US20110160249A1 - 5-lipoxygenase-activating protein inhibitor - Google Patents

5-lipoxygenase-activating protein inhibitor Download PDF

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US20110160249A1
US20110160249A1 US12/993,319 US99331909A US2011160249A1 US 20110160249 A1 US20110160249 A1 US 20110160249A1 US 99331909 A US99331909 A US 99331909A US 2011160249 A1 US2011160249 A1 US 2011160249A1
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canceled
compound
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
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Kevin Murray SCHAAB
Christopher David King
Nicholas Simon STOCK
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Panmira Pharmaceuticals LLC
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Amira Pharmaceuticals Inc
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Assigned to PANMIRA PHARMACEUTICALS, LLC reassignment PANMIRA PHARMACEUTICALS, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AMIRA PHARMACEUTICALS, INC.
Assigned to AMIRA PHARMACEUTICALS, INC. reassignment AMIRA PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KING, CHRISTOPHER DAVID, SCHAAB, KEVIN MURRAY, STOCK, NICHOLAS SIMON
Assigned to PANMIRA PHARMACEUTICALS, LLC reassignment PANMIRA PHARMACEUTICALS, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AMIRA PHARMACEUTICALS, INC.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • compositions that comprise 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, pharmaceutically acceptable salts, pharmaceutically acceptable solvates (including hydrates), amorphous phases, partially crystalline and crystalline forms, prodrugs, metabolites and N-oxides thereof and methods of use thereof in the treatment or prevention of diseases or conditions associated with 5-lipoxygenase-activating protein (FLAP) activity.
  • FLAP 5-lipoxygenase-activating protein
  • Leukotrienes are biological compounds formed from arachidonic acid in the leukotriene synthesis pathway. Leukotrienes are synthesized primarily by eosinophils, neutrophils, mast cells, basophils, dendritic cells, macrophages and monocytes. Leukotrienes have been implicated in biological actions including, by way of example only, smooth muscle contraction, leukocyte activation, cytokine secretion, mucous secretion, and vascular function.
  • FLAP is a member of the MAPEG (membrane associated proteins involved in eicosanoid and glutathione metabolism) family of proteins. FLAP is responsible for binding arachidonic acid and transferring it to 5-lipoxygenase. 5-Lipoxygenase can then catalyze the two-step oxygenation and dehydration of arachidonic acid, converting it into the intermediate compound 5-HPETE (5-hydroperoxyeicosatetraenoic acid), and in the presence of FLAP convert the 5-HPETE to Leukotriene A 4 (LTA 4 ).
  • MAPEG membrane associated proteins involved in eicosanoid and glutathione metabolism
  • LTA 4 is acted on by LTC 4 synthase, which conjugates LTA 4 with reduced glutathione (GSH) to form the intracellular product leukotriene C 4 (LTC 4 ).
  • LTC 4 is transformed to leukotriene D 4 (LTD 4 ) and leukotrine E 4 (LTE 4 ) by the action of gamma-glutamyl-transpeptidase and dipeptidases.
  • LTC 4 synthase plays a pivotal role as the only committed enzyme in the formation of cysteinyl leukotrienes.
  • Described herein is 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid including all pharmaceutically acceptable solvates (including hydrates), amorphous phases, partially crystalline and crystalline forms (including all polymorphs), prodrugs, metabolites and N-oxides thereof (Compound 1) or a pharmaceutically acceptable salt of Compound 1 including all pharmaceutically acceptable solvates (including hydrates), amorphous phases, partially crystalline and crystalline forms (including all polymorphs), prodrugs, metabolites and N-oxides thereof, and methods of uses thereof in the manufacture of medicaments for the treatment of leukotriene mediated diseases, disorders, or conditions. Also described are pharmacokinetic and pharmacodynamic properties of such formulations in mammals, is including humans.
  • Compound 1 is all pharmaceutically acceptable solvates (including hydrates), amorphous phases, partially crystalline and crystalline forms (including all polymorphs), prodrugs, metabolites and N-oxides.
  • pharmaceutically acceptable salt of Compound 1 are all pharmaceutically acceptable solvates (including hydrates), amorphous phases, partially crystalline and crystalline forms (including all polymorphs), prodrugs, metabolites and N-oxides of said pharmaceutically acceptable salt.
  • Compound 2 is all pharmaceutically acceptable solvates (including hydrates), amorphous phases, partially crystalline and crystalline forms (including all polymorphs), prodrugs, metabolites and N-oxides.
  • described is a pharmaceutically acceptable salt of Compound 1.
  • described herein is Compound 1.
  • compositions comprising Compound 1, or a pharmaceutically acceptable salt thereof as the active ingredient in the pharmaceutical composition; and at least one pharmaceutically acceptable inactive ingredient selected from among excipients, diluents, and carriers.
  • a pharmaceutically acceptable salt comprising 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate as the anion, and a cation selected from Na + , K + , Li + , Ca 2+ , NH 4 + , the protonated form of dicyclohexylamine, the protonated form of N-methyl-D-glucamine, the protonated form of tris(hydroxymethyl)methylamine, the protonated form of arginine, and the protonated form of lysine.
  • the cation is selected from Na + , K + , Li + , Ca 2+ , and NH 4 + , In some embodiments, the cation is selected from Na + , K + , and Li + . In some embodiments, the cation is Na + .
  • the pharmaceutically acceptable salt is solvated or desolvated. In some embodiments, the pharmaceutically acceptable salt is desolvated. In some embodiments, the pharmaceutically acceptable salt is solvated. In a specific embodiment, the pharmaceutically acceptable salt is solvated with a Class 3 solvent. In some embodiments, the pharmaceutically acceptable salt is solvated with a Class 3 solvent and water. In a specific embodiment, the Class 3 solvent selected from ethyl acetate, isopropyl acetate, methyl tert-butylether, heptane, isopropanol, and ethanol. In some embodiments, the pharmaceutically acceptable salt is solvated with methyl tert-butylether. In some embodiments, the pharmaceutically acceptable salt comprises a detectable amount of water.
  • the pharmaceutically acceptable salt comprises a detectable amount of palladium that is less than 20 ppm. In some other embodiments, the pharmaceutically acceptable salt comprises a detectable amount of palladium that is less than 10 ppm. In yet other embodiments, the pharmaceutically acceptable salt comprises a detectable amount of palladium that is less than 5 ppm. In yet other embodiments, the pharmaceutically acceptable salt comprises less than 20 ppm of palladium.
  • Compound 1 or a pharmaceutically acceptable salt thereof is in an amorphous phase, a partially crystalline form, or a crystalline form.
  • Compound 1 or a pharmaceutically acceptable salt thereof is in an amorphous phase.
  • Compound 1 or a pharmaceutically acceptable salt thereof is in a crystalline form.
  • the pharmaceutically acceptable salt undergoes a crystal formation (whether by a crystallization, solid-to-solid transformation or crystalline inter-conversion) from methyl tert-butylether.
  • composition comprising Compound 2.
  • Compound 2 is in an amorphous phase, a partially crystalline form, a crystalline form, milled form, or nano-particulate form.
  • the composition comprises a detectable amount of palladium that is less than 20 ppm. In some other embodiments, the composition comprises a detectable amount of palladium that is less than 10 ppm. In yet other embodiments, the composition comprises a detectable amount of palladium that is less than 5 ppm.
  • the composition comprises less than 20 ppm of palladium. In some other embodiments, the composition comprises less than 10 ppm of palladium in yet other embodiments, the composition comprises less than 5 ppm of palladium.
  • the composition comprises crystalline Compound 2. In some embodiments, crystalline Compound 2 is Polymorph Form B. In some embodiments, crystalline Compound 2 is Polymorph Form C. In some embodiments, the composition comprises amorphous Compound 2.
  • the composition comprises crystalline polymorph Form C of Compound 2. In some embodiments, the composition comprises crystalline polymorph Form B of Compound 2. In some embodiments, the composition comprises amorphous Compound 2.
  • the composition comprises crystalline Compound 2 and a detectable amount of amorphous Compound 2.
  • the composition comprises a detectable amount of water.
  • Compound 2 is crystalline and was crystallized from methyl tert-butyl ether.
  • the composition of Compound 2 comprises a detectable amount of solvent selected from 1,2-dimethoxyethane, ethyl acetate, methanol, ethanol, tetrahydrofuran, and methyl tert-butyl ether; wherein the solvents are detected at levels less than about 5000 ppm.
  • the composition comprises a detectable amount of solvent selected from 1,2-dimethoxyethane, ethyl acetate, methanol, ethanol, tetrahydrofuran, and methyl tert-butyl ether; wherein the solvents are detected at levels less than about 4000 ppm.
  • the composition comprises a detectable amount of solvent selected from 1,2-dimethoxyethane, ethyl acetate, methanol, ethanol, tetrahydrofuran, and methyl tert-butyl ether; wherein the solvents are detected at levels less than about 3000 ppm, in some embodiments, the composition comprises a detectable amount of solvent selected from 1,2-dimethoxyethane, ethyl acetate, methanol, ethanol, tetrahydrofuran, and methyl tert-butyl ether; wherein the solvents are detected at levels less than about 2000 ppm.
  • the composition comprises a detectable amount of solvent selected from 1,2-dimethoxyethane, ethyl acetate, methanol, ethanol, tetrahydrofuran, and methyl tert-butyl ether; wherein, the solvents are detected at levels less than about 1000 ppm.
  • Compound 2 has a solubility in water at about pH 10 and at about 25° C. that is greater than about 10 mg/mL.
  • the composition described herein comprises Compound 2 which was crystallized or precipitated from methyl tert-butyl ether. In some embodiments, the composition comprises Compound 2 that underwent a crystal formation (whether by a crystallization, solid-to-solid transformation or crystalline inter-conversion) from methyl tert-butyl ether.
  • composition of Compound 2 comprises a detectable amount of a compound selected from:
  • Compound 2 is greater than 97% pure. In further embodiments, Compound 2 is greater than 98% pure. In yet further embodiments, Compound 2 is greater than 99% pure.
  • described herein is an amorphous form of Compound 2. In some embodiments, described herein is an amorphous form of Compound 2 that has at least one property selected from:
  • described herein is an amorphous form of Compound 2 that has (1a) an XRPD pattern showing a lack of crystallinity.
  • the amorphous form of Compound 2 has (2a) at least one endotherm and at least one exotherm observed by differential scanning calorimetry (DSC).
  • the amorphous form of Compound 2 has (3a) a glass transition temperature of about 127° C.
  • the amorphous form of Compound 2 has (4a) a melting point at about 155° C. followed by a re-crystallisation event at about 200° C. followed by a second melting point at about 288° C. to about 295° C.
  • the amorphous form of Compound 2 has (5a) a phase change to a crystalline form when heated above about 200° C., wherein the crystalline form that is formed above about 200° C. is characterized by an XRPD pattern substantially similar to any one of the XRPD patterns set forth in FIG. 9 .
  • the amorphous form of Compound 2 has (6a) a DSC or a TGA substantially similar to the ones set forth in FIG. 12 .
  • the amorphous form of Compound 2 has (5a) hygroscopicity.
  • the amorphous form of Compound 2 has (6a) chemical stability.
  • the crystalline form of Compound 2 has at least one property selected from:
  • the crystalline form of Compound 2 has at least one property selected from: (1c) an X-ray powder diffraction (XRPD) pattern substantially similar to the one set forth in FIG. 1 and (2c) an XRPD pattern with peaks at about 17.2°2-Theta, at about 18.4°2-Theta, at about 19.1°2-Theta, at about 20.8°2-Theta, and at about 23.8°2-Theta.
  • XRPD X-ray powder diffraction
  • the crystalline form of Compound 2 has (1c) an X-ray powder diffraction (XRPD) pattern substantially similar to the one set forth in FIG. 1 .
  • XRPD X-ray powder diffraction
  • the crystalline form of Compound 2 has (2c) an XRPD pattern with peaks at about 172°2-Theta, at about 18.4°2-Theta, at about 19.1°2-Theta, at about 20.8°2-Theta, and at about 23.8°2-Theta.
  • the crystalline form of Compound 2 has (3c) a single inciting point at about 290° C. to about 295° C. as measured by differential scanning calorimetry (DSC).
  • the crystalline form of Compound 2 has (4c) a DSC or a thermo-gravimetric analysis (TGA) substantially similar to the ones set forth in FIG. 15 .
  • the crystalline form of Compound 2 has (5c) physical and chemical stability (at 5° C., 25° C./60% relative humidity (RH), and or 40° C./75% RH for at least one month in a humidity chamber).
  • the crystalline form of Compound 2 is (6c) non-hygroscopic
  • the crystalline form of Compound 2 has (70) FR spectrum substantially similar to the one set forth in FIG. 19 .
  • the crystalline form of Compound 2 has (8c) an X-ray powder diffraction (XRPD) pattern substantially similar to an XRPD pattern obtained for crystals of Compound 2 obtained from methyl tert-butyl ether or acetonitrile.
  • XRPD X-ray powder diffraction
  • Compound 2 is crystalline polymorph Form B.
  • Compound 2 is crystalline and has at least one of the following properties: (1b) an X-ray powder diffraction (XRPD) pattern substantially similar to the one set forth in FIG. 2 ; (2b) an XRPD pattern with peaks at about 6.6°2-Theta, at about 8.1°2-Theta, at about 19.7°2-Theta, at about 21.0°2-Theta, at about 21.9°2-Theta, and at about 22.1°2-Theta.
  • XRPD X-ray powder diffraction
  • Compound 1 is used for treating asthma, preventing exercise-induced bronchoconstriction, treating or preventing rhinitis (allergic and non-allergic), treating chronic obstructive pulmonary disease, treating cardiovascular disease, treating NSAID-induced gastric lesions, treating pain, treating or preventing ocular disease or treating skin disease in a human.
  • Compound 1 is crystalline, In some embodiments, Compound 1 is amorpous.
  • a pharmaceutically acceptable salt of Compound 1 is used for treating asthma, preventing exercise-induced bronchoconstriction, treating or preventing rhinitis (allergic and non-allergic), treating chronic obstructive pulmonary disease, treating cardiovascular disease, treating NSAID-indused gastric lesions, treating pain, treating or preventing ocular disease or treating skin disease in a human.
  • the pharmaceutically acceptable salt of Compound 1 is Compound 2.
  • crystalline Compound 2 is used for treating asthma, preventing exercise-induced bronchoconstriction, treating or preventing rhinitis (allergic and non-allergic), treating chronic obstructive pulmonary disease, treating cardiovascular disease, treating NSAID-indused gastric lesions, treating pain, treating or preventing ocular disease or treating skin disease in a human.
  • crystalline Compound 2 is Form C.
  • amorphous Compound 2 is used for treating asthma, preventing exercise-induced bronchoconstriction, treating or preventing rhinitis (allergic and non-allergic), treating chronic obstructive pulmonary disease, treating cardiovascular disease, treating NSAID-induced gastric lesions, treating pain, treating or preventing ocular disease or treating skin disease in a human.
  • Compound 1 and/or a pharmaceutically acceptable salt thereof for use in the treatment of asthma are provided.
  • the pharmaceutically acceptable salt is Compound 2.
  • Compound 1 and or a pharmaceutically acceptable salt thereof for use in the treatment of prevention of exercise-induced bronchoconstriction.
  • the pharmaceutically acceptable salt is Compound 2.
  • the pharmaceutically acceptable salt is Compound 2.
  • Compound 1 and/or a pharmaceutically acceptable salt thereof for use in the treatment of chronic obstructive pulmonary disease.
  • the pharmaceutically acceptable salt is Compound 2.
  • Compound 1 and/or a pharmaceutically acceptable salt thereof for use in the treatment of cardiovascular disease are provided.
  • the pharmaceutically acceptable salt is Compound 2.
  • Compound 1 and/or a pharmaceutically acceptable salt thereof for use in the treatment of NSAID-induced gastric lesions.
  • the pharmaceutically acceptable salt is Compound 2.
  • Compound 1 and/or a pharmaceutically acceptable salt thereof for use in the treatment of ocular disease.
  • the pharmaceutically acceptable salt is Compound 2.
  • Compound 1 and/or a pharmaceutically acceptable salt thereof for use in the treatment of pain are provided.
  • the pharmaceutically acceptable salt is Compound 2.
  • Compound 1 and/or a pharmaceutically acceptable salt thereof for use in the treatment of skin disease in a human.
  • the pharmaceutically acceptable salt is Compound 2.
  • compositions comprising Compound 1 and/or pharmaceutically acceptable salts thereof.
  • the pharmaceutical compositions comprise Compound 1.
  • the pharmaceutical compositions comprise a pharmaceutically acceptable salt of Compound 1.
  • the pharmaceutically acceptable salt of Compound 1 is Compound 2.
  • the pharmaceutical compositions further comprise at least one pharmaceutically acceptable inactive ingredient selected from among excipients, diluents, and carriers.
  • the pharmaceutically acceptable salt of Compound 1 comprises 3-[3-(tert-butylsulfanyl)-1-[4-O-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate as the anion, and the cation is a metal cation or an ammonium cation.
  • the cation is selected from Li + , Na + , K + , and NH 4 + .
  • the cation is selected from Li + , Na + , and K + .
  • the cation is Na + .
  • compositions described herein are in a form suitable for oral administration to a mammal.
  • the composition is in the form of a pill, capsule, tablet, aqueous solution, or aqueous suspension.
  • compositions described herein comprise less than about 10 ppm of palladium.
  • the pharmaceutically acceptable salt of Compound 1 is sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate (Compound 2) and Compound 2 is in an amorphous phase, a partially crystalline form, or a crystalline form.
  • the pharmaceutical composition described herein is formulated as a tablet and Compound 2 is in crystalline form.
  • Compound 1 is in an amorphous phase, a partially crystalline form, or a crystalline form.
  • the pharmaceutical composition described herein is formulated as a tablet and Compound 1 is in crystalline form.
  • the pharmaceutical composition described herein is formulated as a tablet and Compound 1 is in amorphous phase.
  • any of the pharmaceutical compositions described herein comprise the crystalline form of Compound 2 that has an X-ray diffraction pattern with characteristic deg 2-theta values at about 17.2°2-Theta, at about 18.4°2-Theta, at about 19.1°2-Theta, at about 20.8°2-Theta, and at about 23.8°2-Theta.
  • Compound 2 described herein is in a crystalline form having an X-ray diffraction pattern substantially similar to the one set forth in FIG. 1 .
  • any of the pharmaceutical compositions described herein comprise Compound 2 in amorphous phase.
  • any of the pharmaceutical compositions described herein comprise Compound 2 in a crystalline form haying an X-ray diffraction pattern with characteristic deg 2-theta values at about 6.6°2-Theta, at about 8.1°2-Theta, at about 19.7°2-Theta, at about 21.0°2-Theta, at about 21.9°2-Theta, and at about 22.1°2-Theta.
  • Compound 2 described herein is in a crystalline form having an X-ray diffraction pattern substantially similar to the one set forth in FIG. 2 .
  • compositions disclosed herein comprise crystalline Compound 2 and a detectable amount of amorphous Compound 2.
  • Compound 2 is in a form/phase that has a solubility in water at a pH of about 9 to about 10 and about 25° C. of greater than about 10 mg/mL.
  • an oral pharmaceutical composition comprising: (a) an alkali metal salt of Compound 1; (b) optional sorbitol or ethanol; and (c) an aqueous buffer solution.
  • the alkali metal is sodium.
  • an oral pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt comprising 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate as the anion, and the cation selected from Na + , K + , and Li + ; (b) an aqueous buffer solution; and optionally (c) ethanol or Poloxamer 124.
  • the cation is Na + .
  • the aqueous buffer solution is an aqueous sodium carbonate buffer solution.
  • the oral pharmaceutical composition further comprises a pharmaceutically acceptable sweetener.
  • the pharmaceutically acceptable sweetener is selected from sucrose, sucralose, simple syrup, and syrpalta, in more specific embodiments, the pharmaceutically acceptable sweetener is sucralose. In other specific embodiments, the pharmaceutically acceptable sweetener is aspartame. In certain embodiments, any of the oral pharmaceutical compositions described herein comprise less than about 10 ppm palladium.
  • the oral pharmaceutical composition has a concentration of up to about 60 mg/mL, about 0.1 mg/mL to about 60 mg/mL, about 1 mg/mL to about 50 mg/mL, about 10 mg/mL to about 50 mg/mL, about to about 20 mg/mL, or about 10 mg/mL of Compound 2.
  • an oral pharmaceutical composition comprising: a, about 1 g of the sodium salt of 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 2); and b. about 100 mL of a solution of 1% (w/w) Poloxamer 124 and 99% (w/w) aqueous sodium carbonate buffer (0.010M, pH9-10), sweetened with sucralose.
  • an oral pharmaceutical composition comprising (a) about 1 gram or about 10 mg/mL of the sodium salt of Compound 1 (Compound 2), and (b) about 100 mL of about 10 mM aqueous sodium carbonate buffer solution with a pH of about 9-10 comprising about 10% w/w absolute ethanol and about 0.003% w/w aspartame.
  • an oral pharmaceutical composition comprising (a) about 10 mg/mL of Compound 2; (b) a solution comprising about 1% w/w poloxamer 124 and about 99% w/w aqueous sodium carbonate buffer (about 0.010M, pH about 9-10); and (c) sucralose (about 5 mg/100 mL).
  • any oral pharmaceutical composition described herein comprises or is formulated in a single dose comprising from about lama to about 1000 mg of a pharmaceutically active salt of Compound 1.
  • the single dose comprises about 10 mg to about 600 mg, about 20 mg to about 600 mg, about 40 mg to about 600 mg or about 50 mg to about 600 mg of a pharmaceutically acceptable salt of Compound 1.
  • the single dose when administered to healthy adult human subjects in the fasted state provides a C max of about 0.1 ⁇ M to about 30 ⁇ M, about 0.2 ⁇ M to about 30 ⁇ M, or about 0.1 ⁇ M to about 5 ⁇ M.
  • the single dose when administered to healthy human subjects in the fasted state provides a t max of about 1 hour to about 4 hours, or about 2 hours to about 3 hours. In some embodiments, the single dose, then administered to healthy human subjects in the fasted state provides an AUC 0-24 of about 4 hr ⁇ M to about 160 hr ⁇ M, about 5 hr ⁇ M to about 110 hr ⁇ M, about 5 hr ⁇ M to about 90 hr ⁇ M, about 5 hr ⁇ M to about 50 hr ⁇ M, about 5 hr ⁇ M to about 25 hr ⁇ M.
  • the single dose of the pharmaceutical composition when administered to healthy adult human subjects in the fasted state provides a C max that is less than about 5 ⁇ M, less than about 9 ⁇ M, or less than about 12 ⁇ M.
  • the single dose of the oral pharmaceutical composition when administered to healthy adult human subjects in the fasted state provides after about 8 hours at least 25%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% reduction in blood LTB 4 levels.
  • the single dose provides after about 24 hours at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% reduction in blood LTE 4 levels.
  • the single dose provides at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% reduction in urinary LTE 4 levels.
  • the pharmaceutically active salt of Compound 1 is Compound 2.
  • the single dose of the oral pharmaceutical composition comprises about 10 mg to about 1 g, about 10 mg to about 600 mg, about 10 mg, about 50 mg, about 150 m, about 300 mg, about 600 mg, or about 1000 mg of Compound 2.
  • any oral pharmaceutical composition described herein comprises or is formulated in a single dose comprising from about 10 mg to about 1000 mg of Compound 1.
  • the single dose comprises about 50 mg to about 1 g, about 10 mg to about 600 mg, or about 50 mg to about 600 mg of Compound 1.
  • the single dose of the oral pharmaceutical composition comprises about 10 mg to about 1 g, about 10 mg to about 600 mg, about 10 mg, about 50 mg, about 150 mg, about 300 mg, about 600 mg, or about 1000 mg of Compound 1.
  • An oral solid dosage form pharmaceutical composition comprising: a) about 10 mg to about 1 g, or about 50 mg to about 1 g, or about 50 mg to about 600 mg of Compound 2; and (b) at least one inactive pharmaceutical ingredient.
  • the oral solid dosage form comprises about 10 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 450 mg or about 600 mg of Compound 2.
  • the oral solid dosage form comprises about 10 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg of Compound 2.
  • the oral solid dosage form pharmaceutical composition comprises less than about 10 ppm palladium.
  • the oral solid dosage form pharmaceutical composition comprises less than about 5000 ppm ethyl acetate. In some embodiments, the oral solid dosage form comprises less than about 5000 ppm ethanol. In some embodiments, the oral solid dosage form pharmaceutical composition comprises a crystalline form of Compound 2. In some embodiments, Compound 2 is in a crystalline form having an X-ray diffraction pattern with characteristic deg 2-theta values at about 17.2°2-Theta, at about 18.4°2-Theta, at about 19.1°2-Theta, at about 20.8°2-Theta, and at about 23.8°2-Theta.
  • Compound 2 is in a crystalline form having an X-ray diffraction spectrum substantially similar to the one set forth in FIG. 1 .
  • Compound 2 is in a crystalline form having an X-ray diffraction pattern with characteristic deg 2-theta values at about 6.6°2-Theta, at about 8.1°2-Theta, at about 19.7°2-Theta, at about 21.0°2-Theta, at about 21.9°2-Theta, and at about 22.1°2-Theta.
  • Compound 2 is in a crystalline form having an X-ray diffraction spectrum substantially similar to the one set forth in FIG. 2 .
  • the oral solid dosage form comprises an amorphous phase (Phase A) of Compound 2.
  • An oral solid dosage form pharmaceutical composition comprising: (a) about 10 mg to about 1 g, or about 50 mg to about 1 g, or about 50 mg to about 600 mg of Compound 1; and (b) at least one inactive pharmaceutical ingredient.
  • the oral solid dosage form comprises about 10 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 450 mg or about 600 mg of Compound 1.
  • the oral solid dosage form pharmaceutical composition comprises less than about 10 ppm palladium.
  • the oral solid dosage form pharmaceutical composition comprises less than about 5000 ppm ethyl acetate.
  • the oral solid dosage form comprises less than about 5000 ppm ethanol.
  • the oral solid dosage form pharmaceutical composition comprises a crystalline form of Compound 1.
  • Compound 1 is in amorphous phase.
  • any of the oral solid dosage form pharmaceutical composition described herein allows for rapid absorption of the active ingredient in the stomach and upper gastrointestinal tract.
  • an oral solid dosage form that is in the form of a tablet.
  • the tablet is an immediate release tablet.
  • the oral solid dosage form that comprises Compound 2 exhibits an in vitro release of Compound 2 in about 1% sodium lauryl sulfate solution at pH of about 7 and about 37° C. of more than about 90% after about 10 minutes.
  • the in vitro release is measured by a drug release test using the United States Pharmacopea (USP) Type 1, basket at about 100 rpm with about 500 mL of about 1% sodium lauryl sulfate solution at pH of about 7 and about 37° C.
  • USP United States Pharmacopea
  • a pharmaceutical composition comprising Compound 2, e.g., an oral solid dosage form, wherein administration of a single dose of the pharmaceutical composition to a healthy adult human subject in the fasted state provides a C max less of than about 5 ⁇ M, and provides after about 8 hours at least an 80% reduction in blood LTB 4 levels.
  • a pharmaceutical composition e.g., an oral solid dosage form pharmaceutical composition, wherein administration of a single dose of the pharmaceutical composition to a healthy adult human subject in the fasted state provides after about 24 hours at least 30% reduction in blood LTB 4 levels.
  • a pharmaceutical composition e.g., an oral solid dosage form pharmaceutical composition, wherein administration of a single dose of the pharmaceutical composition to a healthy adult human subject in the fasted state provides after about 24 hours at least 50% reduction of urinary LTE 4 levels.
  • any oral solid dosage form described herein comprises a binding agent, a disintegrant, and a glidant as inactive pharmaceutical ingredients.
  • the inactive pharmaceutical ingredients comprise silicified microerystalline cellulose (SMCC), mannitol, crospovidone, and magnesium stearate.
  • oral solid dosage form pharmaceutical compositions provided herein comprise from about 1% to about 99%, about 1% to about 30%, about 1% to about 20%, or about 10% by weight to about 20% by weight of Compound 2.
  • compositions that provide at least one metabolite of Compound 1 to a mammal after administration to the mammal.
  • the at least one metabolite is selected from among: 3-[3-tert-butylsulfinyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[3-tert-butylsulfanyl-1-[4-(6-hydroxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid; 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzy
  • the at least one metabolite is the acyl gluconuride of 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid.
  • the pharmaceutical composition comprises a pharmaceutically acceptable (e.g., sodium) salt of 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid.
  • a pharmaceutical composition comprising an active ingredient that inhibits 5-lipoxygenase-activating protein (FLAP) and does not substantially inhibit at least one Cytochrome P450 enzyme selected from CYP 3A4, CYP 1A2, CYP 2A6, CYP 2B6, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, and CYP 2E1 at doses up to 40 ⁇ M or 50 ⁇ M.
  • FLAP 5-lipoxygenase-activating protein
  • the pharmaceutical composition comprising an active FLAP inhibitor has an IC 50 greater than about 40 ⁇ M, or 50 ⁇ M for at least one Cytochrome P450 enzyme selected from CYP 3A4, CYP 1A2, CYP 2A6, CYP 2B6, CYP 2C8, CYP 2C9, CYP 2C19, CYP 21D6, and CYP 2E1.
  • the pharmaceutical composition does not substantially induce Cytochrome P450 CYP 3A4, CYP 2C9, CYP 1A2, CYP 2C19 or CYP 2D6 at doses up to 40 ⁇ M, or up to 50 ⁇ M.
  • the pharmaceutical composition comprising an active FLAP inhibitor has an IC 50 greater than about 40 ⁇ M, or 50 ⁇ M for at least one Cytochrome P450 enzyme selected from CYP 3A4, CYP 2C9, CYP 1A2, CYP 2C19, and CYP 2D6.
  • the FLAP inhibitor is Compound 1, or a pharmaceutically acceptable salt thereof.
  • the FLAP inhibitor is Compound 1.
  • the FLAP inhibitor is Compound 2.
  • an oral solid dosage form pharmaceutical composition comprising: (a) Compound 2; and (b) optionally at least one inactive pharmaceutical ingredient.
  • the oral solid dosage form pharmaceutical composition is in the form of a capsule.
  • the capsule is a hard gelatine capsule.
  • the capsules described herein comprise at least one excipient or no excipients.
  • Compound 2 of the oral dosage form is amorphous, partially crystalline, or crystalline. In specific embodiments, Compound 2 is crystalline.
  • an article of manufacture comprising multiple unit doses of any of the oral solid dosage form pharmaceutical compositions described herein in a high-density polyethylene (HDPE) bottle equipped with a high-density polyethylene (HDPE) cap.
  • the article of manufacture further comprises an aluminum foil induction seal and an optional silica gel desiccant.
  • provided herein are methods of treating asthma in a human comprising administering to the human one or more of the pharmaceutical compositions described herein.
  • provided herein are one or more of the pharmaceutical compositions described herein for use in the treatment of asthma in a human.
  • provided herein is the use of one or more of the pharmaceutical compositions described herein fix the manufacture of a medicament for the treatment of asthma in a human.
  • provided herein are methods of preventing exercise-induced bronchoconstriction in a human comprising administering to the human one or more of the pharmaceutical compositions described herein.
  • provided herein are one or more of the pharmaceutical compositions described herein for use in the prevention of exercise-induced bronchoconstriction in a human.
  • provided herein is the use of one or more of the pharmaceutical compositions described herein for the manufacture of a medicament for the prevention of exercise-induced bronchoconstriction in a human.
  • provided herein are methods of treating allergic rhinitis in a human comprising administering to the human one or more of the pharmaceutical compositions described herein. In certain embodiments, provided herein are methods of treating allergic rhinitis in a human comprising administering to the human one or more of the oral pharmaceutical compositions described herein.
  • the methods further comprise administering at least one additional pharmaceutical agent selected from inhaled corticosteroids, non-steroidal glucocorticoid receptor (GR) agonists, short acting beta-agonists, long acting beta-agonists, and antihistamines.
  • at least one additional pharmaceutical agent selected from inhaled corticosteroids, non-steroidal glucocorticoid receptor (GR) agonists, short acting beta-agonists, long acting beta-agonists, and antihistamines.
  • GR non-steroidal glucocorticoid receptor
  • provided herein are one or more of the pharmaceutical compositions described herein for use in the treatment or prevention of allergic rhinitis in a human. In certain embodiments, provided herein is the use of one or more of the pharmaceutical compositions described herein for the manufacture of a medicament for the treatment or prevention of allergic rhinitis.
  • provided herein are methods of treating chronic obstructive pulmonary disease in a human comprising administering to the human one or more of the pharmaceutical compositions described herein.
  • provided herein are one or more of the pharmaceutical compositions described herein for use in the treatment of chronic obstructive pulmonary disease in a human.
  • provided herein is the use of one or more of the pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease in a human.
  • provided herein are methods of treating cardiovascular disease in a human comprising administering to a human any of the pharmaceutical compositions described herein.
  • provided herein are one or more of the pharmaceutical compositions described herein for use in the treatment of cardiovascular disease in a human.
  • provided herein is the use of one or more of the pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of cardiovascular disease in a human.
  • provided herein are methods of treating NSAID-induced gastric lesions in a human comprising administering to a human any of the pharmaceutical compositions described herein.
  • provided herein are one or more of the pharmaceutical compositions described herein for use in the treatment of NSAID-induced gastric lesions in a human.
  • provided herein is the use of one or more of the pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of NSAID-induced gastric lesions in a human.
  • provided herein are methods of treating pain in a human comprising administering to a human any of the pharmaceutical compositions described herein.
  • provided herein are one or more of the pharmaceutical compositions described herein for use in the treatment of pain in a human.
  • provided herein is the use of one or more of the pharmaceutical compositions described herein liar the manufacture of a medicament for the treatment of pain in a human.
  • provided herein are methods of treating skin disease in a human comprising administering to a human any of the pharmaceutical compositions described herein.
  • provided herein are one or more of the pharmaceutical compositions described herein for use in the treatment of skin disease in a human.
  • provided herein is the use of one or more of the pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of skin disease in a human.
  • provided herein are methods of treating ocular disease in a human comprising administering to a human any of the pharmaceutical compositions described herein.
  • provided herein are one or more of the pharmaceutical compositions described herein for use in the treatment or prevention of ocular disease in a human.
  • provided herein is the use of one or more of the pharmaceutical compositions described herein for the manufacture of a medicament for the treatment or prevention of ocular disease in a human.
  • compositions for oral administration to a mammal that comprises an active ingredient that inhibits FLAP and does not substantially cause increases in liver weight of the mammal.
  • the active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • a method of treating asthma in a human comprising administering to the human an oral pharmaceutical composition as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • an oral pharmaceutical composition as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of asthma in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient, for the manufacture of a medicament for the treatment of asthma in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • the pharmaceutical composition is an oral pharmaceutical composition disclosed herein.
  • a method of preventing exercise-induced bronchoconstriction in a human comprising administering to the human an oral pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient in the oral pharmaceutical composition.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • an oral pharmaceutical composition as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient for use in the prevention of exercise-induced bronchoconstriction in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient, for the manufacture of a medicament for the prevention of exercise-induced bronchoconstriction in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • the pharmaceutical composition is an oral pharmaceutical composition disclosed herein.
  • described herein is a method of treating allergic rhinitis in a human comprising administering to the human an oral pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient the oral pharmaceutical composition.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • an oral pharmaceutical composition as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient for use in the treatment or prevention of allergic rhinitis in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient, for the manufacture of a medicament for the treatment or prevention of allergic rhinitis in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • the pharmaceutical composition is an oral pharmaceutical composition disclosed herein.
  • the methods further comprise administering at least one additional pharmaceutical agent selected from inhaled corticosteroids, short acting beta-agonists, long acting beta-agonists, antihistamines, anticholinergics, non-steroidal GR agonists, antiinfectives and antivirals.
  • at least one additional pharmaceutical agent selected from inhaled corticosteroids, short acting beta-agonists, long acting beta-agonists, antihistamines, anticholinergics, non-steroidal GR agonists, antiinfectives and antivirals.
  • a method of treating chronic obstructive pulmonary disease in a human comprising administering to the human a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt as the active ingredient the oral pharmaceutical composition.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • an oral pharmaceutical composition as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient for use in the treatment of chronic obstructive pulmonary disease in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient, for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease in a human
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • the pharmaceutical composition is an oral pharmaceutical composition disclosed herein.
  • a method of treating cardiovascular disease in a human comprising administering to the human a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient the oral pharmaceutical composition.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • an oral pharmaceutical composition as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient for use in the treatment of cardiovascular disease in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient, for the manufacture of a medicament for the treatment of cardiovascular disease in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • the pharmaceutical composition is an oral pharmaceutical composition disclosed herein.
  • a method of treating pain in a human comprising administering to the human a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient the oral pharmaceutical composition, in some embodiments, the active ingredient is Compound 1. In other embodiments, the active ingredient is Compound 2.
  • an oral pharmaceutical composition as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient for use in the treatment of pain in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient, for the manufacture of a medicament for the treatment of pain in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • the pharmaceutical composition is an oral pharmaceutical composition disclosed herein.
  • a method of treating NSAID-induced gastric lesions in a human comprising administering to the human a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient the oral pharmaceutical composition.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • an oral pharmaceutical composition as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient for use in the treatment of NSAID-induced gastric lesions in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient, for the manufacture of a medicament for the treatment of NSAID-induced gastric lesions in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • the pharmaceutical composition is an oral pharmaceutical composition disclosed herein.
  • a method of treating ocular disease in a human comprising administering to the human a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient the oral pharmaceutical composition.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • an oral pharmaceutical composition as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient for use in the treatment or prevention of ocular disease in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient, for the manufacture of a medicament for the treatment or prevention of ocular disease in a human.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • the pharmaceutical composition is an oral pharmaceutical composition disclosed herein.
  • Compound 1 or a pharmaceutically acceptable salt thereof (e.g. Compound 2) is used to treat patients suffering from leukotriene-dependent conditions or diseases, including, but not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, allergic rhinitis, adult respiratory distress syndrome, and inflammatory conditions.
  • leukotriene-dependent conditions or diseases including, but not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, allergic rhinitis, adult respiratory distress syndrome, and inflammatory conditions.
  • methods for modulating including reducing and/or inhibiting the activity of 5-lipoxygenase activating protein, directly or indirectly, in a mammal comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • methods thr modulating, including reducing and/or inhibiting, the activity of leukotrienes in a mammal, directly or indirectly, comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • methods for treating leukotriene-dependent or leukotriene mediated conditions or diseases comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • methods for treating mammals with an inflammatory and/or allergic condition comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • an oral pharmaceutical composition as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient for use in the treatment or prevention of an inflammatory and/or allergic condition in a mammal.
  • the active ingredient is Compound 1
  • the active ingredient is Compound 2.
  • a pharmaceutical composition as described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient, for the manufacture of a medicament for the treatment or prevention of an inflammatory and/or allergic condition in a mammal.
  • the active ingredient is Compound 1.
  • the active ingredient is Compound 2.
  • the pharmaceutical composition is an oral pharmaceutical composition disclosed herein.
  • compositions for treating inflammation in a mammal comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • a mammal comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • the respiratory disease is asthma.
  • Respiratory disease includes, but is not limited to, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, allergic rhinitis, vasomotor rhinitis, vascular responses, endotoxin shock, fibrogenesis, pulmonary fibrosis, allergic diseases, chronic inflammation, and adult respiratory distress syndrome.
  • kits for treating chronic obstructive pulmonary disease in a mammal comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • Chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis.
  • kits for preventing increased mucosal secretion and/or edema in a mammal comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte recruitment comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • ocular disease for example, ocular inflammation, allergic conjunctivitis, vernal keratoconjunctivitis and papillary conjunctivitis
  • administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • NSAID-induced gastric lesions in a mammal comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • the mammal is a human.
  • the mammal is a human, including embodiments wherein (a) the human has an asthmatic condition or one or more other condition(s) selected from the group consisting of allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, or seasonal asthma, or chronic obstructive pulmonary disease, or pulmonary hypertension or interstitial lung fibrosis.
  • the mammal is an animal model for pulmonary inflammation, examples of which are provided herein.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), including further embodiments in which Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) is (i) administered once-a-day; (ii) is administered twice-a-day; or (iii) is administered multiple times over the span of one day.
  • any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the time between multiple administrations is every 8 hours; (iv) the time between multiple administrations is every 12 hours.
  • the methods of treatment or prevention disclosed herein comprise a drug holiday, wherein the administration of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) is temporarily suspended or the dose being administered is temporarily reduced; at the end of the drug holiday dosing is resumed.
  • the length of the drug holiday varies from 2 days to I year.
  • Compound 1, or a pharmaceutically acceptable salt thereof is used in the manufacture of medicaments for the treatment of leukotriene dependent conditions, disorders, or diseases in a human that is a non-responder to montelukast.
  • the leukotriene dependent condition, disorder, or disease is a respiratory disease or condition.
  • the respiratory disease or condition is asthma.
  • Compound 1 or a pharmaceutically acceptable salt thereof (e.g. Compound 2) for treating any of the diseases or conditions disclosed herein.
  • a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) for use in any of the uses and methods disclosed herein.
  • Compound 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing any of the diseases disclosed herein in a mammal.
  • Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of asthma in a human.
  • Compound 1 or a pharmaceutically acceptable salt thereof e.g. Compound 2 for the manufacture of a medicament for the treatment of allergic rhinitis in a human.
  • Compound 1 or a pharmaceutically acceptable salt thereof e.g. Compound 2 for the manufacture of a medicament for the prevention of allergic rhinitis in a human.
  • Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease in a human.
  • Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of ocular disease in a human.
  • Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cardiovascular disease in a human.
  • Compound 1 or a pharmaceutically acceptable salt thereof e.g. Compound 2 for the manufacture of a medicament for the treatment of skin disease in a human.
  • Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of NSAID-induced gastric lesions in a human.
  • Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of pain in a human.
  • the leukotriene dependent condition, disorder, or disease is a respiratory disease or condition.
  • the respiratory disease or condition is asthma.
  • the non-responder to montelukast is administered Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • the dose of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) that is administered to healthy human patients is reduced in human patients that lack or have a defect in a UDP-glucuronosyltransferase enzyme normally present in the human.
  • a method of increasing the bioavailability of an orally administered dose of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) in healthy human patients comprising orally administering to a mammal: (1) a to dose of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2); and (2) an inhibitor of a UDP-glucuronosyltransferase enzyme normally present in the mammal.
  • the UDP-glucuronosyltransferase enzyme is selected from UGT1A1, UGT1A3, UGT1A6, UGT1A9, and UGT2B7.
  • any of the aforementioned aspects involving the prevention or treatment of inflammation are further embodiments comprising: (a) monitoring inflammation in a mammal; (b) measuring bronchoconstriction in a mammal; (c) measuring eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte and/or lymphocyte recruitment in a mammal; (d) monitoring mucosal secretion in a mammal; (e) measuring mucosal edema in a mammal; (e) measuring levels of LTB 4 in the calcium ionophore-challenged blood of a mammal; (f) measuring levels of LTB 4 in the urinary excretion of a mammal; or (g) identifying a patient by measuring leukotriene-driven inflammatory biomarkers such as LTB 4 , LTC 4 , Il-6, CRP, SAA, MPO, EPO, MCP-1, MIP- ⁇ , sICAMs, Il
  • leukotriene gene haplotype is a leukotriene pathway gene.
  • leukotriene gene haplotype is a FLAP haplotype.
  • the leukotriene-related inflammatory biomarkers are selected from the group consisting of LTB 4 , cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP- ⁇ , sICAM, IL-6, IL-4, and IL-13.
  • the functional marker response is significant lung volume (FEV1).
  • the leukotriene gene SNP or haplotype is a leukotriene pathway gene.
  • the leukotriene gene SNP or haplotype is a FLAP SNP or haplotype.
  • the leukotriene-related inflammatory biomarkers are selected from the group consisting of LTB 4 , cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, sICAM, IL-6, IL-4, and IL-13.
  • the functional marker response is significant lung volume (FEY1).
  • the leukotriene gene SNP or haplotype is a leukotriene pathway gene. In some embodiments, the leukotriene gene SNP or haplotype is a FLAP SNP or haplotype. In some embodiments, the leukotriene-related inflammatory biomarkers are selected from the group consisting of LTB 4 , cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP- ⁇ , SWAM, IL-6, IL-4, and IL-13. In some embodiments, the functional marker response is significant lung volume (FEV1).
  • the leukotriene gene SNP or haplotype is a leukotriene pathway gene. In some embodiments, the leukotriene gene SNP or haplotype is a FLAP SNP or haplotype. In some embodiments, the leukotriene-related inflammatory biomarkers are selected from the group consisting of LTB 4 , cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP- ⁇ , sICAM, IL-6, IL-4, and IL-13. In some embodiments, the functional marker response is significant lung volume (FEV1).
  • the leukotriene gene SNP or haplotype is a leukotriene pathway gene. In some embodiments, the leukotriene gene SNP or haplotype is a FLAP SNP or haplotype. In some embodiments, the leukotriene-related inflammatory biomarkers are selected from the group consisting of LTB 4 , cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP- ⁇ , sICAM, IL-6, IL-4, and IL-13. In some embodiments, the functional marker response is significant lung volume (FEV1). In some embodiments, the information obtained from the three diagnostic methods are used in an algorithm in which the information is analyzed to identify patients in need of treatment Compound 1 or a pharmaceutically acceptable salt thereof and the treatment regimen.
  • the leukotriene-dependent or leukotriene mediated diseases or conditions include, but are not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, rhinitis, allergy, adult respiratory distress syndrome.
  • compositions are also described herein.
  • pharmaceutically acceptable salt of Compound 1 is Compound 2.
  • a process for the preparation of a crystalline form of sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(3-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethylpropionate (Compound 2) comprising the steps of
  • the crystalline form of Compound 2 has an X-ray diffraction pattern with characteristic deg 2-theta values at about 6.6°2-Theta, at about 8.1°2-Theta, at about 19.7°2-Theta, at about 21.0°2-Theta, at about 21.9°2-Theta, and at about 22.1°2-Theta.
  • the crystalline form of Compound 2 has an X-ray diffraction pattern that correlates with the X-ray diffraction pattern displayed in FIG. 2 .
  • the crystalline form of Compound 2 has an X-ray diffraction pattern with characteristic deg 2-theta values at about 17.2°2-Theta, at about 18.4°2-Theta, at about 19.1°2-Theta, at about 20.8°2-Theta, and at about 23.8°2-Theta.
  • the crystalline form of Compound 2 has an X-ray diffraction pattern that correlates with the X-ray diffraction pattern displayed in FIG. 1 .
  • step (h) comprises treating 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester with thiol derivatized silica gel.
  • step (h) comprises treating 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester with thiol derivatized silica gel or activated carbon.
  • step (h) comprises treating 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester with thiol derivatized silica gel and activated carbon.
  • step (h) comprises treating 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester with thiol derivatized silica gel.
  • step (h) comprises treating 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester with activated carbon.
  • step (i) comprises reacting 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester with sodium hydroxide in a suitable solvent.
  • step (i) further comprises crystal formation (whether by a crystallization, solid-to-solid transformation or crystalline inter-conversion) or precipitating Compound 2 from methyl tert-butyl ether.
  • a sample of Compound 2 comprises a detectable amount of palladium that is less than 20 ppm. In one aspect, a sample of Compound 2 comprises less than 20 ppm of palladium.
  • R 1 is C 1 -C 6 alkyl; with a compound of Formula (II)
  • step (A) further comprises isolating the compound of Formula (I) prior to step (B).
  • step (A) further comprises reducing the amount of palladium to less than about 20 ppm.
  • reducing the amount of palladium comprises treatment of compound of Formula (I) with thiol derivatized silica gel.
  • the product from step (A) is isolated. In some embodiments, the product from step (A) is not isolated. In some embodiments, the compound of Formula (III) is prepared using palladium coupling reactions and contains residual palladium. In some embodiments, isolating the product from step (A) comprises reducing residual palladium.
  • activated carbon is used to reduce residual palladium.
  • the activated carbon is DARCO® KB-G, DARCO® KB-WJ.
  • reducing residual palladium comprises derivatized silica gel.
  • reducing residual palladium comprises thiol derivatized silica gel.
  • step (A) is heated to a temperature of about 50° C. to about 90° C.
  • step (B) comprises hydrolysis of the ester moiety of the product of step (A).
  • step (B) comprises treatment of the compound of Formula (I) from step (A) with:
  • step (B) comprises treatment of the compound of Formula (I) from step (i) with LiOH followed by NaOH. In some other embodiments, step (B) comprises treatment of the compound of Formula (I) from step (i) with NaOH.
  • step (B) is carried out in a solvent system comprising tetrahydrofuran, water and an alcohol selected from methanol and ethanol. In some embodiments, step (B) is carried out in a solvent system comprising tetrahydrofuran, water and ethanol.
  • the process for the preparation of Compound 2 further comprises forming crystals of Compound 2 with methyl tert-butyl ether.
  • the crystal formation may occur by a crystallization, solid-to-solid transformation or crystalline inter-conversion.
  • R 1 is —CH 3 or —CH 2 CH 3 . In a specific embodiment, R is —CH 2 CH 3 .
  • the base in step (A) is a cesium base, potassium base or sodium base. In some embodiments, the base is a cesium base. In a specific embodiment, the base is cesium carbonate.
  • X′ is selected from Cl, Br, I, —OSO 2 CF 3 , —OSO 2 (4-methylphenyl), —OSO 2 (phenyl) and —OSO 2 CH 3 .
  • X′ is Cl.
  • the compound of Formula (III) is prepared by:
  • X is a halide or triflate. In some embodiments, X is selected from Cl, Br, I, —OSO 2 CF 3 , —OSO 2 (4-methylphenyl), —OSO 2 (phenyl) and —OSO 2 CH 3 . In some embodiments, X is selected from Cl, Br, I. and —OSO 2 CF 3 , in some embodiments, X is Br.
  • B is selected from
  • B is
  • the first coupling catalyst is a palladium catalyst.
  • the palladium catalyst is tetrakis(triphenylphosphine)palladium (Pd(PPh 3
  • the reaction for the synthesis of compounds of Formula (III) further comprises heating to a temperature of from about 60° C. to about 95° C.
  • the compound of Formula (IV) is prepared by reacting a compound of Formula (VI):
  • X′′ is selected from Cl, Br, I, and —OSO 2 CF 3 .
  • the borylation reagent is selected from pinacolborane, catecholborane, bis(neopentylglycolato)diboron, bis(pinacolato)diboron, bis(hexyleneglycolato)diboron, and bis(catecholato)diboron.
  • the borylation reagent is bis(pinacolato)diboron.
  • the second coupling catalyst is a second palladium catalyst.
  • the second palladium catalyst is dichloro[1,1′-bis(diphenylphosphino)terrocene]palladium (Pd(dppf)Cl 2 ).
  • the reaction further comprises heating to a temperature of from about 60° C. to about 95° C.
  • Formula (VII) is prepared by:
  • step (C) is performed at a temperature of about from 10° C. to about 35° C.
  • X′′ is selected from Br, Cl, and I.
  • R 1 is —CH 2 CH 3 .
  • step (D) comprises reacting the product of step (i) with 2-methyl-2-propanethiol and AlCl 3 in a solvent.
  • step (D) comprises reacting the product of step (i) with a Lewis Acid reagent in a solvent.
  • the Lewis Acid reagent is selected from aluminum trichloride (AlCl 3 ), Fe (III) chloride, boron trifluoride, niobium pentachloride, and lanthanide triflates (such as by way of example only, ytterbium (III) triflate).
  • the solvent of step (D) is dichloromethane.
  • step (D) comprises reacting the product of step (i) with 2-methyl-2-propanethiol and AlCl 3 in a solvent.
  • the disclosed processes provide for the synthesis of Compound 1 and pharmaceutically acceptable salts thereof.
  • the processes disclosed herein are particularly applicable to large scale chemical production of Compound 1 and pharmaceutically acceptable salts thereof.
  • Also described herein are processes for the preparation of Compound 2, in good yield that have good solubility and good oral bioavailability.
  • FIG. 1 illustrates an XRPD pattern of Polymorph Form C of Compound 2.
  • FIG. 2 illustrates an XRPD pattern of Polymorph Form B of Compound 2.
  • FIG. 3 illustrates an XRPD pattern of Amorphous Phase A of Compound 2.
  • FIG. 4 illustrates a comparison of XRPD patterns of Compound 2 in which crystal formation (whether by a crystallization, solid-to-solid transformation or crystalline inter-conversion) or precipitation occurred in various solvents.
  • FIG. 5 illustrates a comparison of the XRPD patterns of Amorphous Phase A of Compound 2 before and after one week at 40° C. and 75% relative humidity.
  • FIG. 6 illustrates a comparison of the XRPD patterns of Polymorph Form B of Compound 2 before and after GVS experiments.
  • FIG. 7 illustrates a comparison of the XRPD patterns of Polymorph Form C of Compound 2 before and after one week at 40° C. and 75% relative humidity.
  • FIG. 8 illustrates a variable temperature XRPD patterns of Amorphous Phase A of Compound 2.
  • FIG. 9 illustrates a comparison of the XRPD patterns of Amorphous Phase A of Compound 2 at 230° C. and 280° C. with the XRPD pattern of Polymorph Form C.
  • FIG. 10 illustrates a variable temperature XRPD patterns of Polymorph Form B of Compound 2.
  • FIG. 11 illustrates a comparison of the XRPD patterns of Polymorph Form B of Compound 2 at 180° C., 220° C. and 260° C. with the XRPD pattern of Polymorph Form C.
  • FIG. 12 illustrates a DSC (bottom) and TGA (top) trace for Amorphous Phase A of Compound 2.
  • FIG. 13 illustrates a modified DSC (bottom) and TGA (top) trace for Amorphous Phase A of Compound 2.
  • FIG. 14 illustrates a DSC (bottom) and TGA (top) trace for Polymorph Form B of Compound 2.
  • FIG. 15 illustrates a DSC (bottom) and TGA (top) trace for Polymorph Form C of Compound 2.
  • FIG. 16 illustrates a GVS diagram for Amorphous Phase A of Compound 2.
  • FIG. 17 illustrates a GVS diagram for Polymorph Form B of Compound 2.
  • FIG. 18 illustrates a GVS diagram for Polymorph Form C of Compound 2.
  • FIG. 19 illustrates an IR Spectrum for Polymorph Form C of Compound 2.
  • FIG. 20 illustrates results of experiments conducted to evaluate CYP induction of Compound 2.
  • FIG. 21 illustrates pharmacokinetic properties of a single dose and multiple dose of an aqueous solution of Compound 2.
  • FIG. 22 illustrates pharmacodynamic properties (blood LTB 4 levels) of single dose administrations of an aqueous solution of Compound 2.
  • FIG. 23 illustrates pharmacodynamic properties (urinary LTE 4 levels) of single dose administration of aqueous solutions of Compound 2.
  • FIG. 24 illustrates plasma concentrations of Compound i observed in the 50 mg multiple dose cohort after administration of Compound 2.
  • FIG. 25 illustrates pharmacodynamic properties (blood LTB 4 levels) of multiple dose administrations of an aqueous solution of Compound 2.
  • Leukotrienes are a class of pro-inflammatory lipid mediators derived from arachidonic acid that play important roles in a number of biological processes.
  • Arachidonic acid is converted to leukotriene A 4 (LTA 4 ) in a two-step process mediated by the enzyme 5-lipoxygenase (5-LO).
  • the initial step is the oxygenation of arachidonic acid to form 5(S)-hydroperoxy-6,8,11,14(E,Z,Z,Z)-eicosatetraenoic acid (5-HPETE) followed by dehydration to produce the unstable epoxide LTA 4 .
  • LTA 4 is converted either to LTB 4 via LTA 4 hydrolase or to LTC 4 through conjugation with glutathione mediated by LTC 4 synthase. Amide bond cleavage converts LTC 4 to LTD 4 and then subsequently to LTE 4 .
  • the initial oxidation step is a process that requires the intimate involvement of both 5-LO and the membrane bound 5-lipoxygenase-activating protein (FLAP). Inhibition of either FLAP or 5-LO results in the inhibition of all leukotriene production.
  • LTB 4 is the ligand for the G protein-coupled receptors (GPCRs) BLT 1 and BLT 2 and both receptors are involved in chemotaxis and cell stimulation in the inflammatory response.
  • GPCRs G protein-coupled receptors
  • Leukotrienes are lipid mediators of inflammation that are involved in the pathogenesis of respiratory and cardiovascular diseases.
  • Cellular activation by immune complexes and other inflammatory stimuli results in an increase of intracellular calcium and the translocation of cytosolic phospholipase A 2 (cPLA7) and 5-lipoxygenase (5-LO) from the cytosol to the nuclear membrane.
  • cPLA7 cytosolic phospholipase A 2
  • 5-LO 5-lipoxygenase-activating protein
  • AA arachidonic acid
  • AA 5-(S)-hydroperoxy-6,8,11,14-eicosatetraenoic acid
  • LTA 4 leukotriene A 4
  • FLAP is an integral membrane protein that belongs the MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism) superfamily. In contrast to other MAPEGs. FLAP has not been shown to have enzymatic activity or to be functionally modulated by glutathione.
  • MAPEG membrane-associated proteins in eicosanoid and glutathione metabolism
  • Leukotrienes are potent mediators of inflammation, and bronchospasm. Leukotrienes are produced mainly by mast cells, eosinophils, monocytes/macrophages and neutrophils response to allergic or inflammatory stimuli.
  • 5-lipoxygenase translocates from a nonmembrane compartment (cytosol or nucleosol) to membranes (nuclear or endoplasmic reticulum) and interacts with FLAP.
  • FLAP transfers arachidonic acid, released from membrane phospholipids by phospholipases, to 5-LO. Then, a two step reaction occurs to convert arachidonic acid to LTA 4 .
  • LTA 4 can be exported from the cell for transcellular metabolism or converted to either LTB 4 or LTC 4 .
  • LTC 4 is exported from cells and converted to LTD 4 and then LTE 4 in blood.
  • LTB 4 activates BLT 1 and BLT 2 receptors, and the cysteinyl leukotrienes activate cysLT 1 and cysLT 2 receptors (and possibly a cysLT 3 receptor).
  • cysteinyl leukotriene-mediated human bronchoconstriction occurs by means of cysLT 1 receptor activation
  • both cysLT 1 and cystLT 2 receptors are present on cells involved in allergic inflammation, including mast cells, eosinophils, and monocytes.
  • a number of orally active drugs affect the leukotriene pathway.
  • Montelukast is a leukotriene receptor antagonist.
  • Prardukast and zafirlukast are leukotriene receptor antagonists used in the treatment of asthma and allergic rhinitis. These drugs antagonize cysLT 1 receptors but not cysLT 2 or LTB 4 receptors.
  • Clinical studies with these cysLT 1 receptor antagonists demonstrate that cysteinyl leukotrienes are important mediators of allergen-induced lung volume decline (early and late phases) as well as chronic asthma.
  • One 5-lipoxygenase inhibitor, zileuton exhibits clinical efficacy in chronic asthma although it is not effective in allergen-challenge studies.
  • MK-0591 Three FLAP inhibitors in clinical trials (MK-0591, MK-866, and BAYX-1005) show efficacy against allergen-induced early and late phases of lung-volume decline. MK-0591 also shows efficacy in chronic asthma studies.
  • Inhaled medications such as beta-agonists and corticosteroids
  • growth may be retarded in children or cataracts may be induced in adults.
  • Compound 1 is a potent FLAP inhibitor that blocks an early step in the leukotriene pathway, i.e., 5-lipoxygenase activation.
  • Compound 1 is pharmacologically active in vitro and after oral administration and well tolerated in nonclinical studies. Furthermore, because it inhibits the formation of LTB 4 and the cysteinyl leukotrienes, Compound 1 offers additional clinical benefits over leukotriene receptor antagonists such as montelukast.
  • FLAP inhibition provides a target for compounds useful in the treatment of leukotriene-dependent or leukotriene mediated diseases or conditions, including, by way of example, vascular and inflammatory disorders, proliferative diseases, respiratory and non-cancerous disorders. FLAP inhibitors are useful in the treatment of leukotriene-dependent or leukotriene mediated diseases or conditions.
  • Compound 1 or “3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethylpropanoic acid” refers to the compound with the following structure:
  • solvates including hydrates
  • amorphous phases including partially crystalline and crystalline forms (including all polymorphs)
  • prodrugs including metabolites and N-oxides thereof.
  • “Compound 2” or “sodium 3-[3-(tert-butylsulfanyl)-1-[4-O-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethylpropionate” refers to the sodium salt of 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethylpropanoic acid including pharmaceutically acceptables solvates (including hydrates), amorphous phases, partially crystalline and crystalline forms (including all polymorphs), prodrugs, metabolites and oxides thereof.
  • Compound 1 contains two basic sites (pyridinyl groups) and one acidic site (carboxylic acid). A wide variety of salts are formed. Salts of Compound 1 include:
  • a metal ion such as for example, an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion, or is replaced by an ammonium cation (NH 4 + );
  • B) salts formed by reacting Compound 1 with a pharmaceutically acceptable organic base which includes alkylamines, such as choline, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like;
  • a pharmaceutically acceptable organic base which includes alkylamines, such as choline, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like;
  • Pharmaceutically acceptable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulf
  • pharmaceutically acceptable excipient refers to a material, such as a carrier, diluent, stabilizer, dispersing agent, suspending agent, thickening agent, etc. which allows processing the active pharmaceutical ingredient (API) into a form suitable for administration to a mammal.
  • the mammal is a human.
  • Pharmaceutically acceptable excipients refer to materials which do not substantially abrogate the desired biological activity or desired properties of the compound (i.e. API), and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • API Active pharmaceutical ingredient or API refers to a compound that possesses a desired biological activity or desired properties.
  • an API is Compound 1.
  • an API is Compound 2.
  • pharmaceutically acceptable salt in reference to Compound 1 refers to a salt of Compound 1, which does not cause significant irritation to a mammal to which it is administered and does not substantially abrogate the biological activity and properties of the compound.
  • solvates include the solvent addition forms (solvates).
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of crystal formation (whether by a crystallization, solid-to-solid transformation or crystalline inter-conversion) with pharmaceutically acceptable solvents such as water, ethanol, methyl tert-butyl ether, isopropanol, acetonitrile, and the like.
  • solvents such as water, ethanol, methyl tert-butyl ether, isopropanol, acetonitrile, and the like.
  • solvates are formed using, but not limited to, Class 3 solvent(s).
  • solvates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • solvates of Compound 1, or salts thereof are conveniently prepared or formed during the processes described herein.
  • Compound 1, or salts thereof exist in unsolvated form.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. Compound 1, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. Compound 1, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • composition refers to a mixture of Compound 1, or pharmaceutically acceptable salt and/or solvate thereof, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, excipients, etc.
  • the pharmaceutical composition facilitates administration of the compound to a mammal.
  • Administration of a combination of agents includes administration of the agents described in a single composition or in a combination therapy wherein one or more agent is administered separately from at least one other agent.
  • Polymorphism the ability of a substance to exist in two or more crystalline phases enables a different arrangement and/or conformation of molecules in the crystal lattice. This arrangement can significantly affect the physiochemical, formulation and processing parameters as well as the shelf life or stability of the substance and excipients. Generally, polymorphs also provide and improved solubility and give improved dissolution rates. Thermodynamic properties such as heat capacity, free energy and chemical potential, vapor pressure, solubility, and thermodynamic activity as well as kinetic properties such as dissolution rates and stability differ among polymorphs. Provided herein are compositions comprising polymorphs of Compound 2.
  • an active pharmaceutical ingredient Compound 1, or pharmaceutically acceptable salt thereof, with a purity of greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 98%, or greater than 99%.
  • an active pharmaceutical ingredient Compound 2 with a purity of greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.
  • any of the forms described herein is utilized in the preparation of a pharmaceutical composition.
  • forms of Compound 1, including pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates disclosed herein include but are not limited to, an amorphous form, partially crystalline forms, crystalline forms, milled forms, and nano-particulate forms.
  • Various crystalline forms are known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. In certain embodiments, polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility.
  • Various factors such as the crystal formation solvent, rate of crystal formation (whether by a crystallization, solid-to-solid transformation or crystalline inter-conversion), and/or storage temperature cause a particular polymorph to be prepared.
  • Compound 2 is precipitated from methyl-t-butyl-ether.
  • Compound 2 undergoes a crystal formation from methyl-t-butyl-ether.
  • Compound 2 undergoes a crystal formation from acetonitrile.
  • Compound 2 undergoes a crystal formation from isopropanol.
  • Compound 2 undergoes a crystal formation from dimethylsulfoxide.
  • Compound 2 undergoes a crystal formation from methyl-t butyl-ether/water.
  • Compound 2 undergoes a crystal formation and is solvated, in specific embodiments, the solvate comprises water, MTBE or a combination thereof.
  • Compound 2 is desolvated.
  • Compound 2 is crystalline.
  • polymorphs of Compound 2 are polymorphs of Compound 2.
  • the polymorph is amorphous or crystalline.
  • the polymorph of Compound 2 is amorphous.
  • the polymorph of Compound 2 is crystalline form.
  • the polymorph of Compound 2 is crystalline form and is solvated.
  • the polymorph of Compound 2 is crystalline form and is desolvated.
  • Compound 2 is Amorphous Phase A.
  • FIG. 3 illustrates the XRPD pattern of amorphous Compound 2.
  • Amorphous Phase A of Compound 2 has at least one property selected from:
  • Amorphous Phase A of Compound 2 has at least two properties selected from (1a) through (6a). In some embodiments, Amorphous Phase A of Compound 2 has at least three properties selected from (1a) through (6a). In some embodiments, Amorphous Phase A of Compound 2 has at least four properties selected from (1a) through (6a).
  • Amorphous Phase A of Compound 2 is defined as having (1a) an XRPD pattern showing a lack of crystallinity.
  • Amorphous Phase A of Compound 2 is defined as having (2a) at least one endotherm and at least one exotherm observed by differential scanning calorimetry (DSC).
  • Amorphous Phase A of Compound 2 is defined as having (3a) a glass transition temperature of about 127° C.
  • Amorphous Phase A of Compound 2 is defined as having (4a) a melting point at about 155° C. followed by a re-crystallisation event at about 200° C. followed by a second melting point at about 288° C. to about 295° C.
  • Amorphous Phase A of Compound 2 is defined as having (5a) a phase change to a crystalline form when heated above about 200° C., wherein the crystalline form that is tot wed above about 200° C. is characterized by an XRPD pattern substantially similar to any one of the XRPD patterns set forth in FIG. 9 .
  • Amorphous Phase A of Compound 2 is defined as having (6a) a DSC or a TGA substantially similar to the ones set forth in FIG. 12 .
  • Amorphous Phase A of Compound 2 is defined as having (5a) hygroscopicity.
  • Amorphous Phase A of Compound 2 is defined as having (6a) chemical stability.
  • crystalline Form B of Compound 2 having at least one property selected from:
  • XRPD pattern substantially similar to any one of the XRPD patterns set forth in FIG. 11 ; (6b) hygroscopicity; and/or (7b) loss of crystallinity after a full sorption/desorption cycle of a GVS experiment.
  • provided herein is a crystalline Form B of Compound 2 having at least two properties selected from (1b) through (7b). In some embodiments, provided herein is a crystalline Form B of Compound 2 hang at least three properties selected from (1b) through (7b). In some embodiments, provided herein is a crystalline Form B of Compound 2 having at least four properties selected from (1b) through (7b).
  • a crystalline Form B of Compound 2 having (1b) an XRPD pattern substantially similar to the one set forth in FIG. 2 .
  • a crystalline Form B of Compound 2 having (2b) an XRPD pattern with peaks at about 6.6°2-Theta, at about 8.1°2-Theta, at about 19.7°2-Theta, at about 21.0°2-Theta, at about 21.9°2-Theta, and at about 22.1°2-Theta.
  • a crystalline Form B of Compound 2 having (3b) an X-ray powder diffraction (XRPD) pattern substantially similar to an XRPD pattern for crystals of Compound 2 obtained from methyl tert-butyl ether (MTBE) or isopropanol.
  • XRPD X-ray powder diffraction
  • a crystalline Form B of Compound 2 having (4b) at least one endotherm and at least one exotherm observed by differential scanning calorimetry (DSC).
  • a crystalline Form B of Compound 2 having (5b) a phase change to a second crystalline form when heated above about 180° C., wherein the second crystalline form that is formed above about 180° C. is characterized by an XRPD pattern substantially similar to any one of the XRPD patterns set forth in FIG.
  • a crystalline Form B of Compound 2 having the property of being (6b) hygroscopic.
  • a crystalline Form B of Compound 2 having (7b) loss of crystallinity after a full sorption/desorption cycle of a GVS experiment.
  • Form B is crystallized from MTBE or isopropanol. In some embodiments, Form B is crystallized from isopropanol. In some embodiments, Form B is obtained from MTBE solutions wherein a protic co-solvent (e.g. water or ethanol) is present during the crystal formation (whether by a crystallization, solid-to-solid transformation or crystalline inter-conversion). In some embodiments, Form B is obtained by crystal formation from a protic solvent such as, but not limited to, isopropanol. In some embodiments, Form B is converted to Form C by removal (dehydration) of protic so vents from the form B crystals.
  • a protic co-solvent e.g. water or ethanol
  • crystalline Compound 2 is in polymorph Form C.
  • Polymorph Form C of Compound 2 has at least one property selected from:
  • polymorph Form C of Compound 2 has at least two properties selected from (1c) through (8c). In certain embodiments, polymorph Form C of Compound 2 has at least three properties selected from (1c) through (5c). In certain embodiments, polymorph Form C of Compound 2 has at least four properties selected from (1c) through (5c). In certain embodiments, polymorph Form C of Compound 2 has at least five properties selected from (1c) through (5c).
  • polymorph Form C of Compound 2 has (1c) an X-ray powder diffraction (XRPD) pattern substantially similar to the one set forth in FIG. 1 .
  • XRPD X-ray powder diffraction
  • polymorph Form C of Compound 2 has (2c) an XRPD pattern with peaks at about 17.2°2-Theta, at about 18.4°2-Theta, at about 19.1°2-Theta, at about 20.8°2-Theta, and at about 23.8°2-Theta.
  • polymorph Form C of Compound 2 has (3c) a single melting point at about 290° C. to about 295° C.
  • polymorph Form C of Compound 2 has (4c) a DSC or a TGA substantially similar to the ones set forth in FIG. 15 .
  • polymorph Form C of Compound 2 has (5c) physical and chemical stability (at 5° C., 25° C./60% RH, and/or 40° C./75% RH for at least one month).
  • polymorph Form C of Compound 2 is (6c) non-hygroscopic.
  • polymorph Form C of Compound 2 has (7c) IR spectrum substantially similar to the one set forth in FIG. 19 .
  • polymorph Form C of Compound 2 has (8c) an X-ray powder diffraction (XRPD) pattern substantially similar to an XRPD pattern for crystals of Compound 2 obtained from methyl tert-butyl ether (MTBE) or acetonitrile.
  • XRPD X-ray powder diffraction
  • polymorph Form C is formed from methyl tert-butyl ether (MTBE). In another aspect, polymorph Form C is formed from acetonitrile.
  • MTBE methyl tert-butyl ether
  • Form C is obtained by removal (dehydration) of protic solvents from the form B crystals.
  • XRPD patterns are obtained in any manner, including by way of non-limiting example, (a) on a Siemens D5000 diffractometer; or (b) on a Bruker AXS C2 GAUDS diffractometer.
  • an XRPD pattern is obtained on a Siemens D5000 diffractometer using CuK ⁇ radiation (40 kV, 40 mA), ⁇ - ⁇ goniometer, divergence of V20 and receiving slits, a graphite secondary monochromator, and/or a scintillation counter.
  • an XRPD pattern is obtained on a Bruker AXS C2 GADDS diffractometer using CuK ⁇ radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for auto-sample positioning, a HiStar 2-dimensional area detector, a Göbel multilayer mirror coupled with a pinhole collimator of 0.3 mm, a beam divergence of approximately 4 mm, a ⁇ - ⁇ continuous scan mode, a sample detector distance of 20 cm, an effective 2 ⁇ range of 3.2°-29.7° and/or a sample exposure to the X-ray beam for about 120 seconds.
  • melting points can be determined in any manner including, by way of non-limiting example, with hot stage microscopy (HSM) or differential scanning calorimetry (DSC).
  • HSM hot stage microscopy
  • DSC differential scanning calorimetry
  • the hot stage microscopy is a Leica LM/DM polarized light microscope combined with a Mettler-Toledo MTFP82HT hot-stage, heating from ambient temperature at a rate of about 10° C./min to about 20° C./min.
  • the DSC measurements are obtained in any manner including, by way of non-limiting example, (a) a TA Instrument Q1000; or (b) a Mettler DSC 823e.
  • the TA Instrument Q1000 is calibrated for energy and temperature using certified indium, a sample of about 0.5 mg to about 3 mg, a pin-holed aluminum pan, a heat rate of about 10° C./min from 25° C. to 350° C., a nitrogen purge rate of about 0.50 mL/mm, uses Thermal Advantage v4.6.6 as the instrument control software, and/or uses Universal Analysis v4.3A as the data analysis software.
  • the Mettler DSC 823e is calibrated for energy and temperature using certified indium, a sample of about 0.5 mg to about 3 mg, a pin-holed aluminum pan, a heat rate of about 10° C./min from 25° C. to 350° C., a nitrogen purge rate of about 50 mL/min, and/or uses STARe v9.01 as the instrument control and data analysis software.
  • Oxidation of 2,5-dimethylpyridine provides 2,5-dimethylpyridine N-oxide.
  • Treatment of 2,5-dimethylpyridine N-oxide with acetic anhydride followed by base, such as sodium hydroxide, provides (5-methyl-pyridin-2-yl)-methanol.
  • (5-Methyl-pyridin-2-yl)-methanol is then treated with thionyl chloride to provide 2-chloromethyl-5-methyl-pyridine hydrochloride.
  • Alkyl isobutyrates of structure 2-1 (where R 1 is an alkyl) are treated with lithium diisopropylamide (LDA), followed by 2,3-dichloro-1-propene, which provides 4-chloro-2,2-dimethyl-pent-4-enoic acid alkyl esters of structure 2-2.
  • R 1 is selected from methyl, ethyl, propyl, isopropyl, and butyl.
  • R 1 is methyl or ethyl.
  • R 1 is ethyl.
  • 4-Chloro-2,2-dimethyl-pent-4-enoic acid alkyl esters of structure 2-2 are treated with bromine to provide 5-bromo-2,2-dimethyl-4-oxo-pentanoic acid alkyl esters of structure 2-3.
  • 5-Bromo-2,2-dimethyl-4-oxo-pentanoic acid alkyl esters of structure 2-3 are treated with 2-methyl-2-propanethiol in the presence of a base to provide 5-tert-butylsulfanyl-2,2-dimethyl-4-oxo-pentanoic acid alkyl esters of structure 2-4.
  • 4-Methoxyphenylhydrazine hydrochloride is reacted with 4-bromobenzyl bromide in the presence of a base to provide N-(4-bromo-benzyl)-N-(4-methoxy-phenyl)-hydrazine hydrochloride.
  • N-(4-bromo-benzyl)-N-(ethoxy-phenyl)-hydrazine hydrochloride is reacted with 5-tert-butylsulfanyl-2,2-dimethyl-4-oxo-pentanoic acid alkyl esters of structure 2-4 (where R 1 is C 1 -C 6 alkyl) to pro vide 3-[1-(4-bromo-benzyl)-3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl]-2,2-dimethyl-propionic acid alkyl esters of structure 3-1.
  • R 1 is selected from methyl, ethyl, propyl, isopropyl, and butyl.
  • R 1 is methyl or ethyl.
  • R 1 is ethyl.
  • alkyl esters of structure 3-1 Demethylation of alkyl esters of structure 3-1 is carried out with 2-methyl-2-propanethiol and aluminum chloride, which provides alkyl esters of structure 3-2.
  • Conversion of the bromide to a boronate ester is achieved with bis(pinacolato)diboron, potassium acetate, and a palladium catalyst.
  • the palladium catalyst is Pd(dppf)Cl 2 .
  • Alkyl esters of structure 3-3 are then coupled with 5-bromo-2-ethoxypyridine under Suzuki mediated coupling, conditions to provide alkyl esters of structure 3-4.
  • the Suzuki mediated coupling conditions include an inorganic base and a palladium catalyst.
  • the Suzuki mediated coupling conditions include potassium carbonate and tetrakis(triphenylphosphine)palladium.
  • Bases used in palladium mediated reactions include, but are not limited to, cesium carbonate, triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, and potassium phosphate.
  • Alkyl esters of structure 3-4 are then treated with a base followed by 2-chloro-5-methylpyridine hydrochloride to provide compounds of structure 3-5.
  • the base is cesium carbonate.
  • compounds of structure 3-5 are treated with a purifying means for reducing the amount of palladium to less than about 20 ppm.
  • the purifying means for reducing the amount of palladium comprises thiol derivatized silica gel.
  • compounds of structure 3-5 are isolated before hydrolysis of the ester. In another aspect, compounds of structure 3-5 are not isolated before hydrolysis of the ester. In one aspect, isolating compounds of structure 3-5 comprises a means for reducing residual palladium. In one aspect, means for reducing residual palladium comprises activated carbon. In yet a further embodiment, the activated carbon is DARC® KB-G, DARCO® KB-WJ. In other embodiments, means for reducing residual palladium comprises derivatized silica gel. In another embodiment, means for reducing residual palladium comprises thiol derivatized silica gel.
  • compounds of structure 3-5 are converted via a two-step procedure to Compound 2 as outlined in Scheme 4.
  • Compound 2 is prepared from compounds of structure 3-5 in high yield, high purity by performing a one-step hydrolysis and salt forming reaction.
  • alkyl esters of structure 3-5 are converted to Compound 2 in a high yielding one-step procedure as outlined in Scheme 5.
  • Compound 2 is formed (whether by a crystallization, solid-to-solid transformation or crystalline inter-conversion) or precipitated from a Class 3 solvent. In one aspect, Compound 2 is formed or precipitated from methyl tert-butyl ether (MTBE). In one aspect. Compound 2 is crystallized from methyl tert-butyl ether (MTBE).
  • MTBE methyl tert-butyl ether
  • a crystalline form of Compound 2 solvated with a Class 3 solvent is selected from ethyl acetate, isopropyl acetate, methyl tert-butyl ether, heptane, isopropanol, and ethanol.
  • the crystalline form of Compound 2 is solvated with MTBE.
  • the crystalline form of Compound 2 is solvated with methyl tert-butyl ether and water.
  • Compound 1 is treated with potassium hydroxide in a solvent to form potassium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethylpropionate.
  • Compound 1 is treated with lithium hydroxide in a solvent to form lithium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethylpropionate.
  • Compound 1 is treated with calcium hydroxide in a solvent to form the calcium salt of 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethylpropanoic acid.
  • Compound 1 is treated with dicyclohexylamine in a solvent to form the corresponding salt.
  • Compound 1 is treated with N-methyl-D-glucamine in a solvent to form the corresponding salt.
  • Compound 1 is treated with tris(hydroxymethyl)methylamine in a solvent to form the corresponding salt.
  • Compound 1 is treated with arginine in a solvent to form the corresponding salt.
  • Compound 1 is treated with lysine in a solvent to form the corresponding salt.
  • alkyl refers to an aliphatic hydrocarbon group.
  • the alkyl moiety is branched, straight chain, or cyclic.
  • the alkyl group may be designated as “C 1 -C 6 alkyl”.
  • an alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, ethenyl, propenyl, allyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Detectable amount refers to an amount that is measurable using standard analytic methods (e.g. ion chromatography, mass spectrometry, NMR, HPLC, gas chromatography, elemental analysis, IR spectroscopy, inductively coupled plasma atomic emission spectrometry, USP ⁇ 231>Method II, etc) (ICH guidances, Q 2 A Text on Validation of Analytical Procedures (March 1995) and Q 2 B Validation of Analytical Procedures: Methodology (November 1996)).
  • standard analytic methods e.g. ion chromatography, mass spectrometry, NMR, HPLC, gas chromatography, elemental analysis, IR spectroscopy, inductively coupled plasma atomic emission spectrometry, USP ⁇ 231>Method II, etc
  • Respiratory disease refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, trachea, bronchi, and lungs.
  • Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia.
  • asthma refers to any disorder of the lungs characterized by variations in pulmonary gas flow associated with airway constriction of whatever cause (intrinsic, extrinsic, or both allergic or non-allergic).
  • the term asthma may be used with one or more adjectives to indicate cause.
  • cardiovascular disease refers to diseases affecting the heart or blood vessels or both, including but not limited to: arrhythmia; atherosclerosis and its sequelae; angina; myocardial ischemia myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue.
  • Ocular disease refers to diseases which affect the eye or eyes and potentially the surrounding tissues as well. Ocular disease includes, butt is not limited to ocular inflammation, conjunctivitis, retinitis, scleritis, uveitis, allergic conjuctivitis, vernal conjunctivitis, pappillary conjunctivitis, and uveoretinitis.
  • Pain refers to acute or chronic pain which may be central or peripheral pain. Pain includes, but is not limited to nociceptive pain, neuropathic pain, inflammatory pain and non-inflammatory pain, for example, peripheral neuropathic pain.
  • skin disease includes but is not limited to eczema, psoriasis, skin disease, neurodermatitis, pruritis, exfoliative dermatitis, allergic dermatitis, pemphigus and hypersensitivity reactions.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction, and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • therapeutically effective amount includes, for example, a prophylactically effective amount. The effective amount will be selected based on the particular patient and the disease level.
  • an effect amount or “a therapeutically effective amount” varies from subject to subject, due to variation in metabolism of drug, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
  • an appropriate “effective” amount in any individual case is deter mined using techniques, such as a dose escalation study
  • co-administration are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • an “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • fibrosis refers to conditions that follow acute or chronic inflammation and are associated with the abnormal accumulation of cells and/or collagen and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, joints, lung, or skin, and includes such disorders as idiopathic pulmonary fibrosis and cryptogenic fibrosing alveolitis.
  • leukotriene-driven mediators refers to molecules able to be produced in a patient that results from excessive production of leukotriene stimulation of cells, such as, by way of example only, LTB 4 , LTC 4 , LTE 4 , cysteinyl leuktorienes, monocyte inflammatory protein (MIP-1 cc), interleukin-8 interleukin-4 (IL-4), interleukin-13 (IL-13), monocyte chemoattractant protein (MCP-1), soluble intracellular adhesion molecule (sICAM; soluble ICAM), myeloperoxidase (MPO), eosinophil peroxidase (EPO), and general inflammation molecules such as interleukin-6 (Il-6), C-reactive protein (CRP), and serum amyloid A protein (SAA).
  • MIP-1 cc monocyte inflammatory protein
  • IL-4 interleukin-8 interleukin-4
  • IL-13 interleukin-13
  • MCP-1 monocyte chemoattractant
  • leukotriene-related mediators refers to molecules able to be produced in a patient that result from excessive production of leukotriene stimulation of cells, such as, by way of example only, LTB 4 , LTC 4 , LTE 4 , cysteinyl leuktorienes, monocyte inflammatory protein (MIP-1 ⁇ ), interleukin-8 (IL-8), interleukin-4 (IL-4), interleukin-13 (IL-13), monocyte chemoattractant protein (MCP-1), soluble intracellular adhesion molecule (sICAM; soluble ICAM), myeloperoxidase (MPO), eosinophil peroxidase (EPO), and general inflammation molecules such as interleukin-6 (Il-6), C-reactive protein (CRP), and serum amyloid A protein (SAA).
  • MIP-1 ⁇ monocyte inflammatory protein
  • IL-8 interleukin-8
  • IL-4 interleukin-4
  • IL-13 interleukin-13
  • MCP-1 monocyte
  • leukotriene-dependent refers to conditions or disorders that would not occur, or would not occur to the same extent, in the absence of one or more leukotrienes.
  • leukotriene-mediated refers to conditions or disorders that occur in the absence of leukotrienes but also occur in the presence of one or more leukotrienes.
  • leukotriene-responsive patient refers to a patient who has been identified by either genotyping of FLAP haplotypes, or genotyping of one or more other genes in the leukotriene pathway and/or, by phenotyping of patients either by previous positive clinical response to another leukotriene modulator, including, by way of example only, zileuton, montelukast, pranlukast, zafirlukast, and/or by their profile of leukotriene-driven mediators that indicate excessive leukotriene stimulation of inflammatory cells, as likely to respond favorably to leukotriene modulator therapy.
  • a “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized (biotransformed).
  • metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases (UGT) catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups (e.g. conjugation reactions).
  • UGT uridine diphosphate glucuronyltransferases
  • Further information on metabolism is available in The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
  • metabolites of the compounds disclosed herein are identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • module refers to a molecule that interacts with a target either directly or indirectly.
  • the interactions include, but are not limited to, the interactions of an agonist and an antagonist.
  • prodrug refers to an agent that is converted into the parent drug in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be Compound 1 which is administered as an ester (“the prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • the term “subject” or “patient” encompasses mammals.
  • the mammal is a human.
  • the mammal is a non-human primate such as chimpanzee, and other apes and monkey species.
  • the mammal is a farm animal such as cattle, horse, sheep, goat, or swine.
  • the mammal is a domestic animal such as rabbit, dog, or cat.
  • the mammal is a laboratory animal, including rodents, such as rats, mice and guinea pigs, and the like.
  • Bioavailability refers to the percentage of the weight of Compound 1, or a pharmaceutically acceptable salt and/or solvate thereof, dosed that is delivered into the general circulation of the animal or human being studied.
  • the total exposure (AUC (0- ⁇ ) ) of a drug when administered intravenously is usually defined as 100% Bioavailable (F %).
  • Oral bioavailability refers to the extent to which Compound 1, or a pharmaceutically acceptable salt and/or solvate thereof, is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.
  • Blood plasma concentration refers to the concentration Compound 1, in the plasma component of blood of a mammal. It is understood that the plasma concentration of Compound 1 may vary significantly between subjects, due 10 variability with respect to metabolism and/or interactions with other therapeutic agents. In one aspect, the blood plasma concentration of Compound 1 varies from subject to subject. Likewise, values such as maximum plasma concentration (C max ) or time to reach maximum plasma concentration (T max ), or total area under the plasma concentration tune curve (AUC (0- ⁇ ) ) vary from subject to subject. Due to this variability, in one embodiment, the amount necessary to constitute “a therapeutically effective amount” of Compound 1 varies from subject to subject.
  • Drug absorption typically refers to the process of movement of drug from site of administration of a drug across a barrier into a blood vessel or the site of action, e.g., a drug moving from the gastrointestinal tract into the portal vein or lymphatic system.
  • a “measurable serum concentration” or “measurable plasma concentration” describes the blood serum or blood plasma concentration, typically measured in mg, pig, or ng of therapeutic agent per nil, di, or I of blood serum, absorbed into the bloodstream after administration. As used herein, measurable plasma concentrations are typically measured in ng/ml or fig/ml.
  • “Pharmacodynamics” refers to the factors which determine the biologic response observed relative to the concentration of drug at a site of action.
  • “Pharmacokinetics” refers to the factors which determine the attainment and maintenance of the appropriate concentration of drug at a site of action.
  • Step state is when the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant plasma drug exposure.
  • Treat” or “treatment” as used herein refers to any treatment of a disorder or disease, such as preventing the disorder or disease from occurring in a subject predisposed to the disorder or disease, but has not yet been diagnosed as having the disorder or disease; inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder either prophylactically and/or therapeutically.
  • the term “treat” is used synonymously with the term “prevent.”
  • “Purifying means for reducing the amount of palladium” or “means for reducing residual palladium” refers to means used for reducing the amount of palladium in samples comprising active pharmaceutical ingredients in order to meet palladium specification guidelines. (“Guideline on the Specification Limits for Residues of Metal Catalysts” European Medicines Agency Pre - authorisation Evaluation of Medicines for Human Use , London, January 2007, Doc. Ref. CPMP/SWP/QWP/4446/00 corr.).
  • reducing the amount of palladium includes, but is not limited, to, treatment with solid trimercaptotriazine (TMT), polystyrene-bound TMT, mercapto-porous polystyrene-bound TMT, polystyrene-bound ethylenediamine, activated carbon, glass bead sponges, SmopexTM, silica bound scavengers, thiol-derivatized silica gel, N-acetyleysteine, n-Bu 3 P, crystallization, extraction, 1-cysteine, n-Bu 3 P/lactic acid. Garrett et al, Adv. Synth. Catal. 2004, 346, 889-900).
  • activated carbon includes but is not limited to DARCO® KB-G, DARCO® KB-WJ.
  • silica bound scavengers include but are not limited to
  • ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
  • Solvents are categorized into three classes. Class 1 solvents are toxic and are to be avoided. Class 2 solvents are solvents to be limited in use during the manufacture of the therapeutic agent. Class 3 solvents are solvents with low toxic potential and of lower risk to human health. Data for Class 3 solvents indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies.
  • Class 1 solvents which are to be avoided, include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethene; and 1,1,1-trichloroethane.
  • Class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-di oxane, 2-ethoxyethanol, ethyleneglycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene and xylene.
  • Class 3 solvents which possess low toxicity, include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.
  • acetic acid acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether (
  • Residual solvents in active pharmaceutical ingredients originate from the manufacture of API. In some cases, the solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of APIs may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent is a critical parameter in the synthetic process.
  • compositions comprising salts of Compound 1 comprise an organic solvent(s). In some embodiments, compositions comprising salts of Compound 1 comprise a residual amount of an organic solvent(s). In some embodiments, compositions comprising salts of Compound 1 comprise a residual amount of a Class 3 solvent. In some embodiments, the organic solvent is a Class 3 solvent.
  • the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.
  • the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, tert-butylmethylether, h
  • compositions comprising a polymorph of a salt of Compound 1.
  • the polymorph is amorphous, semi-crystalline, or crystalline.
  • the polymorph is crystalline.
  • the polymorph is amorphous.
  • compositions comprising crystalline form of a salt of Compound 1. In one aspect, described are compositions comprising crystalline form of Compound 2.
  • compositions comprising amorphous form of a salt of Compound 1. In one aspect, described are compositions comprising amorphous form of Compound 2.
  • compositions comprising a salt of Compound 1 include a detectable amount of an organic solvent.
  • the salt of Compound 1 is a sodium salt.
  • the organic solvent is a Class 3 solvent.
  • the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol,
  • the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, tert-butylmethylether, heptane, isopropanol, and ethanol.
  • the organic solvent is selected from isopropanol, acetonitrile, ethanol, propylene glycol, and methylcellulose in water.
  • the salt of Compound 1 is a sodium salt, potassium salt, lithium salt, calcium salt, ammonium salt, protonated dicyclohexylamine salt, protonated N-methyl-D-glucamine salt, protonated tris(hydroxymethyl)methylamine salt, arginine salt, or lysine salt.
  • the salt of Compound 1 is a sodium salt.
  • compositions comprising Compound 2, wherein the composition comprises a detectable amount of solvent that is less than about 1%, wherein the solvent is selected from 1,2-dimethoxyethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, heptane, and 2-propanol.
  • the composition comprises a detectable amount of solvent which is less than about 5000 ppm.
  • compositions comprising Compound 2, wherein the detectable amount of solvent is less than about 5000 ppm, less than about 4000 ppm, less than about 3000 ppm, less than about 2000 ppm, less than about 1000 ppm, less than about 500 ppm, or less than about 100 ppm.
  • compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which are used pharmaceutically.
  • suitable techniques, carriers, and excipients include those found within, for example, Remington: The Science and Practice of Pharmacy , Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences , Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A.
  • Compound 1, or a pharmaceutically acceptably salt thereof are formulated by combining the active compound with pharmaceutically acceptable carriers or excipients.
  • Such carriers enable Compound 1, or a pharmaceutically acceptably salt thereof (e.g. Compound 2) to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • compositions will include at least one pharmaceutically acceptable carrier, diluent or excipient and Compound 1 as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
  • the oral solid dosage formulations described herein include particles of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) in crystalline form, amorphous form, semi-crystalline form, semi-amorphous form, or mixtures thereof.
  • the oral solid dosage formulations described herein include crystalline particles of Compound 2.
  • the oral solid dosage formulations described herein include crystalline particles of Compound 1 (free acid).
  • the oral solid dosage formulations described herein include amorphous particles of Compound 1 (free acid).
  • compositions described herein include: (a) Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2); and one or more of the following: (b) binders; (c) disintegrants; (d) fillers (diluents); (e) lubricants; (l) glidants (flow enhancers); (g) compression aids; (h) colors; (i) sweeteners; (j) preservatives; (k) suspensing/dispersing agents; (1) film formers/coatings; (in) flavors; (a) printing inks.
  • compositions described herein include one or more of the following in addition to Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2): (a) magnesium stearate; (b) lactose; (c) microcrystalline cellulose; (d) silicified microcrystalline cellulose; (e) mannitol; (f) starch (corn); (g) silicon dioxide; (h) titanium dioxide; (i) stearic acid; (j) sodium starch glycolate; (k) Gelatin; (l) talc, (m) sucrose; (n) aspartame; (a) calcium stearate; (p) povidone, (q) pregelatinized starch; (r) hydroxy propyl methylcellulose; (s) OPA products (coatings & inks); (t) croscarmellose; (u) hydroxy propyl cellulose; (v) ethylcellulose; (w) calcium phosphate (dibasic); (x) crospovid
  • pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxy sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (TNT or povidone) or calcium phosphate.
  • disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the pharmaceutical compositions described herein are formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, solid oral dosage forms, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, capsules, extended release formulations, inhaled powder, inhaled dispersion. IV formulations.
  • formulations provide a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), enabling, for example, once a week, twice a week, three times a week, four times a week, five times a week, once every other day, once-a-day, twice-a-day (b.i.d.), or three times a day (t.i.d.) administration if desired.
  • the formulation provides a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) enabling once-a-day administration.
  • the effective amount of Compound 1, or a pharmaceutically acceptable salt thereof is about 1 mg to about 5 g per dose, about 10 mg to about 2 g per dose, about 10 mg to about 1 g per dose, about 10 mg to about 1 g per dose, about 10 mg to about 0.5 g per dose, or about 10 mg to about 0.4 g per dose.
  • the effective amount of Compound 1, or a pharmaceutically acceptable salt thereof is about 1 mg to about 5 g per dose, about 10 mg to about 2 g per dose, about 10 mg to about 1 g per dose, about 10 mg to about 1 g per dose, about 10 mg to about 0.5 g per dose, or about 10 mg to about 0.4 g per dose.
  • Compound 2 is about 1 mg to about 5 g per day, about 10 mg to about 2 g per day, about 10 mg to about 1 g per day, about 10 mg to about 0.6 g per day, about 10 mg to about 0.5 g per day, or about 10 mg to about 0.4 g per day.
  • the effective amount of Compound 1, or a pharmaceutically acceptable salt thereof is about 5 mg per dose, about 10 mg per dose, about 50 mg per dose, about 150 mg per dose, about 300 mg per dose, about 450 mg per dose, about 600 mg per dose, or about 1000 mg per dose.
  • oral pharmaceutical solutions include about 10 mg/ml to about 50 mg/ml of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2). In one aspect, oral pharmaceutical solutions include about 10 mg/ml to about 40 mg/ml, about 10 mg/ml to about 30 mg/ml, or about 10 mg/ml to about 20 mg/ml of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2). In one aspect, oral pharmaceutical solutions include about 10 mg/ml of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • pediatric oral pharmaceutical solutions include about 1 mg/ml to about 20 mg/ml of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2). In one embodiment, pediatric oral pharmaceutical solutions include about 1 mg/ml to about 15 mg/ml, or about 5 mg/ml to about 15 mg/ml of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2). In some embodiments, pediatric oral pharmaceutical solutions include about 10 mg/ml of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • immediate release tablets include about 5% w/w to about 50% w/w of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2). In some embodiments, immediate release tablets include about 5% w/w to about 40% w/w, or about 10% w/w to about 40% w/w of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • immediate release tablets include about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 33% w/w, about 35% w/w, about 40% w/w of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • immediate release capsules include about 1.25% w/w to about 50% w/w of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2). In some embodiments, immediate release capsules include about 5% w/w to about 40% w/w, about 10% w/w to about 30% w/w, of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2). In some embodiments, immediate release capsules include about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, or about 30% w/w of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • Compound 1, or a pharmaceutically acceptable salt thereof is formulated into an immediate release form that provides for once-a-day administration.
  • Compound 1, or a pharmaceutically acceptable salt thereof e.g. Compound 2
  • an amount of Compound 1, or a pharmaceutically acceptable salt thereof e.g. Compound 2 that is effective to achieve a plasma level commensurate with the concentrations found to be effective in vivo for a period of time effective to elicit a therapeutic effect.
  • solid oral dosage forms impart cohesive qualities.
  • solid oral dosage forms include about 2% w/w to about 10% w/w of binder. In some embodiments, solid oral dosage forms include about 5% w/w of binder. In some embodiments, solid oral dosage forms include about 2% w/w, to about 25% w/w of binder. In some embodiments, solid oral dosage forms include about 5% w/w to about 25% w/w of binder. In some embodiments, solid oral dosage forms include about 18% w/w of binder.
  • the binder is hypromellose (e.g., Methocel E5). In another aspect, the binder is povidone, or starch.
  • Carrier materials include any excipients in pharmaceutics and should be selected on the basis of compatibility with Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) and the release profile properties of the desired dosage form.
  • exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like.
  • Dispersing agents, and/or viscosity modulating agents include materials that control the diffusion and homogeneity of a drug through liquid media or a granulation method or blend method. In some embodiments, these agents also facilitate the effectiveness of a coating or eroding matrix.
  • Diluents increase bulk of the composition to facilitate compression or create sufficient bulk for homogenous blend for capsule filling.
  • disintegrate includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid. “Disintegration agents or disintegrants” facilitate the breakup or disintegration of a substance.
  • the disintegrant is croscarmellose sodium. In another aspect, the disintegrant is sodium starch glycolate or crospovidone.
  • solid oral dosage forms include up to 15% w/w of disintegrant. In some embodiments, solid oral dosage forms include about 0.5% w/w to about 10% w/w of disintegrant. In some embodiments, solid oral dosage forms include about 0.5% w/w to about 5% w/w of disintegrant.
  • Filling agents include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • the filler is lactose (e.g. monohydrate). In another aspect, the filler is mannitol, or dicalcium phosphate. In another aspect, the filler is mannitol, microcrystalline cellulose, dicalcium phosphate or sorbitol.
  • Gastrointestinal fluid is the fluid of stomach secretions of a subject or the saliva of a subject after oral administration of a composition described herein, or the equivalent thereof.
  • An “equivalent of stomach secretion” includes, e.g., an in vitro fluid having similar content and/or pH as stomach secretions such as a 1% sodium dodecyl sulfate solution or 0.1N HCl solution in water.
  • simulated intestinal fluid USP is an aqueous phosphate buffer system at pH 6.8.
  • Solid oral dosage forms include about 0.25% w/w to about 2.5% w/w of lubricant. In another aspect solid oral dosage forms include about 0.5% w/w to about 1.5% w/w of lubricant.
  • the solid dosage forms described herein are in the form of a tablet, (including an immediate release tablet, an extended release tablet, a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, multiparticulate dosage forms, pellets, or granules.
  • a tablet including an immediate release tablet, an extended release tablet, a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet
  • a pill including a sterile packaged powder, a dispensable
  • the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, an immediate release tablet. Additionally, pharmaceutical formulations described herein are administered as a single dosage or in multiple dosages. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four tablets.
  • solid dosage forms e.g., tablets, effervescent tablets, and capsules
  • Compound 1, or a pharmaceutically acceptable salt thereof e.g. Compound 2
  • one or more pharmaceutical excipients to form a bulk blend composition.
  • these bulk blend compositions as homogeneous, it is meant that the Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) particles are dispersed evenly throughout the composition so that the composition is capable of being readily subdivided into equally effective unit dosage forms, such as tablets, pills, or capsules.
  • the individual unit dosages also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent.
  • these formulations are manufactured by conventional techniques.
  • Conventional techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) vet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986).
  • Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.
  • the pharmaceutical solid dosage forms described herein include the Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) compositions described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
  • a compatible carrier such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
  • Compound 1, or a pharmaceutically acceptable salt thereof is rapidly absorbed in the upper gastrointestinal tract, and thus there is a strong correlation between the rate of dissolution and bioavailability. Thus, it is important to optimize the rate of dissolution in biological matrices in order to enhance in viva absorption.
  • disintegrants are often used in the formulation, especially when the dosage forms are compressed with binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form.
  • Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that is filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step.
  • binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself acts as moderate binder.
  • Compressed tablets are solid dosage forms prepared by compacting the bulk blend formulations described above.
  • compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents.
  • the compressed tablets will include a film surrounding the final compressed tablet.
  • the film coating aids in patient compliance (c g, Opadry® coatings or sugar coating). Him coatings comprising Opadry® typically range from about 1% to about 3% of the tablet weight.
  • the compressed tablets include one or more excipients.
  • provided herein are tablets with a hardness of about 5 to about 20 Kp, or about 5 to about 15 Kp or about 8-12 Kp. In further or alternative embodiments, provided herein are tablets with a friability of less than 1%.
  • a capsule is prepared, e.g., by placing the bulk blend formulation described above, inside of a capsule.
  • the formulations non-aqueous suspensions and solutions
  • the formulations are placed in a soft gelatin capsule.
  • the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC.
  • the formulation is placed in a sprinkle capsule, wherein the capsule is swallowed whole or the capsule is opened and the contents sprinkled on food prior to eating.
  • the therapeutic dose is split into multiple (e.g., two, three, or four) capsules.
  • the entire dose of the formulation is delivered in a capsule form.
  • Compound 1, or a pharmaceutically acceptable salt thereof e.g. Compound 2 and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 10 minutes, less than about 15 minutes, less than about 20 minutes, less than about 25 minutes, less than about 30 minutes, less than about 35 minutes, or less than about 40 minutes, after oral administration, thereby releasing the Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) formulation into the gastrointestinal fluid.
  • a mass such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 10 minutes, less than about 15 minutes, less than about 20 minutes, less than about 25 minutes, less than about 30 minutes, less than about 35 minutes, or less than about 40 minutes, after oral administration, thereby releasing the Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) formulation into the gastrointestinal fluid.
  • a powder comprising the Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) formulations described herein are formulated to include one or more pharmaceutical excipients and flavors.
  • a powder is prepared, for example, by mixing the Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) formulation and optional pharmaceutical excipients to form a bulk blend composition.
  • Additional embodiments also comprise a suspending agent and or a vetting agent.
  • This bulk blend is uniformly subdivided into unit dosage packaging or multi-dosage packaging units.
  • the term “uniform” means the homogeneity of the bulk blend is substantially maintained during the packaging process.
  • effervescent powders are prepared.
  • Effervescent salts have been used to disperse medicines in water for oral administration.
  • Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid.
  • the method of preparation of the effervescent granules described herein employs three basic processes: wet granulation, dry granulation and fusion.
  • the fusion method is used for the preparation of most commercial effervescent powders. It should be noted that, although these methods are intended for the preparation of granules, the formulations of effervescent salts described herein, in one embodiment, are also prepared as tablets, according to technology for tablet preparation.
  • wet granulation is one the oldest method of granule preparation.
  • the individual steps in the wet granulation process of tablet preparation include milling and sieving of the ingredients, dry powder mixing, wet massing, granulation, drying and final grinding.
  • the composition is added to the other excipients of the pharmaceutical formulation after they have been wet granulated.
  • Dry granulation involves compressing a powder mixture into a rough tablet or “slug” on a heavy-duty rotary tablet press. The slugs are then broken up into granular particles by a grinding operation, usually by passage through an oscillation granulator. The individual steps include mixing of the powders, compressing (slugging) and grinding (slug reduction or granulation). No wet binder or moisture is involved in any of the steps.
  • the formulation is dry granulated with other excipients in the pharmaceutical formulation. In other embodiments, the formulation is added to other excipients of the pharmaceutical formulation after they have been dry granulated.
  • compositions comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) and at least one dispersing agent or suspending agent for oral administration to a subject.
  • the formulation is a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.
  • a suspension is “substantially uniform” when it is mostly homogenous, that is, when the suspension is composed of approximately the same concentration of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) at any point throughout the suspension (USP Chapter 905).
  • Liquid formulation dosage forms for oral administration are aqueous suspensions selected from, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2 nd Ed., pp. 754-757 (2002).
  • the liquid dosage forms include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent.
  • the aqueous suspensions and dispersions described herein remain in a homogenous state, as defined above by USP Chapter 905, for at least 4 hours.
  • the homogeneity should be determined by a sampling method consistent with regard to determining homogeneity of the entire composition.
  • an aqueous suspension is re-suspended into a homogenous suspension by physical agitation lasting less than 1 minute.
  • an aqueous suspension is re-suspended into a homogenous suspension by physical agitation lasting less than 45 seconds.
  • an aqueous suspension is re-suspended into a homogenous suspension by physical agitation lasting less than 30 seconds, hi still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion.
  • the aqueous suspensions, solutions or dispersions described herein include Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) at a concentration of about 5 mg/ml to about 50 mg/ml of solution.
  • Compound 1 or a pharmaceutically acceptable salt thereof (e.g. Compound 2) at a concentration of about 5 mg/ml to about 50 mg/ml of solution.
  • the aqueous suspensions, solutions or dispersions described herein include Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) at a concentration of about 5 mg/ml to about 30 mg/ml of solution.
  • Compound 1 or a pharmaceutically acceptable salt thereof (e.g. Compound 2) at a concentration of about 5 mg/ml to about 30 mg/ml of solution.
  • the aqueous suspensions, solutions or dispersions described herein include Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) at a concentration of about 10 mg/ml of solution.
  • aqueous dispersions described herein are beneficial for the administration to infants (less than 2 years old), children under 10 years of age and any patient group that is unable to swallow or ingest solid oral dosage forms.
  • the compositions take the form of tablets, lozenges, or gels formulated in a conventional manner (see e.g. U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136).
  • dragee cores are prepared with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions are used, which optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • pharmaceutical preparations which are used orally include push-fit capsules made of gelatin, as well as soft, scaled capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers are added. All formulations for oral administration should be in dosages suitable for such administration.
  • Liquid compositions illustratively take the form of a liquid where the agent (e.g. Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2)) is present in solution, in suspension or both.
  • the liquid composition is aqueous.
  • the aqueous suspension also contains one or more polymers as suspending agents.
  • Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers.
  • useful compositions also comprise an mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • compositions also include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids
  • bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane
  • buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • liquid pharmaceutical compositions also include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • compositions also include one or more preservatives to inhibit microbial activity.
  • Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
  • compositions include one or more surfactants to enhance physical stability or for other purposes.
  • Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
  • compositions include one or more antioxidants to enhance chemical stability where required.
  • Suitable antioxidants include, by way of example only, ascorbic acid, tocopherol, and sodium metabisulfite.
  • aqueous suspension compositions are packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • any standard pharmacokinetic protocol is used to determine blood plasma concentration profile in humans following administration of a formulation described herein that include Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2)), and thereby establish whether that formulation meets the pharmacokinetic criteria set out herein.
  • a randomized single-dose crossover study is performed using a group of healthy adult human subjects. The number of subjects is sufficient to provide adequate control of variation in a statistical analysis, and is typically about 10 or greater, although for certain purposes a smaller group suffices.
  • Each subject receives administration at time zero a single dose of a formulation of Compound I, or a pharmaceutically acceptable salt thereof (e.g.
  • Compound 2 e.g., a dose containing about 10 mg, about 25 mg, about 50 mg, about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 1000 mg of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2)), normally at around 8 am following an overnight fast.
  • the subjects continue to fast and remain in an upright position for about 2 hours after administration of the formulation.
  • Blood samples are collected from each subject prior to administration (e.g., 15 minutes) and at several intervals after administration. In certain instances, several samples are taken within the first hour and taken less frequently thereafter.
  • blood samples are collected at 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours after administration and, 24, 36, 48, 60 and 72 hours after administration. If the same subjects are to be used for study of a second test formulation, a period of at least 10 days should elapse before administration of the second formulation.
  • Plasma is separated from the blood samples by centrifugation and the separated plasma is analyzed for Compound 1 by a validated high performance liquid chromatography/tandem weight spectrometry (LC/APCI-MS/MS) procedure such as, for example, Ramu et al., Journal of Chromatography B, 751 (2001) 49-59).
  • Any formulation giving the desired pharmacokinetic profile is suitable for administration according to the present methods.
  • a pharmaceutical composition or formulation provided herein provides a C max (peak plasma concentration) of less than about 20 ⁇ M, less than about 15 ⁇ M, less than about 10 ⁇ M, or less than about 5 ⁇ M of a Compound 1.
  • a pharmaceutical composition or formulation provided herein reduces urinary LTE 4 levels by at least 50% at 24 hours, at least 60% at 24 hours, at least 70% at 24 hours, at least 80% at 24 hours or at least 90% at 24 hours. In some embodiments, a pharmaceutical composition or formulation provided herein reduces blood LTB 4 levels by at least 50% at 8 hours, at least 60% at 8 hours, at least 70% at S hours, at least 80% at 8 hours or at least 90% at 8 hours. In some embodiments, a pharmaceutical composition or formulation described herein reduces blood LTB 4 levels by at least 5% at 24 hours, at least 10% at 24 hours, at least 20% at 24 hours, or at least 30% at 24 hours.
  • a pharmaceutical composition or formulation provided herein provides a T (time to peak blood plasma concentration) of Compound 1 of less than about 5 hours, less than about 4 hours, less than about 3 hours, or about 2 hours.
  • a pharmaceutical composition or formulation provided herein provides an AUC 0-24 (area under the plasma concentration-time curve) of less than about 150 hr ⁇ M, less than about 120 hr ⁇ M, less than about 110 hr ⁇ M, less than about 100 hr ⁇ M, less than about 90 hr ⁇ M, less than about 50 hr ⁇ M, less than about 25 hr ⁇ M.
  • compositions containing Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), described herein is administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition.
  • amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and/or the judgment of the treating physician.
  • compositions containing Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
  • a patient susceptible to or otherwise at risk of a particular disease, disorder or condition is defined to be a “prophylactically effective amount or dose,” in this use, the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • administration of the compound, compositions or therapies as described herein includes chronic administration, hi specific embodiments, chronic administration is utilized in certain instances wherein the patient's condition does not improve and upon the doctor's discretion.
  • chronic administration includes administration for an extended period of time, including, e.g., throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • administration of the compounds, compositions or therapies described herein is given continuously.
  • the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • the length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days.
  • the dose reduction during a drug holiday is from 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • the compounds, compositions or therapies described herein are administered in at least one priming dose, followed by at least one maintenance dose.
  • a priming dose of the agent(s) is administered until the symptoms of the disorder, disease or condition treated have been reduced (e.g., to a satisfactory level).
  • a maintenance dose of the compounds, compositions or therapies described herein is administered if desired or if necessary.
  • the maintenance dose comprises administration of the agent(s) described herein in an amount sufficient to at least partially maintain the reduction achieved by administration of the priming dose.
  • the maintenance dose compared to the priming dose, includes a decrease in dosage and/or frequency of administration of the agent or one or more of the agents administered in the method. In certain embodiments, however, intermittent treatment with increased frequency and/or dosage amounts may be necessary upon any recurrence of symptoms.
  • the amount of a given agent that corresponds to a priming or maintenance amount varies depending upon factors including, by way of non-limiting example, the specific agent(s) utilized, the disease condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, and/or the route of administration, in various embodiments, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical compositions described herein are in unit dosage forms suitable for single administration of precise dosage amounts.
  • the formulation is divided into unit doses containing appropriate quantities of the active drug.
  • the unit dosage is in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • compositions and methods described herein include compositions and methods for treating, preventing, reversing, halting or slowing the progression of leukotriene-dependent or leukotriene mediated diseases or conditions once it becomes clinically evident, or treating the symptoms associated with or related to leukotriene-dependent or leukotriene mediated diseases or conditions, by administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), or pharmaceutical composition or medicament thereof.
  • the subject already has a leukotriene-dependent or leukotriene mediated disease or condition at the time of administration, or be at risk of developing a leukotriene-dependent or leukotriene mediated disease or condition (e.g., those symptoms described in the medical literature for such diseases).
  • the activity of 5-lipoxygenase activating protein in a mammal is directly or indirectly modulated by the administration of (at least once) an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), to a mammal.
  • modulation includes, but is not limited to, reducing and/or inhibiting the activity of 5-lipoxygenase activating protein.
  • the activity of leukotrienes in a mammal is directly or indirectly modulated, including reducing and/or inhibiting, by the administration of (at least once) an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) to a mammal.
  • Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of 5-lipoxygenase activating protein.
  • the prevention and/or treatment of leukotriene-dependent or leukotriene mediated diseases or conditions comprises administering to a mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • the prevention and/or treatment of inflammation diseases or conditions comprises administering to a mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • Compound 2 include, but are not limited to inflammatory diseases and disorders, cardiovascular disease and disorders, and respiratory diseases and disorders.
  • the leukotriene-dependent or leukotriene mediated diseases or conditions described herein are dependent or mediated alone or in part and directly or indirectly by one or more leukotrienes (e.g., LTE 4 , LTB 4 ).
  • the effective amount of Compound 1, or a pharmaceutically acceptable salt thereof is about 1 mg to about 5 g per dose, about 5 mg to about 2 g per dose, about 10 mg to about 1 g per dose, about 10 mg to about 1 g per dose, to about 10 mg to about 0.5 g per dose, or about 10 mg to about 0.4 g per dose.
  • the effective amount of Compound 1, or a pharmaceutically acceptable salt thereof is about 1 mg to about 5 g per dose, about 5 mg to about 2 g per dose, about 10 mg to about 1 g per dose, about 10 mg to about 1 g per dose, to about 10 mg to about 0.5 g per dose, or about 10 mg to about 0.4 g per dose.
  • Compound 2 is about 1 mg to about 5 g per day, about 10 mg to about 2 g per day, about 10 mg to about 1 g per day, about 10 mg to about 0.6 g per day, about 10 mg to about 0.5 g per day, or about 10 mg to about 0.4 g per day.
  • the effective amount of Compound 1, or a pharmaceutically acceptable salt thereof is about 10 mg per dose, about 50 mg per dose, about 150 mg per dose, about 300 mg per dose, about 450 mg per dose, about 600 mg per dose, or about 1000 mg per dose.
  • included in the prevention/treatment methods described herein are methods for treating and/or preventing respiratory diseases comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • the respiratory disease is asthma.
  • the respiratory disease includes, but is not limited to, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, allergic rhinitis, vasomotor rhinitis, vascular responses, endotoxin shock, fibrogenesis, pulmonary fibrosis, allergic diseases, chronic inflammation, and adult respiratory distress syndrome.
  • allergic (extrinsic) asthma non-allergic (intrinsic) asthma
  • acute severe asthma chronic asthma
  • clinical asthma nocturnal asthma
  • allergen-induced asthma aspirin-sensitive asthma
  • exercise-induced asthma isocapnic hyperventilation
  • child-onset asthma adult-onset asthma
  • cough-variant asthma occupational asthma
  • steroid-resistant asthma seasonal
  • chronic obstructive pulmonary disease comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis.
  • compositions for preventing and/or treating increased mucosal secretion and/or edema in a disease or condition comprising administering to the mammal at least once an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte recruitment comprising administering at least once to the mammal an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • included in the prevention/treatment methods described herein are methods for preventing and/or treating ocular disease comprising administering at least once to the mammal an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • methods for preventing ocular inflammation, allergic conjunctivitis, venial keratoconjunctivitis, and papillary conjunctivitis comprising administering at least once to the mammal an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • cardiovascular disease comprising administering at least once to the mammal an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • NSAID-induced gastric lesions comprising administering at least once to the mammal an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • compositions for preventing and/or treating pain comprising administering at least once to the mammal an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • compositions for preventing and/or treating skin disease comprising administering at least once to the mammal an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • compositions and methods described herein are also used in conjunction with other therapeutic reagents that are selected for their particular usefulness against the condition that is being treated.
  • compositions described herein and, in embodiments where combinational therapy is employed other agents do not have to be administered in the same pharmaceutical composition, and are, because of different physical and chemical characteristics, administered by different routes.
  • the initial administration is made according to established protocols, and then, based upon the observed effects, the dosage, modes of administration and times of administration, further modified.
  • the compounds are administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the disease, the condition of the patient, and the actual choice of compounds used.
  • the determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol is based upon evaluation of the disease being treated and the condition of the patient.
  • the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought is modified in accordance with a variety of factors. These factors include the disorder from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, in one embodiment, the dosage regimen actually employed varies widely and therefore deviates from the dosage regimens set forth herein. In certain embodiments, prevention and/or treatment of a leukotriene-dependent or leukotriene mediated disease or condition with a combination of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) and a second agent allows for the effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) to be decreased.
  • a combination of Compound 1, or a pharmaceutically acceptable salt thereof e.g. Compound 2
  • a second agent allows for the effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) to be decreased.
  • formulations described herein are administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the method of administration, scheduling of administration, and other factors known to medical practitioners.
  • Contemplated pharmaceutical compositions provide a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) enabling, for example, once-a-day, twice-a-day, three times a day, etc. administration.
  • pharmaceutical compositions provide an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) enabling once-a-day dosing.
  • Compound 1 or a pharmaceutically acceptable salt thereof (e.g. Compound 2) in combination with another therapeutic agent.
  • a treatment for asthma involving administration of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) increased therapeutic benefit results by also providing the patient with other therapeutic agents or therapies for asthma.
  • administration to an individual of Compound I, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) in combination with a second agent provides the individual with, e.g., an additive or synergistic benefit.
  • Therapeutically-effective dosages vary when the drugs are used in treatment combinations. Determination of therapeutically-effective dosages of drugs and other agents when used in combination treatment regimens is achieved in any manner. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects can be utilized.
  • the combination therapy allows for either or both of the Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) and the second agent to have a therapeutically effective amount that is lower than would be obtained when administering either agent alone.
  • a combination treatment regimen encompasses, by way of non-limiting example, treatment regimens in which administration of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) is initiated prior to, during, or after treatment with a second agent, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • any of the pharmaceutical compositions disclosed herein are used to treat respiratory diseases, e.g. asthma, and/or to induce bronchodilation in a subject.
  • pharmaceutical compositions disclosed herein are used to treat a subject suffering from a vascular inflammation-driven disorder, such as but not limited to coronary artery disease, atherosclerosis, stroke, peripheral arterial disease, aortic aneurysm, myocardial infarction.
  • combination therapies described herein are used as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of a FLAP inhibitor, e.g Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), and a concurrent treatment.
  • a FLAP inhibitor e.g Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2)
  • the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought is modified, in one embodiment, in accordance with a variety of factors. These factors include, by way of non-limiting example, the type of respiratory disorder and the type of bronchodilation from which the subject suffers, as well as the age, weight, sex, diet, and/or medical condition of the subject.
  • the dosage regimen employed varies and/or deviates from the dosage regimens set forth herein.
  • dosages of the co-administered compounds vary depending on by way of non-limiting example, the type of co-drug employed, on the specific drug employed, and/or on the disease or condition being treated.
  • the multiple therapeutic agents are administered either in any order, including, e.g., simultaneously. If administration is simultaneous, the multiple therapeutic agents are provided, in various embodiments, in a single, unified form, or in multiple forms (by way of example only either as a single pill or as two separate pills). In various embodiments, one of the therapeutic agents is given in multiple doses, or both are given as multiple doses. In certain embodiments wherein administration of the multiple agents is not simultaneous, the timing between administration of the multiple agents is of any acceptable range including, e.g., from more than zero weeks to less than four weeks. In some embodiments, the combination methods, compositions and formulations include Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), a second agent and a third agent. In further embodiments, additional agents are also utilized.
  • Compound 1, or a pharmaceutically acceptable salt thereof e.g. Compound 2
  • combination therapies thereof in one embodiment, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound vary.
  • Compound 1, or a pharmaceutically acceptable salt thereof e.g. Compound 2 (either alone or in a combination) is used as a prophylactic.
  • prophylactic treatment involves continuous administered of the agent(s) to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the agents and/or compositions described herein are administered to a subject during or as soon as possible after the onset of the symptoms.
  • the administration of the agents or compositions described herein is initiated within the first 48 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms.
  • the initial administration is via oral administration, such as, for example, a pill, a capsule, a tablet, a solution, a suspension, and the like, or combination thereof.
  • Compound 1, or a pharmaceutically acceptable salt thereof e.g. Compound 2 is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • administration of the agents, formulations or compositions described herein is for a length of time necessary for the treatment of disease.
  • kits that combine treatment with Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), with treatment with an inhibitor of leukotriene synthesis or with a leukotriene receptor antagonist.
  • the inhibitors of leukotriene synthesis or the leukotriene receptor antagonist act at the same or other points in the leukotriene synthesis pathway in specific embodiments, these types of combination therapies are used for treating leukotriene-dependent or leukotriene mediated diseases or conditions.
  • therapies which combine administration of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) with the administration of an anti-inflammatory agent.
  • such therapies are used in the treatment of leukotriene-dependent or leukotriene mediated diseases or conditions.
  • provided herein are methods for the treatment of leukotriene-dependent or leukotriene mediated conditions or diseases by administering to a patient Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) and another therapeutic agent that is used in the treatment of respiratory conditions or disorders, such as, but not limited to asthma.
  • compositions, and methods of administering such compositions comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) and a therapeutic agent useful for treating respiratory conditions.
  • Therapeutic agents useful for treating respiratory conditions and disorders include, by way of non-limiting example: glucocorticoids, such as, ciclesonide, beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, fluticasone furoate, mometasone furoate, and triamcinolone leukotriene modifiers, such as, montelukast, zafirlukast, pranlukast, and zileuton; mast cell stabilizers, such as, cromoglicate (cromolyn), and nedocromil; antimuscarinics/anticholinergics, such as, ipratropium, oxitropium, and tiotropium; methylxanthines, such as, theophylline and aminophylline; antihistamines, such as, mepyramine (pyrilamine), antazoline, diphenhydramine, carbinoxamine, doxylamine, clemastine
  • Compound 1, or a pharmaceutically acceptable salt thereof is used in combination with one or more other therapeutic agents or the pharmaceutical compositions of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M 1 /M 2 /M 3 receptor antagonist), ⁇ 2 -adrenoreceptor agonists, antiinfective agents, or antihistamines.
  • antiinfective agents include antibiotics and/or antivirals.
  • a combination comprising Compound 1, or a pharmaceutically acceptable salt thereof e.g.
  • Compound 2 includes one or more other therapeutically active agent, where the one or more other therapeutically active agents are selected from an anti-inflammatory agent such as a corticosteroid or an NSAID, an anticholinergic agent, a ⁇ 2 -adrenoreceptor agonist, an antiinfective agent such as an antibiotic or art antiviral, or an antihistamine.
  • an anti-inflammatory agent such as a corticosteroid or an NSAID
  • an anticholinergic agent such as a corticosteroid or an NSAID
  • a ⁇ 2 -adrenoreceptor agonist such as an antibiotic or art antiviral
  • an antihistamine such as an antibiotic or art antiviral
  • One embodiment encompasses combinations comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with a ⁇ 2 -adrenoreceptor agonist, and/or an anticholinergic, and/or a PDE-4 inhibitor, and/or an antihistamine
  • One embodiment encompasses combinations comprising one or two other therapeutic agents, one of which is Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2).
  • the other therapeutic ingredient(s) will be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs (such as esters (e.g. alkyl esters)), or as solvates (e.g. hydrates).
  • the therapeutic ingredients will be used in optically pure form. In another aspect, if appropriate, the therapeutic ingredients will be used in racemic form.
  • ⁇ 2 -adrenoreceptor agonists include salmeterol (as a racemate or a single enantiomer such as the R-enantiomer), satbutamol (as a racemate or a single enantiomer such as the R-enantiomer), formoterol (as a racemate or a single diastereomer such as the R,R-diastereomer), salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol.
  • ⁇ 2 -adrenoreceptor agonists include those described in WO02/066422, WO02/070490, WO02/076933, WO03/024439, WO03/072539, WO03/091204, WO04/016578, WO04/022547, WO04/037807, WO04/037773, WO04/037768, WO04/039762, WO04/039766, WO01/42193 and WO03/042160.
  • ⁇ 2 -adrenoreceptor agonists include: 3-(4- ⁇ [6-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)hexyl]oxy ⁇ butyl)benzenesulfonamide; 3-(3- ⁇ [7-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl ⁇ -amino) heptyl]oxy ⁇ propyl)benzenesulfonamide; 4- ⁇ (1R)-2-[(6- ⁇ 2-[(2,6-dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1-hydroxyethyl ⁇ -2-(hydroxymethyl)phenol; 4- ⁇ (1R)-2-[(6- ⁇ 4-[3-(cyclopentylsulfonyl)phenyl]butoxy ⁇ hexyl)amino]-1-hydroxyethyl
  • the ⁇ 2 -adrenoreceptor agonist is in the form of a salt formed with a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulphamic, suiphanilic, naphthaieneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and 4-phenylbenzoic acid.
  • a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulphamic, suiphanilic, naphthaieneacrylic, benzoic, 4-methoxy
  • Suitable anti-inflammatory agents include corticosteroids.
  • corticosteroids include oral and inhaled corticosteroids and their pro-drugs that have anti-inflammatory activity.
  • examples of corticosteroids include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-1,3-thiazole-5-carbanyl)oxy]-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate), 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -
  • corticosteroids include fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furancarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17 ⁇ -carboxylic acid cyanomethyl ester and 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -
  • the corticosteroid is 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester.
  • corticosteroids include those described in WO 02/088167, WO 02/100879, WO 02/12265, WO 02/12266, WO 05/005451, WO 05/005452, WO 06/072599 and WO 06/072600.
  • Non-steroidal compounds having glucocorticoid agonism that may possess selectivity for transrepression over transactivation and that may be useful in combination therapy include those covered in the following published patent applications and patents: WO 03/082827, WO 98/54159, WO 04/005229, WO 04/009017, WO 04/018429, WO 03/104195, WO03/082787, WO03/082280, WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294, WO04/026248, WO03/061651, WO03/08277, WO06/000401, WO06/000398, WO06/015870, WO06/108699, WO07/000,334, WO07/054,294, WO07/122,165, WO07/144,327 and WO08/074814.
  • anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID's).
  • NSAID's non-steroidal anti-inflammatory drugs
  • NSAID's examples include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (for example, theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (for example montelakast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g.
  • adenosine 2a agonists adenosine 2a agonists
  • cytokine antagonists for example chemokine antagonists, such as a CCR3 antagonist
  • inhibitors of cytokine synthesis or 5-lipoxygenase inhibitors.
  • An iNOS (inducible nitric oxide synthase inhibitor) is preferably for oral administration.
  • iNOS inhibitors include those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875.
  • CCR3 inhibitors include, but are not limited to those disclosed in WO 02/26722.
  • Compound 1, or a pharmaceutically acceptable salt thereof is combined with or administered in combination with a phosphodiesterase 4 (PDE4) inhibitor, especially in the case of a formulation adapted for inhalation.
  • PDE4-specific inhibitor useful in this aspect is any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family, such as PDE3 and PDE5, as well as PDE4.
  • Compounds include cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one and cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol].
  • cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid also known as cilomilast
  • salts, esters, pro-drugs or physical forms which is described in U.S. Pat. No. 5,552,438 issued 3 Sep. 1996; this patent and the compounds it discloses are incorporated herein in full by reference.
  • anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the M or M 3 receptors, dual antagonists of the M 1 /M 3 or M 2 /M 3 , receptors or pan-antagonists of the M 1 /M 2 /M 3 receptors.
  • exemplary compounds for administration via inhalation include ipratropium (for example, as the bromide), oxitropium (for example, as the bromide) and tiotropium (for example, as the bromide).
  • revatropate for example, as the hydrobromide
  • LAS-34273 which is disclosed in WO01/04118.
  • Exemplary compounds for oral administration include pirenzepine, darifenacin (hydrobromide), oxybutynin, terodiline, tolterodine, tolterodine tartrate, otilonium (for example, as the bromide), trospium chloride, solifenacin, and solifenacin succinate.
  • anticholinergic agents include compounds which are disclosed in U.S. patent application 60/487,981 including, for example:
  • Further anticholinergic agents include compounds which are disclosed in U.S. patent application 60/511,009 including, for example: (endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide; 3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionitrile; (endo)-8-methyl-3-(2,2,2-triphenyl-ethyl)-8-aza-bicyclo[3.2.1]octane; 3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide; 3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionic acid; (end
  • Further compounds include; (endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide; (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide; (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide; (endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide; (endo)-3-(2-cyano-2,2-di-thiophen-2-yl-e
  • Compound 1, or a pharmaceutically acceptable salt thereof is combined with or administered in combination with an 141 antagonist.
  • H1 antagonists include, but are not limited to, amelexanox, astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole,
  • Compound 1, or a pharmaceutically acceptable salt thereof is combined with or administered in combination with an H3 antagonist (and/or inverse agonist).
  • H3 antagonist and/or inverse agonist
  • 113 antagonists include, for example, those compounds disclosed in WO 2004/035556, WO 2006/045416, WO 2006/090142, WO 2006/125665, WO 2007/009739 and WO2007/009741.
  • Compound 1, or a pharmaceutically acceptable salt thereof is combined with or administered in combination with an H1/H3 dual antagonist (and/or inverse agonist).
  • H1/H3 dual antagonists include, for example, those compounds disclosed in WO 2004/035556, WO 2007/071691, WO 2007/122156 and WO 2007/135081.
  • Compound 1, or a pharmaceutically acceptable salt thereof is combined with or administered in combination with an H1-H3 dual antagonist selected from 3-(4- ⁇ [4-(4- ⁇ [3-(3,3-dimethyl-1-piperidinyl)propyl]oxy ⁇ phenyl)-1-piperidinyl]carbonyl ⁇ -1-naphthalenyl)propanoic acid and 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1H-azepin-1-yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1(2H)-phthalazinone.
  • H1-H3 dual antagonist selected from 3-(4- ⁇ [4-(4- ⁇ [3-(3,3-dimethyl-1-piperidinyl)propyl]oxy ⁇ phenyl)-1-piperidinyl]carbonyl ⁇ -1-naphthalenyl
  • a combination comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with a PDE4 inhibitor.
  • a combination comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with a ⁇ 2 -adrenoreceptor agonist.
  • a combination comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with a corticosteroid.
  • a combination comprising, Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with another non-steroidal GR agonist.
  • a combination comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with an anticholinergic.
  • a combination comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with an antihistamine.
  • a combination comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with a PDE4 inhibitor and a ⁇ 2 -adrenoreceptor agonist.
  • a combination comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with an anticholinergic and a PDE-4 inhibitor.
  • the individual compounds of such combinations are administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.
  • Appropriate doses of known therapeutic agents will be appreciated by those skilled in the art.
  • compositions together with a pharmaceutically acceptable diluent(s) or carrier(s).
  • composition comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with a PDE4 inhibitor.
  • composition comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with a ⁇ 2 -adrenoreceptor agonist.
  • composition comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with a corticosteroid.
  • composition comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with another non-steroidal GR agonist.
  • composition comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with an anticholinergic.
  • composition comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with an antihistamine.
  • composition comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with a PDE4 inhibitor and a ⁇ 2 -adrenoreceptor agonist.
  • composition comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) together with an anticholinergic and a PDE4 inhibitor.
  • Compound 1, or a pharmaceutically acceptable salt thereof is combined with or administered in combination with one or more agents used to treat used to treat asthma, including, but not limited to: combination Inhalers (fluticasone propionate and salmeterol xinafoate (e.g. Advair), budesonide and formoterol fumarate (e.g.
  • Beta-2 agonists albuterol inhaler; albuterol nebulizer solution; formoterol; isoproterenol oral inhalation; levalbuterol; metaproterenol inhalation; pirbuterol acetate oral inhalation; salmeterol aerosol inhalation; salmeterol powder inhalation; terbutaline inhaler); inhaled corticosteroids (beclomethasone oral inhalation; budesonide inhalation solution; budesonide inhaler; flunisolide oral inhalation; fluticasone inhalation aerosol; fluticasone powder for oral inhalation; mometasone inhalation powder; triamcinolone oral inhalation); leukotriene modifiers (montelukast; zafirlukast; zileuton); mast cell stabilizers (cromolyn inhaler
  • Compound 1, or a pharmaceutically acceptable salt thereof is combined with or administered in combination with one or more agents used to treat allergy, including, but not limited to: antihistamine and decongestant combinations (cetirizine and pseudoephedrine; desloratadine and pseudoephedrine ER; fexofenadine and pseudoephedrine; loratadine and pseudoephedrine); antihistamines (azelastine nasal spray; brompheniramine; brompheniramine oral suspension; carbinoxamine; cetirizine; chlorpheniramine; clemastine; desloratadine; dexchlorpheniramine ER; dexchlorpheniramine oral syrup; diphenhydramine oral; fexofenadine; loratadine; promethazine); decongestants (pseudoephedrine); leukotriene modifiers (montelukast;
  • 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid is combined with or administered in combination with one or more agents used to treat chronic obstructive pulmonary disease (COPD), including, but not limited to anticholinergics—ipratropium bromide oral inhalation); combination inhalers (albuterol and ipratropium (e.g. Combivent, DuoNeb); fluticasone and salmeterol oral inhalation (e.g.
  • COPD chronic obstructive pulmonary disease
  • corticosteroids (dexamethasone tablets; fludrocortisone acetate; hydrocortisone tablets; methylprednisolone; prednisolone prednisone oral; triamcinolone oral); inhaled Beta-2 Agonists (albuterol inhaler; albuterol nebulizer solution; formoterol; isoproterenol oral inhalation; levalbuterol; metaproterenol inhalation; pirbuterol acetate oral inhalation; salmeterol aerosol inhalation; salmeterol powder inhalation; terbutaline inhaler); inhaled Corticosteroids (beclomethasone oral inhalation; budesonide inhalation solution; budesonide inhaler; flunisolide oral inhalation; fluticasone inhalation aerosol; fluticasone powder for oral inhalation; triamcinolone oral inhalation); mukolytics (guamethasone
  • Compound 1, or a pharmaceutically acceptable salt thereof is combined with or administered to a patient in combination with norastemizole. In one embodiment. Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) is combined with or administered to a patient in combination with loratadine. In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) is combined with or administered to a patient in combination with desloratadine. In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) is combined with or administered to a patient in combination with terfenadine.
  • Compound 1, or a pharmaceutically acceptable salt thereof is combined with or administered to a patient in combination with cetirizine. In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) is combined with or administered to a patient in combination with ( ⁇ )-cetirizine. In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) is combined with or administered to a patient in combination with (+)-cetirizine.
  • Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) is combined with or administered to a patient in combination with inhaled corticosteroids.
  • Compound 1, or a pharmaceutically acceptable salt thereof is combined with or administered to a patient in combination with beta2-adrenergic receptor agonists. In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) is combined with or administered to a patient in combination with short acting beta2-adrenergic receptor agonists. In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) is combined with or administered to a patient in combination with long-acting beta2-adrenergic receptor agonists.
  • Compound 2 is used. In more specific embodiments, Compound 2 is in Form C. In other specific embodiments, Compound 2 is in either Phase A or Solvated Form B.
  • Compound 1 (free acid) is used.
  • Compound 1 is in crystalline form.
  • Compound 1 is in amorphous phase.
  • methods for treatment of leukotriene-dependent or leukotriene mediated conditions or diseases includes administering to a patient Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) in combination with leukotriene receptor antagonists including, but are not limited to, CysLT 1 /CysLT 2 dual receptor antagonists, and CysLT 1 receptor anatagonists.
  • leukotriene receptor antagonists including, but are not limited to, CysLT 1 /CysLT 2 dual receptor antagonists, and CysLT 1 receptor anatagonists.
  • CysLT 1 /CysLT 2 dual receptor antagonists include, but are not limited to, BAY u9773, Cuthbert et al EP 00791576 (published 27 Aug.
  • the most appropriate formulation or method of use of such combination treatments depends on the type of leukotriene-dependent or leukotriene mediated disorder, the time period in which Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) acts to treat the disorder and the time period in which the CysLT 1 /CysLT 2 dual receptor antagonist acts to inhibit CysLT receptor activity.
  • Compound 1 or a pharmaceutically acceptable salt thereof (e.g. Compound 2) acts to treat the disorder
  • the CysLT 1 /CysLT 2 dual receptor antagonist acts to inhibit CysLT receptor activity.
  • such combination treatments are used for treating a patient suffering from a respiratory disorder.
  • methods for treatment of leukotriene-dependent or leukotriene mediated conditions or diseases includes administered to a patient compounds, pharmaceutical compositions, or medicaments described herein in combination with a CysLT 1 receptor antagonist.
  • CysLT 1 receptor antagonists include, but are not limited to, zafirlukast, montelukast, prankulast, and derivatives or analogs thereof in one embodiment, such combinations are used to treat leukotriene-dependent or leukotriene mediated disorder, including respiratory disorders.
  • the co-administration of Compound 1, or a pharmaceutically acceptable salt thereof (e.g, Compound 2) with a CysLT 1 receptor antagonist or a dual CysLT 1 /CysLT 2 receptor antagonist has therapeutic benefit over and above the benefit derived from the administration of either Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) or a CysLT 1 R antagonist alone.
  • Compound 1 or a pharmaceutically acceptable salt thereof (e.g. Compound 2) or a CysLT 1 R antagonist alone.
  • partial inhibition of this pathway through the amelioration of the effects of the proinflammatory LTB 4 and cysteinyl leukotrienes combined with the block of the CysLT 1 receptor and/or dual CysLT 1 /CysLT 2 receptor block affords substantial therapeutic benefits, particularly for respiratory diseases.
  • compositions comprising and methods of administering compositions comprising Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), and an anti-inflammatory agent.
  • Anti-inflammatory agents include, by way of non-limiting example, non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids (glucocorticoids).
  • NSAIDs include, but are not limited to aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal carprofen, fenoprofen, fertoprofen calcium, fluorobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, COX-2 specific inhibitors (such as, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumirac
  • Corticosteroids include, but are not limited to: betamethasone (Celestone), prednisone Deltasone), alclometasone, aldosterone, amcinonide, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacort, deoxycorticosterone, desonide, desoximetasone, desoxycortone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone, fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluorinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, flupredniden
  • Corticosteroids do not directly inhibit leukotriene production, therefore co-dosing with steroids, in one embodiment, provide additional anti-inflammatory benefit.
  • methods for treatment of leukotriene-dependent or leukotriene mediated conditions or diseases include administering to a patient Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) in combination with an anti-inflammatory agent including, but not limited to poly-unsaturated fatty acids (PUFAs) such as docosahexanoic acid (DHA), eicosapentanoic acid (EPA) and alpha-linolenic acid (ALA).
  • PUFAs poly-unsaturated fatty acids
  • DHA docosahexanoic acid
  • EPA eicosapentanoic acid
  • ALA alpha-linolenic acid
  • the leukotriene-dependent or leukotriene mediated condition or disease involves eosinophilic, basophilic, and at mast cell inflammation.
  • the eosinophilic, basophilic, and/or mast cell inflammation is pulmonary inflammation.
  • the pulmonary inflammation is the result of a chronic inflammatory condition.
  • the chronic inflammatory disease is characterized by pulmonary inflammation and airway hyperresponsiveness, e.g., asthma.
  • leukotriene-dependent or leukotriene mediated condition or disease is asthma, wherein leukotrienes may be released from mast cells, eosinophils, and/or basophils.
  • the leukotrienes are involved in contraction of airway smooth muscle, an increase in vascular permeability and mucus secretions, and have been reported to attract and activate inflammatory cells in the airways of asthmatics.
  • the methods for treatment of respiratory diseases include administering to a patient Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) either alone or in combination with an anti-inflammatory agent.
  • methods for treatment of leukotriene-dependent or leukotriene mediated conditions or diseases include administering to a patient Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) in combination with NSAIDs and NO-donors or NSAIDs and proton-pump inhibitors.
  • a pharmaceutically acceptable salt thereof e.g. Compound 2
  • compositions comprising such agents and methods of administering such compositions.
  • Compound 1, or a pharmaceutically acceptable salt thereof is combined with or administered in combination with one or more agents that are inhibitors of UDP-glucuronosyltransferase (UGT).
  • UGT inhibitors include those described in U.S. 2003/0215462; U.S. 2004/0014648.
  • co-administration of a UGT inhibitor allows for lower doses of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) to be administered.
  • the screening of “leukotriene-responsive patients” which are selected for treatment with Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), or pharmaceutical compositions or medicaments described herein, is accomplished using techniques and methods described herein.
  • Such techniques and methods include, by way of example, evaluation of gene haplotypes (genotype analysis), monitoring/measurement of biomarkers (phenotype analysis), monitoring/measurement of functional markers (phenotype analysis), which indicate patient response to modulators of the leukotriene pathway, or any combination thereof.
  • Human FLAP has been purified and cloned and is an 18 kilodalton membrane-bound protein which is most highly expressed in human neutrophils.
  • the FLAP gene is located at 13q12 and the gene has been linked to increased risk for both myocardial infarction and stroke in several populations.
  • a number of polymorphisms and haplotypes in the gene encoding FLAP have been identified in individuals (U.S. Patent Application 2005113408; Sayers, Chin. Exp. Allergy, 33(8):1103-10, 2003; Kedda, et al., Clin. Exp. Allergy, 35(3):332-8, 2005). In some cases polymorphisms in certain genes have been demonstrated to correlate with responsiveness to given therapies.
  • patients who are under consideration for treatment with Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), or drug combinations that include Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2) are screened for potential responsiveness to treatment based on their FLAP polymorphisms, or haplotypes (sec also WO 99/052942, herein incorporated by reference).
  • polymorphisms in any of the synthetic or signaling genes dedicated to the leukotriene pathway could result in a patient who is more responsive or less responsive to leukotriene modulator therapy (either FLAP or 5-LO inhibitor or leukotriene receptor antagonists).
  • the genes dedicated to the leukotriene pathway are 5-lipoxygenase, 5-lipoxygenase-activating protein, LTA 4 hydrolase, LTC 4 synthase, LTB 4 receptor 1 (BLT 1 ).
  • LTB 4 receptor 2 (BLT 2 ) cysteinyl leukotriene receptor I (CysLT 1 R), cysteinyl leukotriene receptor 2 (CysLT 2 R).
  • the 5-LO gene has been linked to aspirin intolerant asthma and airway hyperresponsiveness (Choi J H et al. Hum Genet 114:337-344 (2004); Kim, S H et al. Allergy 60:760-765 (2005). Genetic variants in the promoter region of 5-LO have been shown to predict clinical responses to a 5-LO inhibitor in asthmatics (Drazen et al, Nature Genetics, 22, p 168-170, (1999).
  • the LTC 4 synthase gene has been linked to atopy and asthma (Moissidis I et al. Genet Med 7:406-410 (2005).
  • the CysLT 2 receptor has been linked to asthma and atopy (Thompson M D et al.
  • selection of patients who best respond to the leukotriene modulator therapies described herein is based, in part, on knowledge of polymorphisms in the leukotriene pathway genes and also knowledge of the expression of leukotriene-driven mediators.
  • patient selection is made on the basis of leukotriene pathway genotype alone, phenotype alone (biomarkers or functional markers) or any combination of genotype and phenotype.
  • detecting haplotypes is accomplished by methods for detecting sequences at polymorphic sites, and therefore patients are selected using genotype selection of FLAP, 5-LO or other leukotriene pathway gene polymorphisms.
  • the presence or absence of a leukotriene pathway gene polymorphism or haplotype is determined by various methods, including, for example, using enzymatic amplification, restriction fragment length polymorphism analysis, nucleic acid sequencing, electrophoretic analysis of nucleic acid from the individual, or any combination thereof.
  • determination of a SNP or haplotype identifies patients who will respond to, or gain benefit from, treatment with a FLAP inhibitor.
  • methods of diagnosing a susceptibility to myocardial infarction or stroke in an individual comprises determining the presence or absence of certain single nucleotide polymorphisms (SNPs) or of certain haplotypes, wherein the presence of the SNP or the haplotype is diagnostic of susceptibility to myocardial infarction or stroke.
  • SNPs single nucleotide polymorphisms
  • patients who are under consideration for treatment with Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), or drug combinations thereof, are screened for potential responsiveness to treatment based on leukotriene-driven inflammatory biomarker phenotypes.
  • biomarker refers to a characteristic which is measured and evaluated as an indicator of normal biological processes, pathological processes, or pharmacological responses to therapeutic intervention.
  • a biomarker is any substance, structure or process which is measured in the body, or its products, and which influences or predicts the incidence of outcome or disease.
  • Biomarkers are classified into markers of exposure, effect, and susceptibility. Biomarkers are physiologic endpoints, by way of example blood pressure, or they are analytical endpoints, by way of example, blood glucose, or cholesterol concentrations.
  • Techniques, used to monitor and/or measure biomarkers include, but are not limited to, NMR, LC-MS, LC-MS/MS, GC-MS, GC-MS/MS, HPLC-MS, HPLC-MS/MS, FT-MS, FT-MS/MS, ICP-MS, ICP-MS/MS, peptide/protein sequencing, nucleic acid sequencing, electrophoresis techniques, immuno-assays, immuno-blotting, in-situ hybridization, fluorescence in-situ hybridization, PCR, radio-immuno assays, and enzyme-immuno assays.
  • Single nucleotide polymorphisms have also been useful for the identification of biomarkers for propensity to certain diseases and also susceptibility or responsiveness to drugs such as chemotherapeutic agents and antiviral agents.
  • these techniques, or any combination thereof are used to screen patients for leukotriene-dependent or leukotriene mediated diseases or conditions, wherein such patients are beneficially treated with Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), or drug combinations described herein.
  • patients are selected for treatment with Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), or drug combinations described herein by screening for enhanced inflammatory blood biomarkers such as, but not limited to stimulated LTB 4 , LTC 4 , LTE 4 , myeloperoxidase (MPO), eosinophil peroxidase (EPO), C-reactive protein (CRP), soluble intracellular adhesion molecule (sICAM), monocyte chemoattractant protein (MCP-1), monocyte inflammatory protein (MIP-1 ⁇ ), interleukin-6 (IL-6), the TH2 T cell activators interleukin 4 (IL-4), and 13 (IL-13) and other inflammatory cytokines.
  • MPO myeloperoxidase
  • EPO eosinophil peroxidase
  • CRP C-reactive protein
  • sICAM soluble intracellular adhesion molecule
  • MCP-1 monocyte chemoattractant protein
  • MIP-1 ⁇ mon
  • patients with inflammatory respiratory diseases including but not limited to, asthma and COPD, are selected as those most likely to be responsive to leukotriene synthesis inhibition using Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), by using a panel of leukotriene driven inflammatory biomarkers.
  • Compound 1 or a pharmaceutically acceptable salt thereof (e.g. Compound 2), by using a panel of leukotriene driven inflammatory biomarkers.
  • patients who are under consideration for treatment with Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), or drug combinations described herein are screened for response to known modulators of the leukotriene pathway.
  • patient screening by evaluation of functional markers as indicators of a patient's response to known modulators of the leukotriene pathway are used as an alternative to or it is complimentary with, patient screening by leukotriene pathway gene haplotype detection (genotype analysis) and/or monitoring/measurement of leukotriene-driven inflammatory biomarker phenotypes.
  • Functional markers include, but are not limited to any physical characteristics associated with a leukotriene dependent condition or disease, or knowledge of current or past drug treatment regimens.
  • lung function tests are used to screen patients, with such leukotriene-dependent or leukotriene mediated diseases or conditions, for treatment using Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), or pharmaceutical compositions or medicaments thereof.
  • Such tests include, but are not limited to, evaluation of lung volumes and capacities, such as tidal volume, inspiratory reserve volume, expiratory reserve volume, residual volume, inspiratory capacity, functional residual capacity, vital capacity, total lung capacity, respiratory minute volume, alveolar ventilation, timed vital capacity, and ventilatory capacity.
  • Method of measurement of lung volumes and capacities include, but are not limited to, maximum expiratory flow volume curve, forced expiratory volume in 1 sec. (FEV1), peak expiratory flow rate.
  • other lung function tests used as functional markers for patient evaluation described herein include, but are not limited to, respiratory muscle power, maximum inspiratory pressure, maximum expiratory pressure, transdiaphragmatic pressure, distribution of ventilation, single breath nitrogen test, pulmonary nitrogen washout, and gas transfer.
  • the knowledge of a patients past or current treatment regimen is used as a functional marker to assist in screening patients for treatment of leukotriene dependent conditions or diseases using Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), or pharmaceutical compositions or medicaments thereof.
  • such treatment regimens include past or current treatment using zileuton, montelukast, pranlukast, zafirlukast.
  • Compound 1 or a pharmaceutically acceptable salt thereof (e.g. Compound 2), or drug combinations described herein, are screened for functional markers which include, but are not limited to, reduced eosinophil and/or basophil, and/or neutrophil, and/or monocyte and/or dendritic cell and/or lymphocyte recruitment, decreased mucosal secretion, decreased mucosal edema, and/or increased bronchodilation.
  • functional markers include, but are not limited to, reduced eosinophil and/or basophil, and/or neutrophil, and/or monocyte and/or dendritic cell and/or lymphocyte recruitment, decreased mucosal secretion, decreased mucosal edema, and/or increased bronchodilation.
  • a patient sample is analyzed for leukotriene gene haplotypes, by way of example only FLAP haplotypes, and the information obtained identifies a patient in need of treatment using various treatment methods.
  • treatment methods include, but are not limited to, administering a therapeutic effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), or pharmaceutical composition or medicament thereof, alone or in combination with a therapeutic effective amount of a leukotriene receptor antagonist (by way of example, CysLT 1 /CysLT 2 antagonist or CysLT 1 antagonist).
  • a patient sample is analyzed for leukotriene gene haplotypes, by way of example only FLAP haplotypes, and/or phenotype biomarkers, and/or phenotype functional marker responses to leukotriene modifying agents.
  • the patient is then treated using various treatment methods.
  • treatment methods include, but are not limited to, administering a therapeutic effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e, g. Compound 2), or pharmaceutical composition or medicament thereof, alone or in combination with a therapeutic effective amount of a leukotriene receptor antagonist (by way of example, CysLT 1 /CysLT 2 antagonist or CysLT 1 antagonist), or another anti-inflammatory agent.
  • a patient sample is analyzed for leukotriene gene haplotypes, by way of example only, FLAP haplotypes, and phenotype biomarkers, and phenotype functional marker responses to leukotriene modifying agents.
  • the patient is then treated using various treatment methods.
  • Such treatment methods include, but are not limited to, administering a therapeutic effective amount of a FLAP inhibitor, or pharmaceutical composition or medicament which includes a FLAP inhibitor, administering a therapeutic effective amount of a FLAP inhibitor, or pharmaceutical composition or medicament which includes a FLAP inhibitor, in combination with a therapeutic effective amount of a leukotriene receptor antagonist (by way of example, CysLT 1 /CysLT 2 antagonist or CysLT 1 antagonist), or administering a therapeutic effective amount of a FLAP inhibitor, or pharmaceutical composition or medicament which includes a FLAP inhibitor, in combination with a therapeutic effective amount of another anti-inflammatory agent.
  • a leukotriene receptor antagonist by way of example, CysLT 1 /CysLT 2 antagonist or CysLT 1 antagonist
  • kits and articles of manufacture are also described herein.
  • Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers are formed from a variety of materials such as glass or plastic.
  • Packaging materials for use in packaging pharmaceutical products include, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.
  • Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • a wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease, disorder, or condition that would benefit by inhibition of FLAP, or in which FLAP is a mediator or contributor to the symptoms or cause.
  • the container(s) include Compound 1, or a pharmaceutically acceptable salt thereof (e.g. Compound 2), optionally in a composition or in combination with another agent as disclosed herein.
  • Such kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.
  • a kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
  • a label is on or associated with the container.
  • a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
  • the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.
  • the pack for example, contains metal or plastic foil, such as a blister pack.
  • the pack or dispenser device is accompanied by instructions for administration.
  • the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • compositions described as comprising a pharmaceutically acceptable salt described herein encompass pharmaceutical compositions comprising the associated and/or disassociated forms of the salt.
  • a pharmaceutical composition described herein comprising an aqueous solution of Compound 2 encompasses a composition comprising a population of sodium cations and a population of 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate anions.
  • compositions that include a Compound 1, or a pharmaceutically acceptable salt and/or solvate thereof, and pharmacokinetic profiles and pharmacodynamic effects thereof.
  • Compound 1 is optionally prepared as outlined in US 2007/0105866, or as outlined herein.
  • Step 1-1 Synthesis of 2,5-Dimethyl-pyridine 1-oxide
  • 2,5-Lutidine 1419 g was dissolved in chloroform (13.51) and cooled to below 10° C.
  • m-Chloroperoxybenzoic acid 70%, 3354.21 g was added portion-wise to maintain the temperature at below 10° C., and then the reaction was warmed to room temperature and stirred overnight.
  • aqueous 20% sodium hydroxide 2.5 L to 3 L
  • the mixture was stirred for 30 minutes and then allowed to separate.
  • Step 1-2 Synthesis of (5-Methyl-pyridin-2-yl)-methanol
  • Step 2-1 Synthesis of 4-Chloro-2,2-dimethyl-pent-4-enoic acid ethyl ester
  • Diisopropylamine (1.25 eq) was added to a reaction flask containing THF (10.0-fold, V/W of ethyl isobutyrate) under N 2 .
  • the mixture was cooled to less than ⁇ 70° C., and n-butyllithium (2.7M; 1.14 eq) was added to the reaction mixture while the temperature was maintained at less than ⁇ 65° C.
  • the reaction mixture was slowly warmed to room temperature and then stirred for 2 hours under N 2 .
  • reaction mixture was then cooled to less than ⁇ 70° C., and ethyl isobutyrate (1.0 eq) was added, followed by 2,3-dichloro-1-propene (1.09 eq), while the temperature was maintained at less than ⁇ 70° C.
  • the reaction was allowed to warm to room temperature and stirred overnight under N 2 .
  • the reaction was then quenched with ice water (10.0-fold, V/W of starting material), and the pH adjusted to pH 7 with aqueous 6M HCl.
  • the organic layer was separated, washed twice with brine, and dried over Na 2 SO 4 .
  • the solvent was removed in vacuo and the product was taken on to the next step without further purification.
  • Step 2-2 Synthesis of 5-Bromo-2,2-dimethyl-4-oxo-pentanoic acid ethyl ester
  • the organic layer (on the bottom) was separated, with the aqueous layer was extracted with CH 2 Cl 2 until no product was seen in the aqueous layer.
  • the combined organic layers were then washed with aqueous 5% Na 2 CO 3 (6-fold, V/W of starting material) and brine (3.0-fold, V/W of starting material).
  • the organic layer was dried over Na 2 SO 4 and concentrated in vacuo to give the desired product.
  • Step 2-3 Synthesis of 5-tert-Butylsulfanyl-2,2-dimethyl-4-oxo-pentanoic acid ethyl ester
  • Step 3-1 Synthesis of N-(4-Bromo-benzyl)-N-(4-methoxy-phenyl)-hydrazine Hydrochloride
  • the mixture was filtered to collect the solid product, which was subsequently washed with toluene and dried under vacuum at 60-65° C.
  • EtOAc (10.0-fold, V/W of starting material) was then added to the product and the mixture was agitated well.
  • the pH of the solution was adjusted to pH 2 with saturated HCl/EtOAc solution and further agitated for 1 hour.
  • the solid was then collected by filtration, washed with cold EtOAc, and air dried. The product was taken on to the next step without further purification.
  • Step 3-2 Synthesis of 3-[1-(4-Bromo-benzyl)-3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester
  • N-(4-Bromo-benzyl)-N-(4-methoxy-phenyl)-hydrazine hydrochloride (1.0 eq) was added to a reaction flask containing toluene (10.0-fold, V/W of starting material) under N 2 .
  • Acetic acid (5.0-fold, V/W of starting material) was added, followed by 5-tert-butylsulfanyl-2,2-dimethyl-4-oxo-pentanoic acid ethyl ester (1.05 eq) and sodium acetate (2.3 eq), and the reaction mixture was stirred at room temperature for 4 days.
  • Step 3-3 Synthesis of 3-[1-(4-Bromo-benzyl)-3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester
  • the flask was gradually cooled to 0-2° C., and hexane (11.0-fold, V/W of starting material) was slowly added. The mixture was agitated for 2 hours, and the precipitate was isolated by filtration and dried under vacuum to give the desired product.
  • Step 3-4 Synthesis of 3-[3-tert-Butylsulfanyl-5-hydroxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester
  • Step 3-5 Synthesis of 3- ⁇ 3-tert-Butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-hydroxy-1H-indol-2-yl ⁇ -2,2-dimethyl-propionic acid ethyl ester
  • the mixture was agitated for 2 minutes and then allowed to separate over 1 hour, with additional EtOAc (1.4 L) added to facilitate phase separation.
  • the aqueous layer was separated, and the two aqueous layers were combined.
  • EtOAc (5.0 L) was added to the combined aqueous layer, and the mixture was agitated for 3 minutes and allowed to separate over 2 minutes.
  • the aqueous layer was separated, and the two organic layers were combined and treated with activated carbon, Novit Neutral (446.43 g).
  • the mixture was stirred for 17 hours at room temperature, and then filtered through a 1-2′′ pad of Celite.
  • the reaction flask was rinsed twice with EtOAc (1.25 L) and filtered through the pad of Celite, and the filtrate was concentrated to give the crude material.
  • Step 3-6 Synthesis of 3-[3-tert-Butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester
  • the mixture was agitated for 6 minutes and allowed to separate over 5 minutes.
  • the organic layer was separated, and the two organic layers were combined and treated with activated carbon, Novit Neutral (433.07 g) and silica gel, thiol derivatized (91.17 g).
  • the mixture was stirred for 17 hours at room temperature, and then filtered through a 1-2′′ pad of Celite.
  • the flask was rinsed with CH 2 Cl 2 (2.6 L) and filtered through the pad of Celite, and the filtrate was concentrated to give the crude material.
  • EtOH (9.2 L) was added to the solids, and the mixture was stirred slowly for 17 hours and filtered.
  • the isolated solids were dried in a drying oven at 45° C. under vacuum for 2 days to give the desired product (1459.4 g).
  • Step 3-7 Synthesis of 3-[3-tert-Butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, sodium salt
  • Step 3-8 Polymorph Control of 3-[3-tert-Butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, sodium salt
  • Form B is obtained from MTBE solutions wherein a protic co-solvent (such as for example H 2 O or EtOH) is also present during the crystal formation (whether by a crystallization, solid-to-solid transformation or crystalline inter-conversion) event.
  • a protic co-solvent such as for example H 2 O or EtOH
  • the protic co-solvent is present in the MTBE solvent.
  • the protic co-solvent is carried forward from the hydrolysis reaction (i.e. hydrolysis of the ester).
  • Form C is obtained by ensuring removal (dehydration) of any protic co-solvents during the isolation from MTBE.
  • the use of a re-suspension of the crude final material along with heating in anhydrous MTBE is intended to ensure that protic solvents are removed (thereby pushing the crystal form to form C).
  • form B can be converted to form C through the suspension/heating in anhydrous MTBE (with the crystalline inter-conversion presumably proceeding through a process of dehydration).
  • Amorphous Phase A (50 mg) was dissolved in 200 ul of isopropyl alcohol with controlled heating. The resulting solution was left to cool down to room temperature, with crystals forming after about an hour. Both the XRPD pattern and the DSC thermogram of the isolated crystals matched that of crystalline form B.
  • Amorphous Phase A is chemically stable, amorphous and hygroscopic. Hygroscopicity was assessed by GVS, and the amorphous material adsorbed more than 20% of water at 90% RH. The TGA for the amorphous material showed a weight loss of 4.6% at low temperatures and the DSC experiment showed a phase change to the more stable crystalline form.
  • Polymorph Form B is crystalline, solvated with MTBE and H 2 O, and is physically and chemically stable.
  • the melting point range for Form B is 130-170° C.
  • the DSC for Form B showed a phase change to a more stable form.
  • Form B converts to Form C upon heating.
  • GVS experiments show that Form B is a hygroscopic material, taking up to more than 30% of water at 90% RH after a full sorption/desorption cycle.
  • Polymorph Form C is physically and chemically stable (5° C., 25° C./60% RH and 40° C./75% RH for at least one month), crystalline and desolvated.
  • the melting point range for Form C is 295-300° C.
  • Form C reversibly adsorbed ⁇ 9% water at 90% relative humidity and is, therefore, considered to be nonhygroscopic.
  • Form C did not show any weight loss in the TGA prior to degradation and only a melt in the DSC thermogram.
  • Oral dosing in rats of both Amorphous Phase A and polymorph Form C provided equivalent plasma exposures.
  • Crystals obtained from acetonitrile have an XRPD pattern which correlates with the XRPD pattern of Form C.
  • the crystals obtained from isopropanol or dimethylsulfoxide showed different crystalline patterns.
  • the crystals obtained from isopropanol have an XRPD pattern which correlates with the XRPD pattern for Form B.
  • the DSC thermograms for both materials also match.
  • Samples were prepared as 1000 ppm stocks in water. Where sample solubility was low, a suitable solvent such as dimethylsulfoxide was used. Samples were diluted to 50 ppm or 100 ppm with an appropriate solvent prior to testing. Quantification was achieved by comparison with standard solutions of known concentration of the ion being analysed.
  • the stoichiometry of the sodium salts was determined by ion chromatography to be about 1:1.
  • Aqueous solubility was determined by suspending sufficient compound in water to give a maximum final concentration of ⁇ 10 mg ⁇ ml ⁇ 1 of the parent free-form of the compound. The suspension was equilibrated at 25° C. for 24 hours then the pH was measured. The suspension was then filtered through a glass fibre C filter into a 96 well plate. The filtrate was then diluted by a factor of 101. Quantitation was by HPLC with reference to a standard solution of approximately 0.1 mg ⁇ ml ⁇ 1 in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection.
  • HPLC protocol is set forth in Table 3.
  • the solubility in water for both batches of Compound 2 is greater than 10 mg ⁇ ml ⁇ 1 .
  • the pH of the unfiltered saturated solution is above 9 for both materials.
  • the pH of the resultant solution was measured, and the solubility was calculated by HPLC-UV assay of the compound concentration in solution.
  • Aqueous solubility shows the lowest values at about pH 3-7. In this range of pH the compound is present in its neutral form. When the pH is very acidic (pH 1-2) the mildly basic groups can be protonated, and so the solubility increases slightly, although possibly not as much as expected. At basic pH (pH>8) solubility starts increasing markedly, to reach its peak at pH greater than 10, when only the corresponding sodium carboxylate is present in the solution.
  • Table 6 provides solubility data for Compound 2 in various organic solvents.
  • Compound 2 is very soluble in methanol and ethanol and sparingly soluble in acetonitrile and isopropanol.
  • X-Ray powder diffraction patters collected on a Siemens D5000 use CuK ⁇ radiation (40 kV, 40 mA), 0-0 goniometer, divergence of V20 and receiving slits, a graphite secondary monochromator, and a scintillation counter.
  • the instrument was performance checked using a certified Corundum standard (NIST 1976). Samples run under ambient conditions were prepared as flat plate specimens. Approximately 35 mg of sample was gently packed into a ca it cut into polished, zero-background (510) silicon wafer. The sample was rotated in its own plane during analysis. The details of the data collection are: (1) angular range: 2 to 4220; step size: 0.05°20; collection time 4 s/step.
  • X-Ray powder diffraction patients Obtained on a Bruker AXS C2 GADDS diffractometer use CuK ⁇ radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for auto-sample positioning and a FriStar 2-dimensional area detector.
  • X-ray optics consists of a single Gobel multilayer mirror coupled with a pinhole collimator of 0.3 mm.
  • the beam divergence, i.e., the effective size of the X-ray beam on a sample of Compound 2 was approximately 4 mm.
  • a ⁇ - ⁇ continuous scan mode was employed with a sample—detector distance of 20 cm which gives an effective 2 ⁇ range of 3.2°-29.7°.
  • sample was exposed to the X-ray beam for 120 seconds. Samples run under ambient conditions were mounted as date plate specimens. Approximately 1-2 mg of sample was lightly pressed on a glass slide to obtain a flat surface, Samples run under non-ambient conditions were mounted on a silicon wafer with heat-conducting compound. The sample was then heated to the appropriate temperature at about 10° C./min and subsequently held isothermally for about 1 minute before data collection was initiated.
  • XRPD patterns of crystals obtained from isopropanol (IPA), dimethylsulfoxide (DMSO) and acetonitrile (MeCN) are shown in FIG. 4 .
  • Crystals obtained from acetonitrile have an XRPD pattern which correlates with polymorph Form C.
  • the crystals obtained from isopropanol or dimethylsulfoxide showed different crystalline patterns.
  • the crystals obtained from isopropanol have an XRPD pattern which correlates with the XRPD pattern for polymorph Form B.
  • the DSC thermograms for both materials also match.
  • FIG. 8 shows the variable temperature XRPD for Amorphous Phase A.
  • the material remains amorphous at temperatures below 180° C. However, at higher temperatures, the material shows a crystalline pattern until it melts, when it becomes amorphous again.
  • FIG. 9 shows a comparison of XRPD of Amorphous Phase A at high temperatures is with XRPD of Form C.
  • the new crystalline pattern for Amorphous Phase A at 230° C. and 280° C. matches the one for Form C.
  • the differences in the shift of the peaks may be due to a difference in the lattice of the crystal due to thermal expansion.
  • FIG. 10 shows the VT-XRPD of polymorph Form B.
  • Form B is stable at low temperatures. Between 130 and 170° C., a phase change starts occurring. This new crystalline form is stable until it melts at around 300° C. Then, on cooling, the material re-crystallises to produce Form C albeit with lower crystallinity, most likely due to some decomposition occurring.
  • FIG. 11 shows the comparison of the VT-XRPD for Form B with Form C.
  • Form B transforms to Form C upon heating. At 180° C., there is still a mixture of 2 forms, and only above this temperature is there only one form (Form C). This is consistent with the observations extracted from the DSC thermogram for Form B.
  • Amorphous Phase A remains amorphous after a week in the humidity chamber, indicating that no phase change has occurred to a hydrate or otherwise.
  • FIG. 7 One week stability study of polymorph Form C at 40° C. and 75% RH is shown in FIG. 7 .
  • the crystalline pattern for polymorph Form C remains unchanged after a week in the humidity chamber.
  • DSC Differential Scanning Calorimetry
  • TGA Thermo-Gravimetric Analysis
  • DSC data were collected on a TA Instruments Q1000 or a Mettler DSC 823e.
  • DSC data were collected on a TA Instruments Q1000 equipped with a 50 position auto-sampler.
  • the instrument was calibrated for energy and temperature calibration using certified indium. Typically 0, 5-3 mg of each sample, in a pin-holed aluminium pan, was heated at 10° C. ⁇ min ⁇ 1 from 25° C. to 350° C. A nitrogen purge at 50 ml ⁇ min was maintained over the sample.
  • the instrument control software was Thermal Advantage v4.6.6 and the data were analysed using Universal Analysis v4.3A.
  • DSC data were collected on a Mettler DSC 8230 equipped with a 50 position auto-sampler.
  • the instrument was calibrated for energy and temperature using certified indium. Typically 0.5-3 mg of each sample, in a pin-holed aluminium pan, was heated at 10° C. ⁇ min ⁇ 1 from 25° C. to 350° C. A nitrogen purge at 50 ml ⁇ min ⁇ 1 was maintained over the sample.
  • the instrument control and data analysis software was STARe v9.01.
  • TGA data were collected on a Mettler TGA/SDTA 851e equipped with a 34 position auto-sampler.
  • the instrument was temperature calibrated using certified indium. Typically 5-30 mg of each sample was loaded onto a pre-weighed aluminium crucible and was heated at 10° C. ⁇ min ⁇ 1 from ambient temperature to 350° C. A nitrogen purge at 50 ml min ⁇ 1 was maintained over the sample.
  • the instrument control and data analysis software was STARe v9.01.
  • FIG. 12 shows the TGA (top) and DSC (bottom) thermograms for Amorphous Phase A.
  • Amorphous Phase A shows a weight loss of 4.6% at low temperatures. The compound is otherwise stable up to temperatures above 300° C.
  • the DSC three endothermic events are observed and one exothermic phase change. The first event, occurring at 35° C. is associated with the weight loss observed in the TGA. There is another small endotherm at 126° C. followed by an exotherm at 212° C., which likely corresponds to a phase change of the material. The compound then melts at 295° C. These observations are consistent with what was observed by hot-stage microscopy. The DSC experiment showed a phase change to the more stable crystalline form. This point was later confirmed by variable temperature XRPD experiments, and it was further illustrated by hot-stage microscopy.
  • FIG. 13 shows a modulated DSC thermogram for Amorphous Phase A.
  • T g was estimated to be 127° C. (coincidental with the weak endotherm observed in the standard DSC experiment).
  • Another step in the thermogram is observed and the corresponding melt.
  • FIG. 14 shows the results of TGA (top) and DSC (bottom) experiments for polymorph Form B.
  • a weight loss of 4.8% between 80 and 160° C. This could be due to process solvent or to the desolvation of a solvate. Being such a hygroscopic material, the presence of moisture cannot be ruled out.
  • the weight remains constant until the temperature is above 310° C., when decomposition starts.
  • There are some fluctuations on the baseline of the DSC which correlate with the weight losses observed in the TGA.
  • Three more significant events can also be observed. Firstly, a weak endotherm (onset at 158° C.) immediately followed by an exotherm (onset at 173° C.), a phase change and re-crystallisation to a new form.
  • an endothermic event at 297° C., which correlates with the melt of the previous crystalline batch.
  • FIG. 15 shows TGA (top) and DSC (bottom) thermograms for polymorph Form C. No significant weight loss is observed in the TGA experiment for polymorph Form C. The compound starts decomposing at temperatures above 300° C. No events are observed in the DSC thermogram other than a melt at 295° C.
  • Samples were studied on a Leica LM/DM polarised light microscope with a digital video camera for image capture. A small amount of each sample was placed on a glass slide, mounted in immersion oil and covered with a glass slip, the individual particles being separated as well as possible. The sample was viewed with appropriate magnification and partially polarised light, coupled to a X false-colour filter.
  • Amorphous Phase A shows no birefringence at all, which is consistent with the amorphous character of this material. Particles of this material come in different shapes and sizes. Form C appears as clusters of needles of about 40 ⁇ m in diameter. There are, however, some amorphous particles', although the crystalline material constitutes the bulk of this batch.
  • Hot Stage Microscopy was carried out using a Leica LM/DM polarised light microscope combined with a Mettler-Toledo MTFP82HT hot-stage and a digital video camera for image capture. A small amount of each sample was placed onto a glass slide with individual particles separated as well as possible The sample was viewed with appropriate magnification and partially polarised light, coupled to a X false-colour filter, whilst being heated from ambient temperature typically at 10-20° C. ⁇ min ⁇ 1 .
  • Amorphous Phase A undergoes a phase change upon heating.
  • Amorphous Phase A starts melting at around 155° C.; at 200° C. a re-crystallisation occurs.
  • the new crystals start melting at around 288° C. and by 295° C. the material has melted and starts decomposing.
  • Form C only shows a single major event.
  • the particles start melting at temperatures just above 290° C. and by 295° C. all of them have melted, and start decomposing.
  • Sorption isotherms were obtained using a Hiden IGASorp moisture sorption analyser, controlled by CFRSorp software.
  • the sample temperature was maintained at 25° C. by a Huber re-circulating water bath.
  • the humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 250 ml ⁇ min ⁇ 1 .
  • the relative humidity was measured by a calibrated Vaisala RH probe (dynamic range of 0-95% RH), located near the sample.
  • the weight change, (mass relaxation) of the sample as a function of % RH was constantly monitored by the microbalance (accuracy ⁇ 0.001 mg).
  • sample typically 10-20 mg was placed in a tared mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% RH and 25° C. (typical room conditions).
  • a moisture sorption isotherm was performed as outlined below (2 scans giving I complete cycle). The standard isotherm was performed at 25° C. at 10% RH intervals over a 0-90% RH range.
  • the software uses a least squares minimisation procedure together with a model of the mass relaxation, to predict an asymptotic value.
  • the measured mass relaxation value must be within 5% of that predicted by the software, before the next % RH value is selected.
  • the minimum equilibration time was set to 1 hour and the maximum to 4 hours.
  • FIG. 16 shows the GVS diagram for Amorphous Phase A.
  • Amorphous Phase A is a hygroscopic material, taking up to more than 22% of water at 90% RH after a full sorption/desorption cycle. No changes were observed in the XRPD patterns for Amorphous Phase A after the GVS experiment.
  • FIG. 17 shows the GVS diagram for polymorph Form B.
  • Polymorph Form B is a hygroscopic material, taking up to more than 30% of water at 90% RH after a full sorption/desorption cycle. It is even more hygroscopic than the amorphous material.
  • FIG. 18 shows the GVS diagram for Form C.
  • the crystalline form, polymorph Form C is significantly less hygroscopic than the amorphous material, taken up to only 8.2% of water at 90% RH. No changes were observed in the XRPD patterns for polymorph Form C after the GVS experiment.
  • the water content of each sample was measured on a Mettler Toledo DL39 Coulometer using Hydranal Coulomat AG reagent and an argon purge. Weighed solid samples were introduced into the vessel on a platinum TGA pan which was connected to a subaseal to avoid water ingress. Approx 10 mg of sample was used per titration and duplicate determinations were made.
  • the content of water in the amorphous material was determined to be about 5.1% by Coulometric Karl Fisher analysis. This result could explain the weight loss of 4.6% observed in the TGA experiment.
  • the content of water in polymorph Form C was determined to be less than 1% by Coulometric Karl Fisher analysis.
  • the content of water in polymorph Form C was determined to be a detectable amount that is less than 1% by Coulometric Karl Fisher analysis.
  • the content of water in polymorph Form C was determined to be about 0.54%, about 0.56%, or about 0.85% by Coulometric Karl Fisher analysis.
  • the stability indicating method used for the determination of Compound 1 content and content of drug-related impurities is a gradient reversed phase HPLC method utilizing a Waters 150 ⁇ 4.6 mm 3.5 ⁇ m C8 column for separation.
  • the mobile phase is a binary gradient starting with 70% mobile Phase A (0.1% trifluoroacetic acid in water) changing to 30% mobile Phase A.
  • Mobile Phase B consists of 0.1% trifluoroacetic acid in acetonitrile.
  • the sample for analysis is dissolved at a nominal concentration of 0.2 mg/mL in Methanol, and the injection volume for the separation is 10 ⁇ l
  • Detection of the Compound 1 and its related substances is by UV at a wavelength of 260 nm.
  • the specificity, accuracy, linearity (range), precision (system and method), and stability indicating ability of the method were investigated during the method validation process.
  • the results indicate the method to be linear from a concentration of 0.02 mg/mL (10% of nominal) to 0.30 mg/mL ( ⁇ 120% of nominal).
  • the accuracy of the method W as established by injecting samples prepared at 80%, 100%, and 120% of the nominal concentration of 0.2 mg/mL.
  • the results from the accuracy study showed all recoveries to be within 80-120% of theoretical.
  • the stability indicating ability of the method was investigated by injecting samples of Compound 2 forcibly degraded under conditions of acid (0.1N hydrochloric acid), base (0.1N sodium hydroxide), oxidation (10% hydrogen peroxide), and high intensity light (ICH Photostability conditions II). Samples were degraded by a minimum of 10%. No degradant peaks were found to interfere with the main Compound 1 band in the HPLC chromatograms. Therefore, the method demonstrated adequate specificity for use as a stability indicating method.
  • results of the method validation show the method to be suitable for use in release testing and stability testing of Compound 1, or pharmaceutically acceptable salts and/or solvates thereof.
  • Some related impurities in samples containing Compound 2 include, but are not limited to, the following:
  • the total amount of impurities (based on HPLC area) is less than 4%, less than 3.5%, less than 3%, less than 2.5%, less than 2%, less than 1.5%, less than 1%, or less than 0.5%.
  • a sample of Compound 2 described herein has a purity (based on HPLC area) greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 98.2%, greater than 98.98%, greater than 99%, or greater than 99.5%.
  • the test for Residual Solvents is performed to detect trace amounts of solvents used in the synthesis that may be present in the API.
  • the analysis is performed via headspace or direct injection analysis using a gas chromatograph equipped with a flame ionization detector (FID). All residual solvents used in the synthesis are capable of being detected by this method.
  • FID flame ionization detector
  • Potential residual solvents include ethanol, acetonitrile, dichloromethane, methyl-tert-butyl-ether (MTBE), ethyl acetate, tetrahydrofurna, 1,2-dimethoxyethane.
  • ICP-AES inductively coupled plasma atomic emission spectrometry
  • Pd content by ICP-AES is less than about 20 ppm, less than about 15 ppm, less than about 10 ppm, less than about 9 ppm, less than about 8 ppm, less than about 7 ppm, less than about 6 ppm, or less than about 5 ppm.
  • Pd content by ICP-AES is about 10 ppm, about 6 ppm, about 5 ppm, about 4 ppm, about 3 ppm, about 2 ppm, or about 1 ppm.
  • samples or pharmaceutical compositions do not include a detectable amount of palladium.
  • a Nicolet Model 510M-O infrared spectrophotometer equipped with a Harrick internal reflectance nanosampler was used. A small portion of the sample was placed on the internal reflectance nanosampler and a background corrected spectrum from 400 cm ⁇ 1 to 4000 cm ⁇ 1 was collected.
  • Compound 2 was examined for its ability to bind human FLAP using a membrane-binding assay.
  • the affinity of Compound 2 for human FLAP was assessed using membranes from human polymorphonuclear leukocytes and tritiated leukotriene synthesis inhibitor, 3 H-3-[5-(pyrid-2-ylmethoxy)-3-tert-butylthio-1-benzyl-indol-2-yl]-2,2-dimethylpropionic acid, as a ligand.
  • a non-limiting example of such a FLAP binding assay is as follows:
  • Compound 2 was evaluated for its ability to inhibit production of LTB 4 after ionophore stimulation in washed human leukocytes and in human and rat whole blood.
  • a non-limiting example of such a human blood LTB 4 inhibition assay is as follows: Blood was drawn from consenting, human volunteers into heparinized tubes and 125 ⁇ L aliquots added to wells containing 2.5 ⁇ L 50% dimethylsulfoxide (vehicle) or 2.5 ⁇ L drug in 50% dimethylsulfoxide. Samples were incubated for 15 minutes at 37° C.
  • the metabolic profile of Compound 2 was investigated using: (1) rat, dog, monkey, and human hepatic microsomes; (2) rat and human hepatocytes; and (3) bile collected from Sprague-Dawley rats after oral dosing.
  • metabolites which include:
  • Metabolites identified in bile collected from Sprague-Dawley rats after oral dosing include:
  • microsomes were incubated test substrates, which were known to be metabolized by CYP enzymes, with or without Compound 2.
  • Compound 2 was not an inhibitor of P450 (CYP) enzymes according to conversion of substrates to known metabolites with and without Compound 2 in the incubation. No apparent inhibition is observed at concentrations up to and exceeding 40 ⁇ M for CYP3A4, 1A2, 2C9, 2C19, and 2D6 enzymes.
  • CYP P450
  • Compound 2 was not an inducer of P450 CYP3A4 or CYP2C9 in cryopreserved human hepatocytes, according to conversion of substrates to known metabolites with and without Compound 2 in the incubation. Briefly, cryopreserved human hepatocytes thawed and plated according to the manufacturer's instructions (In Vitro Technologies, Gathersburg, Md.). The cells were warmed and then poured into pre-warmed InVitroGRO CP medium, gently resuspended, and then the cells were counted using Trypan Blue exclusion. Cells were then diluted to 0.7 ⁇ 10 ⁇ 6 viable cells/ml with CP medium. Each well received 0.2 ml of the viable cell mixture.
  • the plate was gently shaken to disperse the cells evenly in the well, and the plate was incubated at 37° C., 5% carbon dioxide.
  • medium was replaced with fresh CP medium.
  • CP medium is replaced with HI medium containing Compound 2 tested at 10 ⁇ M, and the positive control, rifampicin was to tested at 25 ⁇ M.
  • Medium was replaced with fresh medium plus test article 24 hrs later.
  • midazolam (50 ⁇ M) and diclofenac (50 ⁇ M) were incubated in 0.15 mL of K-H buffer for 4 hrs.
  • FIG. 20 illustrates the lack of CYP3A4 and 2C9 induction by Compound 2.
  • mice (6/group) received either vehicle, Compound 2 (250 mg/kg), zileuton (250 mg/kg) or APAP (250 mg/kg) daily for 4 days. Twenty-four hours following the final drug administration mice were placed into an enclosed Plexiglas chamber and exposed to CO 2 for a period of 30-60 seconds or until breathing ceased. They were then removed subject to cervical dislocation and blood taken via a cardiac puncture. Mice were next placed in a supine position and a midline incision made. All organs were inspected and the livers removed by careful dissection. Liver weights were recorded as well as any gross abnormalities.
  • compositions that include Compound 1, including pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates thereof include a variety of forms.
  • pharmaceutical compositions were in the form of oral dosage forms.
  • the oral dosage forms were formulated as: oral solutions, oral suspensions, tablets, pills, or capsules.
  • oral aqueous solutions suitable for human use were prepared for oral administration. In one embodiment, oral aqueous solutions were prepared prior to administration.
  • Compound 2 was formulated into solutions suitable for oral administration to a mammal.
  • All components except magnesium stearate were weighed out into a stainless steel container.
  • the powder mixture was passed through a 70-mesh sieve into another SS container.
  • the sieved powder was then transferred to a V-blender with an intensifying bar: (Peterson-Kelly Blend Master 17425102Q) and mixed for 30 min.
  • Magnesium stearate was then added into the V-blender and mixed for another 1 minute.
  • the powder blend was collected in a plastic bottle with screw cap. Certain lots were made using a Colton 4-station rotary tablet press with a 10 mm dia round-shaped B-tooling. Other lots were made using a Piccola 10-station rotary tablet press with a new set of 10 mm dia round-shaped B-tooling.
  • the tablet weight and hardness were checked randomly during compression.
  • the defect tablets including “caking”, “chipping”, “sticking to punch”, “off weight” were removed and the total number of tablets yield was calculated.
  • the tablets were stored in a HDPE bottle without desiccant.
  • Disinteuration tests were performed using a USP disentegration apparatus with a Di-water medium, a temperature of 37° C.+/ ⁇ 2° C. at a rate of 29-32 cycles/minute. The average disintegration time measured was 75 seconds with a standard deviation of 7 seconds.
  • Friability 20 tablets were placed in a No. 10 sieve and a soft brush was used to remove loose dust. The weight of the tablets was recorded. The tablets were then placed into a drum of a USP friability apparatus and rotated 100 times at 25 rpm. The tablets were taken out of the drum and any loose dust was removed with a soft brush. The total weight of the tablets was recorded again to calculate percentage weight loss. The weight loss was about 0.17%.
  • Hardness Tablet hardness measurements were performed with a Schleuniger Model 2E/106 tablet tester. The average hardness determined was 8.5 Kp with a standard deviation of 0.8.
  • an immediate release (IR) tablet formulation as described in Table 31 and 32. Manufacturing process will typically be granulation (dry, wet or melt) or direct compression. Example given below is for 50 mg tablets.
  • immediate release capsule formulations examples include those described in Tables 33 and 34.
  • Compound 2 was investigated in fasted and fed female beagle dogs as a suspension and as a 50 mg immediate release (IR) pill. The results are shown in Table 35.
  • AUC area under plasma concentration-time curve
  • C max peak plasma concentration
  • Cl p systemic plasma clearance
  • F % bioavailability calculated from AUC 0- ⁇
  • iv intravenous
  • NA not applicable
  • NC not calculated
  • t 1/2 terminal half-life
  • T max time to peak plasma concentration
  • Vd ss volume of distribution at steady state
  • f female beagle dog
  • Compound 2 shows a decrease in bioavailability (F) and dose-adjusted AUG (52% and 19%; 26 and 13.6 ⁇ g ⁇ hr/mL, respectively) in the fed animals.
  • the IR pill also shows an approximate 30% reduction in oral bioavailability and dose-adjusted AUC when compared to the oral suspension in the fasted or fed comparator dogs.
  • Compound 2 has a slight decrease in oral absorption in the presence of food and the IR pill form.
  • Sample Size (1) Single Dose Phase: eight (8) subjects (6 active, 2 placebo) per dose level; up to 5 dose levels are planned (a total of 40 subjects if all 5 dose levels are completed); and (2) Multiple Dose Phase: eight (8) subjects (6 active, 2 placebo) per dose level; up to 4 dose levels are planned (a total of 32 subjects if all 4 dose levels are completed).
  • Compound 2 was supplied as an oral powder for reconstitution. Placebo solution matched. Compound 2 (10 mg/mL) is prepared in an aqueous solution comprising 1% (w/w) Lutrol L-44 (Poloxamer 124) and 99% (w/w) aqueous sodium carbonate buffer (0.010 M, pH9-10), and with sucralose (as a sweetener, concentration of about 5 mg/100 mL). The placebo differed only in the absence of the active.
  • Dosage and Dose Progression (1) Single Dose Phase: placebo; and Compound 2 doses; (2) Multiple Dose Phase: placebo; and Compound 2 doses per day for eleven (11) days.
  • the following dosing cohorts were used:

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Effective date: 20080602