packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, glassine foil, aluminum pouches, and blisters or strips composed of aluminum or high-density polyvinyl chloride (PVC), optionally including a desiccant, polyethylene (PE), polyvinylidene dichloride (PVDC), PVC/PE/PVDC, PVC/Aclar and the like.
  • PE
  • the pharmaceutical compositions of the invention can be administered to a patient once daily or about every twenty-four hours. Alternatively, the pharmaceutical compositions of the invention can be administered to a patient twice daily or about every twelve hours. These pharmaceutical compositions are administered as oral formulations in a unit dosage containing about 100 mg of Compound 1. In some instances, a dose of Compound 1 is a single capsule containing about 100 mg. In some instances, a dose of about 200 mg of Compound 1, may comprise two capsules of the invention each containing about 100 mg of Compound 1. In some instances, a dose of about 400 mg of Compound 1, may comprise four capsules of the invention each containing about 100 mg of Compound 1.
  • the compound and pharmaceutically acceptable compositions and formulations of the invention can be employed in combination therapies; that is, Compound 1 and pharmaceutically acceptable compositions 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 therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects).
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease, for example, cystic fibrosis, or condition are known as "appropriate for the disease or condition being treated.”
  • the additional therapeutic agent is selected from one or more CFTR modulators other than Compound 1 of the invention, and one or more antiinflammatory agents.
  • the invention relates to a method of treating pulmonary disorders or inflammatory disorders in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition provided by the invention.
  • the invention relates to a method of treating a CFTR mediated disease in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition provided by the invention.
  • the invention relates to a method of treating cystic fibrosis in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition provided by the invention.
  • the invention relates to a method of treating asthma in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition provided by the invention.
  • the invention relates to a method of treating COPD in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition provided by the invention.
  • the invention relates to a method of treating IBD in a subject comprising administering to a subject in need thereof an effective amount of the
  • the pharmaceutical composition is administered to the subject once a day. In another embodiment, the pharmaceutical composition is administered to the subject twice a day. In one embodiment, when the pharmaceutical composition is a capsule according to Tables 1-14, dosing is once a day. In another embodiment, when the pharmaceutical composition is a capsule according to Tables 1-14, dosing is twice a day. In another embodiment, more than one capsule is dosed at a time.
  • Method 1 - Method 4 described below were used to prepare example capsules of the invention.
  • Step 2 Add Magnesium Stearate (Intragranular) to Step 2) mixture and continue mixing for 2 min at the speed of 47 rpm.
  • roller compact the above mixture to form dry granule (Roller Pressure: 6 MPA, Roller Speed: 2 rpm, Feed Screw Speed: 40 rpm, Screen: 18 Mesh).
  • Method 2 Process for preparation of Capsules of Examples 6-13 described below.
  • Method 4 Additional Method of capsule preparation suitable for larger scale
  • Capsules 1-5 described in Examples 1-5 below grades/brands of excipients were: Lactose Monohydrate: Fast Flo, Foremost; Microcrystalline Cellulose, PH102; Dibasic calcium phosphate : Anhydrous, Innophos; Croscarmellose Sodium: FMC, USA, Magnesium Stearate: Macron, USA; HPC (hydroxypropyl cellulose): Ashland; Colloidal Silicon Dioxide: Compendial, Evonic, Germany.
  • Capsules 1-5 had a total fill weight of 380 mg in a size 1 hypromellose capsule with a fill volume of about 0.5 ml.
  • Capsules 6-13 described in Examples 6-13 grades/brands of excipients were: Lactose Monohydrate: Fast Flo, Foremost; Dibasic calcium phosphate (DCP): Anhydrous, Innophos; Pregelatinized starch: Colorcon; Colloidal Silicon Dioxide: Compendial, Evonic, Germany; Magnesium Stearate: Macron, USA.
  • DCP Dibasic calcium phosphate
  • Pregelatinized starch Colorcon
  • Colloidal Silicon Dioxide Compendial, Evonic, Germany
  • Magnesium Stearate Macron, USA.
  • Capsules 6-14 had a total fill weight of 300 mg in a size 1 hypromellose capsule with a fill volume of about 0.5 ml.
  • Example 1-13 The capsules described in Examples 1-13 were prepared comprising 100 mg of API (i.e. Compound 1 Form A), per capsule. Because the hemi-hydrate form A was used, when 100 mg was weighed out, the amount of active Compound 1 was about 97 mg per capsule for Capsules 1-13.
  • API i.e. Compound 1 Form A
  • Example 1 Capsule 1.
  • a capsule was prepared with the components and amounts listed in Table 1 and was prepared by Method 1.
  • Example 2 Capsule 2.
  • a capsule was prepared with the components and amounts listed in Table 2 and was prepared by Method 1.
  • Capsule 3 was prepared with the components and amounts listed in Table 3 and was prepared by Method 1.
  • Example 4 Capsule 4.
  • Capsule 4 was prepared with the components and amounts listed in Table 4 and was prepared by Method 1. [00269] Table 4: Capsule 4
  • Example 5 Capsule 5.
  • Capsule 5 was prepared with the components and amounts listed in Table 5 and was prepared by Method 1.
  • Example 6 Capsule 6.
  • Capsule 6 was prepared with the components and amounts listed in Table 6 and was prepared by Method 2.
  • Example 7 Capsule 7. [00277] Capsule 7 was prepared with the components and amounts listed in Table 7 and was prepared by Method 2.
  • Example 8 Capsule 8.
  • Capsule 8 was prepared with the components and amounts listed in Table 8 and was prepared by Method 2.
  • Capsule 9 was prepared with the components and amounts listed in Table 9 and was prepared by Method 2.
  • Example 10 Capsule 10. [00286] Capsule 10 was prepared with the components and amounts listed in Table 10 and was prepared by Method 2.
  • Example 11 Capsule 11.
  • Capsule 11 was prepared with the components and amounts listed in Table 10 and was prepared by Method 2.
  • Capsule 11 was also prepared following Method 3.
  • Example 12 Capsule 12.
  • Capsule 12 was prepared with the components and amounts listed in Table 12 and was prepared by Method 2.
  • Example 13 Capsule 13.
  • Capsule 13 was prepared with the components and amounts listed in Table 13 and was prepared by Method 2.
  • Example 14 Capsule 14.
  • Capsule 14 was prepared with the components and amounts listed in Table 11, however the amount of compound 1, form A that was weighed out was corrected for the hemi-hydrate form, to give a total amount of active compound of 100 mg. Because the amount of Compound 1, form A weighed out was greater than 100 mg, the amount of lactose monohydrate was adjusted to keep constant the total fill weight of 300 mg per capsule. Capsule 14 was prepared by Method 4.
  • Compound 1 demonstrates efficacy in asthma, COPD, cystic fibrosis, and IBD models (described in the ' 181 application and in PCT/US2015/054728). [00303] Dissolution assay
  • In vitro dissolution testing is often used to guide the optimization of drug release from various formulations. This method characterizes how the active pharmaceutical ingredient is extracted out of a solid dosage form such as a capsule.
  • the in vitro dissolution profile can indicate the efficiency of in vivo dissolution.
  • a desired dissolution profile might be to have about 80% dissolution in 30 minutes. It is also desired for dissolution profiles to be similar to the dissolution profiles of lower dosage strength capsules.
  • Dissolution method for Tables 15 and 16 The dissolution procedure for capsules uses USP Apparatus 2 with sinkers in 0.05N Potassium Phosphate, pH 6.8 dissolution medium. Dissolution samples are analyzed with a reversed phase HPLC method using a Phenomenex Kinetex C18, 150 x 3.0 mm, 2.6 ⁇ column or equivalent.
  • the mobile phase (isocratic elution) consists of 70% 0.1% FA in water and 30% acetonitrile (v/v). The flow rate is 0.4 mL/minute and the column temperature is maintained at 30°C. Detection is by UV at 268 nm.
  • Table 15 below includes the dissolution profiles of Capsules of Examples 6, 7, 8, and 9.
  • Table 16 below includes the dissolution profiles of Capsules of Examples 10, 11, 12, and 13.
  • Table 16 Dissolution profiles of Capsules of Examples 10-13.
  • Dissolution method for Table 17 The dissolution procedure for capsules uses USP Apparatus 2 with sinkers in 0.05N Potassium Phosphate, pH 6.8 dissolution medium, and 1% Tween 20 is added. Dissolution samples are analyzed with a reversed phase HPLC method using a Phenomenex Kinetex C18, 150 x 3.0 mm, 2.6 ⁇ column or equivalent.
  • the mobile phase (isocratic elution) consists of 70% 0.1% FA in water and 30% acetonitrile (v/v). The flow rate is 0.5 mL/minute and the column temperature is maintained at 30°C. Detection is by UV at 268 nm.
  • Table 17 below includes the dissolution profiles of Capsules of Example 14.
  • Example 16 Assessing CFTR Plasma Membrane (PM) stability with the addition of the GSNOR inhibitor 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid
  • CFBE410- cells stably expressing HRP-tagged F508del-CFTR under the control of a tetracycline transactivator have been engineered as previously described (Phuan et al. Mol Pharmacol. 2014 Jul; 86(1):42-51). This cell model was well-characterized and has been described in detail (Veit G et al, Sci Transl Med. 2014 Jul 23; 6(246)).
  • CFBE41o- cells cells with induced expression of F508del-CFTR were grown for 3 days at 37°C followed by 48 h low- temperature rescue at 26°C. Cells were treated as described below.
  • Relative fluorescent units (RFU, Figure 3) was plotted for each treatment as well as the % of CFTR remaining at the PM for the VX-809 + VX-770 treatment groups ( Figure 4A), and for the VX-661 + VX-770 treatment groups ( Figure 4B).
  • the PM densities (RFU) were determined by cell surface ELISA. The data represents the average and standard deviation from 3 separate experiments. Statistical comparison of values were performed using the student t-test.

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Abstract

La présente invention concerne des formulations de mélange direct comprenant de l'acide 3-chloro-4-(6-hydroxyquinoléine-2-yl)benzoïque. De plus, la présente invention concerne un procédé de traitement ou de diminution de la gravité de la fibrose kystique chez un patient, comprenant l'étape consistant à stabiliser la protéine CFTR à la fois dans la cellule et au niveau de la membrane cellulaire par l'administration au dit patient d'une quantité efficace d'un inhibiteur de la S-nitrosoglutathione réductase (GSNOR).
PCT/US2017/020129 2016-03-03 2017-03-01 Formularions d'un inhibiteur de la s-nitrosoglutathione réductase WO2017151725A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019071078A1 (fr) * 2017-10-06 2019-04-11 Proteostasis Therapeutics, Inc. Composés, compositions et méthodes pour augmenter l'activité de cftr
WO2019089165A1 (fr) * 2017-11-03 2019-05-09 Burch Lauranell Harrison Composition administrée par voie orale pour traiter la fibrose kystique, la bpco, l'asthme et d'autres états inflammatoires

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140163068A1 (en) * 2012-11-02 2014-06-12 Vertex Pharmaceuticals Incorporated Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases
US8921562B2 (en) * 2010-10-08 2014-12-30 N30 Pharmaceuticals, Inc. Substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors
US20150183774A1 (en) * 2010-12-16 2015-07-02 Nivalis Therapeutics, Inc. Novel Substituted Bicyclic Aromatic Compounds as S-Nitrosoglutathione Reductase Inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8921562B2 (en) * 2010-10-08 2014-12-30 N30 Pharmaceuticals, Inc. Substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors
US20150183774A1 (en) * 2010-12-16 2015-07-02 Nivalis Therapeutics, Inc. Novel Substituted Bicyclic Aromatic Compounds as S-Nitrosoglutathione Reductase Inhibitors
US9249132B2 (en) * 2010-12-16 2016-02-02 Nivalis Therapeutics, Inc. Substituted bicyclic aromatic compounds as S-nitrosoglutathione reductase inhibitors
US20140163068A1 (en) * 2012-11-02 2014-06-12 Vertex Pharmaceuticals Incorporated Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019071078A1 (fr) * 2017-10-06 2019-04-11 Proteostasis Therapeutics, Inc. Composés, compositions et méthodes pour augmenter l'activité de cftr
IL273752B1 (en) * 2017-10-06 2023-08-01 Proteostasis Therapeutics Inc Ingredients, compounds and methods for increasing cftr activity
WO2019089165A1 (fr) * 2017-11-03 2019-05-09 Burch Lauranell Harrison Composition administrée par voie orale pour traiter la fibrose kystique, la bpco, l'asthme et d'autres états inflammatoires

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