WO2022177556A1 - Compositions de forme iv essentiellement pure de n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et leurs utilisations - Google Patents

Compositions de forme iv essentiellement pure de n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et leurs utilisations Download PDF

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Publication number
WO2022177556A1
WO2022177556A1 PCT/US2021/018378 US2021018378W WO2022177556A1 WO 2022177556 A1 WO2022177556 A1 WO 2022177556A1 US 2021018378 W US2021018378 W US 2021018378W WO 2022177556 A1 WO2022177556 A1 WO 2022177556A1
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WO
WIPO (PCT)
Prior art keywords
fluoro
dihydroxypropoxy
difluoro
benzamide
iodo
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PCT/US2021/018378
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English (en)
Inventor
Erwin IRDAM
Original Assignee
Warner-Lambert Company Llc
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Filing date
Publication date
Application filed by Warner-Lambert Company Llc filed Critical Warner-Lambert Company Llc
Priority to AU2021428932A priority Critical patent/AU2021428932A1/en
Priority to KR1020237030268A priority patent/KR20230148177A/ko
Priority to PCT/US2021/018378 priority patent/WO2022177556A1/fr
Priority to JP2023549999A priority patent/JP2024507822A/ja
Priority to CA3211395A priority patent/CA3211395A1/fr
Priority to CN202180095226.2A priority patent/CN117500781A/zh
Priority to IL304974A priority patent/IL304974A/en
Priority to EP21710827.3A priority patent/EP4294789A1/fr
Priority to TW111105793A priority patent/TW202245746A/zh
Priority to ARP220100332A priority patent/AR124907A1/es
Publication of WO2022177556A1 publication Critical patent/WO2022177556A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure relates to: a) a crystalline composition that is essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; b) pharmaceutical compositions comprising the crystalline composition that is essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and, optionally, a pharmaceutically acceptable carrier; and c) methods of treating a tumor, a cancer, or a Rasopathy disorder by administering the crystalline composition that is essentially pure Form IV of N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide to a subject in need thereof.
  • N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (“mirdametinib", or "PD-0325901") is a small molecule drug which has been designed to inhibit mitogen-activated protein kinase kinase 1 ("MEK1”) and mitogen- activated protein kinase kinase 2 (“MEK2").
  • MEK1 and MEK2 are proteins that play key roles in the mitogen-activated protein kinase (“MAPK”) signaling pathway.
  • Mirdametinib is a highly potent and specific allosteric non-ATP-competitive inhibitor of MEKl and MEK2.
  • mirdametinib leads to significantly inhibited phosphorylation of the extracellular regulated MAP kinases ERK1 and ERK2, thereby leading to impaired growth of tumor cells both in vitro and in vivo.
  • evidence indicates that inflammatory cytokine-induced increases in MEK/ERK activity contribute to the inflammation, pain, and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.
  • the '856 patent also states that the differential scanning calorimetry ("DSC") of the material produced shows an onset of melting at 110°C, as well as a small peak with an onset at 117°C, consistent with the material being a mixture of two forms.
  • DSC differential scanning calorimetry
  • WO 2006/134469 (“the '469 PCT publication”) also describes a method of synthesizing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide.
  • the '469 PCT publication reports the method yields a product conforming to the polymorphic Form IV disclosed in U.S. Patent Application No. 10/969,681 which issued as the '856 patent.
  • compositions containing more than one polymorphic form are generally undesirable because of the potential of interconversion of one polymorphic form to another.
  • Polymorphic interconversion can lead to differences in the effective dose or physical properties affecting processability of a drug, caused by differences in solubility or bioavailability.
  • a composition containing essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide for use in treatment of a tumor, a cancer, or a Rasopathy disorder.
  • FIG. 1A is a X-ray powder diffraction pattern ("XRPD") corresponding to essentially pure crystalline Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide.
  • XRPD X-ray powder diffraction pattern
  • FIG. 1B is a thermogravimetric analysis thermogram ("TGA”) and a differential scanning calorimetry thermogram (“DSC”) corresponding to essentially pure crystalline Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- pheny 1 amino)-b enzami de .
  • TGA thermogravimetric analysis thermogram
  • DSC differential scanning calorimetry thermogram
  • FIG. 3A is an XRPD corresponding to essentially pure Form IV of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide after storage for 68 months after production at 25°C and 65% relative humidity.
  • FIG. 3B is an XRPD corresponding to essentially pure Form IV of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide after storage for 140 months after production at 25°C and 65% relative humidity.
  • the present disclosure features useful compositions and methods to treat disorders whereby aberrant MEK1 or MEK2 activity is implicated, e.g., a cancer, a tumor, or a Rasopathy disorder, such as neurofibromatosis type 1, in a subject in need thereof.
  • a cancer e.g., a tumor, or a Rasopathy disorder, such as neurofibromatosis type 1, in a subject in need thereof.
  • a Rasopathy disorder such as neurofibromatosis type 1
  • the present disclosure is directed to a crystalline composition of essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide of Formula (I)
  • the crystalline composition of essentially pure N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide does not contain any amount of Form I or Form II detectable by XRPD and/or DSC.
  • the crystalline composition exhibits an XRPD pattern and/or
  • the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 3 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 6 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 1 year at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 5 years at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 68 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for ⁇ 140 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for ⁇ 14 years at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the XRPD pattern is generated using a PANALYTICAL® X'Pert
  • Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and a step size of 0.03° 2 ⁇ with a X'CELERATOR® Real Time Multi-Strip detector configured (a) on the incidental beam side as follows: variable divergence slits (10 mm irradiated length), 0.04 rad Soller slits, fixed anti-scatter slit (0.50°), and 10 mm beam mask, and (b) on the diffracted beam side as follows: variable anti-scatter slit (10 mm observed length) and 0.04 rad Soller slit or a BROKER® D8® ADVANCETM system using Cu Ka (40 kV/40 mA) radiation and a step size of 0.03° 2 ⁇ with a LYNXEYETM detector, configured (a) on the incidental beam side as follows: Goebel mirror, mirror exit slit (0.2 mm), 2.5° Soller slit, beam knife, and (b) on the diff
  • the crystalline composition contains ⁇ 0.2% of dimeric impurity
  • the crystalline composition contains about 0.05% to about 0.19% by weight of dimeric impurity PF-00191189. In some aspects, the crystalline composition contains no detectable amount of dimeric impurity PF-00191189.
  • the present disclosure provides a pharmaceutical composition comprising a crystalline composition described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is for oral administration.
  • the pharmaceutical composition is a solid dosage form.
  • the pharmaceutical composition is a tablet or capsule.
  • the pharmaceutical composition is a tablet.
  • the pharmaceutical composition is a capsule.
  • the capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro- 4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
  • the capsule comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin capsule which
  • the capsule comprises about 5 mg of N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt% of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; and (d) a gelatin capsule which encapsulates components a-c.
  • At least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and dibasic calcium phosphate. In some aspects, at least one of the diluents is microcrystalline cellulose.
  • At least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and alginic acid. In some aspects, at least one of the disintegrants is croscarmellose sodium.
  • At least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, and talc. In some aspects, at least one of the lubricants is magnesium stearate.
  • the present disclosure provides a method of treating a cancer, a tumor, or a Rasopathy disorder comprising administering to a subject in need of such treatment a pharmaceutical composition described herein.
  • the tumor is a neurofibroma.
  • the tumor is a neurofibroma associated with Neurofibromatosis Type 1.
  • the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, or malignant peripheral nerve sheath tumor.
  • the tumor is plexiform neurofibroma.
  • the subject has been diagnosed with a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.
  • the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
  • the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitf s lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
  • the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous nonsmall cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
  • the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
  • an individual dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more than one capsule or tablet.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 10 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylaminoj-benzamide is administered in a total daily dose that does not exceed 6 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 0.1 mg to about 20 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is about 2 mg.
  • the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is about 4 mg. In some aspects, the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 6 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 8 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered about 20 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each.
  • the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is administered two times daily at a dose of about 2 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered two times daily at a dose of about 3 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 10 mg each.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • theN-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 consecutive days in which the total daily dose is administered; followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days in which no N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered.
  • the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
  • the present disclosure provides use of a pharmaceutical composition described herein for the manufacture of a medicament for treating a tumor, a cancer, or a Rasopathy disorder.
  • the present disclosure provides a method of manufacturing a pharmaceutical composition, the method comprising forming a pharmaceutical composition described herein.
  • mirdametinib and “PD-0325901” refer to the single enantiomer N-
  • subject refers to an animal, including, but not limited to, a primate
  • subject e.g., human
  • cow, sheep, goat horse, dog, cat, rabbit, rat, or mouse.
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • the terms “treat,” “treated,” and “treating” mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results.
  • those in need of treatment include those already diagnosed with or suspected of having the disorder.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • therapeutically effective amount is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of a disorder, disease, or condition being treated.
  • therapeutically effective amount also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • a subject is successfully "treated” for a tumor, according to the methods described herein if the patient shows one or more of the following: a reduction in the size of the tumor; relief of one or more symptoms associated with the specific tumor; a reduction in the volume of the tumor; improvement in quality of life; increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), an increased time to progression (TTP), or any combination thereof.
  • nationally or internationally accepted standards of treatment outcomes in a given tumor can be used to determine whether an effective amount of mirdametinib meets any of these particular endpoints (e.g., CR, PFS, PR).
  • a subject is successfully "treated” for cancer, e.g., lung cancer or ovarian cancer, according to the methods described herein if the patient shows one or more of the following: a reduction in the number of or complete absence of cancer cells; relief of one or more symptoms associated with the specific cancer; reduced morbidity and mortality; improvement in quality of life; increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), an increased time to progression (TTP), or any combination thereof.
  • nationally or internationally accepted standards of treatment outcomes in a given cancer can be used to determine whether an effective amount of mirdametinib meets any of these particular endpoints (e.g., CR, PFS, PR).
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid excipient, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Excipients can include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration.
  • antiadherents antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, calcium sulfate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A
  • composition represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient, and can be manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup).
  • the term “about” or “approximately” means within a range of an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In some aspects, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In some aspects, the term “about” or “approximately” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.
  • administration refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system.
  • Administration to an animal subject e.g., to a human
  • crystalline refers to a solid-state form which consists of orderly arrangement of structural units. Different crystalline forms of the same compound, or a salt, hydrate, or solvate thereof, arise from different packing of the molecules in the solid-state, which results in different crystal symmetries and/or unit cell parameter. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility.
  • Crystalline forms are commonly characterized by X-ray powder diffraction
  • XRPD XRPD
  • An XRPD pattern of reflections is commonly considered a fingerprint of a particular crystalline form.
  • the relative intensities of the XRPD peaks can widely vary depending on, inter alia, the sample preparation technique, crystal size distribution, filters, the sample mounting procedure, and the particular instrument employed. In some instances, new peaks may be observed or existing peaks may disappear, depending on the type of instrument or the settings. In some instances, any particular peak in an XRPD pattern may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on the type of instrument or the settings, the sensitivity of the instrument, measuring conditions, and/or purity of the crystalline form.
  • any particular peak in an XRPD may appear in a symmetric shape or in an asymmetric shape, e.g., having a shoulder.
  • instrument variation and other factors can affect the 2-theta values. A skilled artisan understanding these variations is capable of discriminating or ascertaining the defining features or characteristics of a particular crystal form using XRPD, as well as using other known physicochemical techniques.
  • anhydrate refers to a crystalline form wherein the compound contains no structural water within the crystal lattice.
  • the term “essentially pure” with respect to Form IV means that the composition comprising Form IV contains no detectable amount of another polymorphic form (e.g., Form I or Form II), as determined by observing no detectable differences in an XRPD and/or DSC pattern between a single Form IV crystal and the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide.
  • Form IV of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can include impurities, such as, but not limited to, synthetic reactants or by-products generated during the chemical synthesis.
  • the term “aberration” as applied to a gene refers to a mutation, chromosomal loss or fusion, epigenetic chemical modification, or other event which alters the sequence, level of expression, or processed mRNA sequence associated with a gene relative to the sequence, level of expression, or processed mRNA sequence associated with the wild-type gene.
  • Essentially pure Form IV compositions that are essentially pure Form IV, and methods to treat a patient in need of a therapeutic comprising administration of essentially pure Form IV are described herein.
  • the present disclosure relates to an essentially pure crystalline composition of N-
  • These properties include, but are not limited to: (1) packing properties such as molar volume, bulk density and hygroscopicity, (2) thermodynamic properties such as melting temperature, vapor pressure and solubility, (3) kinetic properties such as dissolution rate and stability (including stability at ambient conditions, especially to moisture and under storage conditions), (4) surface properties such as surface area, wettability, interfacial tension and shape, (5) mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and (6) filtration properties. These properties can affect, for example, the processing and storage of the compound and pharmaceutical compositions comprising the compound.
  • a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide that improves upon one or more of these properties relative to other crystalline forms of the compound is desirable.
  • Isolating pharmaceutically acceptable crystalline forms of the compound that can be manufactured and formulated on a commercial scale can be a challenge.
  • the present disclosure is directed to essentially pure Form IV of
  • the crystalline composition is stable, as demonstrated by a substantially unchanged XRPD pattern and/or DSC profile over time.
  • the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 year, 2 years, 3 years, 4 years, 5 years, 68 months, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 140 months, 12 years, 13 years, 14 years, or 15 years at standard warehouse conditions (15°C- 25°C and ⁇ 65% relative humidity).
  • the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 3 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 6 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 1 year at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 5 years at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 68 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for ⁇ 140 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for ⁇ 14 years at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • the XRPD pattern is generated using a PANALYTICAL® X'Pert
  • Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and a step size of 0.03° 2 ⁇ with a X'CELERATOR® Real Time Multi-Strip detector configured (a) on the incidental beam side as follows: variable divergence slits (10 mm irradiated length), 0.04 rad Soller slits, fixed anti-scatter slit (0.50°), and 10 mm beam mask, and (b) on the diffracted beam side as follows: variable anti-scatter slit (10 mm observed length) and 0.04 rad Soller slit or a BROKER® D8® ADVANCETM system using Cu Ka (40 kV/40 mA) radiation and a step size of 0.03° 2 ⁇ with a LYNXEYETM detector, configured (a) on the incidental beam side as follows: Goebel mirror, mirror exit slit (0.2 mm), 2.5° Soller slit, beam knife, and (b) on the diff
  • the crystalline composition contains ⁇ 0.2% of dimeric impurity
  • the crystalline composition contains about 0.05% to about 0.19% by weight of dimeric impurity PF-00191189. In some aspects, the crystalline composition contains about 0.05% to about 0.15% by weight of dimeric impurity PF- 00191189. In some aspects, the crystalline composition contains about 0.05% to about 0.10% by weight of dimeric impurity PF-00191189. In some aspects, the crystalline composition contains no detectable amount of dimeric impurity PF-00191189.
  • the amount of dimeric impurity PF-00191189 is determined using High Performance Liquid Chromatography (“HPLC”).
  • HPLC High Performance Liquid Chromatography
  • reversed- phase liquid chromatography using an ultraviolet detector at 275 nm is used.
  • the crystalline composition exhibits a DSC profile which does not have an endothermic event with onset at about 117°C.
  • Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 1A, a TGA profile substantially as shown in FIG. IB; and/or a DSC profile substantially as shown in FIG. 1B.
  • the present disclosure provides a pharmaceutical composition comprising a crystalline composition described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is for oral administration.
  • the pharmaceutical composition is a tablet or capsule.
  • the pharmaceutical composition is a tablet.
  • the pharmaceutical composition is a capsule.
  • the pharmaceutical composition comprises about 0.1 mg to about
  • the pharmaceutical composition comprises about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of the crystalline composition of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition comprises about 2 mg of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 3 mg of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro- 2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the pharmaceutical composition comprises about 4 mg of the crystalline composition of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 5 mg of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- pheny 1 amino)-b enzami de .
  • the pharmaceutical composition comprises about 0.25 wt/wt% to about 7 wt/wt% of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein.
  • the pharmaceutical composition comprises about 0.25 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%,
  • the pharmaceutical composition comprises about 0.5 wt/wt% of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide described herein. In some aspects, the pharmaceutical composition comprises about 0.8 wt/wt% of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide described herein.
  • the pharmaceutical composition comprises one or more diluents.
  • the pharmaceutical composition comprises about 70 wt/wt% to about 95 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition comprises about 85 wt/wt % to about 95 wt/wt % of one or more diluents.
  • the pharmaceutical composition comprises about 70 wt/wt %, about 71 wt/wt %, about 72 wt/wt %, about 73 wt/wt %, about 74 wt/wt %, about 75 wt/wt %, about 76 wt/wt %, about 77 wt/wt %, about 78 wt/wt %, about 79 wt/wt %, about 80 wt/wt %, about 81 wt/wt %, about 82 wt/wt %, about 83 wt/wt %, about 84 wt/wt %, about 85 wt/wt %, about 86 wt/wt %, about 87 wt/wt %, about 88 wt/wt %, about 89 wt/wt %, about 90 wt/wt %, about
  • At least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and dibasic calcium phosphate. In some aspects, at least one of the diluents is microcrystalline cellulose. In some aspects, the diluent is microcrystalline cellulose.
  • the pharmaceutical composition comprises about 70 wt/wt% to about 95 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 85 wt/wt % to about 95 wt/wt % microcrystalline cellulose.
  • the pharmaceutical composition comprises about 70 wt/wt %, about 71 wt/wt %, about 72 wt/wt %, about 73 wt/wt %, about 74 wt/wt %, about 75 wt/wt %, about 76 wt/wt %, about 77 wt/wt %, about 78 wt/wt %, about 79 wt/wt %, about 80 wt/wt %, about 81 wt/wt %, about 82 wt/wt %, about 83 wt/wt %, about 84 wt/wt %, about 85 wt/wt %, about 86 wt/wt %, about 87 wt/wt %, about 88 wt/wt %, about 89 wt/wt %, about 90 wt/wt %, about
  • the pharmaceutical composition comprises about 3.5 wt/wt % to about 6 wt/wt % of one or more disintegrants. In some aspects, the pharmaceutical composition comprises about 3.5 wt/wt % about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt%, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, about 5 wt/wt %, about 5.1 wt/wt %, about 5.2
  • At least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and alginic acid. In some aspects, at least one of the disintegrants is croscarmellose sodium. In some aspects, the disintegrant is croscarmellose sodium. In some aspects, the pharmaceutical composition comprises about 3.5 wt/wt % to about 6 wt/wt % croscarmellose sodium.
  • the pharmaceutical composition comprises about 3.5 wt/wt % about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt%, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, about 5 wt/wt %, about 5.1 wt/wt %, about 5.2 wt/wt %, about 5.3 wt/wt %, about 5.4 wt/wt %, about 5.5 wt/wt %, about
  • the pharmaceutical composition comprises about 5 wt/wt % croscarmellose sodium. [0076] In some aspects, the pharmaceutical composition comprises 0 wt/wt % to about 2 wt/wt % of one or more lubricants.
  • the pharmaceutical composition comprises 0 wt/wt %, about 0.1 wt/wt %, about 0.2 wt/wt %, about 0.3 wt/wt %, about 0.4 wt/wt %, about 0.5 wt/wt %, about 0.6 wt/wt %, about 0.7 wt/wt %, about 0.8 wt/wt %, about 0.9 wt/wt %, about 1 wt/wt %, about 1.1 wt/wt %, about 1.2 wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %, about 1.6 wt/wt %, about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9 wt/wt %, or about 2 wt/wt %, about
  • At least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, and talc. In some aspects, at least one of the lubricants is magnesium stearate. In some aspects, the lubricant is magnesium stearate.
  • the pharmaceutical composition comprises 0 wt/wt %, about 0.1 wt/wt %, about 0.2 wt/wt %, about 0.3 wt/wt %, about 0.4 wt/wt %, about 0.5 wt/wt %, about 0.6 wt/wt %, about 0.7 wt/wt %, about 0.8 wt/wt %, about 0.9 wt/wt %, about 1 wt/wt %, about 1.1 wt/wt %, about 1.2 wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %, about 1.6 wt/wt %, about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9 wt/wt %, or about 2 wt/wt %, about
  • the pharmaceutical composition is a capsule.
  • the capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline composition ofN- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or
  • the capsule comprises about 2 mg of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro- 4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a ge
  • the capsule comprises about 3 mg of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro- 4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a ge
  • the capsule comprises about 4 mg of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro- 4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a ge
  • the capsule comprises about 5 mg of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt% of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; and (d) a gelatin capsule which encapsulates components a-c.
  • the present disclosure provides a method of treating a tumor, a cancer, or a Rasopathy disorder comprising administering to a subject in need of such treatment a pharmaceutical composition described herein.
  • the tumor is a neurofibroma.
  • the tumor is a neurofibroma associated with Neurofibromatosis Type 1.
  • the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, or malignant peripheral nerve sheath tumor.
  • the tumor is plexiform neurofibroma.
  • the subject has been diagnosed with a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.
  • the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
  • the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitf s lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
  • the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous nonsmall cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
  • the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
  • an individual dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more than one capsule or tablet.
  • a dose of 3 mg of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can be administered as two capsules - one containing 2 mg and the other containing 1 mg or as three capsules each containing 1 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is provided in an amount of about 0.1 mg to about 20 mg per dose of the pharmaceutical compositions described herein.
  • the N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg per dose.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is provided in an amount of about 1 mg per dose. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is provided in an amount of about 2 mg per dose.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is provided in an amount of about 3 mg per dose. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is provided in an amount of about 4 mg per dose.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is provided in an amount of about 10 mg per dose.
  • the pharmaceutical composition comprising N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered one time, two times, three times, or four times per day.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered two times per day.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide can be divided so the patient receives equal doses at each administration.
  • the patient can receive 2 mg (e.g., as two 1 mg capsules) in the morning and 2 mg (e.g., as one 2 mg capsule) in the evening.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide can be divided so the patient receives different doses at each administration.
  • the patient can receive 1 mg (e.g., as one 1 mg capsule) in the morning and 3 mg (e.g., as one 1 mg capsule and one 2 mg capsule) in the evening.
  • the present disclosure provides a method of treating a tumor, a cancer, or a Rasopathy disorder comprising administering to a patient in need of such treatment a pharmaceutical composition described herein, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is administered two times daily of about 0.1 mg to about 10 mg each.
  • 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered via a pharmaceutical composition described herein, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided at a total daily dose that does not exceed 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 15 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 12 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 10 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered in a total daily dose that does not exceed 2 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered in a total daily dose that does not exceed 1 mg.
  • the present disclosure provides a method of treating a tumor, a cancer, or a Rasopathy disorder comprising administering to a patient in need of such treatment a pharmaceutical composition described herein, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg.
  • the total daily dose of the N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 1 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is administered once daily at a dose of about 2 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered once daily at a dose of about 3 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 5 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 6 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 7 mg. In some aspects, the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is administered once daily at a dose of about 9 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered once daily at a dose of about 10 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 11 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 12 mg.
  • the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 13 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is administered once daily at a dose of about 14 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered once daily at a dose of about 15 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 16 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 17 mg. In some aspects, the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 18 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is administered once daily at a dose of about 19 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered once daily at a dose of about 20 mg.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each.
  • the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.25 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered two times daily at a dose of about 0.5 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each. In some aspects, the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered two times daily at a dose of about 3 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 5 mg each. In some aspects, the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 6 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered two times daily at a dose of about 7 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 8 mg each.
  • the total daily dose of the N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 9 mg each. In some aspects, the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 10 mg each.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • theN-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 consecutive days in which the total daily dose is administered; followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days in which no N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • the of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered.
  • the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising 28 days in which the total daily dose is administered.
  • the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
  • the present disclosure provides use of a pharmaceutical composition described herein for the manufacture of a medicament for treating a cancer, a tumor, or a Rasopathy disorder.
  • Step 1 Preparation of “Side Chain”, PD-0337792
  • the dimeric impurity is formed initially by the reaction of imidazole (CDI-activated acid) in the presence of excess acid PD-0315209 forming dimer (a) and possibly (b) which are then carried through in the subsequent IPGA coupling and acid hydrolysis steps forming dimer (c) and (d), respectively.
  • Impurity d is referred to as PF- 00191189.
  • the reaction can be easily carried out in the laboratory either by charging both solids, FIPFA and CDI, followed by solvent (acetonitrile) or charging solids CDI into a slurry of FIPFA in acetonitrile. None of the solids is initially soluble in acetonitrile.
  • the acid activation reaction was fast (almost instantaneous), forming highly soluble imidazolide product that turned the slurry into a clear homogenous solution while CO2 gas evolution occurs.
  • Form I has the highest melting point ( ⁇ 117°C) and is enantiotropically related to Form IV (m.p. 112°C), which is the more stable form below the estimated transition temperature of 73°C.
  • Form II is the low melting form (m.p. ⁇ 85°C).
  • the corrective procedure for this case includes transforming the low melting forms (Form II) to all Form I at temperatures close to or above 73 °C followed by a slow ( ⁇ 4 h period) cooling to 20 °C.
  • PD-0325901 is separated from process impurities and degradants by reversed- phase liquid chromatography with UV detection at 275 nm. Identification of PD- 0325901 is performed by obtaining either an infrared or proton NMR spectrum, in addition to the HPLC retention time. For purity evaluation, process impurities and degradants are identified by their characteristic relative retention times and quantitated by area normalization.
  • Chromatographic Conditions Agilent Zorbax SB C18, 5 pm, 4.6 x 250 mm (or equivalent); flow rate is 1.0 mL/min; column temperature is 30 °C; detector wavelength is 275 nm; diluent is 50/50 acetonitrile/water; mobile phase A is 0.1% trifluoroacetic acid (TFA) in water; mobile phase B is methanol; and the gradient conditions below.
  • the assay is determined against a reference standard and reported on an anhydrous, solvent free basis. Quantification of specified and unspecified impurities is reported by area percent. Total impurities is the sum of all impurities present above the reporting threshold of 0.05%.
  • a suitable single crystal of Form IV was prepared by a method involving a different coupling agent than was used in the method disclosed in Examplel. However, the crystal yielded Form IV with the same XRPD characteristics as Form IV prepared by the method of Example 1, and was therefore of suitable purity for Form IV analysis.
  • the simulated PXRD pattern was calculated from the low temperature (100 K) structure and room temperature (298 K, 25 °C) unit cell parameters shown below. Unit cell at room temperature was initially determined by Difference Vectors method based on 235 reflections harvested from 151, 1° diffraction frames. Unit cell parameters were subsequently refined during data integration by Saint (Bruker (2020). SAINT. Data Reduction Software) and are based on 903 reflections recorded between 19.1 and 1.1 A resolution. The simulated pattern was consistent with an experimental Form IV pattern as shown in FIG. 1 A.
  • HG Hard Gelatin a Based on a theoretical potency of 1.000. Actual quantity may be adjusted based on the actual potency, b Quantity of microcrystalline cellulose may be adjusted for slight potency changes of PD-0325901.
  • Stability of Form IV material was determined by comparing the XRPD spectrum of a batch to a reference standard XRPD spectrum. This analysis was performed at batch release, and the XRPD spectrum obtained corresponded to that of the reference standard of Form IV (FIG. 2). The Form IV batch was then stored at 25°C and 65% relative humidity. XRPD analysis of the stored Form IV was performed at 68 months (FIG. 3A) and again at 140 months (FIG. 3B). Undetectable changes in the XRPD spectra over time indicated stability of Form IV at 25°C and ⁇ 65% relative humidity.
  • E2 The crystalline composition of El, wherein the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 3 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • E3. The crystalline composition of El or E2, wherein the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 6 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • E4. The crystalline composition of any one of E1-E3, wherein the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 1 year at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • E5. The crystalline composition of any one of E1-E4, wherein the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for 68 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • E6 The crystalline composition of any one of E1-E5, wherein the crystalline composition exhibits an XRPD pattern and/or DSC profile which is substantially unchanged after storage for >140 months at standard warehouse conditions (15°C-25°C and ⁇ 65% relative humidity).
  • E7 The crystalline composition of any one of E2-E6, wherein the XRPD pattern is generated using: a PANALYTICAL ® X'Pert Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and a step size of 0.03° 2 ⁇ with a X'CELERATOR ® Real Time Multi-Strip detector, configured
  • variable divergence slits (10 mm irradiated length), 0.04 rad Soller slits, fixed anti-scatter slit (0.50°), and 10 mm beam mask, and
  • variable anti-scatter slit (10 mm observed length) and 0.04 rad Soller slit; or a BRUKER ® D8 ® ADVANCETM system using Cu Ka (40 kV/40 mA) radiation and a step size of 0.03° 20 with a LYNXEYETM detector, configured
  • E8 The crystalline composition of any one of E1-E7, wherein the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a rate of temperature increase of about 15°C/min.
  • E9. The crystalline composition of any one of E1-E8, wherein the crystalline composition contains ⁇ 0.2% of dimeric impurity PF-00191189.
  • E10 The crystalline composition of any one of E1-E9, wherein the crystalline composition contains about 0.05% to about 0.19% by weight of dimeric impurity PF- 00191189.
  • E12. A pharmaceutical composition comprising the crystalline composition of any one of El-El 1 and a pharmaceutically acceptable carrier.
  • E13 The pharmaceutical composition of E12, wherein the pharmaceutical composition is for oral administration.
  • E14 The pharmaceutical composition of E13, wherein the pharmaceutical composition is a solid dosage form.
  • E15 The pharmaceutical composition of any one of E12-E14, wherein the pharmaceutical composition is a tablet or capsule.
  • E16 The pharmaceutical composition of E15, wherein the pharmaceutical composition is a tablet.
  • E17 The pharmaceutical composition of E15, wherein the pharmaceutical composition is a capsule.
  • E18 The pharmaceutical composition of E17, wherein the capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide, wherein each component of the capsule is as follows: a) about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lub
  • E19 The pharmaceutical composition of E17, wherein the capsule comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide, wherein each component of the capsule is as follows: a) about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lub
  • E20 The pharmaceutical composition of El 7, wherein the capsule comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide, wherein each component of the capsule is as follows: a) about 2.5 wt/wt% to about 7.0 wt/wt% of the crystalline composition of N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; and d) a gelatin capsule which encapsulates components a-c.
  • E21 The pharmaceutical composition of any one of E18-E20, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and dibasic calcium phosphate.
  • E22 The pharmaceutical composition of E21, wherein at least one of the diluents is microcrystalline cellulose.
  • E23 The pharmaceutical composition of any one of E18-E22, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and alginic acid.
  • E24 The pharmaceutical composition of E23, wherein at least one of the disintegrants is croscarmellose sodium.
  • E25 The pharmaceutical composition of any one of E18-E24, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, and talc.
  • E26 The pharmaceutical composition of E25, wherein at least one of the lubricants is magnesium stearate.
  • E27 A method of treating a tumor, a cancer, or a Rasopathy disorder comprising administering to a subject in need of such treatment the pharmaceutical composition of any one of E12-E26.
  • E28 The method of E27, wherein the tumor is a neurofibroma.
  • E29 The method of E28, wherein the tumor is a neurofibroma associated with
  • E30 The method of any one of E27-E29, wherein the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, or malignant peripheral nerve sheath tumor.
  • E31 The method of E30, wherein the tumor is plexiform neurofibroma.
  • E32 The method of E27, wherein the subject has been diagnosed with a
  • Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • E33 The method of E27, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.
  • the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer,
  • E34 The method of E33, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
  • E35 The method of E33, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitfs lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
  • E36 The method of E33, wherein the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
  • E37 The method of any one of E27-E36, wherein the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
  • E38 The method of any one of E27-E37, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg.
  • E39 The method of any one of E27-E37, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 10 mg.
  • E40 The method of any one of E27-E37, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg.
  • E41 The method of any one of E27-E37, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
  • E42 The method of any one of E27-E41, wherein the total daily dose of the N-
  • E43 The method of E42, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg.
  • E44 The method of E42, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg.
  • E45 The method of E42, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg.
  • E46 The method of E42, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 6 mg.
  • E47 The method of E42, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg.
  • E48 The method of E42, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.
  • E49 The method of any one of E27-E42, wherein the total daily dose of the N-
  • E50 The method of E49, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each.
  • E51 The method of E49, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each.
  • E52 The method of E49, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each.
  • E53 The method of E49, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 3 mg each.
  • E54 The method of E49, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each.
  • E55 The method of E49, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 10 mg each.
  • E56 The method of any one of E27-E55, wherein an individual dose of the N-
  • E57 The method of any one of E27-E56, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E58 The method of any one of E27-E56, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 consecutive days in which the total daily dose is administered; followed by (b) 7 consecutive days in which no N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E59 The method of any one of E27-E56, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E60 The method of any one of E27-E56, wherein the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-((R)- 2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E61 The method of any one of E57-E60, wherein the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
  • E62 Use of the pharmaceutical composition of any one of E12-E26 for the manufacture of a medicament for treating a tumor, a cancer, or a Rasopathy disorder.
  • E63 The use of any one of E62, wherein the tumor is a neurofibroma.
  • E64 The use of E63, wherein the tumor is a neurofibroma associated with
  • E65 The use of any one of E62-E64, wherein the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, or malignant peripheral nerve sheath tumor.
  • E66 The use of E65, wherein the tumor is plexiform neurofibroma.
  • E67 The use of E62, wherein the subject has been diagnosed with a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
  • E68 The use of E62, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.
  • skin cancer malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, chol
  • E69 The use of E68, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
  • E70 The use of E68, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitf s lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
  • E71 The use of E68, wherein the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
  • E72 The use of any one of E62-E71, wherein the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
  • E73 The use of any one of E62-E72, wherein the N-((R)-2,3-dihydroxypropoxy)-
  • 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg.
  • E74 The use of any one of E62-E72, wherein the N-((R)-2,3-dihydroxypropoxy)-
  • 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 10 mg.
  • E75 The use of any one of E62-E72, wherein the N-((R)-2,3-dihydroxypropoxy)-
  • 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg.
  • E76 The use of any one of E62-E72, wherein the N-((R)-2,3-dihydroxypropoxy)-
  • 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
  • E77 The use of any one of E62-E75, wherein the total daily dose of the N-((R)-
  • E78 The use of E76, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg.
  • E79 The use of E77, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg.
  • E80 The use of E77, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg.
  • E81 The use of E77, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 6 mg.
  • E82 The use of E77, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg.
  • E83 The use of E77, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.
  • E84 The use of any one of E62-E76, wherein the total daily dose of the N-((R)-
  • E85 The use of E84, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each.
  • E86 The use of E84, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each.
  • E87 The use of E84, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each.
  • E88 The use of E84, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 3 mg each.
  • E89 The use of E84, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each.
  • E90 The use of E76, wherein the total daily dose of the N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 10 mg each.
  • E92 The use of any one of E62-E91, wherein the N-((R)-2,3-dihydroxypropoxy)-
  • 3.4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered.
  • E93 The use of any one of E62-E91, wherein the N-((R)-2,3-dihydroxypropoxy)-
  • 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 consecutive days in which the total daily dose is administered; followed by (b) 7 consecutive days in which no N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide is administered.
  • 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E96 The use of any one of E92-E95, wherein the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.

Abstract

La présente divulgation concerne : a) une composition cristalline de forme IV essentiellement pure de N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide ; b) des compositions pharmaceutiques comprenant la composition cristalline de forme IV essentiellement pure de N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide, et, éventuellement, un excipient pharmaceutiquement acceptable ; et c) des méthodes de traitement d'une tumeur, d'un cancer ou d'un trouble de type RASopathie par l'administration de la composition cristalline de forme IV essentiellement pure de N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide à un sujet qui en a besoin.
PCT/US2021/018378 2021-02-17 2021-02-17 Compositions de forme iv essentiellement pure de n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et leurs utilisations WO2022177556A1 (fr)

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AU2021428932A AU2021428932A1 (en) 2021-02-17 2021-02-17 Compositions of essentially pure form iv of n-((r)-2,3- dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodophenylamino)- benzamide and uses thereof
KR1020237030268A KR20230148177A (ko) 2021-02-17 2021-02-17 N-((r)-2,3-디하이드록시프로폭시)-3,4-디플루오로-2-(2-플루오로-4-요오도페닐아미노)-벤즈아미드의 본질적으로 순수한 형태 iv의 조성물 및 이의 용도
PCT/US2021/018378 WO2022177556A1 (fr) 2021-02-17 2021-02-17 Compositions de forme iv essentiellement pure de n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et leurs utilisations
JP2023549999A JP2024507822A (ja) 2021-02-17 2021-02-17 Ｎ－（（ｒ）－２，３－ジヒドロキシプロポキシ）－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードフェニルアミノ）－ベンズアミドの本質的に純粋な形態ｉｖの組成物及びその使用
CA3211395A CA3211395A1 (fr) 2021-02-17 2021-02-17 Compositions de forme iv essentiellement pure de n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide et leurs utilisations
CN202180095226.2A CN117500781A (zh) 2021-02-17 2021-02-17 N-((r)-2,3-二羟基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯氨基)-苯甲酰胺的基本上纯的形式iv的组合物及其用途
IL304974A IL304974A (en) 2021-02-17 2021-02-17 Preparations of mainly pure configuration IV of N-((R)-3,2-dihydroxypropoxy)-4,3-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and their uses
EP21710827.3A EP4294789A1 (fr) 2021-02-17 2021-02-17 Compositions de forme iv essentiellement pure de n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et leurs utilisations
TW111105793A TW202245746A (zh) 2021-02-17 2022-02-17 Ｎ－（（ｒ）－２，３－二羥基丙氧基）—３，４—二氟—２—（２—氟—４—碘—苯基胺基)—苯甲醯胺之基本上純的形式ｉｖ之組合物及其用途
ARP220100332A AR124907A1 (es) 2021-02-17 2022-02-17 Composiciones de forma iv esencialmente pura de n-((r)-2,3-dihidroxipropoxi)-3,4-difluoro-2-(2-fluoro-4-yodo-fenilamino)-benzamida y usos de las mismas

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AU2021428932A1 (en) 2023-09-21
CN117500781A (zh) 2024-02-02
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CA3211395A1 (fr) 2022-08-25
AR124907A1 (es) 2023-05-17

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