WO2013142875A1 - Treatment of brain cancer - Google Patents

Treatment of brain cancer Download PDF

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Publication number
WO2013142875A1
WO2013142875A1 PCT/US2013/033751 US2013033751W WO2013142875A1 WO 2013142875 A1 WO2013142875 A1 WO 2013142875A1 US 2013033751 W US2013033751 W US 2013033751W WO 2013142875 A1 WO2013142875 A1 WO 2013142875A1
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WO
WIPO (PCT)
Prior art keywords
yloxy
triazolo
pyridin
methylphenyl
dihydrooxazol
Prior art date
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PCT/US2013/033751
Other languages
French (fr)
Inventor
Patrice A. Lee
Shannon L. WINSKI
Kevin Koch
Original Assignee
Array Biopharma Inc.
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=48048296&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2013142875(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to EP20210661.3A priority Critical patent/EP3842044A1/en
Priority to LTEP13714497.8T priority patent/LT2827900T/en
Priority to CA2867723A priority patent/CA2867723C/en
Priority to EP13714497.8A priority patent/EP2827900B1/en
Priority to SI201331019T priority patent/SI2827900T1/en
Priority to KR1020147029340A priority patent/KR102160462B1/en
Priority to PL18162971T priority patent/PL3400943T3/en
Priority to RU2014142700A priority patent/RU2672575C2/en
Priority to PL13714497T priority patent/PL2827900T3/en
Priority to CN201380015856.XA priority patent/CN104203279B/en
Priority to JP2015501952A priority patent/JP2015514075A/en
Priority to EP23163332.2A priority patent/EP4252855A3/en
Priority to NZ630843A priority patent/NZ630843A/en
Priority to KR1020207027176A priority patent/KR102317166B1/en
Priority to AU2013234921A priority patent/AU2013234921A1/en
Application filed by Array Biopharma Inc. filed Critical Array Biopharma Inc.
Priority to RS20180484A priority patent/RS57140B1/en
Priority to UAA201411479A priority patent/UA122044C2/en
Priority to SG11201405954YA priority patent/SG11201405954YA/en
Priority to DK13714497.8T priority patent/DK2827900T3/en
Priority to EP18162971.8A priority patent/EP3400943B1/en
Priority to ES13714497.8T priority patent/ES2673165T3/en
Priority to MX2014011437A priority patent/MX354024B/en
Priority to KR1020217033686A priority patent/KR102490961B1/en
Priority to US14/387,533 priority patent/US20150110780A1/en
Publication of WO2013142875A1 publication Critical patent/WO2013142875A1/en
Priority to PH12014502032A priority patent/PH12014502032A1/en
Priority to IL234627A priority patent/IL234627B/en
Priority to HK15107019.5A priority patent/HK1206276A1/en
Priority to AU2017272232A priority patent/AU2017272232C1/en
Priority to HRP20180659TT priority patent/HRP20180659T1/en
Priority to CY20181100493T priority patent/CY1120204T1/en
Priority to IL261659A priority patent/IL261659A/en
Priority to US16/402,068 priority patent/US11504370B2/en
Priority to AU2019203618A priority patent/AU2019203618B2/en
Priority to IL269205A priority patent/IL269205B/en
Priority to CY20211100126T priority patent/CY1123837T1/en
Priority to AU2021261849A priority patent/AU2021261849A1/en
Priority to US17/975,709 priority patent/US20230190749A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/4353Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • N4-(4-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for the treatment of brain cancer is provided herein.
  • N4-(4-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine also called "ARRY-380"
  • N4-(4-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine has been tested in human clinical trials for hyperproliferative diseases, particularly cancer, and more particularly metastatic breast cancer, colorectal cancer, and salivary gland cancer (see Koch, Kevin.
  • ARRY-380 A Selective, Oral HER2 Inhibitor for the Treatment of Solid Tumors.
  • Amplification or over-expression of ErbB2 has been shown to play a role in the pathogenesis and progression of certain cancers, such as breast, ovarian, gastric, uterine, colorectal and non-small cell lung cancer.
  • ErbB2+ breast cancer patients and a serious unmet medical need.
  • Patients with ErbB2+ breast cancer have a significantly increased incidence of brain metastases following trastuzumab therapy.
  • One aspect of the present invention provides N4-(4-([l ,2,4]Triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in treating brain cancer.
  • Another aspect provides a method of treating brain cancer in a mammal comprising administering a therapeutically effective amount of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to the mammal.
  • Another aspect provides a method of treating brain cancer in a patient having brain cancer comprising administering a therapeutically effective amount of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol to the patient.
  • Another aspect provides a method of treating or preventing brain cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)- 3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2- ((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol.
  • Another aspect provides a use of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol in the manufacture of a medicament for the treatment of brain cancer.
  • Another aspect provides a pharmaceutical composition for the treatment of brain cancer, comprising N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6- (4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4- ([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof.
  • Figure 1 shows the results of the growth of NCI-N87 cells implanted intracranially in mice.
  • Figure 2 shows the results of xenograft growth study of NCI-N87 cells implanted intracranially in mice.
  • Figure 3 shows the results of xenograft growth study of NCI-N87 cells implanted intracranially in mice.
  • Figure 4 shows the plasma results of brain pharmacokinetic study in mice.
  • Figure 5 shows the brain results of brain pharmacokinetic study in mice.
  • Figure 6 shows the results of xenograft growth study of BT474 cells implanted intracranially in mice.
  • Figure 7 shows the results of xenograft growth study of NCI-N87 cells implanted subcutaneously in mice.
  • amorphous means a solid in a solid state that is a non-crystalline state. Amorphous solids generally possess crystal-like short range molecular arrangement, but no long range order of molecular packing as found in crystalline solids. The solid state form of a solid may be determined by polarized light microscopy, x-ray powder diffraction, differential scanning calorimetry, or other standard techniques known to those of skill in the art.
  • amorphous solid dispersion means a solid comprising a drug 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)-N6- (4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol as the drug substance component and a dispersion polymer, wherein the amorphous solid dispersion contains the drug substance component in a substantially amorph
  • the substantially amorphous solid state form means at least 80% amorphous drug substance component. In certain embodiments, the substantially amorphous solid state form means at least 85% drug substance component. In certain embodiments, the substantially amorphous solid state form means at least 90% amorphous drug substance component. In certain embodiments, the substantially amorphous solid state form means at least 95% amorphous drug substance component.
  • composition polymer means a polymer that allows for N4-(4-
  • the dispersion polymer may contain a mixture of two or more polymers.
  • examples of dispersion polymers include, but are not limited to, vinyl polymers and copolymers, vinylpyrrolidine vinylacetate copolymer ("PVP-VA”), polyvinyl alcohols, polyvinyl alcohol polyvinyl acetate copolymers, polyvinyl pyrrolidine (“PVP”), acrylate and methacrylate copolymers, methylacrylic acid methyl methacrylate copolymer (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”),
  • CMEC carboxymethylethyl cellulose
  • CAP cellulose acetate phthalate
  • CAS cellulose acetate succinate
  • HPMCAP hydroxypropyl methyl cellulose acetate phthalate
  • CAT cellulose acetate trimellitate
  • HPMC AT hydroxypropyl methyl cellulose acetate trimellitate
  • CMCAB carboxymethylcellulose acetate butyrate
  • drug substance component means the N4-(4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol component of the solid dispersion.
  • 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, mice, hamsters, and primates, including humans.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • solid dispersion means a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component.
  • the solid dispersion discussed herein comprises one component of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol, the drug substance component, dispersed throughout another component, particularly a dispersion polymer.
  • spray drying means processes involved in breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture in a spray drying apparatus where there is a strong driving force for evaporation of solvent from the droplets.
  • spray drying is used conventionally and broadly. Spray drying processes and spray drying equipment are described generally in Perry, Robert H., and Don W. Green (eds.). Perry's Chemical Engineers' Handbook. New York: McGraw-Hill, 2007 (8 th edition).
  • terapéuticaally effective amount or “effective amount” mean an amount of a compound described herein that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular 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 upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • treat refers to therapeutic, prophylactic, palliative or preventative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • ARRY-380 is an active metabolite of ARRY-380.
  • (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol has higher brain penetration than either ARRY-380 or lapatinib (see Example 1).
  • This active metabolite helps maintain sustained levels of drug in the brain after oral dosing of ARRY- 380, which may contribute to enhanced activity.
  • N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for use in the treatment of brain cancer is provided.
  • (2-((4-((4-([l,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of brain cancer is provided.
  • (2-((4-((4-((4-([l,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of brain cancer comprising administering N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine is provided.
  • Brain cancer includes anaplastic astrocytoma, anaplastic mixed glioma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, germinoma, glioblastoma multiforme, gliosarcoma, low grade astrocytoma, low grade mixed oligoastrocytoma, low grade oligodendroglioma, central nervous system lymphoma, meduUoblastoma, meningioma, pilocytic astrocytoma, acoustic neuroma, chordoma, craniopharyngioma, brain stem glioma, ependymoma, optic nerve glioma, subependymoma, metastaic brain tumors, pituitary tumors, primitive neuroectodermal and scwannoma.
  • the brain cancer is local or metastatic brain cancer that is ErbB2 driven. In certain embodiments, the brain cancer is local or metastatic brain cancer that is driven by ErbB2. In certain embodiments, the brain cancer is local or metastatic brain cancer that is caused by ErbB2 over-expression and amplification. In certain
  • the brain cancer is local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification. In certain embodiments, the brain cancer is local or metastatic brain cancer that is caused by ErbB2 over-expression. In certain embodiments, the brain cancer is local or metastatic brain cancer that is caused by ErbB2 amplification. In certain embodiments, the brain cancer is local or metastatic brain cancer that is ErbB2 positive.
  • Brain cancer includes gliomas, meningiomas, pituitary adenomas and nerve sheath tumors. Brain cancer also includes anaplastic astrocytoma, anaplastic mixed glioma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, germinoma, glioblastoma multiforme, gliosarcoma, low grade astrocytoma, low grade mixed oligoastrocytoma, low grade oligodendroglioma, central nervous system lymphoma, meduUoblastoma, meningioma (particularly WHO Grade II and III), and pilocytic astrocytoma.
  • Brain cancer also includes acoustic neuroma, pilocytic astrocytoma (WHO Grade I), low-grade astrocytoma (WHO Grade II), anaplastic astrocytoma (WHO Grade III), glioblastoma multiforme (WHO Grade IV), chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, meduUoblastoma, meningioma, metastaic brain tumors, oligodendroglioma, pituitary tumors, primitive neuroectodermal, and scwannoma.
  • the brain cancer is ErbB2 positive.
  • the brain cancer is caused by ErbB2 over-expression or amplification.
  • the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for use in the treatment of brain cancer is administered from about 0.1 to about 2000 mg per day.
  • the total dose need not be administered all at once.
  • the administration is from about 25 to about 1600 mg per day.
  • the administration is from about 100 to about 1600 mg per day.
  • the administration is from about 800 to about 1600 mg per day.
  • the administration is at 800 to 1600 mg per day. In certain embodiments, the administration is from about 800 to about 1300 mg per day. In certain embodiments, the administration is at 800 to 1300 mg per day. In certain embodiments, the administration is from about 1 100 to about 1300 mg per day. In certain embodiments, the administration is at 1 100 to 1300 mg per day. In certain embodiments,
  • the administration is from about 1200 to about 1300 mg per day. In certain embodiments, the administration is at 1200 to 1300 mg per day. In certain embodiments, the administration is from about 1200 mg per day. In certain embodiments, the administration is at 1200 mg per day.
  • the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for the treatment of brain cancer is administered from about 400 to about 800 mg twice per day. In certain embodiments, the administration is at 400 to 800 mg twice per day. In certain embodiments, the administration is from about 400 to about 650 mg twice per day. In certain embodiments, the administration is at 400 to 650 mg twice per day. In certain embodiments, the administration is from about 550 to about 650 mg twice per day. In certain embodiments, the administration is at 550 to 650 mg twice per day. In certain embodiments, the
  • administration is from about 600 to about 650 mg twice per day. In certain embodiments, the administration is at 600 to 650 mg twice per day. In certain embodiments, the administration is at about 600 mg twice per day. In certain embodiments, the administration is at 600 mg twice per day.
  • 3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for the treatment of brain cancer is administered from about 0.1 to about 2000 mg per day.
  • the total dose need not be administered all at once.
  • the total dose need not be administered all at once.
  • administration is from about 25 to about 1800 mg per day. In certain embodiments, the administration is from about 25 to about 1600 mg per day. In certain embodiments, the administration is from about 100 to about 1800 mg per day. In certain embodiments, the administration is from about 100 to about 1600 mg per day. In certain embodiments, the administration is from about 800 to about 1600 mg per day. In certain embodiments, the administration is at 800 to 1600 mg per day. In certain embodiments, the administration is from about 800 to about 1300 mg per day. In certain embodiments, the administration at 800 to 1300 mg per day. In certain embodiments, the administration is from about 1 100 to about 1300 mg per day. In certain embodiments, the administration is at 1 100 to 1300 mg per day. In certain embodiments, the administration is from about 1200 to about 1300 mg per day. In certain embodiments, the administration is at 1200 to 1300 mg per day. In certain embodiments, the administration is at 1200 to 1300 mg per day. In certain embodiments, the administration is from about 25 to about 1800 mg per day. In certain embodiments, the administration
  • the administration is at about 1200 mg per day. In certain embodiments, the administration is at 1200 mg per day.
  • 3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for the treatment of brain cancer is admininstered from about 100 to about 1000 mg twice per day.
  • the administration is from about 100 to about 800 mg twice per day.
  • the administration is from about 100 to about 750 mg twice per day.
  • the administration is from about 100 to about 600 mg twice per day.
  • the administration is from about 200 to about 800 mg twice per day.
  • the administration is from about 400 to about 800 mg twice per day.
  • the administration is at 400 to 800 mg twice per day.
  • the administration is from about 400 to about 650 mg twice per day. In certain embodiments, the administration is at 400 to 650 mg twice per day. In certain embodiments, the administration is from about 550 to about 650 mg twice per day. In certain embodiments, the administration is at 550 to 650 mg twice per day. In certain embodiments, the
  • administration is from about 600 to about 650 mg twice per day. In certain embodiments, the administration is at 600 to 650 mg twice per day. In certain embodiments, the administration is at about 600 mg twice per day. In certain embodiments, the administration is at 600 mg twice per day.
  • the mixture of N4-(4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for the treatment of brain cancer is administered from about 0.1 to about 2000 mg per day. The total dose need not be
  • the administration is from about 25 to about 1800 mg per day. In certain embodiments, the administration is from about 25 to about 1600 mg per day. In certain embodiments, the administration is from about 100 to about 1800 mg per day. In certain embodiments, the administration is from about 100 to about 1600 mg per day. In certain embodiments, the administration is from about 800 to about 1600 mg per day. In certain embodiments, the administration is at 800 to 1600 mg per day. In certain embodiments, the administration is from about 800 to about 1300 mg per day. In certain embodiments, the administration is at 800 to 1300 mg per day. In certain embodiments, the administration is from about 1 100 to about 1300 mg per day. In certain embodiments, the administration is at 1 100 to 1300 mg per day.
  • the administration is from about 1200 to about 1300 mg per day. In certain embodiments, the administration is at 1200 to 1300 mg per day. In certain embodiments, the administration is at about 1200 mg per day. In certain embodiments, the administration is at 1200 mg per day.
  • the mixture of N4-(4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for the treatment of brain cancer is administered from about 100 to about 1000 mg twice per day.
  • the administration is from about 100 to about 800 mg twice per day. In certain embodiments, the administration is from about 100 to about 750 mg twice per day. In certain embodiments, the administration is from about 100 to about 600 mg twice per day. In certain embodiments, the administration is from about 200 to about 800 mg twice per day. In certain embodiments, the administration is from about 400 to about 800 mg twice per day. In certain embodiments, the administration is at 400 to 800 mg twice per day. In certain embodiments, the administration is from about 400 to about 650 mg twice per day. In certain embodiments, the administration is at 400 to 650 mg twice per day. In certain embodiments, the administration is from about 550 to about 650 mg twice per day. In certain embodiments, the administration is at 550 to 650 mg twice per day.
  • the administration is from about 600 to about 650 mg twice per day. In certain embodiments, the administration is at 600 to 650 mg twice per day. In certain embodiments, the administration is at about 600 mg twice per day. In certain embodiments, the administration is at 600 mg twice per day.
  • Solid dispersions are generally prepared by dissolving the drug substance and the dispersion polymer in a suitable solvent to form a feed solution, and then the feed solution may 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 the drug substance component and the dispersion polymer in a suitable solvent to prepare a feed solution.
  • the feed solution may be pumped through an atomizer into a drying chamber.
  • the feed solution can be atomized by conventional means known in the art, such as a two-fluid sonicating nozzle, a pressure nozzle, a rotating nozzle and a two-fluid non-sonicating nozzle.
  • a typical drying chamber uses hot gases, such as forced air, nitrogen, nitrogen-enriched air, or argon to dry particles.
  • the size of the drying chamber may be adjusted to achieve particle properties or throughput.
  • solid dispersion are preferably prepared by conventional spray drying techniques, other techniques known in the art may be used, such as melt extrusion, freeze drying, rotary evaporation, drum drying or other solvent removal processes.
  • the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP, HPMCAS and HPMC and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP- VA, methylacrylic 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, HPMCAS Grade M, HPMC and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® LI 00, HPMCP H-55, CAP, HPMCAS Grade M and HPMC.
  • the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMCAS, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMCAS. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® LI 00, HPMCP H-55, CAP and HPMCAS Grade M, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMCAS Grade M.
  • the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMC, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMC. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® LI 00, HPMCP H-55, CAP and HPMC, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMC.
  • the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP and CAP, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP and CAP. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55 and CAP, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® LI 00, HPMCP H-55 and CAP.
  • the dispersion polymer is PVP-VA.
  • the dispersion polymer is methylacrylic acid methyl methacrylate copolymer. In certain embodiments, the dispersion polymer is Eudragit®. In certain embodiments, the dispersion polymer is Eudragit® LI 00.
  • the dispersion polymer is HPMCP. In certain embodiments, the dispersion polymer is HPMCP H-55.
  • the dispersion polymer is CAP.
  • the dispersion polymer is HPMC AS. In certain embodiments, the dispersion polymer is HPMCAS Grade M.
  • the dispersion polymer is preferably neutral or basic.
  • the dispersion polymer is selected from PVP-VA and HPMC. In certain embodiments, the dispersion polymer is HPMC.
  • Suitable solvents are a solvent or mixture of solvents in which both drug substance component and the dispersion polymer have adequate solubility (solubility greater than 1 mg/mL).
  • a mixture of solvents may be used if each component of the solid dispersion (i.e., drug substance component and dispersion polymer) requires different solvents to obtain the desired solubility.
  • the solvent may be volatile with a boiling point of 150°C or less.
  • the solvent should have relatively low toxicity and be removed from the dispersion to a level that is acceptable to The International Committee on Harmonization ("ICH”) guidelines. Removal of solvent to this level may require a subsequent processing step, such as tray drying.
  • suitable solvents include, but are not limited to, alcohols, such as methanol (“MeOH”), ethanol (“EtOH”), n-propanol, isopropanol ("IP A”) 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.
  • THF tetrahydrofuran
  • ACN acetonitrile
  • methylene chloride toluene
  • 1,1,1- trichloroethane 1,1,1- trichloroethane.
  • Lower volatility solvents such as dimethyl acetate or dimethylsulfoxide (“DMSO”), may be used.
  • Mixtures of solvents with water may also be used, so long as the dispersion polymer and the drug substance are sufficiently soluble to make the spray drying process practicable.
  • nonaqueous solvents
  • the suitable solvent is selected from MeOH and THF, and mixtures thereof.
  • the suitable solvent is MeOH:THF solvent system of about 1 :3.
  • the suitable solvent is a 1 :3 MeOH:THF solvent system.
  • the suitable solvent is selected from MeOH, 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 a THF:MeOH:water solvent system of about 80: 10: 10. In certain embodiments, the suitable solvent is a 80: 10: 10 THF MeOH: water solvent system. In certain embodiments, the suitable solvent is a
  • the suitable solvent is a 82:8: 10 THF:MeOH:water solvent system.
  • the suitable solvent is a THF:MeOH:water solvent system of about 82.2:8.2:9.6.
  • the suitable solvent is a 82.2:8.2:9.6 THF:MeOH:water solvent system.
  • the amount of drug substance component in the solid dispersion ranges from about 0.1% to about 70% by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion ranges from 0.1% to 70%> by weight relative to the dispersion polymer.
  • the amount of drug substance component in the solid dispersion ranges from about 1% to about 60%> by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion ranges from 1% to 60% by weight relative to the dispersion polymer.
  • the amount of drug substance component in the solid dispersion ranges from about 5% to about 60% by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion ranges from 5% to 60% by weight relative to the dispersion polymer.
  • the amount of drug substance component in the solid dispersion ranges from about 55% to about 65 % by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion ranges from 55% to 65% by weight relative to the dispersion polymer. In certain
  • the amount of drug substance component in the solid dispersion is about 60%> by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion is 60%> by weight relative to the dispersion polymer.
  • the amount of drug substance component in the solid dispersion ranges from about 25% to about 35% by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion ranges from 25% to 35% by weight relative to the dispersion polymer. In certain embodiments,
  • the amount of drug substance component in the solid dispersion is about 30% by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion is 30% by weight relative to the dispersion polymer.
  • the amount of drug substance component in the solid dispersion ranges from about 45% to about 55% by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion ranges from 45% to 55% by weight relative to the dispersion polymer. In certain embodiments,
  • the amount of drug substance component in the solid dispersion is about 50% by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion is 50% by weight relative to the dispersion polymer.
  • the solid dispersion is an amorphous solid dispersion.
  • the solid dispersion is administered orally. In certain embodiments, the solid dispersion is in a tablet. In certain embodiments, the amorphous solid dispersion is in a tablet.
  • the therapeutic agent is selected from trastuzumab, capecitabine, bevacizumab, and taxanes. In certain embodiments, the therapeutic agent is selected from trastuzumab, capecitabine, bevacizumab, paclitaxel and docetaxel. In certain embodiments, the therapeutic agent is trastuzumab. In certain embodiments, the therapeutic agent is capecitabine. In certain embodiments, the therapeutic agent is bevacizumab. In certain embodiments, the therapeutic agent is paclitaxel. In certain embodiments, the therapeutic agent is docetaxel.
  • the previous treatment for brain cancer is selected from surgery, radiation therapy and chemotherapy or mixtures thereof.
  • the previous treatment for brain cancer is selected from surgery, conventional external radiation therapy, three-dimensional conformal radiation therapy, intensity modulated radiation therapy, stereotactic radiosurgery, fractionated stereotactic radiation therapy, proton radiation therapy, internal or implant radiation therapy, temozolomide, bevacizumab, carmustine, lomustine, procarbazine, vincristine, tumor treating fields therapy, everolimus, procarbazine, lomustine, cisplatin, carboplatin and methotrexate or mixtures thereof.
  • the previous treatment for breast cancer is selected from surgery, sentinel lymph node biopsy followed by surgery, radiation therapy, chemotherapy, hormone therapy and targeted therapy.
  • the previous treatment for breast cancer is selected from
  • lumpectomy partial mastectomy, segmental mastectomy, total mastectomy, modified radical mastectomy, external radiation, internal radiation, ado-trastuzumab emtansine, anastrozole, bevacizumab, capecitabine, carboplatin, cyclophosphamide, darbepoetin alfa, daunorubicin, denosumab, docetaxel, doxorubicin, epirubicin, epoetin alfa, eribulin, everolimus, exemestane, filgrastim, fluorouracil, fluoxymesterone, fulvestrant, gemcitabine, goserelin, ixabepilone, lapatinib, letrozole, leucovorin, leuprolide, megestrol, methotrexate,
  • mitoxantrone mutamycin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, pamidronate, pegfilgrastim, pertuzumab, raloxifene, tamoxifen, thiotepa, toremifene, trastuzumab, trastuzumab emtansine, triptorelin, vincristine, vinorelbine and zoledronic acid or mixtures thereof.
  • the previous treatment for breast cancer is selected from bevacizumab, capecitabine, carboplatin, cyclophosphamide, daunorubicin, docetaxel, doxorubicin, epirubicin, eribulin, everolimus, fluorouracil, gemcitabine, ixabepilone, methotrexate, mitoxantrone, mutamycin, paclitaxel, paclitaxel albumin- stabilized nanoparticle formulation, tamoxifen, trastuzumab, trastuzumab emtansine, vincristine and vinorelbine or mixtures thereof.
  • a method of treating brain cancer in a mammal comprising administering a therapeutically effective amount of N4-(4-([l,2,4]triazolo[l,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazolm 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to the mammal is provided.
  • a method of treating brain cancer in a patient having brain cancer comprising administering a therapeutically effective amount of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol to the patient is provided.
  • a method of treating or preventing brain cancer in a mammal in need of such treatment comprises administering to said mammal a therapeutically effective amount of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)- 3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2- ((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol.
  • the effective amount is a therapeutically effective amount.
  • Another embodiment provides the use of N4-(4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., 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.
  • the pharmaceutical compositions may also include one or more additional components, such as buffers, dispersion agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, 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 manufacturing of the
  • composition i.e., medicament (see Ansel; Gennaro; and Rowe above).
  • the components of the pharmaceutical composition should be pharmaceutically acceptable.
  • compositions for the treatment of brain cancer comprising:
  • the pharmaceutical composition for the treatment of brain cancer comprises:
  • compositions for the treatment of brain cancer comprising:
  • the pharmaceutical composition for the treatment of brain cancer comprises:
  • compositions for the treatment of brain cancer comprising:
  • the pharmaceutical composition for the treatment of brain cancer comprises:
  • compositions for the treatment of brain cancer comprising:
  • the pharmaceutical composition for the treatment of brain cancer comprises:
  • compositions for the treatment of brain cancer comprising:
  • the pharmaceutical composition for the treatment of brain cancer comprises: (a) 25 to 60 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof;
  • compositions for the treatment of brain cancer comprising:
  • the pharmaceutical composition for the treatment of brain cancer comprises:
  • the pharmaceutical composition for the treatment of brain cancer comprises a solid disepersion of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
  • the pharmaceutical composition for the treatment of brain cancer comprises a solid disepersion of (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol.
  • the osmogen is selected from NaCl and KC1, and mixtures thereof.
  • the lubricant is magnesium stearate.
  • the glidant is colloidal silicon dioxide.
  • the binder / diluent is microcrystalline cellulose. In certain embodiments, the binder / diluent acts as both a binder and a diluent.
  • the binder is microcrystalline cellulose.
  • the diluent is microcrystalline cellulose.
  • the filler is lactose.
  • the disintegrant is selected from crospovidone and sodium bicarbonate (NaHCOs), and mixtures thereof.
  • NaHCOs sodium bicarbonate
  • the disintegrant is selected from crospovidone and sodium bicarbonate (NaHCOs), and mixtures thereof.
  • disintegrant is selected from crospovidone and sodium bicarbonate. In certain embodiments, the disintegrant is sodium bicarbonate. In certain embodiments, the disintegrant is
  • the composition contains sodium bicarbonate. N4-(4-1)
  • Sodium bicarbonate helps to slow the degradation to the carbamate impurity. Sodium bicarbonate also helps to provide consistent tablet disintegration when the tablets are exposed to different humidities.
  • compositions for the treatment of brain cancer comprising:
  • compositions for the treatment of brain cancer comprising:
  • the pharmaceutical composition for the treatment of brain cancer comprises:
  • compositions for the treatment of brain cancer comprising:
  • the pharmaceutical composition for the treatment of brain cancer comprises:
  • compositions for the treatment of brain cancer comprising:
  • the pharmaceutical composition for the treatment of brain cancer comprises:
  • compositions for the treatment of brain cancer comprising:
  • the pharmaceutical composition for the treatment of brain cancer comprises:
  • compositions for the treatment of brain cancer comprising:
  • the pharmaceutical composition for the treatment of brain cancer comprises:
  • composition for the treatment of brain cancer comprising:
  • the pharmaceutical composition for the treatment of brain cancer comprises:
  • the pharmaceutical composition preferably contains a therapeutically effective amount of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol or mixtures thereof.
  • each individual dose contains a portion of a therapeutically effective amount of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof, such that multiple doses of the composition may be required (for example, two or more tablets are required for a therapeutically effective amount).
  • the pharmaceutical composition contains a therapeutically effective amount it means that the composition may be one dose (for example,
  • mice were euthanized by C0 2 inhalation. Brain and plasma were collected for analyses. Figure 2 shows the percentage of surviving mice.
  • Figure 3 shows that N4-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine significantly decreases phospho- ErbB2 / total ErbB2 in the brain.
  • Nude female BALB/c mice were administered a single PO dose (dose volume 10 mL/kg) of lapatanib (50 mg/kg, 30 % Captisol®) and N4-(4-([l,2,4]triazolo[l,5-a]pyridin- 7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (75 mg/kg, 30 % Captisol, weigh out compound and add 30 % Captisol® to give 7.5 mg/mL solution, then add 5 N HC1 in 200 increments until it forms a clear, yellow solution).
  • mice were separated into groups and their PK was studied at 4 time points (0.5, 1, 2 and 4 hours, 4 mice per group per timepoint).
  • the animals were euthanized by C0 2 inhalation at the time points.
  • Whole blood was drawn (300 ⁇ by cardiac puncture and plced in an eppendorf tube containing ethylenediaminetetraacetic acid ("EDTA") (37.5 ⁇ , 1.5%).
  • EDTA ethylenediaminetetraacetic acid
  • the samples were centrifuged, and the plasma was decanted and frozen at -20 °C until delivered to analytical chemistry.
  • the brains were collected.
  • the animals were perfused with 5-10 mL of saline, and the brains were removed, weighed and placed into a fast prep tube for DMPK analysis.
  • mice were administered vehicle (acidified 30 % Captisol®, pH about 4.5, 10 mL/kg, PO, BID), lapatanib (50 mg/kg, PO, BID, 30 % Captisol®), neratinib (40 mg/kg, QD, PO, acidified 30 % Captisol®) and N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine (75 mg/kg, PO, BID, 30 % Captisol, weigh out compound and add 30 %
  • Captisol® to give 7.5 mg/mL solution, then add 5 N HCl in 200 increments until it forms a clear, yellow solution). The mice were monitored daily for general health and
  • NCI Nude nu/nu female mice
  • Tumor cells (NCI-N87 gastric carcinoma cells, NCI, Bethesda, MD 1 X 10 7 ) were implanted into the mice via subcutaneous injection (100 ⁇ ) directly on the right flank. To ensure good tumor take, the cells should be greater than 90 % viable (thus, the intitial cell suspension of 1 X 10 7 cells/mL were injected for 1 X 10 6 cells injected / 100 ⁇ ). The tumors were allowed to grow to 150 ⁇ 50 mm 3 . The tumor size was measured, and the mice were weighed.
  • mice were administered vehicle (30 % Captisol®, 150 g in 500 mL DI water, PO, BID), lapatanib (50 mg/kg, PO, BID, 30 % Captisol®), lapatanib (100 mg/kg, PO, BID, 30 % Captisol®), N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (50 mg/kg, PO, QD, 30 %
  • a solid dispersion was prepared containing 30 weight percent N4-(4-
  • Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
  • the solid dispersion was suspended in H 2 0 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 total drug species (colloidal + free) was 63.46 ⁇ g/mL and 245.05 ⁇ g/mL*hr, respectively.
  • the Cmax and AUC for the free drug species was 52.50 ⁇ g/mL and 204.12 ⁇ g/mL*hr, respectively.
  • a solid dispersion was prepared containing 30 weight percent N4-(4-
  • Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
  • the solid dispersion was suspended in H 2 0 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 total drug species (colloidal + free) was 22.70 ⁇ g/mL and 71.06 ⁇ g/mL*hr, respectively.
  • the Cmax and AUC for the free drug species was 9.26 ⁇ g/mL and 35.49 ⁇ g/mL*hr, respectively.
  • a solid dispersion was prepared containing 30 weight percent N4-(4-
  • Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
  • the solid dispersion was suspended in H 2 0 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 total drug species (colloidal + free) was 25.00 ⁇ g/mL and 96.66 ⁇ g/mL*hr, respectively.
  • the Cmax and AUC for the free drug species was 16.15 ⁇ g/mL and 56.81 ⁇ g/mL*hr, respectively.
  • a solid dispersion was prepared containing 30 weight percent N4-(4-
  • Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
  • the solid dispersion was suspended in H 2 0 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 total drug species (colloidal + free) was 1 1.62 ⁇ g/mL and 36.69 ⁇ g/mL*hr, respectively.
  • the Cmax and AUC for the free drug species was 5.64 ⁇ g/mL and 20.58 ⁇ g/mL*hr, respectively.
  • a solid dispersion was prepared containing 30 weight percent N4-(4-
  • Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
  • the solid dispersion was suspended in H 2 0 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 total drug species (colloidal + free) was 19.04 ⁇ g/mL and 68.09 ⁇ g/mL*hr, respectively.
  • the Cmax and AUC for the free drug species was 13.50 ⁇ g/mL and 51.74 ⁇ g/mL*hr, respectively.
  • a solid dispersion was prepared containing 60 weight percent N4-(4-
  • Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
  • the solid dispersion was suspended in H 2 0 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 total drug species (colloidal + free) was 34.80 ⁇ g/mL and 133.76 ⁇ g/mL*hr, respectively.
  • the Cmax and AUC for the free drug species was 21.88 ⁇ g/mL and 84.43 ⁇ g/mL*hr, respectively.
  • Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
  • the solid dispersion was suspended in H 2 0 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 total drug species (colloidal + free) was 26.82 ⁇ g/mL and 84.49 ⁇ g/mL*hr, respectively.
  • the Cmax and AUC for the free drug species was 9.85 ⁇ g/mL and 34.89 ⁇ g/mL*hr, respectively.
  • a solid dispersion was prepared containing 60 weight percent N4-(4-
  • Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
  • the solid dispersion was suspended in H 2 0 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 total drug species (colloidal + free) was 32.21 ⁇ g/mL and 38.28 ⁇ g/mL*hr, respectively.
  • the Cmax and AUC for the free drug species was 9.96 ⁇ g/mL and 38.28 ⁇ g/mL*hr, respectively.
  • a solid dispersion was prepared containing 60 weight percent N4-(4-
  • Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
  • the solid dispersion was suspended in H 2 0 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 total drug species (colloidal + free) was 51.98 ⁇ g/mL and 144.91 ⁇ g/mL*hr, respectively.
  • the Cmax and AUC for the free drug species was 15.07 ⁇ g/mL and 59.69 ⁇ g/mL*hr, respectively.
  • a solid dispersion was prepared containing 60 weight percent N4-(4-
  • Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
  • the solid dispersion was suspended in H 2 0 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 total drug species (colloidal + free) was 26.45 ⁇ g/mL and 96.21 ⁇ g/mL*hr, respectively.
  • the Cmax and AUC for the free drug species was 10.96 ⁇ g/mL and 42.83 ⁇ g/mL*hr, respectively.
  • a solid dispersion was prepared containing 50 weight percent N4-(4-
  • Tablets containing the solid dispersions of any of Examples 6 to 16 may be prepared in a conventional manner comprising:
  • tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating.
  • the tablets contained 150 mg of API.
  • Tablets containing the solid dispersions of any of Examples 2 to 12 may be prepared in a conventional manner comprising:
  • tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating.
  • the tablets contained 150 mg of API.
  • Tablets containing the solid dispersions of any of Examples 2 to 12 may be prepared in a conventional manner comprising:
  • tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating.
  • the tablets contained 150 mg of API.
  • Step 1 (E)-N'-(2-Cyano-4-(3-(l-hydroxy-2-methylpropan-2-yl)thioureido) phenyl)-N,N-dimethylformimidamide was coupled with 4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylaniline in isopropyl acetate: acetic acid (65 :35 v/v) at 45°C to yield l-(4-((4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(l-hydroxy -2-methylpropan-2-yl)thiourea (91%).
  • Step 2 l-(4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl) amino)quinazolin-6-yl)-3-(l-hydroxy-2-methylpropan-2-yl)thiourea was agitated in tetrahydrofuran under basic conditions (2.5N NaOH), followed by the addition of p- toluenesulfonyl chloride.
  • Step 3 N4-(4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-
  • Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
  • the crystals (particles) were suspended in H 2 0 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 was 0.44 ⁇ g/mL and 5.49 ⁇ g/mL*hr, respectively.
  • the solid dispersion of Example 6 was prepared as a suspension in water and administered orally.
  • the micronized suspension of Example 21 was prepared as a suspension with SyrSpend® SF Dry reconstituted with water and administered orally. To reduce variability, beagles were crossed over from pentagastrin to famotidine after a 5 day washout period.
  • Pentagastrin is a pH modifier to modify gastric pH to about 2 to 3
  • famotidine is a pH modifier to modify gastric pH to about 5 to 7.5
  • Group A received pentagastrin pretreatment, the micronized suspension of Example 21, followed by a 5 day washout period, then famotidine pretreatment, and finally the micronized suspension of Example 21.
  • Group B received pentagastrin pretreatment, the solid dispersion of Example 6, followed by a 5 day washout period, then famotidine pretreatment, and finally the solid dispersion of Example 6.
  • Group C received the micronized suspension of Example 21, followed by a 5 day washout period, and finally the solid dispersion of Example 6. Results are shown in Table 6.

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Abstract

Compounds for the treatment of brain cancer are provided herein. Pharmaceutical compositions comprised of those compounds for the treatment of brain cancer are also provided herein.

Description

TREATMENT OF BRAIN CANCER
BACKGROUND OF THE INVENTION
[0001] FIELD OF THE INVENTION
[0002] N4-(4-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for the treatment of brain cancer is provided herein.
[0003] DESCRIPTION OF THE STATE OF THE ART
[0004] N4-(4-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (also called "ARRY-380"), which has the structure:
Figure imgf000002_0001
is a selective ErbB2 (HER2) inhibitor described in WO 2007/059257, which is incorporated by reference in its entirety. N4-(4-([l,2,4]Triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine has been tested in human clinical trials for hyperproliferative diseases, particularly cancer, and more particularly metastatic breast cancer, colorectal cancer, and salivary gland cancer (see Koch, Kevin.
"ARRY-380: A Selective, Oral HER2 Inhibitor for the Treatment of Solid Tumors."
American Association of Cancer Research 102nd Annual Meeting, April 3, 2011; which may also be found at: http://www.arraybiopharma.com/_documents/Publication/
Pub Attachment462.pdf) .
[0005] Amplification or over-expression of ErbB2 has been shown to play a role in the pathogenesis and progression of certain cancers, such as breast, ovarian, gastric, uterine, colorectal and non-small cell lung cancer.
[0006] In breast cancer patients, brain metastases are a leading cause of death in
ErbB2+ breast cancer patients and a serious unmet medical need. Patients with ErbB2+ breast cancer have a significantly increased incidence of brain metastases following trastuzumab therapy. There is an increasing incidence of brain metastases as women are living longer due to better treatments for systemic disease.
[0007] Accordingly, there remains a need for the treatment of brain cancer. SUMMARY OF THE INVENTION
[0008] One aspect of the present invention provides N4-(4-([l ,2,4]Triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in treating brain cancer.
[0009] Another aspect provides a method of treating brain cancer in a mammal comprising administering a therapeutically effective amount of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to the mammal.
[0010] Another aspect provides a method of treating brain cancer in a patient having brain cancer comprising administering a therapeutically effective amount of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol to the patient.
[0011] Another aspect provides a method of treating or preventing brain cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)- 3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2- ((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol.
[0012] Another aspect provides a use of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol in the manufacture of a medicament for the treatment of brain cancer.
[0013] Another aspect provides a pharmaceutical composition for the treatment of brain cancer, comprising N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6- (4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4- ([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof.
BRIEF DESCRIPTION OF THE FIGURES
[0014] Figure 1 shows the results of the growth of NCI-N87 cells implanted intracranially in mice.
[0015] Figure 2 shows the results of xenograft growth study of NCI-N87 cells implanted intracranially in mice.
[0016] Figure 3 shows the results of xenograft growth study of NCI-N87 cells implanted intracranially in mice.
[0017] Figure 4 shows the plasma results of brain pharmacokinetic study in mice.
[0018] Figure 5 shows the brain results of brain pharmacokinetic study in mice.
[0019] Figure 6 shows the results of xenograft growth study of BT474 cells implanted intracranially in mice.
[0020] Figure 7 shows the results of xenograft growth study of NCI-N87 cells implanted subcutaneously in mice.
DETAILED DESCRIPTION OF THE INVENTION
[0021] Reference will now be made in detail to certain embodiments. While enumerated embodiments will be described, it will be understood that they 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. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.
[0022] DEFINITIONS
[0023] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20%. [0024] The term "amorphous" means a solid in a solid state that is a non-crystalline state. Amorphous solids generally possess crystal-like short range molecular arrangement, but no long range order of molecular packing as found in crystalline solids. The solid state form of a solid may be determined by polarized light microscopy, x-ray powder diffraction, differential scanning calorimetry, or other standard techniques known to those of skill in the art.
[0025] The phrase "amorphous solid dispersion" means a solid comprising a drug 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)-N6- (4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol as the drug substance component and a dispersion polymer, wherein the amorphous solid dispersion contains the drug substance component in a substantially amorphous solid state form. In certain embodiments, the substantially amorphous solid state form means at least 80% amorphous drug substance component. In certain embodiments, the substantially amorphous solid state form means at least 85% drug substance component. In certain embodiments, the substantially amorphous solid state form means at least 90% amorphous drug substance component. In certain embodiments, the substantially amorphous solid state form means at least 95% amorphous drug substance component.
[0026] The phrase "dispersion polymer" means a polymer that allows for N4-(4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol to be dispersed throughout such that a solid dispersion may form. The dispersion polymer is preferably neutral or basic. The dispersion polymer may contain a mixture of two or more polymers. Examples of dispersion polymers include, but are not limited to, vinyl polymers and copolymers, vinylpyrrolidine vinylacetate copolymer ("PVP-VA"), polyvinyl alcohols, polyvinyl alcohol polyvinyl acetate copolymers, polyvinyl pyrrolidine ("PVP"), acrylate and methacrylate copolymers, methylacrylic acid methyl methacrylate copolymer (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 cellulose ("HPC"), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate ("HPMCAS"), hydroxypropyl methyl cellulose phthalate ("HPMCP"),
carboxymethylethyl 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 ("HPMC AT"), and carboxymethylcellulose acetate butyrate ("CMCAB"), and the like.
[0027] The term "drug substance component" means the N4-(4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol component of the solid dispersion.
[0028] 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, mice, hamsters, and primates, including humans.
[0029] The phrase "pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
[0030] The phrase "solid dispersion" means a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component. The solid dispersion discussed herein comprises one component of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol, the drug substance component, dispersed throughout another component, particularly a dispersion polymer.
[0031] The phrase "spray drying" means processes involved in breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture in a spray drying apparatus where there is a strong driving force for evaporation of solvent from the droplets. The phrase spray drying is used conventionally and broadly. Spray drying processes and spray drying equipment are described generally in Perry, Robert H., and Don W. Green (eds.). Perry's Chemical Engineers' Handbook. New York: McGraw-Hill, 2007 (8th edition).
[0032] The phrases "therapeutically effective amount" or "effective amount" mean an amount of a compound described herein that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular 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 upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
[0033] The terms "treat" or "treatment" refer to therapeutic, prophylactic, palliative or preventative measures. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
[0034] TREATMENT OF BRAIN CANCER
[0035] Provided herein is N4-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for use in treating brain cancer.
[0036] It has been found that (2-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol (also called "AR00440993"), which has the structure:
Figure imgf000007_0001
is an active metabolite of ARRY-380. (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol has higher brain penetration than either ARRY-380 or lapatinib (see Example 1). This active metabolite helps maintain sustained levels of drug in the brain after oral dosing of ARRY- 380, which may contribute to enhanced activity.
[0037] In certain embodiments, N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for use in the treatment of brain cancer is provided.
[0038] In certain embodiments, (2-((4-((4-([l,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of brain cancer is provided.
[0039] In certain embodiments, N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4- ((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof for use in the treatment of brain cancer are provided.
[0040] In certain embodiments, (2-((4-((4-([l,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of brain cancer comprising administering N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine is provided.
[0041] Brain cancer includes anaplastic astrocytoma, anaplastic mixed glioma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, germinoma, glioblastoma multiforme, gliosarcoma, low grade astrocytoma, low grade mixed oligoastrocytoma, low grade oligodendroglioma, central nervous system lymphoma, meduUoblastoma, meningioma, pilocytic astrocytoma, acoustic neuroma, chordoma, craniopharyngioma, brain stem glioma, ependymoma, optic nerve glioma, subependymoma, metastaic brain tumors, pituitary tumors, primitive neuroectodermal and scwannoma.
[0042] In certain embodiments, the brain cancer is local or metastatic brain cancer that is ErbB2 driven. In certain embodiments, the brain cancer is local or metastatic brain cancer that is driven by ErbB2. In certain embodiments, the brain cancer is local or metastatic brain cancer that is caused by ErbB2 over-expression and amplification. In certain
embodiments, the brain cancer is local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification. In certain embodiments, the brain cancer is local or metastatic brain cancer that is caused by ErbB2 over-expression. In certain embodiments, the brain cancer is local or metastatic brain cancer that is caused by ErbB2 amplification. In certain embodiments, the brain cancer is local or metastatic brain cancer that is ErbB2 positive.
[0043] Brain cancer includes gliomas, meningiomas, pituitary adenomas and nerve sheath tumors. Brain cancer also includes anaplastic astrocytoma, anaplastic mixed glioma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, germinoma, glioblastoma multiforme, gliosarcoma, low grade astrocytoma, low grade mixed oligoastrocytoma, low grade oligodendroglioma, central nervous system lymphoma, meduUoblastoma, meningioma (particularly WHO Grade II and III), and pilocytic astrocytoma. Brain cancer also includes acoustic neuroma, pilocytic astrocytoma (WHO Grade I), low-grade astrocytoma (WHO Grade II), anaplastic astrocytoma (WHO Grade III), glioblastoma multiforme (WHO Grade IV), chordoma, central nervous system lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, meduUoblastoma, meningioma, metastaic brain tumors, oligodendroglioma, pituitary tumors, primitive neuroectodermal, and scwannoma. In certain embodiments, the brain cancer is ErbB2 positive. In certain embodiments, the brain cancer is caused by ErbB2 over-expression or amplification.
[0044] In certain embodiments, the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for use in the treatment of brain cancer is administered from about 0.1 to about 2000 mg per day. The total dose need not be administered all at once. In certain embodiments, the administration is from about 25 to about 1600 mg per day. In certain embodiments, the administration is from about 100 to about 1600 mg per day. In certain embodiments, the administration is from about 800 to about 1600 mg per day. In certain embodiments, the administration is at 800 to 1600 mg per day. In certain embodiments, the administration is from about 800 to about 1300 mg per day. In certain embodiments, the administration is at 800 to 1300 mg per day. In certain embodiments, the administration is from about 1 100 to about 1300 mg per day. In certain embodiments, the administration is at 1 100 to 1300 mg per day. In certain
embodiments, the administration is from about 1200 to about 1300 mg per day. In certain embodiments, the administration is at 1200 to 1300 mg per day. In certain embodiments, the administration is from about 1200 mg per day. In certain embodiments, the administration is at 1200 mg per day.
[0045] In certain embodiments, the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for the treatment of brain cancer is administered from about 400 to about 800 mg twice per day. In certain embodiments, the administration is at 400 to 800 mg twice per day. In certain embodiments, the administration is from about 400 to about 650 mg twice per day. In certain embodiments, the administration is at 400 to 650 mg twice per day. In certain embodiments, the administration is from about 550 to about 650 mg twice per day. In certain embodiments, the administration is at 550 to 650 mg twice per day. In certain embodiments, the
administration is from about 600 to about 650 mg twice per day. In certain embodiments, the administration is at 600 to 650 mg twice per day. In certain embodiments, the administration is at about 600 mg twice per day. In certain embodiments, the administration is at 600 mg twice per day.
[0046] In certain embodiments, the (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-
3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for the treatment of brain cancer is administered from about 0.1 to about 2000 mg per day. The total dose need not be administered all at once. In certain embodiments, the
administration is from about 25 to about 1800 mg per day. In certain embodiments, the administration is from about 25 to about 1600 mg per day. In certain embodiments, the administration is from about 100 to about 1800 mg per day. In certain embodiments, the administration is from about 100 to about 1600 mg per day. In certain embodiments, the administration is from about 800 to about 1600 mg per day. In certain embodiments, the administration is at 800 to 1600 mg per day. In certain embodiments, the administration is from about 800 to about 1300 mg per day. In certain embodiments, the administration at 800 to 1300 mg per day. In certain embodiments, the administration is from about 1 100 to about 1300 mg per day. In certain embodiments, the administration is at 1 100 to 1300 mg per day. In certain embodiments, the administration is from about 1200 to about 1300 mg per day. In certain embodiments, the administration is at 1200 to 1300 mg per day. In certain
embodiments, the administration is at about 1200 mg per day. In certain embodiments, the administration is at 1200 mg per day.
[0047] In certain embodiments, the (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-
3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for the treatment of brain cancer is admininstered from about 100 to about 1000 mg twice per day. In certain embodiments, the administration is from about 100 to about 800 mg twice per day. In certain embodiments, the administration is from about 100 to about 750 mg twice per day. In certain embodiments, the administration is from about 100 to about 600 mg twice per day. In certain embodiments, the administration is from about 200 to about 800 mg twice per day. In certain embodiments, the administration is from about 400 to about 800 mg twice per day. In certain embodiments, the administration is at 400 to 800 mg twice per day. In certain embodiments, the administration is from about 400 to about 650 mg twice per day. In certain embodiments, the administration is at 400 to 650 mg twice per day. In certain embodiments, the administration is from about 550 to about 650 mg twice per day. In certain embodiments, the administration is at 550 to 650 mg twice per day. In certain embodiments, the
administration is from about 600 to about 650 mg twice per day. In certain embodiments, the administration is at 600 to 650 mg twice per day. In certain embodiments, the administration is at about 600 mg twice per day. In certain embodiments, the administration is at 600 mg twice per day.
[0048] In certain embodiments, the mixture of N4-(4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for the treatment of brain cancer is administered from about 0.1 to about 2000 mg per day. The total dose need not be
administered all at once. In certain embodiments, the administration is from about 25 to about 1800 mg per day. In certain embodiments, the administration is from about 25 to about 1600 mg per day. In certain embodiments, the administration is from about 100 to about 1800 mg per day. In certain embodiments, the administration is from about 100 to about 1600 mg per day. In certain embodiments, the administration is from about 800 to about 1600 mg per day. In certain embodiments, the administration is at 800 to 1600 mg per day. In certain embodiments, the administration is from about 800 to about 1300 mg per day. In certain embodiments, the administration is at 800 to 1300 mg per day. In certain embodiments, the administration is from about 1 100 to about 1300 mg per day. In certain embodiments, the administration is at 1 100 to 1300 mg per day. In certain embodiments, the administration is from about 1200 to about 1300 mg per day. In certain embodiments, the administration is at 1200 to 1300 mg per day. In certain embodiments, the administration is at about 1200 mg per day. In certain embodiments, the administration is at 1200 mg per day. [0049] In certain embodiments, the mixture of N4-(4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for the treatment of brain cancer is administered from about 100 to about 1000 mg twice per day. In certain embodiments, the administration is from about 100 to about 800 mg twice per day. In certain embodiments, the administration is from about 100 to about 750 mg twice per day. In certain embodiments, the administration is from about 100 to about 600 mg twice per day. In certain embodiments, the administration is from about 200 to about 800 mg twice per day. In certain embodiments, the administration is from about 400 to about 800 mg twice per day. In certain embodiments, the administration is at 400 to 800 mg twice per day. In certain embodiments, the administration is from about 400 to about 650 mg twice per day. In certain embodiments, the administration is at 400 to 650 mg twice per day. In certain embodiments, the administration is from about 550 to about 650 mg twice per day. In certain embodiments, the administration is at 550 to 650 mg twice per day. In certain embodiments, the administration is from about 600 to about 650 mg twice per day. In certain embodiments, the administration is at 600 to 650 mg twice per day. In certain embodiments, the administration is at about 600 mg twice per day. In certain embodiments, the administration is at 600 mg twice per day.
[0050] In certain embodiments, the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4- ((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof for the treatment of brain cancer is administered as an oral dosage form.
[0051] In certain embodiments, the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4- ((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof for the treatment of brain cancer is provided in a solid dispersion dosage form. In certain embodiments, the N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof for the treatment of brain cancer is provided in a solid dispersion oral dosage form. [0052] Solid dispersions are generally prepared by dissolving the drug substance and the dispersion polymer in a suitable solvent to form a feed solution, and then the feed solution may 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 the drug substance component and the dispersion polymer in a suitable solvent to prepare a feed solution. The feed solution may be pumped through an atomizer into a drying chamber. The feed solution can be atomized by conventional means known in the art, such as a two-fluid sonicating nozzle, a pressure nozzle, a rotating nozzle and a two-fluid non-sonicating nozzle. Then, the solvent is removed in the drying chamber to form the solid dispersion. A typical drying chamber uses hot gases, such as forced air, nitrogen, nitrogen-enriched air, or argon to dry particles. The size of the drying chamber may be adjusted to achieve particle properties or throughput.
[0053] Although the solid dispersion are preferably prepared by conventional spray drying techniques, other techniques known in the art may be used, such as melt extrusion, freeze drying, rotary evaporation, drum drying or other solvent removal processes.
[0054] In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP, HPMCAS and HPMC and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP- VA, methylacrylic 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, HPMCAS Grade M, HPMC and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® LI 00, HPMCP H-55, CAP, HPMCAS Grade M and HPMC.
[0055] In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMCAS, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMCAS. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® LI 00, HPMCP H-55, CAP and HPMCAS Grade M, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMCAS Grade M.
[0056] In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMC, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMC. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® LI 00, HPMCP H-55, CAP and HPMC, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMC.
[0057] In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP and CAP, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP and CAP. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55 and CAP, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® LI 00, HPMCP H-55 and CAP.
[0058] In certain embodiments, the dispersion polymer is PVP-VA.
[0059] In certain embodiments, the dispersion polymer is methylacrylic acid methyl methacrylate copolymer. In certain embodiments, the dispersion polymer is Eudragit®. In certain embodiments, the dispersion polymer is Eudragit® LI 00.
[0060] In certain embodiments, the dispersion polymer is HPMCP. In certain embodiments, the dispersion polymer is HPMCP H-55.
[0061] In certain embodiments, the dispersion polymer is CAP.
[0062] In certain embodiments, the dispersion polymer is HPMC AS. In certain embodiments, the dispersion polymer is HPMCAS Grade M.
[0063] 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 HPMC.
[0064] Suitable solvents are a solvent or mixture of solvents in which both drug substance component and the dispersion polymer have adequate solubility (solubility greater than 1 mg/mL). A mixture of solvents may be used if each component of the solid dispersion (i.e., drug substance component and dispersion polymer) requires 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 should have relatively low toxicity and be removed from the dispersion to a level that is acceptable to The International Committee on Harmonization ("ICH") guidelines. Removal of solvent to this level may require a subsequent processing step, such as tray drying. Examples of suitable solvents include, but are not limited to, alcohols, such as methanol ("MeOH"), ethanol ("EtOH"), n-propanol, isopropanol ("IP A") 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. Lower volatility solvents, such as dimethyl acetate or dimethylsulfoxide ("DMSO"), may be used. Mixtures of solvents with water may also be used, so long as the dispersion polymer and the drug substance are sufficiently soluble to make the spray drying process practicable. Generally, due to the hydrophobic nature of low solubility drugs, nonaqueous solvents may be used, meaning the solvent comprises less than about 10 weight % water.
[0065] In certain embodiments, the suitable solvent is selected from MeOH and THF, and mixtures thereof. In certain embodiments, the suitable solvent is MeOH:THF solvent system of about 1 :3. In certain embodiments, the suitable solvent is a 1 :3 MeOH:THF solvent system.
[0066] In certain embodiments, the suitable solvent is selected from MeOH, 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 a THF:MeOH:water solvent system of about 80: 10: 10. In certain embodiments, the suitable solvent is a 80: 10: 10 THF MeOH: water solvent system. In certain embodiments, the suitable solvent is a
THF MeOH: water solvent system of about 82:8: 10. In certain embodiments, the suitable solvent is a 82:8: 10 THF:MeOH:water solvent system. In certain embodiments, the suitable solvent is a THF:MeOH:water solvent system of about 82.2:8.2:9.6. In certain embodiments, the suitable solvent is a 82.2:8.2:9.6 THF:MeOH:water solvent system.
[0067] In certain embodiments, the amount of drug substance component in the solid dispersion ranges from about 0.1% to about 70% by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion ranges from 0.1% to 70%> by weight relative to the dispersion polymer.
[0068] In certain embodiments, the amount of drug substance component in the solid dispersion ranges from about 1% to about 60%> by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion ranges from 1% to 60% by weight relative to the dispersion polymer.
[0069] In certain embodiments, the amount of drug substance component in the solid dispersion ranges from about 5% to about 60% by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion ranges from 5% to 60% by weight relative to the dispersion polymer.
[0070] In certain embodiments, the amount of drug substance component in the solid dispersion ranges from about 55% to about 65 % by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion ranges from 55% to 65% by weight relative to the dispersion polymer. In certain
embodiments, the amount of drug substance component in the solid dispersion is about 60%> by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion is 60%> by weight relative to the dispersion polymer.
[0071] In certain embodiments, the amount of drug substance component in the solid dispersion ranges from about 25% to about 35% by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion ranges from 25% to 35% by weight relative to the dispersion polymer. In certain
embodiments, the amount of drug substance component in the solid dispersion is about 30% by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion is 30% by weight relative to the dispersion polymer.
[0072] In certain embodiments, the amount of drug substance component in the solid dispersion ranges from about 45% to about 55% by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion ranges from 45% to 55% by weight relative to the dispersion polymer. In certain
embodiments, the amount of drug substance component in the solid dispersion is about 50% by weight relative to the dispersion polymer. In certain embodiments, the amount of drug substance component in the solid dispersion is 50% by weight relative to the dispersion polymer.
[0073] In certain embodiments, the solid dispersion is an amorphous solid dispersion.
In certain embodiments, the solid dispersion is administered orally. In certain embodiments, the solid dispersion is in a tablet. In certain embodiments, the amorphous solid dispersion is in a tablet.
[0074] In certain embodiments, the administration of N4-(4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof is administered orally. In certain embodiments, the administration of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof is administered in the form of a tablet.
[0075] In certain embodiments, the treatment of brain cancer with N4-(4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof is in combination with another therapeutic agent. Such therapeutic agents are suitably present in combination in amounts that are effective for the purpose intended. The compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.
[0076] In certain embodiments, the therapeutic agent is selected from trastuzumab, capecitabine, bevacizumab, and taxanes. In certain embodiments, the therapeutic agent is selected from trastuzumab, capecitabine, bevacizumab, paclitaxel and docetaxel. In certain embodiments, the therapeutic agent is trastuzumab. In certain embodiments, the therapeutic agent is capecitabine. In certain embodiments, the therapeutic agent is bevacizumab. In certain embodiments, the therapeutic agent is paclitaxel. In certain embodiments, the therapeutic agent is docetaxel.
[0077] In certain embodiments, the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4- ((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof for use in treating brain cancer, is used after previous treatment for cancer.
[0078] In certain embodiments, the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4- ((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof for use in treating brain cancer, is used after previous treatment for brain cancer. In certain embodiments, the previous treatment for brain cancer is selected from surgery, radiation therapy and chemotherapy or mixtures thereof. In certain embodiments, the previous treatment for brain cancer is selected from surgery, conventional external radiation therapy, three-dimensional conformal radiation therapy, intensity modulated radiation therapy, stereotactic radiosurgery, fractionated stereotactic radiation therapy, proton radiation therapy, internal or implant radiation therapy, temozolomide, bevacizumab, carmustine, lomustine, procarbazine, vincristine, tumor treating fields therapy, everolimus, procarbazine, lomustine, cisplatin, carboplatin and methotrexate or mixtures thereof.
[0079] In certain embodiments, the N4-(4-([l,2,4]triazolo[l,5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof for use in treating brain cancer, is used after previous treatment for breast cancer. In certain embodiments, the previous treatment for breast cancer is selected from surgery, sentinel lymph node biopsy followed by surgery, radiation therapy, chemotherapy, hormone therapy and targeted therapy. In certain embodiments, the previous treatment for breast cancer is selected from
lumpectomy, partial mastectomy, segmental mastectomy, total mastectomy, modified radical mastectomy, external radiation, internal radiation, ado-trastuzumab emtansine, anastrozole, bevacizumab, capecitabine, carboplatin, cyclophosphamide, darbepoetin alfa, daunorubicin, denosumab, docetaxel, doxorubicin, epirubicin, epoetin alfa, eribulin, everolimus, exemestane, filgrastim, fluorouracil, fluoxymesterone, fulvestrant, gemcitabine, goserelin, ixabepilone, lapatinib, letrozole, leucovorin, leuprolide, megestrol, methotrexate,
mitoxantrone, mutamycin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, pamidronate, pegfilgrastim, pertuzumab, raloxifene, tamoxifen, thiotepa, toremifene, trastuzumab, trastuzumab emtansine, triptorelin, vincristine, vinorelbine and zoledronic acid or mixtures thereof. In certain embodiments, the previous treatment for breast cancer is selected from bevacizumab, capecitabine, carboplatin, cyclophosphamide, daunorubicin, docetaxel, doxorubicin, epirubicin, eribulin, everolimus, fluorouracil, gemcitabine, ixabepilone, methotrexate, mitoxantrone, mutamycin, paclitaxel, paclitaxel albumin- stabilized nanoparticle formulation, tamoxifen, trastuzumab, trastuzumab emtansine, vincristine and vinorelbine or mixtures thereof.
[0080] In another embodiment, a method of treating brain cancer in a mammal comprising administering a therapeutically effective amount of N4-(4-([l,2,4]triazolo[l,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazolm 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to the mammal is provided.
[0081] In another embodiment, a method of treating brain cancer in a patient having brain cancer comprising administering a therapeutically effective amount of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol to the patient is provided.
[0082] In another embodiment, a method of treating or preventing brain cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)- 3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2- ((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol.
[0083] In another embodiment, a method of treating brain cancer in a mammal using
(2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol comprising administering an effective amount of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl- 4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine to the mammal is provided.
[0084] In another embodiment, a method of treating brain cancer using (2-((4-((4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol in a patient having brain cancer comprising administering an effective amount of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine to the patient is provided.
[0085] In another embodiment, a method of treating or preventing local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification using (2-((4-((4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol in a mammal in need of such treatment, wherein the method comprises administering to the mammal an effective amount of N4-(4- ([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine is provided.
[0086] In certain embodiments, the effective amount is a therapeutically effective amount.
[0087] Another embodiment provides the use of N4-(4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-
7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol in the manufacture of a medicament for the treatment of brain cancer.
[0088] Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., 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.
[0089] The pharmaceutical compositions may also include one or more additional components, such as buffers, dispersion agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, 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 manufacturing of the
pharmaceutical product, i.e., medicament (see Ansel; Gennaro; and Rowe above). The components of the pharmaceutical composition should be pharmaceutically acceptable.
[0090] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) about 1 to about 70 weight % of a solid dispersion of N4-(4- ([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof;
(b) about 0.1 to about 20 weight % of a disintegrant;
(c) about 0.1 to about 25 weight % of an osmogen;
(d) about 0.1 to about 10 weight % of a glidant; (e) about 0.1 to about 10 weight % of a lubricant; and
(f) about 0.1 to about 25 weight % of a binder / diluent.
In a further embodiment, the pharmaceutical composition for the treatment of brain cancer comprises:
(a) 1 to 70 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-
7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof;
(b) 0.1 to 20 weight % 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.
[0091] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) about 25 to about 60 weight % of a solid dispersion of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof;
(b) about 5 to about 15 weight % of a disintegrant;
(c) about 15 to about 25 weight % of an osmogen;
(d) about 0.1 to about 3 weight % of a glidant;
(e) about 0.1 to about 3 weight % of a lubricant; and
(f) about 10 to about 25 weight % of a binder / diluent.
In a further embodiment, the pharmaceutical composition for the treatment of brain cancer comprises:
(a) 25 to 60 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof;
(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.
[0092] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) about 40 to about 60 weight % of a solid dispersion of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof;
(b) about 5 to about 15 weight % of a disintegrant;
(c) about 15 to about 25 weight % of an osmogen;
(d) about 0.1 to about 3 weight % of a glidant;
(e) about 0.1 to about 3 weight % of a lubricant; and
(f) about 10 to about 25 weight % of a binder / diluent.
In a further embodiment, the pharmaceutical composition for the treatment of brain cancer comprises:
(a) 40 to 60 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof;
(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.
[0093] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) about 1 to about 70 weight % of a solid dispersion of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof;
(b) about 0.1 to about 20 weight % of a disintegrant;
(c) about 0.1 to about 25 weight % of an osmogen;
(d) about 0.1 to about 10 weight % of a glidant;
(e) about 0.1 to about 10 weight % of a lubricant; and
(f) about 0.1 to about 25 weight % of a filler.
In a further embodiment, the pharmaceutical composition for the treatment of brain cancer comprises:
(a) 1 to 70 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof;
(b) 0.1 to 20 weight % 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.
[0094] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) about 25 to about 60 weight % of a solid dispersion of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof;
(b) about 1 to about 10 weight % of a disintegrant;
(c) about 15 to about 25 weight % of an osmogen;
(d) about 0.1 to about 3 weight % of a glidant;
(e) about 0.1 to about 3 weight % of a lubricant; and
(f) about 10 to about 25 weight % of a filler.
In a further embodiment, the pharmaceutical composition for the treatment of brain cancer comprises: (a) 25 to 60 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof;
(b) 1 to 10 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 filler.
[0095] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) about 40 to about 60 weight % of a solid dispersion of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof;
(b) about 1 to about 10 weight % of a disintegrant;
(c) about 15 to about 25 weight % of an osmogen;
(d) about 0.1 to about 3 weight % of a glidant;
(e) about 0.1 to about 3 weight % of a lubricant; and
(f) about 10 to about 25 weight % of a filler.
In a further embodiment, the pharmaceutical composition for the treatment of brain cancer comprises:
(a) 40 to 60 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof;
(b) 1 to 10 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 filler.
[0096] In certain embodiments, the pharmaceutical composition for the treatment of brain cancer comprises a solid disepersion of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
[0097] In certain embodiments, the pharmaceutical composition for the treatment of brain cancer comprises a solid disepersion of (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol.
[0098] In certain embodiments, the osmogen is selected from NaCl and KC1, and mixtures thereof.
[0099] In certain embodiments, the lubricant is magnesium stearate.
[00100] In certain embodiments, the glidant is colloidal silicon dioxide.
[00101] In certain embodiments, the binder / diluent is microcrystalline cellulose. In certain embodiments, the binder / diluent acts as both a binder and a diluent.
[00102] In certain embodiments, the binder is microcrystalline cellulose.
[00103] In certain embodiments, the diluent is microcrystalline cellulose.
[00104] In certain embodiments, the filler is lactose.
[00105] In certain embodiments, the disintegrant is selected from crospovidone and sodium bicarbonate (NaHCOs), 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.
[00106] In certain embodiments, the composition contains sodium bicarbonate. N4-(4-
([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine may slowly degrade, through hydrolysis or other means, to a carbamate impurity:
Figure imgf000025_0001
Sodium bicarbonate helps to slow the degradation to the carbamate impurity. Sodium bicarbonate also helps to provide consistent tablet disintegration when the tablets are exposed to different humidities.
[00107] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6- (4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof; and
(b) sodium bicarbonate.
[00108] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) about 1 to about 70 weight % of a solid dispersion of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof; and
(b) about 0.1 to about 30 weight % sodium bicarbonate.
In a further embodiment, the pharmaceutical composition for the treatment of brain cancer comprises:
(a) 1 to 70 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof; and
(b) 0.1 to 30 weight % sodium bicarbonate.
[00109] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) about 1 to about 70 weight % of a solid dispersion of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof; (b) about 0.1 to about 30 weight % sodium bicarbonate; and
(c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
In a further embodiment, the pharmaceutical composition for the treatment of brain cancer comprises:
(a) 1 to 70 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof;
(b) 0.1 to 30 weight % sodium bicarbonate; and
(c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
[00110] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) about 25 to about 60 weight % of a solid dispersion of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof; and
(b) about 1 to about 15 weight % of sodium bicarbonate.
In a further embodiment, the pharmaceutical composition for the treatment of brain cancer comprises:
(a) 25 to 60 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof; and
(b) 1 to 15 weight % of sodium bicarbonate.
[00111] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) about 25 to about 60 weight % of a solid dispersion of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof;
(b) about 1 to about 15 weight % of sodium bicarbonate; and
(c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
In a further embodiment, the pharmaceutical composition for the treatment of brain cancer comprises:
(a) 25 to 60 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof;
(b) 1 to 15 weight % of sodium bicarbonate; and
(c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
[00112] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) about 40 to about 60 weight % of a solid dispersion of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof; and
(b) about 1 to about 15 weight % of sodium bicarbonate.
In a further embodiment, the pharmaceutical composition for the treatment of brain cancer comprises:
(a) 40 to 60 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof; and
(b) 1 to 15 weight % of sodium bicarbonate. [00113] Certain embodiments provide a pharmaceutical composition for the treatment of brain cancer comprising:
(a) about 40 to about 60 weight % of a solid dispersion of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof;
(b) about 1 to about 15 weight % of sodium bicarbonate;
(c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
In a further embodiment, the pharmaceutical composition for the treatment of brain cancer comprises:
(a) 40 to 60 weight % of a solid dispersion of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or mixtures thereof;
(b) 1 to 15 weight % of sodium bicarbonate;
(c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
[00114] The pharmaceutical composition preferably contains a therapeutically effective amount of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol or mixtures thereof. However, in some embodiments, each individual dose contains a portion of a therapeutically effective amount of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol or mixtures thereof, such that multiple doses of the composition may be required (for example, two or more tablets are required for a therapeutically effective amount). Thus, in this application when it states that the pharmaceutical composition contains a therapeutically effective amount it means that the composition may be one dose (for example, one tablet) or multiple doses (for example, two tablets).
EXAMPLES
[00115] In the Examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius.
Example 1
Growth of NCI-N87 Gastric Carcinoma in Nude Mice Implanted Intracranially
[00116] Tumor cells (NCI-N87 gastric carcinoma cells, NCI, Bethesda, MD) were implanted in nude BALB/c female mice (Charles River Laboratories International, Inc.) via intracranial injection directly into the brain. The mice were separated into four groups (N = 5) and were injected with vehicle (saline), 1 X 105 tumor cells, 2.5 X 105 tumor cells, or 5 X 105 tumor cells. The results are shown in Figure 1. Brain tumor cell burden was associated with decreased survival in the NCI-N87 model.
[00117] In a pilot study using 14C albumin as the tracer and mannitol as the positive control for blood brain barrier (BBB) disruption, it was confirmed that the intracranial inoculation procedure did not mechanically disrupt the blood brain barrier.
Example 2
Inhibition of NCI-N87 Gastric Carcinoma Xenograft Growth in Mice Implanted
Intracranially
[00118] Anesthetized nude BALB/c female mice (Taconic Laboritories Inc.,
Germantown, NY) were inoculated with human tumor cells (NCI-N87 gastric carcinoma cells, NCI, Bethesda, MD) intracranially at lamba suture. 5 X 105 cells in saline were implanted via intracranial injection. The mice were separated into three groups (N = 12); vehicle (acidified 30 % Captisol®, pH about 4.5), 50 mg/kg lapatanib PO BID (30 %
Captisol®), and 75 mg/kg N4-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine PO BID (acidified 30 % Captisol®, pH about 4.5). Dosing began two days after implantation. The dose may have been reduced as necessary if drug-related weight loss (approximately 5 %) was observed. The mice were monitored twice daily for general health and behavioral/neurological effects, and body weights (BW) were determined twice weekly. At first sign of neurological problem or body weight loss of greater than 20 %, the mice were euthanized by C02 inhalation. Brain and plasma were collected for analyses. Figure 2 shows the percentage of surviving mice. Figure 3 shows that N4-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine significantly decreases phospho- ErbB2 / total ErbB2 in the brain.
Example 3
Brain Pharmacokinetic (PK) Study in Mice
[00119] Nude female BALB/c mice were administered a single PO dose (dose volume 10 mL/kg) of lapatanib (50 mg/kg, 30 % Captisol®) and N4-(4-([l,2,4]triazolo[l,5-a]pyridin- 7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (75 mg/kg, 30 % Captisol, weigh out compound and add 30 % Captisol® to give 7.5 mg/mL solution, then add 5 N HC1 in 200 increments until it forms a clear, yellow solution). The mice were separated into groups and their PK was studied at 4 time points (0.5, 1, 2 and 4 hours, 4 mice per group per timepoint). The animals were euthanized by C02 inhalation at the time points. Whole blood was drawn (300 μΐ by cardiac puncture and plced in an eppendorf tube containing ethylenediaminetetraacetic acid ("EDTA") (37.5 μί, 1.5%). The samples were centrifuged, and the plasma was decanted and frozen at -20 °C until delivered to analytical chemistry. The brains were collected. The animals were perfused with 5-10 mL of saline, and the brains were removed, weighed and placed into a fast prep tube for DMPK analysis.
[00120] The brain penetration of (2-((4-((4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol was significantly higher than lapatanib or N4-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. The plasma concertration ^g/mL) of the compounds is shown in Figure 4 and Table 1. The brain concentration (ng/g) of the compounds is shown in Figure 5 and Table 2. The brain:plasma ratio results are shown in Table 3.
Table 1
Average Plasma Concentration ^g/mL)
Time Point
(hour) Lapatanib AR Y-380 AR00440993
0.5 1913.75 3350.00 20.20
1 4310.00 6417.50 67.33
2 1743.75 6012.50 134.40
4 1942.50 2640.00 70.43 Table 2
Figure imgf000032_0001
Example 4
Inhibition of BT474 Breast Carcinoma Xenograft Growth in Mice Implanted Intracranially
[00121] Nude NCr female mice (Taconic Laboritories Inc., Germantown, NY) were split into four groups (N = 13). 17P-estradiol (0.5 mg)/progesterone (10 mg) pellets (35-day release) were implanted 1 day prior to BT-474 tumor cell inoculation. Tumor cells (1 X 106 BT474 breast carcinoma cells, ATCC, Manassas, VA) were implanted into the mice via intracranial injection directly into the brain. Treatment with vehicle or drugs began 2 days post-tumor cell implantation. The mice were administered vehicle (acidified 30 % Captisol®, pH about 4.5, 10 mL/kg, PO, BID), lapatanib (50 mg/kg, PO, BID, 30 % Captisol®), neratinib (40 mg/kg, QD, PO, acidified 30 % Captisol®) and N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine (75 mg/kg, PO, BID, 30 % Captisol, weigh out compound and add 30 %
Captisol® to give 7.5 mg/mL solution, then add 5 N HCl in 200 increments until it forms a clear, yellow solution). The mice were monitored daily for general health and
behavioral/neurological effects, and body weights were determined twice weekly. At first sign of neurological problem or body weight loss of greater than 20 %, the mice were euthanized by C02 inhalation. Brain and plasma were collected for analyses. Figure 6 shows the percentage of surviving mice.
Example 5
Anti-Tumor Efficacy on N87 Human Gastric Cancer in Murine Xenograft Model
[00122] Nude nu/nu female mice (NCI, Bethesda, MD) were split into five groups (N
= 8). Tumor cells (NCI-N87 gastric carcinoma cells, NCI, Bethesda, MD 1 X 107) were implanted into the mice via subcutaneous injection (100 μί) directly on the right flank. To ensure good tumor take, the cells should be greater than 90 % viable (thus, the intitial cell suspension of 1 X 107 cells/mL were injected for 1 X 106 cells injected / 100 μί). The tumors were allowed to grow to 150 ± 50 mm3. The tumor size was measured, and the mice were weighed. The mice were administered vehicle (30 % Captisol®, 150 g in 500 mL DI water, PO, BID), lapatanib (50 mg/kg, PO, BID, 30 % Captisol®), lapatanib (100 mg/kg, PO, BID, 30 % Captisol®), N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (50 mg/kg, PO, QD, 30 %
Captisol) and N4-(4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (100 mg/kg, PO, QD, 30 % Captisol). The tumor volume was measured. The number of partial responses in the mice was as follows: lapatanib (50 mg/kg) 0, lapatanib (100 mg/kg) 1 , ARRY-380 (50 mg/kg) 1 , ARRY-380 (100 mg/kg) 4. The results are shown in Figure 7.
Example 6
30% Solid Dispersion using PVP-VA
[00123] A solid dispersion was prepared containing 30 weight percent N4-(4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine and PVP-VA using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1 :3) solvent system, a 5% spray solution concentration, an inlet temperature of 100°C at a flow rate of 22 mL/minute, drying gas flow rate of 35 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 19.6 g (87.7% yield) of the solid dispersion. Physicochemical analysis results are in Table 4. Residual solvent analysis showed that the dispersion had less than 0.5% THF and no detectable MeOH.
[00124] Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 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 total drug species (colloidal + free) was 63.46 μg/mL and 245.05 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 52.50 μg/mL and 204.12 μg/mL*hr, respectively.
Example 7
30% Solid Dispersion using Eudragit
[00125] A solid dispersion was prepared containing 30 weight percent N4-(4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine and Eudragit LI 00 using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1 :3) solvent system, a 5% spray solution concentration, an inlet temperature of 100°C at a flow rate of 22 mL/minute, drying gas flow rate of 35 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 18.6 g (82.7% yield) of the solid dispersion. Physicochemical analysis results are in Table 4. Residual solvent analysis showed that the dispersion had about 4.5% THF and no detectable MeOH.
[00126] Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 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 total drug species (colloidal + free) was 22.70 μg/mL and 71.06 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 9.26 μg/mL and 35.49 μg/mL*hr, respectively.
Example 8
30% Solid Dispersion using HPMCP
[00127] A solid dispersion was prepared containing 30 weight percent N4-(4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCP H-55 using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1 :3) solvent system, a 5% spray solution concentration, an inlet temperature of 100°C at a flow rate of 22 mL/minute, drying gas flow rate of 35 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 20.3 g (90.3%> yield) of the solid dispersion. Physicochemical analysis results are in Table 4. Residual solvent analysis showed that the dispersion had less than 0.5% THF and no detectable MeOH.
[00128] Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 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 total drug species (colloidal + free) was 25.00 μg/mL and 96.66 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 16.15 μg/mL and 56.81 μg/mL*hr, respectively.
Example 9
30% Solid Dispersion using CAP
[00129] A solid dispersion was prepared containing 30 weight percent N4-(4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine and CAP using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1 :3) solvent system, a 5% spray solution concentration, an inlet temperature of 100°C at a flow rate of 22 mL/minute, drying gas flow rate of 35 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 20.0 g (90.4%> yield) of the solid dispersion. Physicochemical analysis results are in Table 4. Residual solvent analysis showed that the dispersion had less than 0.5% THF and no detectable MeOH.
[00130] Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 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 total drug species (colloidal + free) was 1 1.62 μg/mL and 36.69 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 5.64 μg/mL and 20.58 μg/mL*hr, respectively.
Example 10
30% Solid Dispersion using HPMCAS
[00131] A solid dispersion was prepared containing 30 weight percent N4-(4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCAS Grade M using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1 :3) solvent system, a 5% spray solution concentration, an inlet temperature of 80°C at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 163.19 mg (48.3% yield) of the solid dispersion. Physicochemical analysis results are in Table 4. Residual solvent analysis showed that the dispersion had less than 0.5% THF and no detectable MeOH.
[00132] Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 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 total drug species (colloidal + free) was 19.04 μg/mL and 68.09 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 13.50 μg/mL and 51.74 μg/mL*hr, respectively.
Table 4
Figure imgf000036_0001
Example 11
60% Solid Dispersion using PVP-VA
[00133] A solid dispersion was prepared containing 60 weight percent N4-(4-
([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine and PVP-VA using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1 :3) solvent system, a 5%> spray solution concentration, an inlet temperature of 80°C at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 135.0 mg (88.2% yield) of the solid dispersion.
[00134] Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 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 total drug species (colloidal + free) was 34.80 μg/mL and 133.76 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 21.88 μg/mL and 84.43 μg/mL*hr, respectively.
Example 12
60% Solid Dispersion using Eudragit
[00135] A solid dispersion was prepared containing 60 weight percent N4-(4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine and Eudragit LI 00 using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1 :3) solvent system, a 5% spray solution concentration, an inlet temperature of 80°C at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 88.1 mg (52.4% yield) of the solid dispersion.
[00136] Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 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 total drug species (colloidal + free) was 26.82 μg/mL and 84.49 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 9.85 μg/mL and 34.89 μg/mL*hr, respectively.
Example 13
60% Solid Dispersion using HPMCP
[00137] A solid dispersion was prepared containing 60 weight percent N4-(4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCP H-55 using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1 :3) solvent system, a 5% spray solution concentration, an inlet temperature of 80°C at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 98.0 mg (58.0% yield) of the solid dispersion.
[00138] Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 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 total drug species (colloidal + free) was 32.21 μg/mL and 38.28 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 9.96 μg/mL and 38.28 μg/mL*hr, respectively.
Example 14
60% Solid Dispersion using CAP
[00139] A solid dispersion was prepared containing 60 weight percent N4-(4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine and CAP using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1 :3) solvent system, a 5% spray solution concentration, an inlet temperature of 80°C at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 74.9 mg (44.6%> yield) of the solid dispersion.
[00140] Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 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 total drug species (colloidal + free) was 51.98 μg/mL and 144.91 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 15.07 μg/mL and 59.69 μg/mL*hr, respectively.
Example 15
60% Solid Dispersion using HPMCAS
[00141] A solid dispersion was prepared containing 60 weight percent N4-(4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCAS Grade M using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1 :3) solvent system, a 5% spray solution concentration, an inlet temperature of 80°C at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 1 13.3 mg (67.2% yield) of the solid dispersion.
[00142] Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 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 total drug species (colloidal + free) was 26.45 μg/mL and 96.21 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 10.96 μg/mL and 42.83 μg/mL*hr, respectively.
Example 16
50% Solid Dispersion using P VP-PA
[00143] A solid dispersion was prepared containing 50 weight percent N4-(4-
([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine and PVP-VA using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1 :3) solvent system, a 3.9% spray solution concentration, an inlet temperature of 100°C at a flow rate of 30 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 50°C under vacuum for about 72 hours. The spray drying yielded 28.7 g (72.7% yield) of the solid dispersion.
Example 17
Pharmaceutical Composition 1
[00144] Tablets containing the solid dispersions of any of Examples 6 to 16 may be prepared in a conventional manner comprising:
Function Ingredient % of Blend
API Solid dispersion as 50
prepared in Example
16
Disintegrant Crospovidone - 6
Polyplasdone®
Osmogen NaCl 5
Osmogen KC1 5
Glidant Colloidal Silicon 0.5
Dioxide
Figure imgf000040_0001
[00145] In one preparation, tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating. The tablets contained 150 mg of API.
Example 18
Pharmaceutical Composition 2
[00146] Tablets containing the solid dispersions of any of Examples 2 to 12 may be prepared in a conventional manner comprising:
Function Ingredient % of Blend
API Solid dispersion as 50
prepared in Example
16
Disintegrant Crospovidone - 6
Polyplasdone®
Disintegrant NaHC03 3
Osmogen NaCl 5
Osmogen KC1 5
Glidant Colloidal Silicon 0.5
Dioxide
Lubricant Magnesium Stearate 0.25
I xlrauraiuil r
Binder / Diluent Microcrystalline 16.25
cellulose - Avicel®
Osmogen NaCl 4.625
Osmogen KC1 4.625 Function Ingredient % of Blend
Disintegrant Polyplasdone 4
Glidant Colloidal Silicon 0.5
Dioxide
Lubricant Magnesium Stearate 0.25
[00147] In one preparation, tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating. The tablets contained 150 mg of API.
Example 19
Pharmaceutical Composition 3
[00148] Tablets containing the solid dispersions of any of Examples 2 to 12 may be prepared in a conventional manner comprising:
Figure imgf000041_0001
[00149] In one preparation, tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating. The tablets contained 150 mg of API. Example 20
Stability Screen
[00150] A stability screen of the spray dried dispersions was completed at 40°C, 75% relative humidity under open conditions, in glass vials, over a period of 8 days. Results are shown in Table 5.
Table 5
Figure imgf000042_0001
[00151] The main degradant observed was a carbamate impurity, likely due to the acidic nature of some of these polymers. XRPD analysis over the course of the study showed no evidence of crystallization for any solid dispersion of Examples 6-9.
Example 21
-(4-([1 ^1triazolo[l ,5-alpyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihvdrooxazol-2-vDquinazoline-4,6-diamine freebase hemi-ethanolate
[00152] Step 1 : (E)-N'-(2-Cyano-4-(3-(l-hydroxy-2-methylpropan-2-yl)thioureido) phenyl)-N,N-dimethylformimidamide was coupled with 4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylaniline in isopropyl acetate: acetic acid (65 :35 v/v) at 45°C to yield l-(4-((4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(l-hydroxy -2-methylpropan-2-yl)thiourea (91%).
[00153] Step 2: l-(4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl) amino)quinazolin-6-yl)-3-(l-hydroxy-2-methylpropan-2-yl)thiourea was agitated in tetrahydrofuran under basic conditions (2.5N NaOH), followed by the addition of p- toluenesulfonyl chloride. Water was charged to yield N4-(4-([l ,2,4]triazolo[l , 5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-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).
[00154] Step 3 : N4-(4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-
(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine from Step 2 was triturated in ethanol at greater than 65°C to provide N4-(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine Form B Ethanol (89%).
[00155] Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The crystals (particles) were suspended in H20 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 was 0.44 μg/mL and 5.49 μg/mL*hr, respectively.
Example 22
In vivo Pharmacokinetics in Beagles
[00156] The solid dispersion of Example 6 was tested against a crystalline, micronized suspension formulation (d(v, 0.9) = 3.0μιη) of Example 21 under normal fasted conditions, as well as with pretreatment using pentagastrin or famotidine. The solid dispersion of Example 6 was prepared as a suspension in water and administered orally. The micronized suspension of Example 21 was prepared as a suspension with SyrSpend® SF Dry reconstituted with water and administered orally. To reduce variability, beagles were crossed over from pentagastrin to famotidine after a 5 day washout period. Pentagastrin is a pH modifier to modify gastric pH to about 2 to 3, and famotidine is a pH modifier to modify gastric pH to about 5 to 7.5 (Zhou, Rong, 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 21, followed by a 5 day washout period, then famotidine pretreatment, and finally the micronized suspension of Example 21. Group B received pentagastrin pretreatment, the solid dispersion of Example 6, followed by a 5 day washout period, then famotidine pretreatment, and finally the solid dispersion of Example 6. Group C received the micronized suspension of Example 21, followed by a 5 day washout period, and finally the solid dispersion of Example 6. Results are shown in Table 6.
Table 6
AUCmf
Pretreatment Dosing Formulation Cmax g mL)
^g*hr/mL)
Micronized Suspension of Example 12 7.43 ± 1.77 1.88 ± 0.35
None
Solid Dispersion of Example 1 10.0 ± 2.7 2.29 ± 0.54
6 μg/kg Micronized Suspension of Example 12 17.2 ± 2.7 3.29 ± 0.13 Pentagastrin
Solid Dispersion of Example 1 13.0 ± 3.6 3.12 ± 0.62 AUCmf
Pretreatment Dosing Formulation Cmax ^g mL)
^g*hr/mL)
40 mg/kg Micronized Suspension of Example 12 1.74 ± 0.39 0.514 ± 0.092 Famotidine
Solid Dispersion of Example 1 6.32 ± 2.88 1.45 ± 0.54
[00157] 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 foregoing description is considered as illustrative only of the principles of the invention.
[00158] The words "comprise," "comprising," "include," "including," and "includes" when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

Claims

What is claimed is:
1. The compound N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification, wherein said N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)- N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is administered as a tablet at 600 mg twice a day in combination with trastuzumab, capecitabine, bevacizumab, paclitaxel or docetaxel.
2. The compound (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification, wherein said (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is administered as a tablet at 0.1 to 2000 mg a day in combination with trastuzumab, capecitabine, bevacizumab, paclitaxel or docetaxel.
3. N4-(4-([ 1 ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification.
4. N4-(4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification of Claim 3, wherein the N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol is administered as an oral dosage form.
5. N4-(4-([ 1 ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to Claims 3 or 4, wherein the N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol is in a tablet.
6. N4-(4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to any one of Claims 3 to 5, wherein the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol is in combination with another therapeutic agent.
7. N4-(4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to Claim 6, wherein the therapeutic agent is selected from trastuzumab, capecitabine, bevacizumab, paclitaxel and docetaxel.
8. N4-(4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to any one of Claims 3 to 7, wherein the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol is used after previous treatment for brain cancer.
9. N4-(4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to Claim 8, wherein the previous treatment for brain cancer is selected from surgery, radiation therapy and chemotherapy or mixtures thereof.
10. N4-(4-([ 1 ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to Claim 9, wherein the previous treatment for brain cancer is selected from surgery, conventional external radiation therapy, three-dimensional conformal radiation therapy, intensity modulated radiation therapy, stereotactic radiosurgery, fractionated stereotactic radiation therapy, proton radiation therapy, internal or implant radiation therapy, temozolomide, bevacizumab, carmustine, lomustine, procarbazine, vincristine, tumor treating fields therapy, everolimus, procarbazine, lomustine, cisplatin, carboplatin and methotrexate or mixtures thereof.
1 1. N4-(4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to any one of Claims 3 to 7, wherein the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol is used after previous treatment for breast cancer.
12. N4-(4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to Claim 1 1 , wherein the previous treatment for breast cancer is selected from surgery, sentinel lymph node biopsy followed by surgery, radiation therapy, chemotherapy, hormone therapy and targeted therapy.
13. N4-(4-([ 1 ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to Claim 1 1 , wherein the previous treatment for breast cancer is selected from lumpectomy, partial mastectomy, segmental mastectomy, total mastectomy, modified radical mastectomy, external radiation, internal radiation, methotrexate, paclitaxel albumin-stabilized nanoparticle formulation, ado- trastuzumab emtansine, doxorubicin, fluorouracil, everolimus, anastrozole, exemestane, capecitabine, cyclophosphamide, docetaxel, epirubicin, exemestane, toremifene, fulvestrant, letrozole, gemcitabine, trastuzumab, ixabepilone, lapatinib, tamoxifen, pertuzumab and toremifene, or mixtures thereof.
14. N4-(4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to any one of Claims 3 to 13, wherein N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine is used.
15. N4-(4-([ 1 ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to Claim 14, wherein the N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine for use in the treatment of brain cancer is administered from about 550 to about 650 mg twice per day.
16. N4-(4-([ 1 ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to any one of Claims 3 to 13, wherein (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is used.
17. N4-(4-([ 1 ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol for use in treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification according to Claim 16, wherein the (2-((4-((4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol is administered from about 25 to about 1800 mg per day.
18. A method of treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification in a mammal comprising administering a therapeutically effective amount of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol to the mammal.
19. A method of treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification in a patient having brain cancer comprising administering a therapeutically effective amount of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4- ((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol to the patient.
20. A method of treating or preventing local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification in a mammal in need of such treatment, wherein the method comprises administering to thed mammal a therapeutically effective amount of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl- 4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin- 7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol.
21. The method of any one of Claims 18 to 20, wherein the N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol is administered as an oral dosage form.
22. The method of any one of Claims 18 to 21 , wherein the N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol is in a tablet.
23. The method of any one of Claims 18 to 22, wherein the method includes another therapeutic agent.
24. The method of Claim 23, wherein the therapeutic agent is selected from trastuzumab, capecitabine, bevacizumab, paclitaxel and docetaxel.
25. The method of any one of Claims 18 to 24, wherein the method is used after previous treatment for brain cancer.
26. The method of Claim 25, wherein the previous treatment for brain cancer is selected from surgery, radiation therapy and chemotherapy or mixtures thereof.
27. The method of Claim 25, wherein the previous treatment for brain cancer is selected from surgery, conventional external radiation therapy, three-dimensional conformal radiation therapy, intensity modulated radiation therapy, stereotactic radiosurgery, fractionated stereotactic radiation therapy, proton radiation therapy, internal or implant radiation therapy, temozolomide, bevacizumab, carmustine, lomustine, procarbazine, vincristine, tumor treating fields therapy, everolimus, procarbazine, lomustine, cisplatin, carboplatin and methotrexate or mixtures thereof.
28. The method of any one of Claims 18 to 24, wherein the method is used after previous treatment for breast cancer.
29. The method of Claim 28, wherein the previous treatment for breast cancer is selected from surgery, sentinel lymph node biopsy followed by surgery, radiation therapy, chemotherapy, hormone therapy and targeted therapy.
30. The method of Claim 28, wherein the previous treatment for breast cancer is selected from lumpectomy, partial mastectomy, segmental mastectomy, total mastectomy, modified radical mastectomy, external radiation, internal radiation, methotrexate, paclitaxel albumin-stabilized nanoparticle formulation, ado-trastuzumab emtansine, doxorubicin, fluorouracil, everolimus, anastrozole, exemestane, capecitabine, cyclophosphamide, docetaxel, epirubicin, exemestane, toremifene, fulvestrant, letrozole, gemcitabine, trastuzumab, ixabepilone, lapatinib, tamoxifen, pertuzumab and toremifene, or mixtures thereof.
31. The method of any one of Claims 18 to 30, wherein N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine is administered.
32. The method of Claim 31 , wherein about 550 to about 650 mg twice per day of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine is administered.
33. The method of any one of Claims 18 to 30, wherein (2-((4-((4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol is administered.
34. The method of Claim 33, wherein about 25 to about 1800 mg per day of (2- ((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is administered.
35. The use of N4-(4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6- (4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol in the manufacture of a medicament for the treatment of local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification.
36. The use of Claim 35, wherein the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is in the form of an oral dosage form.
37. The use of Claims 35 or 36, wherein the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin- 7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6- yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is in the form of a tablet.
38. The use of any one of Claims 35 to 37, wherein the use is in combination with another therapeutic agent.
39. The use of Claim 38, wherein the therapeutic agent is selected from
trastuzumab, capecitabine, bevacizumab, paclitaxel and docetaxel.
40. The use of any one of Claims 35 to 39, wherein the use is after previous treatment for brain cancer.
41. The use of Claim 40, wherein the previous treatment for brain cancer is selected from surgery, radiation therapy and chemotherapy or mixtures thereof.
42. The use of Claims 40, wherein the previous treatment for brain cancer is selected from surgery, conventional external radiation therapy, three-dimensional conformal radiation therapy, intensity modulated radiation therapy, stereotactic radiosurgery, fractionated stereotactic radiation therapy, proton radiation therapy, internal or implant radiation therapy, temozolomide, bevacizumab, carmustine, lomustine, procarbazine, vincristine, tumor treating fields therapy, everolimus, procarbazine, lomustine, cisplatin, carboplatin and methotrexate or mixtures thereof.
43. The use of any one of Claims 35 to 39, wherein the use is after previous treatment for breast cancer.
44. The use of Claim 43, wherein the previous treatment for breast cancer is selected from surgery, sentinel lymph node biopsy followed by surgery, radiation therapy, chemotherapy, hormone therapy and targeted therapy.
45. The use of Claim 43, wherein the previous treatment for breast cancer is selected from lumpectomy, partial mastectomy, segmental mastectomy, total mastectomy, modified radical mastectomy, external radiation, internal radiation, methotrexate, paclitaxel albumin-stabilized nanoparticle formulation, ado-trastuzumab emtansine, doxorubicin, fluorouracil, everolimus, anastrozole, exemestane, capecitabine, cyclophosphamide, docetaxel, epirubicin, exemestane, toremifene, fulvestrant, letrozole, gemcitabine, trastuzumab, ixabepilone, lapatinib, tamoxifen, pertuzumab and toremifene, or mixtures thereof.
46. The use of any one of Claims 35 to 45, wherein N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine is used.
47. The use of Claim 46, wherein about 550 to about 650 mg twice per day of N4- (4-([ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine is used.
48. The use of any one of Claims 35 to 45, wherein (2-((4-((4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol is used.
49. The use of Claim 48, wherein about 25 to about 1800 mg per day of (2-((4-((4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4- methyl-4,5-dihydrooxazol-4-yl)methanol is used.
50. (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of local or metastatic brain cancer that is caused by ErbB2 over- expression or amplification comprising administering N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
51. (2-((4-((4-([ 1 ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of local or metastatic brain cancer that is caused by ErbB2 over- expression or amplification of Claim 50, wherein the N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is administered as an oral dosage form.
52. (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of local or metastatic brain cancer that is caused by ErbB2 over- expression or amplification of Claims 50 or 51 , wherein the N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine is in a tablet.
53. (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of local or metastatic brain cancer that is caused by ErbB2 over- expression or amplification according to any one of Claims 50 to 52, wherein the N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine is in combination with another therapeutic agent.
54. (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of local or metastatic brain cancer that is caused by ErbB2 over- expression or amplification of Claim 54, wherein the therapeutic agent is selected from trastuzumab, capecitabine, bevacizumab, paclitaxel and docetaxel.
55. (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of local or metastatic brain cancer that is caused by ErbB2 over- expression or amplification according to any one of Claims 50 to 54, wherein the N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine is used after previous treatment for brain cancer.
56. (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of local or metastatic brain cancer that is caused by ErbB2 over- expression or amplification of Claim 55, wherein the previous treatment for brain cancer is selected from surgery, radiation therapy and chemotherapy or mixtures thereof.
57. (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of local or metastatic brain cancer that is caused by ErbB2 over- expression or amplification of Claim 55, wherein the previous treatment for brain cancer is selected from surgery, conventional external radiation therapy, three-dimensional conformal radiation therapy, intensity modulated radiation therapy, stereotactic radiosurgery,
fractionated stereotactic radiation therapy, proton radiation therapy, internal or implant radiation therapy, temozolomide, bevacizumab, carmustine, lomustine, procarbazine, vincristine, tumor treating fields therapy, everolimus, procarbazine, lomustine, cisplatin, carboplatin and methotrexate or mixtures thereof.
58. (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of local or metastatic brain cancer that is caused by ErbB2 over- expression or amplification according to any one of Claims 50 to 54, wherein the N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamineis used after previous treatment for breast cancer.
59. (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of local or metastatic brain cancer that is caused by ErbB2 over- expression or amplification of Claim 58, wherein the previous treatment for breast cancer is selected from surgery, sentinel lymph node biopsy followed by surgery, radiation therapy, chemotherapy, hormone therapy and targeted therapy.
60. (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of local or metastatic brain cancer that is caused by ErbB2 over- expression or amplification of Claim 58, wherein the previous treatment for breast cancer is selected from lumpectomy, partial mastectomy, segmental mastectomy, total mastectomy, modified radical mastectomy, external radiation, internal radiation, methotrexate, paclitaxel albumin-stabilized nanoparticle formulation, ado-trastuzumab emtansine, doxorubicin, fluorouracil, everolimus, anastrozole, exemestane, capecitabine, cyclophosphamide, docetaxel, epirubicin, exemestane, toremifene, fulvestrant, letrozole, gemcitabine, trastuzumab, ixabepilone, lapatinib, tamoxifen, pertuzumab and toremifene, or mixtures thereof.
61. (2-((4-((4-([l ,2,4]Triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for use in the treatment of local or metastatic brain cancer that is caused by ErbB2 over- expression or amplification according to any one of Claims 50 to 60, wherein the N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine for use in the treatment of brain cancer is administered from about 550 to about 650 mg twice per day.
62. A method of treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification in a mammal using (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin- 7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4- yl)methanol comprising administering an effective amount of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine to the mammal.
63. A method of treating local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification using (2-((4-((4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3- methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol in a patient having brain cancer comprising administering an effective amount of N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine to the patient.
64. A method of treating or preventing local or metastatic brain cancer that is caused by ErbB2 over-expression or amplification using (2-((4-((4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5- dihydrooxazol-4-yl)methanol in a mammal in need of such treatment, wherein the method comprises administering to the mammal an effective amount of N4-(4-([l ,2,4]triazolo[l ,5- a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline- 4,6-diamine.
65. The method of any one of Claims 62 to 64, wherein the N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine is administered as an oral dosage form.
66. The method of any one of Claims 62 to 65, wherein the N4-(4- ([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine is in a tablet.
67. The method of any one of Claims 62 to 66, wherein the method includes another therapeutic agent.
68. The method of Claim 67, wherein the therapeutic agent is selected from trastuzumab, capecitabine, bevacizumab, paclitaxel and docetaxel.
69. The method of any one of Claims 62 to 68, wherein the method is used after previous treatment for brain cancer.
70. The method of Claim 69, wherein the previous treatment for brain cancer is selected from surgery, radiation therapy and chemotherapy or mixtures thereof.
71. The method of Claim 69, wherein the previous treatment for brain cancer is selected from surgery, conventional external radiation therapy, three-dimensional conformal radiation therapy, intensity modulated radiation therapy, stereotactic radiosurgery, fractionated stereotactic radiation therapy, proton radiation therapy, internal or implant radiation therapy, temozolomide, bevacizumab, carmustine, lomustine, procarbazine, vincristine, tumor treating fields therapy, everolimus, procarbazine, lomustine, cisplatin, carboplatin and methotrexate or mixtures thereof.
72. The method of any one of Claims 62 to 68, wherein the method is used after previous treatment for breast cancer.
73. The method of Claim 72, wherein the previous treatment for breast cancer is selected from surgery, sentinel lymph node biopsy followed by surgery, radiation therapy, chemotherapy, hormone therapy and targeted therapy.
74. The method of Claim 72, wherein the previous treatment for breast cancer is selected from lumpectomy, partial mastectomy, segmental mastectomy, total mastectomy, modified radical mastectomy, external radiation, internal radiation, methotrexate, paclitaxel albumin-stabilized nanoparticle formulation, ado-trastuzumab emtansine, doxorubicin, fluorouracil, everolimus, anastrozole, exemestane, capecitabine, cyclophosphamide, docetaxel, epirubicin, exemestane, toremifene, fulvestrant, letrozole, gemcitabine, trastuzumab, ixabepilone, lapatinib, tamoxifen, pertuzumab and toremifene, or mixtures thereof.
75. The method of any one of Claims 62 to 74, wherein about 550 to about 650 mg twice per day of N4-(4-([l ,2,4]triazolo[l ,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is administered.
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DK13714497.8T DK2827900T3 (en) 2012-03-23 2013-03-25 AMORF FIXED DISPERSION FOR USE IN THE TREATMENT OF BRAIN CANCER
US14/387,533 US20150110780A1 (en) 2012-03-23 2013-03-25 Treatment of brain cancer
CA2867723A CA2867723C (en) 2012-03-23 2013-03-25 Treatment of brain cancer
EP13714497.8A EP2827900B1 (en) 2012-03-23 2013-03-25 Amorphous solid dispersion for use in the treatment of brain cancer
SI201331019T SI2827900T1 (en) 2012-03-23 2013-03-25 Amorphous solid dispersion for use in the treatment of brain cancer
KR1020147029340A KR102160462B1 (en) 2012-03-23 2013-03-25 Treatment of brain cancer
PL18162971T PL3400943T3 (en) 2012-03-23 2013-03-25 Compounds for use in the treatment of brain metastases in a patient with erbb2+ breast cancer
RU2014142700A RU2672575C2 (en) 2012-03-23 2013-03-25 Treatment of brain cancer
PL13714497T PL2827900T3 (en) 2012-03-23 2013-03-25 Amorphous solid dispersion for use in the treatment of brain cancer
CN201380015856.XA CN104203279B (en) 2012-03-23 2013-03-25 The treatment of the cancer of the brain
JP2015501952A JP2015514075A (en) 2012-03-23 2013-03-25 Brain cancer treatment
EP23163332.2A EP4252855A3 (en) 2012-03-23 2013-03-25 Compounds for use in the treatment of brain metastases in a patient with erbb2+ breast cancer
NZ630843A NZ630843A (en) 2012-03-23 2013-03-25 Treatment of brain cancer
EP18162971.8A EP3400943B1 (en) 2012-03-23 2013-03-25 Compounds for use in the treatment of brain metastases in a patient with erbb2+ breast cancer
AU2013234921A AU2013234921A1 (en) 2012-03-23 2013-03-25 Treatment of brain cancer
LTEP13714497.8T LT2827900T (en) 2012-03-23 2013-03-25 Amorphous solid dispersion for use in the treatment of brain cancer
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IL234627A IL234627B (en) 2012-03-23 2014-09-14 Amorphous solid dispersion for treatment of brain cancer
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HRP20180659TT HRP20180659T1 (en) 2012-03-23 2018-04-25 Amorphous solid dispersion for use in the treatment of brain cancer
CY20181100493T CY1120204T1 (en) 2012-03-23 2018-05-14 AMORPHIC SOLID SOLAR DISPOSAL FOR USE IN BRAND CANCER TREATMENT
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CY20211100126T CY1123837T1 (en) 2012-03-23 2021-02-16 COMPOUNDS FOR USE IN THE TREATMENT OF BRAIN METASTASES IN A PATIENT WITH ERBB2+ BREAST CANCER
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3400943B1 (en) 2012-03-23 2020-12-02 Array Biopharma, Inc. Compounds for use in the treatment of brain metastases in a patient with erbb2+ breast cancer
US11207324B2 (en) 2017-04-28 2021-12-28 Seagen Inc. Treatment of HER2 positive cancers

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT2765990T (en) 2011-10-14 2018-01-25 Array Biopharma, Inc. Solid dispersion
JP2014530243A (en) 2011-10-14 2014-11-17 アレイ バイオファーマ、インコーポレイテッド ARRY-380 polymorphs, selective HERB2 inhibitors, and pharmaceutical compositions containing them
WO2018165015A1 (en) * 2017-03-09 2018-09-13 The Board Of Trustees Of The Leland Stanford Junior University Treatment of pediatric brain tumors with targeting of cd47 pathway
BR112020015581A2 (en) 2018-01-31 2021-02-02 Deciphera Pharmaceuticals, Llc combination therapy for the treatment of gastrointestinal stromal tumors
CN112566665A (en) * 2018-04-09 2021-03-26 莫舍·吉拉迪 Treatment of tumors with TTfields and Aurora kinase inhibitors
CN109942576B (en) * 2019-03-07 2020-09-11 上海工程技术大学 Irbinitinib and preparation method of intermediate
CN111825604A (en) * 2019-04-16 2020-10-27 宁波药腾医药科技有限公司 Synthesis method of cartinib and intermediate product thereof
JP2022544234A (en) 2019-08-12 2022-10-17 デシフェラ・ファーマシューティカルズ,エルエルシー Ripretinib for treating gastrointestinal stromal tumors
EP4327827A3 (en) * 2019-12-30 2024-05-29 Deciphera Pharmaceuticals, LLC Amorphous kinase inhibitor formulations and methods of use thereof
IL293864A (en) 2019-12-30 2022-08-01 Deciphera Pharmaceuticals Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007059257A2 (en) 2005-11-15 2007-05-24 Array Biopharma Inc. N4-phenyl-quinaz0line-4 -amine derivatives and related compounds as erbb type i receptor tyrosine kinase inhibitors for the treatment of hyperproliferative diseases

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH690163A5 (en) * 1995-07-28 2000-05-31 Symphar Sa Derivatives substituted gem-diphosphonates useful as anti-cancer.
US6350786B1 (en) 1998-09-22 2002-02-26 Hoffmann-La Roche Inc. Stable complexes of poorly soluble compounds in ionic polymers
RU2255765C2 (en) * 2000-01-21 2005-07-10 Чилдренз Хоспитал Лос-Анджелес Method for inhibiting cerebral tumors growth due to selected antagonists of integrins
WO2001091794A2 (en) 2000-05-30 2001-12-06 Virginia Commonwealth University Vitamin d3 analogs as radiosensitizers for the treatment of cancer
CN103664802B (en) 2003-08-14 2015-08-05 阿雷生物药品公司 As the quinazoline analogs of receptor tyrosine kinase inhibitors
BRPI0511754A (en) 2004-06-03 2008-01-02 Smithkline Beechman Cork Ltd use of a compound or salts or solvates thereof
CN1989112A (en) * 2004-06-03 2007-06-27 史密丝克莱恩比彻姆(科克)有限公司 Cancer treatment method
CN101374864A (en) 2006-01-31 2009-02-25 诺瓦提斯公司 Il-17 antagonistic antibodies
JP2010540460A (en) * 2007-09-24 2010-12-24 トラガラ ファーマシューティカルズ,インク. Treatment of cancer using a mixture of a COX-2 inhibitor and an anti-HER2 [ErbB2] antibody or a mixture of a COX-2 inhibitor and a HER2 [ErbB2] receptor tyrosine kinase inhibitor
AR070865A1 (en) 2008-03-18 2010-05-12 Genentech Inc COMBINATIONS OF AN ANTIBODY-ANTI-HER2 PHARMACO AND CHEMOTHERAPEUTIC AGENTS AND METHODS OF USE
LT2765990T (en) * 2011-10-14 2018-01-25 Array Biopharma, Inc. Solid dispersion
JP2014530243A (en) * 2011-10-14 2014-11-17 アレイ バイオファーマ、インコーポレイテッド ARRY-380 polymorphs, selective HERB2 inhibitors, and pharmaceutical compositions containing them
HUE053156T2 (en) 2012-03-23 2021-06-28 Array Biopharma Inc Compounds for use in the treatment of brain metastases in a patient with erbb2+ breast cancer

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007059257A2 (en) 2005-11-15 2007-05-24 Array Biopharma Inc. N4-phenyl-quinaz0line-4 -amine derivatives and related compounds as erbb type i receptor tyrosine kinase inhibitors for the treatment of hyperproliferative diseases

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Perry's Chemical Engineers' Handbook", 2007, MCGRAW-HILL
ANSEL, HOWARD C. ET AL.: "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems", 2004, LIPPINCOTT, WILLIAMS & WILKINS
GENNARO, ALFONSO R. ET AL.: "Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT, WILLIAMS & WILKINS
KOCH KEVIN: "ARRY-380: A Selective, Oral HER2 inhibitor for the Treatment of Solid Tumors", INTERNET CITATION, 3 April 2011 (2011-04-03), pages 1 - 29, XP002692140, Retrieved from the Internet <URL:http://www.arraybiopharma.com/_documents/Publication/PubAttachment462.pdf> [retrieved on 20130214] *
KOCH; KEVIN: "ARRY-380: A Selective, Oral HER2 Inhibitor for the Treatment of Solid Tumors", AMERICAN ASSOCIATION OF CANCER RESEARCH 102 ANNUAL MEETING, 3 April 2011 (2011-04-03), Retrieved from the Internet <URL:http://www.arraybiopharma.com/ documents/Publication/ PubAttachment462.pdf>
ROWC, RAYMOND C.: "Handbook of Pharmaceutical Excipients", 2005, PHARMACEUTICAL PRESS
S L MOULDER ET AL: "Arry-380, a selective HER2 inhibitor: From drug design to clinical evaluation", 14 January 2011 (2011-01-14), EORTC Conference, pages 1, XP055064078, Retrieved from the Internet <URL:http://www.arraybiopharma.com/_documents/Publication/PubAttachment491.pdf> [retrieved on 20130524] *
ZHOU, RONG 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, February 2005 (2005-02-01), pages 188 - 192, XP019370779, DOI: doi:10.1007/s11095-004-1185-3

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3400943B1 (en) 2012-03-23 2020-12-02 Array Biopharma, Inc. Compounds for use in the treatment of brain metastases in a patient with erbb2+ breast cancer
US11504370B2 (en) 2012-03-23 2022-11-22 Array Biopharma Inc. Treatment of brain cancer
US11207324B2 (en) 2017-04-28 2021-12-28 Seagen Inc. Treatment of HER2 positive cancers
US11666572B2 (en) 2017-04-28 2023-06-06 Seagen Inc. Treatment of HER2 positive cancers

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