Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
  • C07D217/24—Oxygen atoms

Definitions

• the present embodiments provide compounds and pharmaceutical compositions useful for the treatment of cancer, such as, for example, 4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2-methylisoquinolin-l-one.
• the present embodiments provide a bromodomain inhibitor
• Compound 1 compound 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- l-one
• Compound 1 compound 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- l-one
• At least one embodiment provides a pharmaceutical composition comprising crystalline Form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl- isoquinolin- l-one.
• the crystalline Form A of 4-[2-(cyclopropyl- methoxy)-5-methylsulfonylphenyl]-2-methyliso-quinolin- l-one exhibits X-ray powder diffraction (XRPD) 2theta (20) reflection peaks at 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6, and 24.5 2 ⁇ .
• XRPD X-ray powder diffraction
• At least one embodiment provides a pharmaceutical composition comprising amorphous 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- l-one.
• the pharmaceutical composition comprises
• a related embodiment provides a pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one to solid matrix polymer is from about 1 : 1 to about 1 :9.
• Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2-methylisoquinolin-l-one to solid matrix polymer is 1: 1.
• Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropyl- methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one to solid matrix polymer is 1:2. Another embodiment provides the pharmaceutical composition wherein the ratio of 4- [2- (cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one to solid matrix polymer is 1:3. Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyliso-quinolin-l-one to solid matrix polymer is 1:4.
• Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one to solid matrix polymer is 1:5. Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- 1-one to solid matrix polymer is 1 :6. Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2- methylisoquinolin-l-one to solid matrix polymer is 1 :7.
• At least one embodiment provides a solid matrix comprising a polyvinyl- pyrrolididone derivative
• At least one embododiment provides a solid matrix comprising a cellulose derivative.
• the cellulose derivative may be at least one of hydroxypropylmethy- cellulose, hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate, or hydroxypropylmethylcellulose acetate succinate.
• Another embodiment provides the pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethycellulose.
• Another embodiment provides the pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethy-cellulose phthalate.
• Another embodiment provides the pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethylcellulose acetate succinate.
• the pharmaceutical composition comprises amorphous the 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one and a solid polymer matrix.
• the pharmaceutical composition comprises a spray dried dispersion of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one, and, optionally, further comprises a solid polymer matrix.
• the pharmaceutical composition comprises micronized 4-[2-(cyclopropylmethoxy)-5-methyl- sulfonylphenyl]-2-methylisoquinolin-l-one, and, optionally, further comprises a solid polymer matrix.
• At least one embodiment provides a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one, wherein the 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one has been prepared by a process comprising spray drying.
• At least one embodiment provides a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one, wherein the 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one has been prepared by a process comprising rapid expansion of supercritical CO2 solution
• At least one embodiment provides a pharmaceutical composition
• a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one and a solid matrix polymer, wherein the 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl- isoquinolin-l-one has been processed by spray drying, and the solid matrix polymer is a polyvinylpyrrolididone derivative.
• At least one embodiment provides a pharmaceutical composition
• a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one and a solid matrix polymer, wherein the 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2- methylisoquinolin-l-one is processed by spray drying, and the solid matrix polymer is a cellulose derivative.
• At least one embodiment provides a medicament for the treatment of cancer, wherein the medicament comprises a pharmaceutical composition comprising 4-[2-(cyclopropyl- methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one, wherein the pharmaceutical composition includes a spray dried dispersion of the 4-[2-(cyclopropylmethoxy)-5-methyl- sulfonylphenyl]-2-methylisoquinolin-l-one, optionally with a solid matrix polymer.
• At least one embodiment provides a medicament for the treatment of cancer, wherein the medicament comprises a pharmaceutical composition comprising 4-[2-(cyclopropylmeth-oxy)-5-methyl- sulfonylphenyl]-2-methylisoquinolin-l-one, wherein the pharmaceutical composition is prepared by a process that includes spray dried dispersion, optionally with a solid matrix polymer.
• the cancer may be nuclear protein in testis (NUT) midline carcinoma (NMC), prostate cancer, breast cancer, bladder cancer, lung cancer, or melanoma.
• the cancer may be Burkitts lymphoma.
• the cancer may be glioblastoma (GBM), basal cell carcinoma, pancreatic, multiple myeloma, or acute myeloid leukemia (AML).
• At least one embodiment provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising 4-[2-(cyclopropyl-methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one, wherein the pharmaceutical composition is prepared by a process that includes spray dried dispersion.
• the cancer is NMC, prostate cancer, breast cancer, bladder cancer, lung cancer, or melanoma.
• the cancer is Burkitts lymphoma.
• the cancer is GBM, basal cell carcinoma, pancreatic, multiple myeloma, or AML.
• FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline Form A of Compound 1.
• FIG. 2 shows an XRPD pattern of amorphous Compound 1.
• FIG. 3 presents data from a differential scanning calorimetry (DSC) experiment for crystalline form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- 1-one (Compound 1).
• FIG. 4 shows data from a gravimetric vapour sorption (GVS)/(DVS) isotherm plot experiment for crystalline form A of Compound 1. ⁇ Cycle 1 Sorp; ⁇ Cycle 1 Desorp;
• FIG. 5 is a bar graph of AUG 0-20hr (hr ng/mL) from a full rat pharmacokinetic (PK) study of crystalline form A of Compound 1. Dosing was PO at 10 mg/kg, 30 mg/kg, 100 mg/kg, or 300 mg/kg.
• FIG. 6 shows data from a 6 hr mouse PK study in which Compound 1 was processed as a spray dried dispersion (SDD) in four different formulations comprising
• FIG. 7 illustrates an XRPD pattern of amorphous Compound 1 in a SDD.
• FIG. 8a illustrates a rat PK study using a SDD comprising Compound 1, showing AUC 0-24hr (hr*ng/mL); dosing by oral administration (PO) at 10 mg/kg, 30 mg/kg, 100 mg/kg, or 300 mg/kg.
• FIG. 8b illustrates a dog PK study using a SDD comprising Compound 1, showing AUC 0-24hr (hr*ng/mL); dosing PO at 1 mg/kg, 3 mg/kg, orlO mg/kg.
• FIG. 9 illustrates plasma exposure levels of Compound 1 in rat after oral administration of various SDD preparations.
• the bromodomain inhibitor compound described herein is a bromodomain 4 (BRD4) inhibitor.
• BRD4 inhibition was observed, in addition to other cancer-related inhibitory activity, in several different cell lines (Raji, human Burkitts lymphoma cells; HL-60, human proleukemia cells; and NCI-H460, human non-small cell lung cancer cells). See U.S. Patent Appl. No. 14/517,705.
• 4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2-methylisoquinolin-l-one or Compound 1 and the like includes crystalline forms, amorphous forms, solvates, hydrates, and pharmaceutically acceptable salts thereof, unless the context requires specificity (e.g., "Form A"); as well as pharmaceutical compositions that include this compound.
• structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms or unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
• Compound 1 may be prepared in various solid forms, including but not limited to, amorphous phase, crystalline forms, milled forms, micronized forms, nano-particulate forms.
• Compound 1 is amorphous.
• Compound 1 is amorphous and anhydrous.
• Compound 1 is crystalline.
• Compound 1 is crystalline and anhydrous.
• Compound 1 is crystalline and milled.
• Compound 1 is crystalline and in a micronized form.
• Compound 1 is amorphous and in a micronized form.
• Compound 1 is crystalline and in a nano-particle form. In some embodiments, Compound 1 is amorphous and dispersed with additional organic materials. In some embodiments, Compound 1 is amorphous and combined with a polymer matrix excipient. In some embodiments, Compound 1 is amorphous and processed by spray- dried dispersion.
• Compound 1 may be in the form of a solvate.
• Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and may be formed during the process of drug substance synthesis or isolation, or drug product formulation or isolation, with pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile, and the like.
• solvents such as water, ethanol, methanol, methyl tert-butyl
• solvates are formed using, but not limited to, Class 3 solvent(s). Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Impurities: Guidelines for Re idual Solvents, Q3C(R5) (February 2011).
• solvates of Compound 1 are anhydrous. Hydrates are particular solvates formed when the solvent is water; and alcoholates are formed when the solvent is alcohol.
• solvates of Compound 1 are hydrates.
• Compound 1 exists in unsolvated form.
• Compound 1 is amorphous.
• amorphous Compound 1 has an X-Ray Powder Diffraction (XRPD) pattern showing a lack of crystallinity.
• FIG. 2 illustrates an XRPD pattern of amorphous Compound 1.
• XRPD X-Ray Powder Diffraction
• One embodiment provides a pharmaceutical composition comprising amorphous 4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2-methylisoquinolin-l-one.
• Compound 1 is crystalline. In some embodiments,
• Compound 1 is crystalline Form A.
• FIG. 1 demonstrates an XRPD pattern of crystalline
• composition comprising crystalline form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2- methylisoquinolin- 1-one.
• One embodiment provides a pharmaceutical composition comprising crystalline Form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- 1-one exhibiting at least one XRPD reflection peak selected from 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6, and 24.5 2 ⁇ .
• One embodiment provides a pharmaceutical composition comprising crystalline Form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- 1-one exhibiting at least two XRPD reflection peaks selected from 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6, and 24.5 2 ⁇ .
• One embodiment provides a pharmaceutical composition comprising crystalline form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one exhibiting at least three XRPD reflection peaks selected from 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6, and 24.5 2 ⁇ .
• One embodiment provides a pharmaceutical composition comprising crystalline form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquino- lin-l-one exhibiting at least four XRPD reflection peaks selected from 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6, and 24.5 2 ⁇ .
• One embodiment provides a pharmaceutical composition comprising crystalline form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- 1-one exhibiting XRPD reflection peaks at 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6, and 24.5 26».
• One embodiment provides a pharmaceutical composition comprising crystalline Form A of 4- [2- (cyclopropylmethoxy)-5 -methylsulfonylphenyl] -2-methylisoquinolin- 1 -one exhibiting the XRPD pattern of FIG. 1.
• crystalline forms of 4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl] -2-methylisoquinolin- 1 -one are prepared as outlined in the Examples. It is noted that solvents, temperatures and other reaction conditions presented herein may vary.
• GMP Good Manufacturing Practice
• Preferred solvents are those that are suitable for use in GMP facilities and consistent with industrial safety concerns. Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Impurities: Guidelines for Residual Solvents, Q3C(R5), (February 2011).
• 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 geno toxicity studies.
• Class 1 solvents for which measurable amounts thereof are avoided in drug products, 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,
• Class 3 solvents which possess low toxicity, include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, feri-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-l-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.
• acetic acid acetone, anisole, 1-butanol, 2-butanol, butyl acetate, feri-butylmethyl
• 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.
• the solvent is a critical parameter in the synthetic process.
• the amount of residual solvent carried over from API to finished drug product may also be considered.
• compositions comprising Compound 1 include an organic solvent(s). In some embodiments, compositions comprising Compound 1 comprise a residual amount or trace amount of an organic solvent(s). In some embodiments, compositions comprising Compound 1 comprise a residual amount of a Class 3 solvent. In some
• 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, i ⁇ ?ri-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate,
• the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, i ⁇ ?ri-butylmethylether, heptane, isopropanol, and ethanol.
• acceptable or “pharmaceutically acceptable”, with respect to a pharmaceutical composition, formulation, or ingredient, means having no persistent detrimental effect on the general health of the subject being treated, does not abrogate the biological activity or properties of the compound, and is considered relatively nontoxic.
• amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
• Bioavailability refers to the percentage of API (e.g., Compound 1) in a dose that is delivered into the general circulation of the animal or human being studied. The total exposure (AUC(o-oo)) of a drug when administered intravenously is usually defined as 100% bioavailable (F%).
• Oral bioavailability refers to the extent to which API (e.g., Compound 1) 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 of Compound 1 in the plasma component of blood of a subject. It is understood that the plasma concentration of Compound 1 may vary significantly between subjects, due to variability with respect to metabolism and/or possible interactions with other therapeutic agents. In accordance with one embodiment disclosed herein, the blood plasma concentration of Compound 1 may vary from subject to subject. Likewise, values such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (T max ), or total area under the plasma concentration time curve (AUC(o-oo)) may vary from subject to subject. Due to this variability, the amount necessary to constitute "a therapeutically effective amount" of Compound 1 may vary from subject to subject.
• an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound 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 including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects.
• An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.
• the term "therapeutically effective amount” includes, for example, a prophylactically effective amount.
• an “effective amount” of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that “an effect amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of Compound 1, 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. By way of example only, therapeutically effective amounts may be determined by routine experimentation, including but not limited to a dose escalation clinical trial.
• the terms “enhance” or “enhancing” means to increase or prolong either in potency or duration a desired effect.
• “enhancing” the effect of therapeutic agents refers to the ability to increase or prolong, either in potency or duration, the effect of therapeutic agents on during treatment of a disease, disorder or condition.
• An “enhancing- effective amount,” as used herein, refers to an amount adequate to enhance the effect of a therapeutic agent in the treatment of a disease, disorder or condition. When used in a patient, amounts effective 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.
• 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.
• a modulator refers to a compound that alters an activity of a molecule.
• a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator.
• a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule.
• an inhibitor completely prevents one or more activities of a molecule.
• a modulator is an activator, which increases the magnitude of at least one activity of a molecule.
• the presence of a modulator results in an activity that does not occur in the absence of the modulator.
• “Pharmaceutically acceptable salt” includes both acid and base addition salts.
• a pharmaceutically acceptable salt of any one of the substituted heterocyclic derivative compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
• Pharmaceutically acceptable salts of the Compound 1 are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
• prophylactically effective amount refers that amount of a composition applied to a patient which will relieve to some extent one or more of the symptoms of a disease, condition or disorder being treated. In such prophylactic applications, such amounts may depend on the patient's state of health, weight, and the like. It is considered well within the skill of the art for one to determine such prophylactically effective amounts by routine experimentation, including, but not limited to, a dose escalation clinical trial.
• subject refers to an animal which is the object of treatment, observation, or experiment.
• a subject may be, but is not limited to, an animal, such as a mammal, including a human or non-human primate.
• patient and subject may be used interchangeably.
• target activity refers to a biological activity capable of being modulated by a selective modulator.
• Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.
• treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
• treatment include, but are not limited to, prophylactic and/or
• compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used
• a pharmaceutical composition or pharmaceutical formulation refers to a mixture of Compound 1 with other excipients, e.g., carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or means for sustained or control release.
• a pharmaceutical composition may facilitate administration of the Compound 1 to a subject, such as a mammal.
• therapeutically effective amounts of Compound 1 are generally administered in a pharmaceutical composition to a subject having a disease, disorder, or condition to be treated.
• the subject may be a mammal, such as a human.
• a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors.
• Compound 1 may be used singly or in combination with one or more therapeutic agents as components of mixtures.
• Compound 1 may be used as a sole therapeutic treatment, or in combination with one or more therapeutic agents or treatment modalities in the treatment of the disease condition.
• compositions comprising crystalline Compound 1 are formulated for solid oral administration. In other embodiments, pharmaceutical compositions comprising crystalline Compound 1 are formulated for other-than-oral
• compositions described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, tablets, capsules, pills, immediate release formulations, fast melt formulations, sustained release formulations, controlled release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, or formulations comprising mixed immediate and controlled release forms.
• compositions described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
• parenteral e.g., intravenous, subcutaneous, intramuscular
• intranasal e.g., buccal
• topical e.g., buccal
• rectal e.g., transdermal administration routes.
• compositions including Compound 1 may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, micronization, spray dry dispersion, nanoparticle formation, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping, or compression processes.
• the pharmaceutical compositions described herein can be formulated for administration to a subject (e.g., mammal) via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal or transdermal administration routes.
• one embodiment provides a pharmaceutical composition
• a pharmaceutical composition comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one, wherein the 4- [2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one is processed by spray drying, and the solid matrix polymer is a polyvinylpyrrolididone derivative.
• One embodiment provides a pharmaceutical composition
• a pharmaceutical composition comprising
• Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one to solid matrix polymer is from about 1: 1 to about 1 :9. Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methyl-sulfonylphenyl]-2- methylisoquinolin- 1-one to solid matrix polymer is 1 : 1. Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methyl- sulfonylphenyl]-2-methylisoquinolin- 1-one to solid matrix polymer is 1:2.
• Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropyl-methoxy)-5- methylsulfonylphenyl]-2-methylisoquinolin- 1-one to solid matrix polymer is 1:3. Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropyl- methoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- 1-one to solid matrix polymer is 1:4. Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclo- propylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one to solid matrix polymer is 1 :5.
• Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one to solid matrix polymer is 1:6. Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- 1-one to solid matrix polymer is 1:7. Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- 1-one to solid matrix polymer is 1:8.
• Another embodiment provides the pharmaceutical composition wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin- 1-one to solid matrix polymer is 1 :9.
• Another embodiment provides the pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethycellulose.
• Another embodiment provides the pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethycellulose phthalate.
• Another embodiment provides the pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethylcellulose acetate stearate.
• Another embodiment provides the pharmaceutical composition wherein the cellulose derivative is hydroxypropylmethylcellulose acetate succinate.
• Another embodiment provides the pharmaceutical composition wherein the 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one is amorphous and the composition is prepared by SDD.
• compositions described herein which include Compound 1, can be formulated into any suitable dosage form, including but not limited to, solid oral dosage forms, controlled release formulations, fast melt formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
• Dosage forms for oral use can be obtained by mixing at least one suitable solid excipient with at least Compound 1, optionally grinding the resulting mixture to form granules, and processing the mixture of granules, optionally after adding suitable auxiliaries, to obtain tablets or dragee cores.
• Suitable excipients include, for example, pharmaceutically acceptable fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulosic preparations such as, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxy- methylcellulose; or other excipients such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulosic preparations such as, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxy- methylcellulose; or other excipients such as polyviny
• croscarmellose sodium polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
• compositions for oral use also include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the push-fit capsules can contain the active ingredients, i.e., Compound 1, in admixture with excipients such as fillers, e.g., lactose; binders such as starches; or lubricants such as talc or magnesium stearate; and, optionally, stabilizers.
• the active compound(s) may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
• solid dosage forms disclosed herein may be in the form of a tablet (including 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”), a solid dispersion, a solid solution, a bioerodible dosage form, sustained release dosage form, controlled release dosage form, pulsatile release dosage form, multiparticulate dosage form, or pellets or granules, or may be in the form of an aerosol.
• a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or
• the dosage form is a powder. In still other embodiments, the dosage form is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, dosage forms described herein may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the dosage form is administered in two, or three, or four, capsules or tablets.
• solid dosage forms e.g., tablets, effervescent tablets, and capsules
• a bulk blend composition e.g., tablets, effervescent tablets, and capsules
• the individual unit dosage formss may also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These dosage forms can be manufactured by conventional pharmacological techniques.
• Conventional pharmacological 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) wet granulation, or (6) fusion. See, e.g., Lachman et al., THEORY & PRACTICE OF INDUS. PHARM. (Lea & Febiger, 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.
• Drug absorption is a complex process driven by many physicochemical factors. For example, particle size may play a major role in absorption of slowly dissolving drugs. The dissolution rate of solid particles is often proportional to surface area, and surface area is directly related to particle size. Dosage forms for oral use can be obtained by milling or other physical means to reduce particle size of API, excipients, or mixtures thereof. Micronization is the process of reducing the diameter of a solid material's particle size. In at least one embodiment, Compound 1 is micronized. In some embodiments, micronized Compound 1 is obtained by physical means such as milling or grinding.
• micronized Compound 1 is micronized via the Rapid Expansion of the Supercritical CO2 Solution (RESS) process.
• the micronized Compound 1 has a particle size distribution from about 200 nm to about 600 nm, from about 600 nm to about 1,000 nm, from about 1,000 nm to about 1,400 nm, or from about 1400 nm to about 1,800 nm.
• the micronized Compound 1 is crystalline Form A.
• the micronized Compound 1 is amorphous.
• At least one embodiment provides a pharmaceutical composition
• a pharmaceutical composition comprising 4- [2- (cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one, wherein the 4- [2- (cyclopropylmethoxy)-5 -methylsulfonylphenyl] -2-methylisoquinolin- 1 -one is processed by spray drying.
• One embodiment provides a pharmaceutical composition
• a pharmaceutical composition comprising
• Dosage forms for oral use can also be obtained by use of spray drying, melt extrusion, or thermo-kinetic mixing technology.
• the material resulting from the use of spray dry technology is a dispersion of amorphous API within a solid matrix.
• the resulting solid dispersions exhibit increased drug surface area, reduced drug crystallinity, and may offer increased stability of the API during storage.
• the solid matrix is typically a water soluble or water miscible organic or inorganic polymer.
• Suitable matrix polymers include those derived from sugars such as lactose, glucose, sucrose (e.g., Dipac ® ), dextrose, dextrin, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab ® ), polysaccharide acids, microcrystalline dextrose, amylose; cellulose preparations such as starch, maize starch, wheat starch, rice starch, pregelatinized starch potato starch, micro- crystalline cellulose (e.g., Avicel ® ), larch arabogalactan; proteins such as gelatin; natural or synthetic gum such as acacia, ghatti gum, mucilage of isapol husks, gum tragacanth; organic polymers such as methylcellulose, microcrystalline cellulose, croscarmellose, sodium croscarmellose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxye
• the pharmaceutical solid dosage forms described herein include Compound 1 that has been processed by spray drying.
• the dosage form described herein comprises is a solid matrix comprising Compound 1 that has been incorporated into the solid matrix via spray dried dispersion.
• the pharmaceutical solid dosage forms described herein can include Compound 1 and at least one pharmaceutically acceptable additive 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 film coating is provided around the formulation of Compound 1.
• some or all of the particles of the Compound 1 are coated.
• some or all of the particles of the Compound 1 are microencapsulated.
• the particles of the Compound 1 are neither microencapsulated nor coated.
• Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose,
• hydroxypropylmethylcellulose acetate stearate sucrose, microcrystalline cellulose, lactose, mannitol and the like.
• Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethy cellulose (HPMC), hydroxypropyl- methycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
• 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.
• Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ® , or sodium starch glycolate such as Promogel ® or Explotab ® , a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel ® , Avicel ® PH101, Avicel ® PH102, Avicel ® PH105, Elcema ® P100, Emcocel ® , Vivacel ® , Ming Tia ® , and Solka-Floc ® , methylcellulose, cros- carmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol ® ), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross- linked starch such as sodium starch glycolate, a cross-
• the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross- linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, or a gum.
• the disintegrating agent is croscarmellose sodium.
• Binders impart cohesiveness to solid oral dosage form formulations.
• binders aid in the formation of plugs that can be 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.
• Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel ® ), hydroxypropyl-methylcellulose (e.g.
• binder levels of 20% to 70% can be used in powder-filled gelatin capsule formulations. Binder usage levels in tablet formulations vary depending on the application of direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers that may act as moderate binders. Formulators skilled in art can determine the binder level for the formulation, but binder levels of up to 70% in tablet formulations are common.
• Suitable lubricants or glidants for use in the solid dosage forms described herein may include stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali- metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet ® , boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypoly- ethylene glycol such as CarbowaxTM, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.
• alkali- metal and alkaline earth metal salts such as aluminum, calcium
• the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments, the lubricant is magnesium stearate.
• Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.
• the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.
• non-water-soluble diluent represents compounds typically used in the formulation of pharmaceutical compostions and dosage forms, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and microcellulose (e.g., having a density of about 0.45 g/cm 3 , e.g. Avicel, powdered cellulose), and talc.
• Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10 ® ), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.
• quaternary ammonium compounds e.g., Polyquat 10 ®
• Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ® (BASF), and the like.
• the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan
• the surfactant is sodium lauryl sulfate.
• Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, polysorbate-80, hydroxyethylcellulose, hydroxypropylmethylcellulose-acetate- succinate (HPMCAS), sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans
• carboxymethylcellulose methylcellulose, sodium carboxy-methylcellulose, hydroxypropyl- methylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.
• Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, tocopherols, or tocotrienols.
• BHT butylated hydroxytoluene
• additives used in the solid dosage forms described herein there is considerable overlap between additives used in the solid dosage forms described herein.
• the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms described herein.
• the amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.
• one or more layers of the pharmaceutical formulation are plasticized.
• a plasticizer is generally a high boiling point solid or liquid.
• Plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition.
• Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
• Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above.
• compressed tablets that are designed to dissolve in the mouth include one or more flavoring agents.
• the compressed tablets include a film surrounding the final compressed tablet (i.e., a film coating).
• the film coating can provide a delayed release of Compound 1 from the formulation.
• the film coating aids in patient compliance (e.g., Opadry ® coatings or sugar coating for easing oral administration). Film coatings including Opadry ® typically range from about 1% to about 3% of the tablet weight.
• compressed tablets include one or more additional excipients.
• a capsule may be prepared, for example, by placing the bulk blend of the formulation of Compound 1 inside of a capsule.
• the formulations nonaqueous 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 may be swallowed whole or the capsule may be 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.
• the particles of Compound 1 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 in a predetermined time frame after oral administration, thereby releasing the formulation into the gastrointestinal fluid: such as in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes.
• dosage forms may include microencapsulated formulations.
• one or more other compatible materials are present in the
• microencapsulation material examples include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.
• Materials useful for the microencapsulation include materials compatible with Compound 1 , which sufficiently isolate Compound 1 from other non-compatible excipients or components of the formulation.
• Materials compatible with Compound 1 microencapsulation may include those that delay the in vivo release of Compound 1.
• Exemplary microencapsulation materials useful for delaying the release of the formulations including compounds described herein include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel ® or Nisso HPC, low- substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat ® , Metolose SR, Methocel ® -E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as HPC) such as Klucel ® or Nisso HPC, low- substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat ® , Metolose
• Methocel ® -A hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose ® , Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel ® ,
• Aqualon ® -EC, Surelease ® Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethyl- celluloses such as Natrosol ® , carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon ® -CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR ® , monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit ® EPO, Eudragit ® L30D-55, Eudragit ® FS 30D Eudragit ® L100-55, Eudragit ® L100, Eudragit ® S100, Eudragit ® RD100, Eudragit ® E100, Eudragit ® L12.5, Eudragit ® S12.5, Eudragit ® NE30D,
• plasticizers such as polyethylene glycols, e.g., polyethylene glycols
• PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material.
• Microencapsulated Compound 1 may be formulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath.
• the particles of Compound lare microencapsulated prior to being formulated into one of the above forms are coated prior to being further formulated by using standard coating procedures, such as those described in REMINGTON' S, 2000).
• the solid dosage formulations of the Compound 1 are plasticized (coated) with one or more layers.
• a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition.
• Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
• a powder including the formulations with Compound 1 may be formulated to include one or more pharmaceutical excipients and flavors. Such a powder may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi- dosage packaging units.
• compositions that include particles of Compound land at least one dispersing agent or suspending agent for oral administration to a subject.
• the formulations may be a powder or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.
• Chromatin is the complex of DNA and protein that makes up chromosomes.
• Histones are the major protein component of chromatin, acting as spools around which DNA winds. Changes in chromatin structure are affected by covalent modifications of histone proteins and by non-histone binding proteins. Several classes of enzymes are known which modify histones at various sites.
• Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than the underlying DNA sequence. Molecular mechanisms that play a role in epigenetic regulation include DNA methylation and chromatin/histone modifications.
• the genomes of eukaryotic organisms are highly organized within the nucleus of the cell. Tremendous compaction is required to package the 3 billion nucleotides of the human genome into the nucleus of a cell, where the chromosomes exist in a complex of nucleic acids and proteins called chromatin. Histones are the chief protein components of chromatin. There are a total of six classes of histones (HI, H2A, H2B, H3, H4, and H5) organized into two classes: core histones (H2A, H2B, H3, and H4) and linker histones (HI and H5).
• HI histones
• the basic unit of chromatin is a nucleosome, which comprises about 147 base pairs of DNA wrapped around a core histone octamer which includes two copies each of the core histones: H2A, H2B, H3, and H4. These nucleosome units are then further organized and condensed by the aggregation and folding of nucleosomes to form the highly condensed chromatin structure. A range of different states of condensation are possible, and the tightness of chromatin structure varies during the cell cycle, being most compact during the process of cell division.
• chromatin structure plays a critical role in regulating gene transcription, which cannot occur efficiently in highly condensed chromatin.
• Chromatin structure is controlled by a series of post translational modifications to histone proteins, notably to histones H3 and H4, and most commonly within the "histone tails" which extend beyond the core nucleosome structure. These post translational modifications include acetylation, methylation, phosphorylation, ribosylation sumoylation, ubiquitination, citrullination, deimination, and biotinylation.
• the cores of histones H2A and H3 can be modified. Given the function of histones in chromatin, histone modifications are integral to diverse biological processes such as gene expression, DNA replication, DNA repair, and chromosome condensation.
• Histone acetylation is generally associated with the activation of gene transcription, as the modification is known to loosen the interaction of the DNA and the histone octamer by changing the electrostatic state.
• specific proteins are known to bind to acetylated lysine residues within histones in order to function according to the epigenetic code.
• Bromodomains are small (-110 amino acids) distinct domains within proteins that commonly, but not exclusively, bind to acetylated lysine residues in the context of histones. Approximately fifty proteins are known to contain bromodomains, and they have a range of functions within the cell.
• the BET family of bromodomain containing proteins comprises four proteins (BRD2, BRD3, BRD4, and BRD-t) which contain tandem bromodomains capable of binding to two acetylated lysine residues that are positioned in close proximity, increasing the specificity of the interaction.
• Bromodomain-containing proteins that recognize acetylated lysines on histones have been implicated in proliferative disease.
• homozygous BRD4 knockout mice are compromised in their ability to maintain an inner cell mass and die shortly after embryo implantation, and heterozygote BRD4 knockouts display pre- and postnatal growth defects associated with reduced proliferation rates.
• BRD4 regulates genes expressed during M/Gl, including growth-associated genes, and remains bound to chromatin throughout the cell cycle. Dey, et al., 20 Mol. Biol. Cell 4899 (2009). BRD4 also associates physically with Mediator and P-TEFb (a heterodimer of Cyclin-dependent kinase 9 [CDK9], cyclin K, cyclin T, or cyclin T2a or T2b) to facilitate transcriptional elongation. Yang et al., 24 Oncogene 1653 (2005); Yang et al., 19 Mol. Cell 535 (2005). CDK9 is linked to c-Myc-dependent transcription, and is thus a validated target in chronic lymphocytic leukemia (CLL). Phelps et al., 113 Blood 2637 (2009); Rahl et al., 141 Cell 432 (2010).
• CLL chronic lymphocytic leukemia
• BRD4 is translocated to the nuclear protein in testis (NUT protein) in patients with lethal midline carcinoma, an aggressive form of human squamous carcinoma.
• NUT protein nuclear protein in testis
• RNAi in vitro analysis with RNAi supports a causal role for BRD4 in a recurrent chromosomal translocation, t(15;19)(ql3;pl3.1), which defines a lethal midline carcinoma.
• French et al., 63 Cancer Res. 304 (2003) inhibition of the BRD4 bromodomains has been found to result in growth arrest/differentiation of BRD4-NUT cell lines in vitro and in vivo.
• Bromodomain-containing proteins have also been implicated in inflammatory diseases.
• BET proteins e.g., BRD2, BRD3, BRD4, and BRDT
• BET proteins regulate assembly of histone acetylation-dependent chromatin complexes that control inflammatory gene expression. Hargreaves et al., 138 Cell 129 (2009); LeRoy et al., 30 Molec. Cell 51 (2008); Jang et al., 19 Molec. Cell 523 (2005); Yang et al., 19 Molec. Cell 535 (2005).
• BET bromodomain inhibition protects against LPS-induced endotoxic shock and bacteria-induced sepsis in vivo. Nicodeme et al., Suppression of Inflammation by a Synthetic Histone Mimic, 468 Nature 1119 (2010).
• Bromodomain-containing proteins have also been found to play a role in viral infection.
• BRD4 is implicated in the primary and persistent phases of human papilloma virus (HPV) infection of basal epithelia, in which BRD4 binding maintains the viral genome as an extra-chromosomal episome.
• HPV human papilloma virus
• BRD4 binding to the HPV transcriptional activator protein, E2 (early protein 2), tethers the viral genome to infected-cell chromosomes.
• E2 headly protein 2
• BRD4-E2 binding is crucial for both transactivating E2 and repressing transcription of two HPV oncoproteins (early protein 6 [E6] and early protein 7 [E7]).
• BRD4 Disruption of BRD4 or the BRD4-E2 interaction blocks E2-dependent gene activation.
• BRD4 also functions to tether other classes of viral genomes (e.g., Herpes virus, Epstein-Barr virus) to the chromatin of infected cells. Kurg, in DNA REPLICATION - CURRENT ADVANCES 613 (Seligmann, ed., InTech, Rijeka, Croatia, 2011).
• Bromodomain-containing proteins has also been found to bind to acetylated lysine residues on proteins other than histones.
• CBP CREB binding protein transcriptional coactivator
• the interaction between the bromodomain and acetyl-p53 follows DNA damage and promotes p53-induced transcriptional activation of the CDK inhibitor p21 and cell cycle arrest.
• BAZ2B Another novel bromodomain-containing protein is BAZ2B, whose biological function, is believed to function similarly to ACF1, the Drosophila BAZ2B ortholog.
• ACF complexes play roles in establishing regular nucleosome spacing during chromatin assembly and influencing different remodeling outcomes at target loci.
• One embodiment provides a method of regulating gene transcription in a cell comprising contacting a bromodomain-containing protein with a compound of Compound 1. Another embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising contacting the bromodomain with a compound of Compound 1.
• compositions described herein are generally useful for the inhibition of activity of one or more proteins involved in epigenetic regulation.
• at least one embodiment provides a method of modulating epigenetic regulation mediated by one or more proteins containing acetyl-lysine recognition motifs, also known as bromodomains (e.g., BET proteins, such as BRD2, BRD3, BRD4, or BRDT, and non-BET proteins, such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, or BRPFl) or a mutant thereof, by contacting a cell, or chomatin within a cell, with Compound 1.
• acetyl-lysine recognition motifs also known as bromodomains
• non-BET proteins such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, or BRPFl
• At least one embodiment provides a method of modulating epigenetic regulation mediated by one or more proteins containing acetyl-lysine recognition motifs, also known as bromodomains (e.g., BET proteins, such as BRD2, BRD3, BRD4, or BRDT, and non-BET proteins, such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, or BRPFl), or a mutant thereof, by administering to a subject a pharmaceutical composition comprising Compound 1.
• the bromodomain-containing protein is a BET protein.
• the BET protein is BRD4.
• Some embodiments provide a method of inhibiting the activity of a bromodomain- containing protein, such as a BET protein (BRD2, BRD3, BRD4, or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, or BRPFl) or a mutant thereof, by contacting a cell, or chomatin within a cell, with Compound 1.
• a bromodomain- containing protein such as a BET protein (BRD2, BRD3, BRD4, or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, or BRPFl) or a mutant thereof, by contacting a cell, or chomatin within a cell, with Compound 1.
• Some embodiments provide a method of inhibiting the activity of a bromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4, or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, or BRPFl), or a mutant thereof, in a subject, comprising the step of administering to the subject a pharmaceutical composition comprising Compound 1.
• the bromodomain-containing protein is a BET protein.
• the BET protein is BRD4.
• a method of inhibiting the activity of a bromodomain-containing protein such as a BET protein (BRD2, BRD3, BRD4, or BRDT), non- BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, or BRPFl) or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with Compound 1.
• a bromodomain-containing protein such as a BET protein (BRD2, BRD3, BRD4, or BRDT), non- BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAFl, or BRPFl) or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with Compound 1.
• the bromodomain-containing protein is a BET protein.
• the BET protein is BRD4.
• one aspect is a method of treating a subject having cancer, a neoplastic disease and other proliferative disorder, the method comprising administration of a pharmaceutical composition comprising Compound 1 to the subject.
• a human patient is treated with a pharmaceutical composition comprising Compound 1 as described herein, wherein Compound 1 is present in an amount effective to measurably inhibit bromodomain-containing protein activity (such as BRD2, BRD3, BRD4, or BRDT) in the subject.
• bromodomain-containing protein activity such as BRD2, BRD3, BRD4, or BRDT
• the invention further provides a method of treating a subject, such as a human, suffering from cancer, a neoplastic disease, or other proliferative disorder.
• the method comprises administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising Compound 1 as described herein, which functions by inhibiting a bromodomain (e.g., BRD4) and, in general, by modulating gene expression, thus inducing various cellular effects, in particular induction or repression of gene expression, arresting cell proliferation, inducing cell differentiation, or inducing apoptosis.
• a bromodomain e.g., BRD4
• the invention further relates to a method for treating or ameliorating cancer, neoplastic disease, or another proliferative disorder by administration of an effective amount of a pharmaceutical composition comprising Compound 1 as described herein, to a mammal, in particular a human, in need of such treatment.
• a pharmaceutical composition comprising Compound 1 as described herein, to a mammal, in particular a human, in need of such treatment.
• the disease to be treated by the methods of the present invention is cancer.
• One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising
• At least one embodiment provides a medicament for treating a cancer, neoplastic disease, or other proliferative disorder wherein the medicament comprises Compound 1 as described herein.
• the medicament may comprise a pharmaceutical composition comprising Compound 1 and a polymer matrix.
• the medicament may comprise a pharmaceutical composition in which Compound 1 is amorphous Compound 1 or Form A Compound 1.
• the medicament may comprise a pharmaceutical composition in which Compound 1 is micronized.
• the cancer treated by a medicament comprising Compound 1 is NUT midline carcinoma, prostate cancer, breast cancer, bladder cancer, lung cancer, or melanoma.
• the cancer is Burkitts lymphoma.
• the cancer is gliobastoma (GBM), basal cell carcinoma, pancreatic carcinoma, multiple myeloma, or acute myeloid leukemia (AML).
• reagents and solvents were used as received from commercial suppliers, such as Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.),
• Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services.
• a reference for the preparation and selection of pharmaceutical salts of the substituted heterocyclic derivative compounds described herein is Stahl & Wermuth, HANDBOOK OF PHARMACEUTICAL SALTS (Verlag Helvetica Chimica Acta, Zurich, 2002).
• WO 2010/069504 WO 2010/069504; WO 2006/030032; WO 2005/095384; US 2005/0222159; WO 2013/064984; Mishra et al., 2013 Eur. J. Org. Chem. 693 (2013); Vachhani et al., 69 Tetrahedron 359 (2013); Xie et al., 45 Eur. J. Med. Chem. 210 (2010); Mukaiyama et al., 15 Bioorg. & Med. Chem.
• Step 1 2-methyl- -(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one
• Step 2 4 -methylsulfonylphenyl]-2-methylisoquinolin-l-one
• N2 was bubbled through a mixture of 2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one (51 mg, 0.14 mmol), 2-bromo-l- (cyclopropylmethoxy)-4-methylsulfonylbenzene (30 mg, 0.13 mmol), aqueous 1M K3PO4 (0.3 mL) and Pd(dppf)Cl2 (10 mg, 0.013 mmol) in dioxane (1.15 mL), which was then microwaved at 100°C for 1 hr, and then filtered through a plug of anhydrous Na2S0 4 using ethyl acetate to transfer and rinse.
• Step 1 2- 5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one
• Step 2 4-[ -(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one
• Compound 1 was performed as follows. His-tagged BRD4 was cloned, expressed, and purified to homogeneity. Filipakopoulos et al., 468 Nature 1067-73 (2010). BRD4 binding and inhibition was assessed by monitoring the interaction of biotinylated H4-tetraacetyl peptide (AnaSpec, H4K5/8/12/16(Ac), biotin-labeled) with the target using the AlphaScreen technology (Life Technologies).
• a colorimetric cellular proliferation assay (Cell-MTS assay) was performed to assess the ability of the heterocyclic derivative BRD4 inhibitors disclosed herein to effect the proliferation of established cancer cell lines.
• the Cell-MTS assay is a 7-day plate-based colorimetric assay that quantifies the amount of newly generated NADH in the presence or absence of test compound.
• the NADH level is used for the quantification of cancer cell proliferation.
• Assay Method Established cancer cell lines with a variety of driving mutations were obtained from American Type Culture Collection (ATCC) and routinely passaged according to ATCC protocols. For routine assay, these cells were seeded at densities that enabled -90% confluence after 7 days of culture. Raji, human Burkitts lymphoma cells, (cMYC) were seeded at 15,000 cells per 96-well. HL-60, human proleukemia cells, (NRAS, pl6, p53, c-Myc amplified) were seeded at 5,000 cells per 96-well.
• ATCC American Type Culture Collection
• cMYC human Burkitts lymphoma cells
• HL-60 human proleukemia cells, (NRAS, pl6, p53, c-Myc amplified) were seeded at 5,000 cells per 96-well.
• NCI-H460, human non-small cell lung cancer cells, (KRAS, PIK3CA, STLK11, pl6) were seeded at 3,000 cells per 96-well. Plated cells were incubated for 24 hr, and thereafter cells received an 11 -point dilution of Compound 1 with final concentration ranges from 100 ⁇ to 2.0 nM. Cells were incubated in the presence of the drug for 168 hr at 37°C, and 5% CO2. At the end of this incubation period, 80 iL of media is removed and 20 xL of CellTiter96 ® . AQueous Non-Radioactive Cell Proliferation Assay solution (Promega) was added.
• IC50 values were calculated using the IDBS XLfit software package and include background subtracted OD490 values and normalization to DMSO controls. Cellular proliferation IC50 values were uploaded and archived using the Chem Biography Platform. Table 1 provides the results of the in vitro enzyme inhibition assay experiments and the in vitro cell-based assay experiments performed with Compound 1.
• XRPD patterns were also collected on a Bruker AXS D8 Advance diffractometer using Cu Ka radiation (40 kV, 40 mA), ⁇ - 2 ⁇ goniometer, and divergence of V4 and receiving slits, a Ge monochromator and a Lynxeye detector.
• the software used for data collection was Diffrac Plus XRD Commander v2.6.1 and the data were analysed and presented using Diffrac Plus EVA vl5.0.0.0.
• FIG. 1 shows the XRPD diffractogram of Form A Compound 1.
• Significant XRPD reflection peaks include, but are not United to, the peaks at 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6, and 24.5 2 ⁇ .
• DSC data were collected on a Mettler DSC 823E equipped with a thirty-four (34) position auto-sampler.
• the instrument was calibrated for energy and temperature using certified indium. Typically, 0.5 mg - 5 mg of each sample (e.g., 4.877 mg), in a pin-holed aluminium pan, was heated at 10°C/min from 25 °C to 350°C. A nitrogen purge at 50 niL/min was maintained over the sample.
• the instrument control and data analysis software was STARe vl2.1. Wg A5 -l, Integral -599.85 mJ normalized -122.99 Jg A -l. Onset was exhibited at 224.33°C; a sharp endotherm attributable to the melt of the sample appeared at 224.95°C, and is illustrated in FIG. 3.
• Sorption isotherms were obtained using a SMS DVS Intrinsic moisture sorption analyser, controlled by DVS Intrinsic Control software vl.0.1.2 (or v 1.0.1.3).
• the sample temperature was maintained at 25 °C by the instrument controls.
• the humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 mL/min.
• the relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0%RH - 100%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 ⁇ 0.005 mg).
• FIG. 4 illustrates a graph of the sorption isotherm data.
• Example 9 Pharmacokinetic study to determine dose proportionality in rat after oral administration of crystalline Form A of Compound 1
• Spray-dried dispersions were prepared by mixing a solution of Compound 1 in dichloromethane with either polyvinylpyrrolidone (PVP K12 PF) or hydroxypropyl methylcellulose (Methocel E5 LV) in ratios of Compound l :polymer of either 1 : 1 or 1 :3, resulting in four unique combinations, followed by spray-drying each preparation using a lab scale Buchi spray dryer (Buchi B290 parameters: inlet T° 80°C; outlet T° 57°C; aspirator 100%; nozzle air 30 mm; pump speed 25%; setup: open loop).
• Example 11 PK study to determine plasma exposure levels in mouse 6 hours after oral administration of various SDD preparations of Compound 1
• FIG. 6 illustrates the results of this experiment.
• composition comprising PVP polymer with a Compound l:polymer ratio of 1: 1,
• Compound 1 had a mean AUC 0-6hr of 7,193 hr ng/mL.
• composition comprising PVP polymer with a Compound l:polymer ratio of 1:3, Compound 1 had a mean AUC 0-6hr of 8,872 hr ng/mL.
• Compound 1 had a mean AUC 0-6hr of 10,484 hr ng/mL.
• composition comprising HPMC polymer with a Compound Lpolymer ratio of 1 :3, Compound 1 had a mean AUC 0-6hr of 24,430 hr ng/mL.
• Example 12 Preparation of SDD of Compound 1 with HPMC in a Compound Lpolymer ratio of 1 :3.
• the spray-dried dispersion was prepared by mixing a solution of Compound 1 in dichloromethane with hydroxypropyl methylcellulose (Methocel E5 LV) (HPMC) in a 1 :3 Compound Lpolymer ratio, stirring the mixture overnight, and then spray-drying using a lab scale Buchi spray dryer.
• Methodoel E5 LV hydroxypropyl methylcellulose
• Example 13 XRPD study of Compound 1) as a SDD with HPMC
• Example 14 PK study to determine dose proportionality in rat or dog after oral administration of SDD of Compound 1
• Compound 1 prepared as a 25% Compound LHPMC SDD as described in Example 12 displayed approximate dose proportionality through dose ranges of 10 mg/kg to 300 mg/kg when administered as an oral dosage form (0.5% methylcellulose (MC) suspension) to female Sprague Dawley rats. Results are shown in FIG 8a. Approximate dose proportionality is evidenced through a dose range from 1 mg/kg - 10 mg/kg when Compound 1 prepared as a 25% Compound LHPMC SDD as described in Example 12 was administered as an oral dosage form (0.5% MC suspension) to male beagle dogs. Results are shown in FIG. 8b.
• Example 15 Preparation of SDDs of Compound 1 using various grades of HPMCAS
• Spray-dried dispersions were prepared by mixing a solution of Compound 1 in (90: 10) acetone: water with hydroxypropylmethylcellulose acetate succinate M or H
• process parameters inlet T° 93-109°C; outlet T° 42-43°C; atomizing pressure 110 psi; feed rate 29 g/min; glass flow rate 450 g/min).
• Example 16 PK study to determine plasma exposure levels in rat after oral administration of various SDD preparations of Compound 1.
• composition comprising HPMCAS-M polymer with a Compound l:polymer ratio of 1 :3, Compound 1 had a mean AUC 0-24hr of 24,558 hr*ng/mL.
• composition comprising HPMCAS-H polymer with a Compound l :polymer ratio of 1:3, Compound 1 had a mean AUC 0-24hr of 27,469 hr*ng/mL.
• Example 17 Preparation of Spray-dried dispersions of Compound 1 with HPMCAS-H.
• Spray-dried dispersions were prepared by mixing a solution of Compound 1 in (90: 10) acetone:water with hydroxypropylmethylcellulose acetate succinate (HPMCAS-HG) in ratios of Compound l :polymer of either 1 : 1, 1 :2.85, or 1 :3, followed by spray-drying each preparation using a custom bench scale Lab Spray Dryer (Bend Research BLD-35; process paramaters: inlet T 84-94°C; outlet T 40-42°C; atomization pressure 120 psi; nozzle - pressure swirl/Schlick 2.0 ; solution spray rate 25 g/min; airflow 475 g/min; setup: open loop).
• HPMCAS-HG hydroxypropylmethylcellulose acetate succinate
• Example 18 Immediate release tablet containing 10 mg of Compound 1.
• An immediate release tablet containing 10 mg of Compound 1 was generally prepared as follows.
• the raw materials described in Table 2 (below) were blended, sieved, and blended again prior to granulation.
• the blended raw materials were granulated using a dry granulation process.
• the dry granulated materials were blended with the extragranular materials.
• the blended materials were compressed into tablets using 6 mm SRC (standard round concave) tooling.
• Example 19 Immediate release tablet containing 100 mg of Compound 1.
• One version of an immediate release tablet containing 100 mg of Compound 1 was generally prepared as follows.
• the raw materials described in Table 3 (below) were blended, sieved, and blended again prior to granulation.
• the blended raw materials were granulated using a dry granulation process.
• the dry granulated materials were blended with the extragranular materials.
• the blended materials were compressed into tablets using concave modified oval tooling (9.1 mm x 18.1 mm).
• Example 20 Immediate release tablet containing 200 mg of Compound 1.
• One version of an immediate release tablet containing 200 mg of Compound 1 is prepared as follows.
• the raw materials described in Table 4 (below) are blended, sieved, and blended again prior to granulation.
• the blended raw materials are granulated using a dry granulation process.
• the dry granulated materials are blended with the extragranular materials.
• the blended materials are the compressed into tablets.

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