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    • 专利摘要:
    solid dispersion. a solid dispersion of n4-(4-([1,2,4]triazo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-n6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine and solid dispersion preparation processes are provided herein. furthermore, a pharmaceutical composition comprising a solid dispersion of n4-(4-([1,2,4]triazo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-n6-( 4,4-Dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and uses thereof are provided herein.
    公开号:BR112014009092B1
    申请号:R112014009092-0
    申请日:2012-10-12
    公开日:2022-01-18
    发明作者:David Shank Fry；Christopher M. Lindemann；Michael Preigh；Corey Jay Bloom；Christopher Donavan Craig；Devon Brevard Dubose；Jeff GAUTSCHI；Dan Smithey
    申请人:Array Biopharma Inc；
    IPC主号:
    专利说明:

    BACKGROUND OF THE INVENTION FIELD OF THE INVENTION
    [001] The solid dispersion of N 4-(4-([1,2,4]triazo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl- 4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine is shown herein. Also, a pharmaceutical composition, comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine is shown herein. DESCRIPTION OF THE STATE OF THE TECHNIQUE
    [002] N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-di -hydro-oxazol-2-yl)quinazoline-4,6-diamine (also called "ARRY-380"), which has the structure:
    is a selective ErbB2 (HER2) inhibitor described in WO 2007/059257, which is incorporated by reference in its entirety. N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro -oxazol-2-yl)quinazoline-4,6-diamine has been tested in human clinical trials for hyperproliferative diseases, especially cancer (see Koch, Kevin. "ARRY-380: A Selective, Oral HER2 Inhibitor for the Treatment of Solid Tumors."" 102nd Annual Meeting of the American Association for Cancer Research, April 3, 2011; which can also be found: http://www.arraybiopharma.com/_documents/Publication/Pu bAttachment462.pdf).
    [003] The composition of powder in capsule ("PIC") of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 -(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine was prepared and administered to cancer patients, and the overall interpatient variability for the area under the curves of plasma concentration or time ("CUA") and peak concentration ("Cmax") was moderate to high.
    [004] There remains a need to prepare a pharmaceutical composition containing N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4 -dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine which minimizes inter-patient variability in pharmacokinetics. SUMMARY OF THE INVENTION
    [005] The solid dispersion comprising N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl- 4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine is described herein.
    [006] The pharmaceutical composition comprising N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl- 4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine is described herein.
    [007] A pharmaceutical composition comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine is described herein.
    [008] The pharmaceutical composition comprising a solid spray dispersion N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4 -dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine is described herein.
    [009] The processes for preparing the solid dispersion and pharmaceutical composition and the methods of using the pharmaceutical composition are also described herein. BRIEF DESCRIPTION OF THE FIGURES
    [0010] Figure 1 shows a comparison of XRPD scans of the solid dispersions of 30% amorphous and crystalline N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3- methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine, with an approximation of solid amorphous dispersions.
    [0011] Figure 2 shows a dissolution profile of the solid dispersion of 30% N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [0012] Figure 3 shows a dissolution profile of the 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [0013] Figure 4 shows a dissolution profile of the solid dispersion of 30% N4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [0014] Figure 5 shows a dissolution profile of the 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [0015] Figure 6 shows a dissolution profile of the 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [0016] Figure 7 shows a comparison of XRPD scans of 60% amorphous and crystalline solid dispersions N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3 -methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine, with an approximation of solid amorphous dispersions.
    [0017] Figure 8 shows a dissolution profile of the 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [0018] Figure 9 shows a dissolution profile of the 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [0019] Figure 10 shows a dissolution profile of the 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [0020] Figure 11 shows a dissolution profile of the 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [0021] Figure 12 shows a dissolution profile of the 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [0022] Figure 13 shows a dissolution comparison of a tablet from the solid dispersion and a crystalline composition of the PIC. DETAILED DESCRIPTION OF THE INVENTION
    [0023] References will now be in detail for certain modalities, examples of which are illustrated in this document. While enumerated embodiments will be described, it will be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention, as defined by the claims. One skilled in the art will recognize many similar or equivalent methods and materials described herein that could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials differ or contradict this application, including, but not limited to defined terms, term usage, described techniques, or the like, this application controls. DEFINITIONS
    [0024] The term "fence" is used in this document to mean approximately, in the region, approximately, or around. When the term "fence" is used in conjunction with a numerical range, it modifies that range, extending the limits above and below the stated numerical values. In general, the term "fence" is used in this document to modify a numerical value above and below the indicated value by a variation of 20%.
    [0025] As used herein, the recitation of a numerical scale for a variable is intended to convey that the invention may be practiced with the variable equal to any of the values within that range. Thus, for a variable that is inherently discrete, the variable can be equal to any integer value of the numeric range, including the range endpoints. Likewise, for a variable that is inherently continuous, the variable can be equal to any actual value in the numeric range, including the range endpoints. As an example, a variable that is described as having values between 0 and 2, can be 0, 1, or 2 for variables that are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other value. real for variables that are inherently continuous.
    [0026] The term "amorphous" means a solid in the solid state is a non-crystalline state. Amorphous solids generally have a short-range molecular arrangement like crystal, but no long-range order of molecular packaging like those found in crystalline solids. The solid state shape of a solid can be determined by polarized light microscopy, x-ray diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or other standard techniques known to those skilled in the art.
    [0027] The phrase "amorphous solid dispersion" means a solid consisting of a medicinal substance and a dispersion polymer. The amorphous solid dispersion discussed herein comprises amorphous N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4- dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and a dispersion polymer, wherein the solid amorphous dispersion contains N4-(4-([1,2,4]triazolo [1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N-6(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in a substantially amorphous solid state form. In certain embodiments, the amorphous solid state form substantially means that the N4-(4-([1,2,4]triazolo[1,5-a]pyridins-7-yloxy)-3-methylphenyl)-N 6- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine component in the solid amorphous dispersion is at least 80% amorphous N-4-(4-([ 1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl) quinazoline-4,6-diamine. In certain embodiments, the amorphous solid state form substantially means that N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4 ,4-Dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine component in the solid amorphous dispersion is at least 85% amorphous N4-(4-([1,2, 4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4, 6-diamine. In certain embodiments, the amorphous solid state form substantially means that the N4-(4-([1,2,4]triazolo[1,5-a]pyridins-7-yloxy)-3-methylphenyl)-N6-(4 ,4-Dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine component in the solid amorphous dispersion is at least 90% amorphous N4-(4-([1,2, 4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6 -diamine. In certain embodiments, the amorphous solid state form substantially means that the N4-(4-([1,2,4]triazolo[1,5-a]pyridins-7-yloxy)-3-methylphenyl)-N6-(4 ,4-Dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine component in the solid amorphous dispersion is at least 95% amorphous N4-(4-([1,2, 4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6 -diamine.
    [0028] The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is typically characterized by abnormal or unregulated cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include squamous cell cancer (e.g. squamous epithelial cell cancer), lung cancer including small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma and squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastric or stomach cancer, including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatomegaly, cancer of the breast, colon cancer, rectal cancer, colorectal cancer, brain, endometrial or uterine carcinoma, salivary gland carcinoma, renal or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, penile carcinoma , skin cancer, including melanoma, as well as head and neck cancer.
    [0029] The phrase "dispersion polymer" means a polymer that allows N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine to be dispersed throughout such that a solid dispersion can form. The dispersion polymer is preferably neutral or basic. The dispersion polymer may contain a mixture of two or more polymers. Examples of polymer dispersions include, but are not limited to, vinyl polymers and copolymers, vinyl acetate vinylpyrrolidine copolymer ("PVP-VA"), polyvinyl alcohols, polyvinyl alcohol acetate copolymers, polyvinyl pyrrolidine ("PVP") copolymers of acrylate and methacrylate, methyl methacrylate copolymer of methylacrylic acid (such as Eudragit®), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers (also referred to as poloxamers), graft copolymer comprised of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (such as Soluplus®), cellulosic polymers such as hydroxypropyl methyl cellulose acetate ("HPMCA"), hydroxypropyl methyl cellulose ("HPMC"), hydroxypropyl ("HPC"), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate and ethyl hydroxyethyl cellulose, hydroxypropyl methyl cellulose acetate ("HPMCAS"), hydroxy propyl methyl cellulose phthalate ("HPMCP"), carboxymethyl ethyl cellulose ("CMEC"), cellulose acetate phthalate ("CAP"), cellulose acetate succinate ("CAS"), hydroxypropyl methyl cellulose acetate phthalate ("HPMCAP") , cellulose acetate trimellitate ("CAT"), hydroxypropyl methyl cellulose acetate trimellitate ("HPMCAT") and carboxymethyl cellulose aceto butyrate ("CMCAB") and the like.
    [0030] The term "mammal" means a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, rats, hamsters and primates, including humans.
    [0031] The phrase "pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and/or toxicologically with the other ingredients comprising a composition and/or the mammal being treated therewith.
    [0032] The phrase "pharmaceutically acceptable salt", as used herein, refers to pharmaceutically acceptable inorganic or organic salts of a compound described herein.
    [0033] The phrase "solid dispersion" means a system in a solid state comprising at least two components, where one component is dispersed throughout the other component. The solid dispersion discussed herein comprises a component of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4 -dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine dispersed throughout another component, particularly a dispersion polymer.
    [0034] The phrase "spray drying" means processes involved in separating the liquid mixtures into small droplets (atomization) and rapidly removing the solvent from the mixture in a spray drying apparatus where there is a strong driving force for evaporating the solvent droplets. The phrase spray drying is used conventionally and widely. Spray drying processes and spray drying equipment are generally described in Perry, Robert H. and Don W. Green (eds.). Perry's Chemical Engineers' Handbook. New York: McGraw-Hill, 2007 (8th edition).
    [0035] The phrases "therapeutically effective amount" or "effective amount" means an amount of a compound described herein which, when administered to a mammal, necessitates such treatment, sufficient to (i) treat or prevent the particular disease, condition , or disorder, (ii) alleviate, ameliorate, or eliminate one or more symptoms of the specific disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound that will correspond to such an amount will vary depending on factors such as the specific compound, the condition of the disease and its severity, the identity (e.g., weight) of the mammal in need of treatment, but nevertheless it may be determined routinely by one skilled in the art.
    [0036] The terms "treat" or "treatment" refer to therapeutic, prophylactic, palliative or preventive measures. Beneficial or desired clinical outcomes include, but are not limited to, alleviating symptoms, decreasing the extent of disease, stabilized disease state (i.e., not worsening), slowing or slowing disease progression, improving or mitigating disease status. disease and remission (either partial or complete), whether detectable or undetectable. "Treatment" can also mean the prolongation of survival, compared to the expected survival if not receiving treatment. Those in need of treatment include those who already have the condition or disorder, as well as those most likely to have the disorder or those in whom the disease should be prevented. SOLID DISPERSIONS AND PHARMACEUTICAL COMPOSITIONS
    [0037] Provided herein is the solid dispersion of N4-(4-([1,2,4]triazo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4, 4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [0038] Solid dispersions are generally prepared by dissolving the medicinal substance and the dispersion polymer in a suitable solvent to form a feed solution, and then the feed solution can be spray dried to form the solid dispersion (and remove the solvent). Spray drying is a known process. Spray drying is generally performed by dissolving N 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl -4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and the polymer dispersed in a suitable solvent to prepare a feed solution. The feed solution can be pumped through an atomizer into a drying chamber. The feed solution may be atomized by conventional means known in the art, such as a two-fluid ultrasound nozzle, a pressure nozzle, a rotating nozzle and a two-fluid non-ultrasonic nozzle. Then the solvent is removed in the drying chamber for the solid dispersion. A typical drying chamber uses hot gases such as forced air, nitrogen, nitrogen enriched air or argon to dry particles. The drying chamber size can be adjusted to obtain particle properties or transfer rate.
    [0039] Although the solid dispersion is preferably prepared by conventional spray drying techniques, other techniques known in the art such as melt extrusion, lyophilization, rotary evaporation, cylinder drying or other solvent removal processes can be used.
    [0040] In one embodiment, a process for preparing the solid dispersion is provided, comprising: (a) dissolving N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)- 3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and a polymer dispersed in a suitable solvent; and (b) evaporating the solvent to form the solid dispersion.
    [0041] In another embodiment, solvent evaporation in step (b) is performed by spray drying, melt extrusion, freeze drying, rotary evaporation, cylinder drying or other solvent removal processes.
    [0042] In certain embodiments, the dispersion polymer is selected from PVP-VA, methyl acrylic acid methyl methacrylate copolymer, HPMCP, CAP, HPMCAS and HPMC and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methyl methacrylate copolymer of methylacrylic acid, HPMCP, CAP, HPMCAS and HPMC. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP, M-Class HPMCAS, HPMC and blends thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP, Class M HPMCAS and HPMC.
    [0043] In certain embodiments, the dispersion polymer is selected from PVP-VA, methyl acrylic acid methyl methacrylate copolymer, HPMCP, CAP, HPMCAS and HPMC, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methyl acrylic acid methyl methacrylate copolymer, HPMCP, CAP, HPMCAS and HPMC. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and M-class HPMCAS, and blends thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and Class M HPMCAS.
    [0044] In certain embodiments, the dispersion polymer is selected from PVP-VA, methyl acrylic acid methyl methacrylate copolymer, HPMCP, CAP, and HPMC, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methyl acrylic acid methyl methacrylate copolymer, HPMCP, CAP, and HPMC. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMC, and blends thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMC.
    [0045] In certain embodiments, the dispersion polymer is selected from PVP-VA, methyl acrylic acid methyl methacrylate copolymer, HPMCP and CAP, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methyl methacrylate copolymer of methylacrylic acid, HPMCP and CAP. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55 and CAP, and blends thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55 and CAP.
    [0046] In certain embodiments, the dispersion polymer is PVP-VA.
    [0047] In certain embodiments, the dispersion polymer is methyl methacrylate copolymer of methylacrylic acid. In certain embodiments, the dispersion polymer is Eudragit®. In certain embodiments, the dispersion polymer is Eudragit® L100.
    [0048] In certain embodiments, the dispersion polymer is HPMCP. In certain embodiments, the dispersion polymer is HPMCP H-55.
    [0049] In certain embodiments, the dispersion polymer is CAP.
    [0050] In certain embodiments, the dispersion polymer is HPMCAS. In certain embodiments, the dispersion polymer is Class M HPMCAS.
    [0051] In certain embodiments, the dispersion polymer is preferably neutral or basic. In certain embodiments, the dispersion polymer is selected from PVP-VA and HPMC. In certain embodiments, the dispersion polymer is HPMCP.
    [0052] Suitable solvents are a solvent or mixture of solvents wherein both N 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and the dispersion polymer has adequate solubility (solubility greater than 1 mg/mL). of solvents can be used if each component of the solid dispersion (i.e. N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and polymer dispersion) require different solvents to obtain the desired solubility. The solvent may be volatile with a boiling point of 150°C or less. In addition, the solvent must have relatively low toxicity and removed from the dispersion to a level acceptable to the International Harmonization Committee ("ICH") on guidelines. Solvent removal at this level may require a subsequent processing step, such as a drying tray. Examples of suitable solvents include, but are not limited to, alcohols such as methanol ("MeOH"), ethanol ("EtOH"), n-propanol, isopropanol ("IPA") and butanol; ketones such as acetone, methyl ethyl ketone ("MEK") and methyl isobutyl ketone; esters such as ethyl acetate ("EA") and propyl acetate; and various other solvents, such as tetrahydrofuran ("THF"), acetonitrile ("ACN"), methylene chloride, toluene, and 1,1,1-trichloroethane. Low volatility solvents such as dimethyl acetate or dimethyl sulfoxide ("DMSO") can be used. Mixtures of solvents with water can also be used, as long as the polymer and N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl) - N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine are sufficiently soluble to make spray drying the process feasible. In general, due to the hydrophobic nature of low-solubility drugs, non-aqueous solvents can be used, i.e., the solvent comprises less than about 10% by weight of water.
    [0053] In certain embodiments, the suitable solvent is selected from MeOH and THF, and mixtures thereof. In certain embodiments, the suitable solvent is MeOH:THF of the solvent system of about 1:3. In certain embodiments, the suitable solvent is a 1:3 MeOH:THF solvent system.
    [0054] In certain embodiments, the suitable solvent is selected from MeOH and THF and water, and mixtures thereof. In certain embodiments, the suitable solvent is selected from MeOH, THF and water. In certain embodiments, the suitable solvent is THF:MeOH:solvent system in water of about 80:10:10. In certain embodiments, the suitable solvent is an 80:10:10 THF:MeOH:water solvent system. In certain embodiments, the suitable solvent is the THF:MeOH:water solvent system of about 82:8:10. In certain embodiments, the suitable solvent is an 82:8:10 THF:MeOH:water solvent system. In certain embodiments, the suitable solvent is THF:MeOH:solvent-in-water system of about 82.2:8.2:9.6. In certain embodiments, the suitable solvent is the 82.2:8.2:9.6 THF:MeOH:water solvent system.
    [0055] In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4 -dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges of about 0.1% to about 70% by relative weight for the dispersion polymer. In certain embodiments, the amount of N4(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4 ,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion scales from 0.1% to 70% by weight with respect to the dispersion polymer.
    [0056] In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4 -dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges of about 1% to about 60% by relative weight for the dispersion polymer. In certain embodiments, the amount of N4(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4 ,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion scales from 1% to 60% by weight with respect to the dispersion polymer.
    [0057] In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4 -dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges of about 5% to about 60% by relative weight for the dispersion polymer. In certain embodiments, the amount of N4(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4 ,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion scales from 5% to 60% by weight with respect to the dispersion polymer.
    [0058] In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4 -dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges of about 55% to about 65% by relative weight for the dispersion polymer. In certain embodiments, the amount of N4(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4 ,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion scales from 55% to 65% by weight with respect to the dispersion polymer. In certain embodiments, the amount of N4(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4 ,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion of 60% by weight with respect to the dispersion polymer. In certain embodiments, the amount of N4(4-([1,2,4]triazolo[1,5-α]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4, 5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion of 60% by weight with respect to the dispersion polymer.
    [0059] In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4 -dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges of about 25% to about 35% by relative weight for the dispersion polymer. In certain embodiments, the amount of N-4(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl -4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion scales from 25% to 35% by weight with respect to the dispersion polymer. In certain embodiments, the amount of N-4(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl -4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion of 30% by weight with respect to the dispersion polymer. In certain embodiments, the amount of N-4(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl- 4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion of 30% by weight with respect to the dispersion polymer.
    [0060] In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4 -dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges of about 45% to about 55% by relative weight for the dispersion polymer. In certain embodiments, the amount of N4(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4 ,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion scales from 45% to 55% by weight with respect to the dispersion polymer. In certain embodiments, the amount of N4(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4 ,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion of 50% by weight with respect to the dispersion polymer. In certain embodiments, the amount of N-4(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl- 4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion of 50% by weight with respect to the dispersion polymer.
    [0061] In certain embodiments, the solid dispersion is an amorphous solid dispersion.
    [0062] Another embodiment provides a pharmaceutical composition comprising a solid dispersion of N4(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine is a dispersion polymer and a carrier or excipient.
    [0063] Appropriate excipients and carriers are well known to those skilled in the art and are described in detail, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
    [0064] Pharmaceutical compositions may also include one or more additional components, such as buffers, dispersing agents, surfactants, wetting agents, lubricating agents, emulsifiers, preserving agents, antioxidants, opacifying agents, glidants, processing aids, coloring agents, sweeteners. , perfume, flavoring agents, diluents, and other known additives to provide an elegant presentation of the drug, i.e., a compound described herein or pharmaceutical composition thereof, or aid in the manufacture of the pharmaceutical, i.e., drug (see Ansel; Gennaro; and Rowe above). The components of the pharmaceutical composition must be pharmaceutically acceptable.
    [0065] Certain embodiments provide a pharmaceutical composition comprising: (a) about 1 to about 70% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a] pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine;(b) of 0.1 to about 20% by weight of a disintegrant; (c) from 0.1 to about 25% by weight of an osmogen; (d) from 0.1 to about 10% by weight of a glidant; (e) from 0.1 to about 10% by weight of a lubricant; and (f) about 0.1 to about 25% by weight of a binder/diluent.
    [0066] In another embodiment, the pharmaceutical composition comprises: (a) from 1 to about 70% by weight of a solid dispersion of N 4-(4-([1,2,4]triazolo[1,5-a] pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; (b) weight of 0 .1 to 20% of a disintegrant; (c) 0.1 to 25% weight of an osmogen; (d) 0.1 to 10% weight of a glidant; (e) 0.1 to 10% weight of a lubricant; and (f) 0.1 to 25% weight of a binder/diluent.
    [0067] Certain embodiments provide a pharmaceutical composition comprising: (a) from 25 to about 60% by weight of a solid dispersion of N 4-(4-([1,2,4]triazolo[1,5-a] pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine;(b) from 5 to about 15% by weight of a disintegrant; (c) from 15 to about 25% by weight of an osmogen; (d) from 0.1 to about 3% by weight of a glidant; (e) from 0. 1 to about 3% by weight of a lubricant; and (f) from 10 to about 25% by weight of a binder/diluent.
    [0068] In another embodiment, the pharmaceutical composition comprises: (a) from 25 to about 60% by weight of a solid dispersion of N 4-(4-([1,2,4]triazolo[1,5-a] pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; (b) weight of 5 15% of a disintegrant; (c) 15 to 25% weight of an osmogen; (d) 0.1 to 3% weight of a glidant; (e) 0.1 to 3% weight of a lubricant; and (f) 10 to 25% weight of a binder/diluent.
    [0069] Certain embodiments provide a pharmaceutical composition comprising: (a) from 40 to about 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; (b) from 5 to about from 15% by weight of a disintegrant; (c) from 15 to about 25% by weight of an osmogen; (d) from 0.1 to about 3% by weight of a glidant; (e) from 0.1 at about 3% by weight of a lubricant; and (f) from 10 to about 25% by weight of the binder/diluent.
    [0070] In another embodiment, the pharmaceutical composition comprises: (a) 40 to 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7- yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; (b) 5 to 15% weight of a disintegrant; (c) 15 to 25% weight of an osmogen; (d) 0.1 to 3% weight of a glidant; (e) 0.1 to 3% weight of a lubricant; and (f) 10 to 25% weight of a binder/diluent.
    [0071] Certain embodiments provide a pharmaceutical composition comprising: (a) from 1 to about 70% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine;(b) of 0.1 to about 20% by weight of a disintegrant; (c) from 0.1 to about 25% by weight of an osmogen; (d) from 0.1 to about 10% by weight of a glidant; (e) from 0.1 to about 10% by weight of a lubricant; and (f) from 0.1 to about 25% by weight of a filler.
    [0072] In another embodiment, the pharmaceutical composition comprises: (a) from 1 to about 70% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; (b) weight of 0. 1 to 20% of a disintegrant; (c) 0.1 to 25% weight of an osmogen; (d) 0.1 to 10% weight of a glidant; (e) 0.1 to 10% weight of a lubricant; and (f) 0.1 to 25% weight of a filler.
    [0073] Certain embodiments provide a pharmaceutical composition comprising: (a) from 25 to about 60% by weight of a solid dispersion of N 4-(4-([1,2,4]triazolo[1,5-a] pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine;(b) from 1 to about 10% by weight of a disintegrant; (c) from 15 to about 25% by weight of an osmogen; (d) from 0.1 to about 3% by weight of a glidant; (e) from 0.1 to about 3% by weight of a lubricant; and (f) from 10 to about 25% of the weight of a filler.
    [0074] In another embodiment, the pharmaceutical composition comprises: (a) from 25 to about 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine;(b) weight from 1 to 10% of a disintegrant; (c) 15 to 25% weight of an osmogen; (d) 0.1 to 3% weight of a glidant; (e) 0.1 to 3% weight of a lubricant; and (f) 10 to 25% weight of a filler.
    [0075] Certain embodiments provide a pharmaceutical composition comprising: (a) from 40 to about 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; (b) from 1 to about from 10% by weight of a disintegrant; (c) from 15 to about 25% by weight of an osmogen; (d) from 0.1 to about 3% by weight of a glidant; (e) from 0.1 at about 3% by weight of a lubricant; and (f) from 10 to about 25% of the weight of a filler.
    [0076] In another embodiment, the pharmaceutical composition comprises: (a) 40 to 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7- yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; (b) weight of 1 to 10% of a disintegrant; (c) 15 to 25% weight of an osmogen; (d) 0.1 to 3% weight of a glidant; (e) 0.1 to 3% weight of a lubricant; and (f) 10 to 25% weight of a filler.
    [0077] In certain embodiments, the osmogen is selected from NaCl and KCl, and their mixtures.
    [0078] In certain embodiments, the lubricant is magnesium stearate.
    [0079] In certain embodiments, the glidant is colloidal silicon dioxide.
    [0080] In certain embodiments, the binder/diluent is microcrystalline cellulose. In certain embodiments, the binder/diluent acts as both a binder and a diluent.
    [0081] In certain embodiments, the binder is microcrystalline cellulose.
    [0082] In certain embodiments, the diluent is microcrystalline cellulose.
    [0083] In certain embodiments, the filler is lactose.
    [0084] In certain embodiments, the disintegrant is selected from crospovidone and sodium bicarbonate (NaHCO3), and mixtures thereof. In certain embodiments, the disintegrant is selected from crospovidone and sodium bicarbonate. In certain embodiments, the disintegrant is sodium bicarbonate. In certain embodiments, the disintegrant is crospovidone.
    [0085] In certain embodiments, the composition contains sodium bicarbonate. N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydro- oxazol-2-yl)quinazoline-4,6-diamine can slowly degrade, through hydrolysis or other means, to a carbamate impurity:

    [0086] Sodium bicarbonate helps to slow down the degradation to the carbamate impurity. Baking soda also helps to provide consistent tablet disintegration when the tablets are exposed to different humidities.
    [0087] Certain embodiments provide a pharmaceutical composition comprising: (a) N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-( 4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; and (b) sodium bicarbonate.
    [0088] Certain embodiments provide a pharmaceutical composition comprising: (a) from 1 to about 70% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; and (b) from 0.1 to about 30% by weight of sodium bicarbonate.
    [0089] In another embodiment, the pharmaceutical composition comprises: (a) from 1 to about 70% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; and (b) 0.1 to 30% weight of the sodium bicarbonate.
    [0090] Certain embodiments provide a pharmaceutical composition comprising: (a) from 1 to about 70% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; (b) 0.1 to about 30% weight of the sodium bicarbonate; and (c) the remaining weight represents other pharmaceutically acceptable excipients and carriers.
    [0091] In another embodiment, the pharmaceutical composition comprises: (a) from 1 to about 70% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; (b) weight of 0. 1 to 30% of sodium bicarbonate; and (c) the remaining weight represents other pharmaceutically acceptable excipients and carriers.
    [0092] Certain embodiments provide a pharmaceutical composition comprising: (a) from 25 to about 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; and (b) from 1 to about 15% by weight of sodium bicarbonate.
    [0093] In another embodiment, the pharmaceutical composition comprises: (a) from 25 to about 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; and (b) 1 to 15% weight of the sodium bicarbonate.
    [0094] Certain embodiments provide a pharmaceutical composition comprising: (a) from 25 to about 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; (b) from 1 to about 15% by weight of sodium bicarbonate; and (c) the remaining weight represents other pharmaceutically acceptable excipients and carriers.
    [0095] In another embodiment, the pharmaceutical composition comprises: (a) from 25 to about 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine;(b) weight from 1 to 15% sodium bicarbonate; and (c) the remaining weight represents other pharmaceutically acceptable excipients and carriers.
    [0096] Certain embodiments provide a pharmaceutical composition comprising: (a) from 40 to about 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; and (b) from 1 to about 15% by weight of sodium bicarbonate.
    [0097] In another embodiment, the pharmaceutical composition comprises: (a) 40 to 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7- yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; and (b) 1 to 15% weight of the sodium bicarbonate.
    [0098] Certain embodiments provide a pharmaceutical composition comprising: (a) from 40 to about 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine -7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; (b) from 1 to about of 15% by weight of sodium bicarbonate; (c) the remaining weight represents other pharmaceutically acceptable excipients and carriers.
    [0099] In another embodiment, the pharmaceutical composition comprises: (a) 40 to 60% by weight of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7 -yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine; (b) weight from 1 to 15% of sodium bicarbonate; (c) the remaining weight represents other pharmaceutically acceptable excipients and carriers.
    [00100] The pharmaceutical composition preferably contains a therapeutically effective amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine. However, in some embodiments, each individual dose contains a portion of the therapeutically effective amount of N4-(4 -([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydro-oxazol-2- yl)quinazoline-4,6-diamine, such that multiple doses of the composition may be necessary (e.g., two or more tablets are required for a therapeutically effective amount). Thus, in this application when the pharmaceutical composition is said to contain a therapeutically effective amount it is meant that the composition can be one dose (e.g. one tablet) or multiple doses (e.g. two tablets). In certain embodiments, the pharmaceutical composition contains between 1 and 500 mg of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [00101] In certain embodiments, the pharmaceutical composition contains between 25 and 400 mg of N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [00102] In certain embodiments, the pharmaceutical composition contains between 100 and 300 mg of N4-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine.
    [00103] The pharmaceutical compositions described herein may be administered by any convenient route appropriate to the condition being treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), ocular, vaginal, intraperitoneal, intrapulmonary and intranasal. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension suitable for injection or infusion.
    [00104] The compounds may be administered in any convenient administrative form, for example, tablets, powders, capsules, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
    [00105] The pharmaceutical compositions described herein are normally administered orally. The pharmaceutical compositions described herein are normally administered as a tablet, capsule, hard or soft gelatine capsule, pill, granules or suspension. METHODS OF TREATMENT WITH COMPOUNDS OF THE INVENTION
    [00106] Also provided are methods of treating or preventing disease or condition when administering the pharmaceutical composition described herein. In one embodiment, a human patient is treated with a pharmaceutical composition described herein in an amount to inhibit ErbB2 activity. In one embodiment, a human patient is treated with a pharmaceutical composition described herein in an amount to inhibit an ErbB2 activity.
    [00107] In another embodiment, a method of treating a hyperproliferative disease in a mammal comprising administering the pharmaceutical composition described herein to the mammal is provided.
    [00108] In certain embodiments, the hyperproliferative disease is cancer.
    [00109] In another embodiment, a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a pharmaceutical composition described herein. Cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, squamous cell carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, carcinoma of liver and bile passages, renal carcinoma, myeloid disorders, lymphoid disorders , hair cells, buccal cavity and pharynx (oral), lips, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's lymphoma and leukemia. Another embodiment provides for the use of a disclosed pharmaceutical composition in the manufacture of a drug for the treatment of cancer.
    [00110] In another embodiment, the cancer is ErbB2 positive.
    [00111] In another modality, breast, gastric, biliary, colorectal, lung, NSCLC, pancreas, head and neck, ovarian, uterine and brain cancer are selected.
    [00112] In another embodiment, the cancer is selected from breast, gastric, biliary, colorectal, lung, pancreas, head and neck NSCLC, ovarian and uterine cancer.
    [00113] In another modality, breast, gastric, colorectal, lung and ovarian cancer are selected.
    [00114] In another embodiment, the cancer is selected from breast, gastric, ovarian and uterine cancer.
    [00115] In another modality, breast, gastric, colorectal, NSCLC and ovarian cancer are selected.
    [00116] In another embodiment, the cancer is selected from breast, lung, pancreas, colorectal and head and neck cancers.
    [00117] In another embodiment, the cancer is breast cancer.
    [00118] In another embodiment, the cancer is gastric cancer.
    [00119] In another embodiment, the cancer is biliary cancer.
    [00120] In another embodiment, the cancer is colorectal cancer.
    [00121] In another embodiment, the cancer is lung cancer.
    [00122] In another embodiment, the cancer is NSCLC.
    [00123] In another embodiment, the cancer is pancreatic cancer.
    [00124] In another embodiment, the cancer is head and neck cancer.
    [00125] In another embodiment, the cancer is ovarian cancer.
    [00126] In another embodiment, the cancer is uterine cancer.
    [00127] In another embodiment, the cancer is brain cancer.
    [00128] In another embodiment, a method of treating or preventing a disease or disorder modulated by ErbB2, comprising administering to a mammal in need of such treatment an effective amount of a pharmaceutical composition described herein. Examples of such diseases and disorders include, but are not limited to, cancer.
    [00129] Another embodiment provides the use of a described pharmaceutical composition in the manufacture of a drug for the treatment of cancer.
    [00130] Another embodiment provides the solid dispersions described herein for the treatment of disease. In another embodiment, the disease is a hyperproliferative disease. In another embodiment, the hyperproliferative disease is cancer.
    [00131] Another embodiment provides the pharmaceutical compositions described herein for treating the disease. In another embodiment, the disease is a hyperproliferative disease. In another embodiment, the hyperproliferative disease is cancer. EXAMPLES
    [00132] For illustrative purposes, the following Examples are included. However, it is to be understood that these Examples do not limit the invention and are intended only to suggest a method of practicing the invention. Persons skilled in the art will recognize that the described chemical reactions can be readily adapted to prepare the compounds described herein, and alternative methods for preparing the compounds are considered within the scope of the present invention. For example, the synthesis of compounds described herein can be successfully accomplished by modifications apparent to those skilled in the art, for example, appropriately protecting interfering groups, using other appropriate reagents known in the art other than those described, and/or making modifications routine reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing the compounds described herein. Persons skilled in the art will also recognize that the solid dispersions and compositions described can be readily adapted to prepare other dispersions and compositions, and alternative methods of preparation, dispersions and compositions, as well as alternative compositions, are considered within the scope of the present invention. . Example 1 30% of Solid Dispersion using PVP-VA
    [00133] The solid dispersion was prepared containing 30 weight percent of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 - (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and PVP-VA using a mini spray dryer B Buchi-290. The solid dispersion was spray drying of a MeOH:THF (1:3) solvent system, a spray solution concentration of 5%, an inlet temperature of 100°C, with a flow rate of 22 mL/ minute, drying gas flow of 35m3/hour, nozzle pressure of 552 KPa (80 psig), nozzle gas flow of 0.66 m3/hour and a nozzle type of 1.5 mm. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. Spray drying yielded 19.6 g (87.7% yield) of the solid dispersion. The results of the physicochemical analyzes are shown in Table 1. The XRPD examination is shown in Figure 1. Residual solvent analysis revealed that the dispersion had less than 0.5% THF and no detectable MeOH.
    [00134] The dissolution test was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 2. The Cmax and AUC for the total drug species (colloidal + free) were 63.46 μg/mL and 245.05 μg/mL*h, respectively. The Cmax and AUC for the free drug species were 52.50 μg/mL and 204.12 μg/mL*h, respectively. Example 230% of Solid Scatter using Eudragit
    [00135] The solid dispersion was prepared containing 30 weight percent of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 - (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and Eudragit L100 using a mini spray dryer B Buchi-290. The solid dispersion was spray drying of a MeOH:THF (1:3) solvent system, a spray solution concentration of 5%, an inlet temperature of 100°C, with a flow rate of 22 mL/ minute, drying gas flow of 35m3/hour, nozzle pressure of 552 KPa (80 psig), nozzle gas flow of 0.66 m3/hour and a nozzle type of 1.5 mm. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. Spray drying yielded 18.6 g (82.7% yield) of the solid dispersion. The results of the physicochemical analyzes are in Table 1. The XRPD examination is shown in Figure 1. Residual solvent analysis showed that the dispersion had about 4.5% THF and no detectable MeOH.
    [00136] The dissolution test was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 3. The Cmax and AUC for the total drug species (colloidal + free) were 22.70 μg/mL and 71.06 μg/mL*h, respectively. The Cmax and AUC for the free drug species were 9.26 μg/mL and 35.49 μg/mL*h, respectively. 330% Solid Dispersion example using HPMCP
    [00137] The solid dispersion was prepared containing 30 weight percent of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 - (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and HPMCP H-55 using a mini spray dryer B Buchi-290. The solid dispersion was spray drying of a MeOH:THF (1:3) solvent system, a spray solution concentration of 5%, an inlet temperature of 100°C, with a flow rate of 22 mL/ minute, drying gas flow of 35m3/hour, nozzle pressure of 552 KPa (80 psig), nozzle gas flow of 0.66 m3/hour and a nozzle type of 1.5 mm. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. Spray drying yielded 20.3 g (90.3% yield) of the solid dispersion. The results of the physicochemical analyzes are shown in Table 1. The XRPD examination is shown in Figure 1. Residual solvent analysis revealed that the dispersion had less than 0.5% THF and no detectable MeOH.
    [00138] The dissolution test was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 4. The Cmax and AUC for the total drug species (colloidal + free) were 25.00 μg/mL and 96.66 μg/mL*h, respectively. The Cmax and AUC for the free drug species were 16.15 μg/mL and 56.81 μg/mL*h, respectively. Example 430% of Solid Dispersion using CAP
    [00139] The solid dispersion was prepared containing 30 weight percent of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 - (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and CAP using a Buchi-290 B mini spray dryer. The solid dispersion was spray drying of a MeOH:THF (1:3) solvent system, a spray solution concentration of 5%, an inlet temperature of 100°C, with a flow rate of 22 mL/ minute, drying gas flow of 35m3/hour, nozzle pressure of 552 KPa (80 psig), nozzle gas flow of 0.66 m3/hour and a nozzle type of 1.5 mm. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. Spray drying yielded 20.0 g (90.4% yield) of the solid dispersion. The results of the physicochemical analyzes are shown in Table 1. The XRPD examination is shown in Figure 1. Residual solvent analysis revealed that the dispersion had less than 0.5% THF and no detectable MeOH.
    [00140] The dissolution test was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 5. The Cmax and AUC for the total drug species (colloidal + free) were 11.62 μg/mL and 36.69 μg/mL*h, respectively. The Cmax and AUC for the free drug species were 5.64 μg/mL and 20.58 μg/mL*h, respectively. Example 530% of Solid Dispersion using HPMCAS
    [00141] The solid dispersion was prepared containing 30 weight percent of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 - (4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and Class M HPMCAS using a Buchi-290 B mini spray dryer. The solid dispersion was spray drying of a MeOH:THF (1:3) solvent system, a spray solution concentration of 5%, an inlet temperature of 80°C, with a flow rate of 22 mL/ minute, drying gas flow of 40m3/hour, nozzle pressure of 552 KPa (80 psig), nozzle gas flow of 0.66 m3/hour and a nozzle type of 1.5mm. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. Spray drying yielded 163.19 mg (48.3% yield) of the solid dispersion. The results of the physicochemical analyzes are shown in Table 1. The XRPD examination is shown in Figure 1. Residual solvent analysis revealed that the dispersion had less than 0.5% THF and no detectable MeOH.
    [00142] The dissolution test was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 6. The Cmax and AUC for the total drug species (colloidal + free) were 19.04 μg/mL and 68.09 μg/mL*h, respectively. The Cmax and AUC for the free drug species were 13.50 μg/mL and 51.74 μg/mL*h, respectively.
    Example 660% of Solid Dispersion using PVP-VA
    [00143] The solid dispersion was prepared containing 60 weight percent of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 - (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and PVP-VA using a mini spray dryer B Buchi-290. The solid dispersion was spray drying of a MeOH:THF (1:3) solvent system, a spray solution concentration of 5%, an inlet temperature of 80°C, with a flow rate of 22 mL/ minute, drying gas flow of 40m3/hour, nozzle pressure of 552 KPa (80 psig), nozzle gas flow of 0.66 m3/hour and a nozzle type of 1.5mm. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. Spray drying yielded 135.0 mg (88.2% yield) of the solid dispersion. The XRPD exam is shown in Figure 7.
    [00144] The dissolution test was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 8. The Cmax and AUC for the total drug species (colloidal + free) were 34.80 μg/mL and 133.76 μg/mL*h, respectively. The Cmax and AUC for the free drug species were 21.88 μg/mL and 84.43 μg/mL*h, respectively. Example 760% of Solid Dispersion using Eudragit
    [00145] The solid dispersion was prepared containing 60 weight percent of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 - (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and Eudragit L100 using a mini spray dryer B Buchi-290. The solid dispersion was spray-drying a solvent system of MeOH:THF (1:3), a spray solution concentration of 5%, an inlet temperature of 80°C, with a flow rate of 22 mL/ minute, drying gas flow of 40m3/hour, nozzle pressure of 552 KPa (80 psig), nozzle gas flow of 0.66 m3/hour and a nozzle type of 1.5mm. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. Spray drying yielded 88.1 mg (52.4% yield) of the solid dispersion. The XRPD exam is shown in Figure 7.
    [00146] The dissolution test was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 9. The Cmax and AUC for the total drug species (colloidal + free) were 26.82 μg/mL and 84.49 μg/mL*h, respectively. The Cmax and AUC for the free drug species were 9.85 μg/mL and 34.89 μg/mL*h, respectively. Example 860% of Solid Dispersion using HPMCP
    [00147] The solid dispersion was prepared containing 60 weight percent of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 - (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and HPMCP H-55 using a mini spray dryer B Buchi-290. The solid dispersion was spray drying of a MeOH:THF (1:3) solvent system, a spray solution concentration of 5%, an inlet temperature of 80°C, with a flow rate of 22 mL/ minute, drying gas flow of 40m3/hour, nozzle pressure of 552 KPa (80 psig), nozzle gas flow of 0.66 m3/hour and a nozzle type of 1.5mm. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. Spray drying yielded 98.0 mg (58.0% yield) of the solid dispersion. The XRPD exam is shown in Figure 7.
    [00148] The dissolution test was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are shown in Figure 10. The Cmax and AUC for the total drug species (colloidal + free) were 32.21 μg/mL and 38.28 μg/mL*h, respectively. The Cmax and AUC for the free drug species were 9.96 μg/mL and 38.28 μg/mL*h, respectively. Example 960% of Solid Dispersion using CAP
    [00149] The solid dispersion was prepared containing 60 weight percent of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 - (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and CAP using a Buchi-290 B mini spray dryer. The solid dispersion was spray drying of a MeOH:THF (1:3) solvent system, a spray solution concentration of 5%, an inlet temperature of 80°C, with a flow rate of 22 mL/ minute, drying gas flow of 40m3/hour, nozzle pressure of 552 KPa (80 psig), nozzle gas flow of 0.66 m3/hour and a nozzle type of 1.5mm. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. Spray drying yielded 74.9 mg (44.6% yield) of the solid dispersion. The XRPD exam is shown in Figure 7.
    [00150] The dissolution test was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are shown in Figure 11. The Cmax and AUC for the total drug species (colloidal + free) were 51.98 μg/mL and 144.91 μg/mL*h, respectively. The Cmax and AUC for the free drug species were 15.07 μg/mL and 59.69 μg/mL*h, respectively. 1060% Solid Dispersion example using HPMCAS
    [00151] The solid dispersion was prepared containing 60 weight percent of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 - (4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and Class M HPMCAS using a Buchi-290 B mini spray dryer. The solid dispersion was spray drying of a MeOH:THF (1:3) solvent system, a spray solution concentration of 5%, an inlet temperature of 80°C, with a flow rate of 22 mL/ minute, drying gas flow of 40m3/hour, nozzle pressure of 552 KPa (80 psig), nozzle gas flow of 0.66 m3/hour and a nozzle type of 1.5mm. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. Spray drying yielded 113.3 mg (67.2% yield) of the solid dispersion. The XRPD exam is shown in Figure 7.
    [00152] The dissolution test was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 12. The Cmax and AUC for the total drug species (colloidal + free) were 26.45 μg/mL and 96.21 μg/mL*h, respectively. The Cmax and AUC for the free drug species were 10.96 μg/mL and 42.83 μg/mL*h, respectively. Example 1150% of Solid Dispersion using PVP-PA
    [00153] The solid dispersion was prepared containing 50 weight percent of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 - (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and PVP-VA using a mini spray dryer B Buchi-290. The solid dispersion was spray drying of a MeOH:THF (1:3) solvent system, a spray solution concentration of 3.9%, an inlet temperature of 100°C, with a flow rate of 30 mL/minute, drying gas flow of 40m3/hour, nozzle pressure of 552 KPa (80 psig), nozzle gas flow of 0.66 m3/hour and a 1.5mm nozzle type. Secondary drying of the dispersion was done at 50°C under vacuum for about 72 hours. Spray drying yielded 28.7 g (72.7% yield) of the solid dispersion. Example 12N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5-di- hydro-oxazol-2-yl)quinazoline-4,6-diamine hemiethanolate free base
    [00154] Step 1: (E)-N'-(2-Cyano-4-(3-(1-hydroxy-2-methylpropane-2-yl)thioureide)phenyl)-N,N-dimethylformimidamide was coupled with 4 - ([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline in isopropyl acetate:acetic acid (65:35 v/v) at 45°C to produce 1-(4 -((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazoline-6-yl)-3-(1-hydroxy-2- methyl-2-yl)thiourea (91%).
    [00155] Step 2: 1-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazoline-6-yl) -3-(1-hydroxy-2-methylpropan-2-yl)thiourea was stirred in tetrahydrofuran under basic conditions of (2.5N NaOH), followed by the addition of p-toluenesulfonyl chloride. Water was charged to yield N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4, 5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine (96%) as a mixture of polymorphs (generally a mixture containing one or more of Form C, Form G hemi-THF, Form G mono- THF, Form M or Form P).
    [00156] Step 3: N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4, 5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine from step 2 was triturated in ethanol at greater than 65°C to provide N4-(4-([1,2,4]triazolo[1 ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine of Form B Ethanol (89%).
    [00157] The XRPD crystalline hemi-ethanolate (Form B Ethanol) scans are shown in Figures 1 and 7.
    [00158] The dissolution test was performed at a pH of 6.5 in phosphate buffer. The crystals (particles) were suspended in H2O and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The Cmax and AUC for the free drug species were 0.44 μg/mL and 5.49 μg/mL*h, respectively. Example 13Pharmaceutical Composition 1
    [00159] Tablets containing the solid dispersions of any one of Examples 1 to 11 may be prepared in a conventional manner which includes:

    [00160] In one preparation, tablets were made using OPADRY II 85F92727 at 3% by weight, as a long coat. The tablets contained 150 mg of API. Example 14Pharmaceutical Composition 2
    [00161] Tablets containing the solid dispersions of any one of Examples 1 to 11 may be prepared in a conventional manner which includes:


    [00162] In one preparation, tablets were made using OPADRY II 85F92727 at 3% by weight, as a long coat. The tablets contained 150 mg of API. Example 15Pharmaceutical Composition 3
    [00163] Tablets containing the solid dispersions of any one of Examples 1 to 11 may be prepared in a conventional manner which includes:

    [00164] In one preparation, tablets were made using OPADRY II 85F92727 at 3% by weight, as a long coat. The tablets contained 150 mg of API. Example 16 The Reference Pharmaceutical Composition - Powder in Capsule
    [00165] The PIC composition was prepared containing 25mg or 100mg of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 -(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine as prepared in example 12. The PIC composition was prepared in size 00 white opaque hard gelatine capsules .
    [00166] The dissolution test comparison was performed comparing the hemi-ethanolate crystalline PIC composition of example 16 and the solid dispersion tablet (Example 11) PVP-VA 50% of example 13 in 900 mL of the 10mm citrate buffer at 37°C and a pH of 4.5, using USP Apparatus II at 75 rpm. The results are shown in Figure 13. Example 17Stability Screen
    [00167] A spray drying stability screen of the dispersions was completed at 40°C, with 75% relative humidity when opening conditions, in glass vials, over a period of 8 days. The results are shown in TABLE 2.

    [00168] The main degradant observed was the carbamate impurity, probably due to the acidic nature of some of these polymers. XRPD analysis throughout the study showed no evidence of crystallization for any solid dispersion of Examples 1-4. Example 18In vivo Pharmacokinetics in Beagles
    [00169] The solid dispersion of Example 1 was tested against the crystalline, micronized suspension formulation (d(v, 0.9) = 3.0μm) of Example 12 under normal fasted conditions, as well as with pretreatment using pentagastrin or Famotidine. The solid dispersion of Example 1 was prepared as a suspension in water and administered orally. The micronized suspension of Example 12 was prepared as a suspension with SyrSpend® SF Seca reconstituted with water and administered orally. To reduce variability, the beagles were switched from pentagastrin to famotidine after a 5-day washout period. Pentagastrin is a pH modifier to change gastric pH to about 2 to 3, and Famotidine is a pH modifier to change gastric pH to about 5 to 7.5 (Zhou, Rong, de et al." pH-Dependent Dissolution in Vitro and Absorption in Vivo of Weakly Basic Drugs: Development of a Canine Model." Pharm. Res. Vol. 22, No. 2 (Feb. 2005): pp. 188-192 ). There were four beagles per group. Group A received pentagastrin pretreatment, the micronized suspension of Example 12, followed by a 5 day washout period, then the famotidine pretreatment, and finally the micronized suspension of Example 12. Group B received the pentagastrin pretreatment, the solid dispersion of Example 1, followed by a 5 day washout period, then the famotidine pretreatment, and finally the continuous dispersion of Example 1. Group B C received the micronized suspension of Example 12, followed by a 5 day washout period, and finally the solid dispersion of Example 1. The results are shown in TABLE 3.

    [00170] It will be understood that the enumerated embodiments are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention, as defined by the claims. Thus, the above description is considered to be illustrative only of the principles of the invention.
    [00171] The words "comprise", "comprising", "include", "including," and "includes" when used in this specification and the following statements are intended to specify the presence of declared characteristics, integers, components, or steps, but they do not exclude the presence or addition of one or more other characteristics, integers, components, steps, or respective groups.
    权利要求:
    Claims (24)
    [0001]
    1. Solid dispersion, characterized in that it comprises N4-(4-([1,2,4]triazo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4 -dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine amorphous and a dispersion polymer, wherein the dispersion polymer is PVP-VA.
    [0002]
    2. Solid dispersion according to claim 1, characterized in that N4-(4-([1,2,4]triazo[1,5-α]pyridine-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine is present in an amount of 0.1% to 50% by weight relative to the dispersion polymer .
    [0003]
    3. Solid dispersion according to claim 1, characterized in that N4-(4-([1,2,4]triazo[1,5-α]pyridine-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine is present in an amount of 5% to 35% by weight relative to the dispersion polymer.
    [0004]
    4. Solid dispersion according to claim 1, characterized in that N4-(4-([1,2,4]triazo[1,5-α]pyridine-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine is present in an amount of 25% to 35% by weight relative to the dispersion polymer.
    [0005]
    5. Solid dispersion according to claim 1, characterized in that at least 80% of N4-(4-([1,2,4]triazo[1,5-a]pyridine-7-yloxy)-3 -methylphenyl)-N 6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine is in amorphous form.
    [0006]
    6. Solid dispersion according to claim 1, characterized in that at least 95% of N4-(4-([1,2,4]triazo[1,5-a]pyridine-7-yloxy)-3 -methylphenyl)-N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine is in amorphous form.
    [0007]
    7. Pharmaceutical composition, characterized in that it comprises a solid dispersion as defined in claim 1, and one or more pharmaceutically acceptable excipients.
    [0008]
    8. Pharmaceutical composition according to claim 7, characterized in that the composition is a tablet.
    [0009]
    9. Pharmaceutical composition, characterized in that it comprises: (a) from 1 to 70% of the weight of solid dispersion as defined in claim 1; (b) from 0.1 to 20% of the weight of a disintegrant; (c) from 0.1 to 25% by weight of an osmotic agent; (d) from 0.1 to 10% by weight of a glidant; (e) from 0.1 to 10% by weight of a lubricant; and (f) from 0.1 to 25% by weight of a binding agent.
    [0010]
    10. Pharmaceutical composition, characterized in that it comprises: (a) from 1 to 70% of the weight of solid dispersion as defined in claim 1; (b) from 0.1 to 20% of the weight of a disintegrant; (c) from 0.1 to 25% by weight of an osmotic agent; (d) from 0.1 to 10% by weight of a glidant; (e) from 0.1 to 10% by weight of a lubricant; and (f) from 0.1 to 25% by weight of a filler.
    [0011]
    11. Pharmaceutical composition according to claim 9, characterized in that the binding agent is 10 to 25% by weight.
    [0012]
    12. Pharmaceutical composition according to claim 9, characterized in that the disintegrant is 5 to 15% by weight.
    [0013]
    13. Pharmaceutical composition according to claim 10, characterized in that the filler is 10 to 25% by weight.
    [0014]
    14. Pharmaceutical composition according to claim 9, characterized in that the disintegrant is 1 to 10% by weight.
    [0015]
    15. Pharmaceutical composition according to claim 9, characterized in that the osmotic agent is 15 to 25% by weight.
    [0016]
    16. Pharmaceutical composition according to claim 9, characterized in that the sliding agent is 0.1 to 3% by weight.
    [0017]
    17. Pharmaceutical composition according to claim 9, characterized in that the lubricant is 0.1 to 3% by weight.
    [0018]
    18. Pharmaceutical composition, characterized in that it comprises: (a) solid dispersion as defined in claim 1; and (b) sodium bicarbonate.
    [0019]
    19. Pharmaceutical composition, characterized in that it comprises: (a) from 1 to 70% of the weight of the solid dispersion as defined in claim 1; and (b) from 0.1 to 30% by weight of sodium bicarbonate.
    [0020]
    20. Pharmaceutical composition according to claim 9, characterized in that the solid dispersion is 25 to 60% by weight.
    [0021]
    21. Pharmaceutical composition according to claim 9, characterized in that the solid dispersion is 40 to 60% by weight.
    [0022]
    22. Pharmaceutical composition according to claim 9, characterized in that the composition is a tablet.
    [0023]
    Use of a solid dispersion as defined in claim 1 for preparing a pharmaceutical composition for treating ErbB2 positive breast cancer.
    [0024]
    24. Process of preparing a solid dispersion as defined in claim 1, characterized in that it comprises the steps of: (a) dissolving N4-(4-([1,2,4]triazole[1,5-a] pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)quinazoline-4,6-diamine and a suitable solvent dispersion polymer to form a feed solution; and (b) spray evaporating the solvent from the feed solution to form a solid dispersion.
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    同族专利:
    公开号 | 公开日
    AU2017210499C1|2021-04-29|
    AU2012322039B2|2017-08-17|
    CN108498465A|2018-09-07|
    MY169072A|2019-02-12|
    CY1119837T1|2018-06-27|
    CA2852058C|2021-06-01|
    AU2019200243C1|2021-04-29|
    JP5944514B2|2016-07-05|
    WO2013056108A2|2013-04-18|
    AU2019200243B2|2020-06-11|
    EP2765990B1|2017-09-06|
    RU2648448C2|2018-03-26|
    CL2014000930A1|2014-07-18|
    CA2852058A1|2013-04-18|
    DK2765990T3|2017-11-13|
    RS56608B1|2018-02-28|
    BR112014009092A2|2017-04-18|
    LT2765990T|2018-01-25|
    PL2765990T3|2018-01-31|
    AU2012322039A1|2014-06-05|
    JP2016027062A|2016-02-18|
    NO2021029I1|2021-07-09|
    HUE035247T2|2018-05-02|
    MX353970B|2018-02-07|
    KR20140075798A|2014-06-19|
    AU2012322039C1|2021-04-29|
    AU2017210499A1|2017-08-17|
    IL232103D0|2014-05-28|
    ZA201606123B|2021-05-26|
    US20170136022A1|2017-05-18|
    AU2017210499B2|2019-01-24|
    CN103998023A|2014-08-20|
    HRP20171578T1|2017-12-01|
    CO6960547A2|2014-05-30|
    ES2650608T3|2018-01-19|
    TWI722189B|2021-03-21|
    PT2765990T|2017-11-14|
    CR20140228A|2014-08-21|
    SI2765990T1|2017-11-30|
    RU2014119283A|2015-11-20|
    TWI594769B|2017-08-11|
    MX2014004551A|2015-02-12|
    WO2013056108A3|2013-06-27|
    JP2014528484A|2014-10-27|
    US9457093B2|2016-10-04|
    CN103998023B|2018-06-15|
    IL232103A|2018-11-29|
    SG11201401459YA|2014-07-30|
    AU2019200243A1|2019-01-31|
    TW202131902A|2021-09-01|
    KR102000312B1|2019-07-15|
    EP2765990A2|2014-08-20|
    NZ624942A|2016-06-24|
    US20210220361A1|2021-07-22|
    TW201728323A|2017-08-16|
    CA3114454A1|2013-04-18|
    ME02913B|2018-04-20|
    US20140296267A1|2014-10-02|
    TW201330876A|2013-08-01|
    US20190275043A1|2019-09-12|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-07-16| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-08-13| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-11-09| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2022-01-18| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 12/10/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201161547620P| true| 2011-10-14|2011-10-14|
    US61/547,620|2011-10-14|
    US201261606207P| true| 2012-03-02|2012-03-02|
    US61/606,207|2012-03-02|
    PCT/US2012/060044|WO2013056108A2|2011-10-14|2012-10-12|Solid dispersion|
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