WO2014191920A1 - N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2hp yrido[4,3-d]pyrimidin-1 -yl]phenyl}acetamide en vue d'une utilisation dans le traitement du cancer - Google Patents

N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2hp yrido[4,3-d]pyrimidin-1 -yl]phenyl}acetamide en vue d'une utilisation dans le traitement du cancer Download PDF

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Publication number
WO2014191920A1
WO2014191920A1 PCT/IB2014/061757 IB2014061757W WO2014191920A1 WO 2014191920 A1 WO2014191920 A1 WO 2014191920A1 IB 2014061757 W IB2014061757 W IB 2014061757W WO 2014191920 A1 WO2014191920 A1 WO 2014191920A1
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Prior art keywords
compound
human
mekinist
pyrimidin
tetrahydro
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PCT/IB2014/061757
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English (en)
Inventor
Roya Behbahani
Mohammed R. Hamid
Daniele OUELLET
Kiran Patel
Debra Ann ROGAN
Eric Michael RICHARDS
Michael R. Streit
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Glaxosmithkline Intellectual Property (No.2) Limited
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Publication of WO2014191920A1 publication Critical patent/WO2014191920A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to a method of treating cancer in a human by the in vivo administration of N- ⁇ 3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl ⁇ acetamide dimethyl sulfoxide solvate, represented by the following formula (I) and hereinafter referred to as Compound A
  • cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death.
  • Apoptosis (programmed cell death) plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuronal diseases, cardiovascular diseases and cancer.
  • One of the most commonly studied pathways, which involves kinase regulation of apoptosis, is cellular signaling from growth factor receptors at the cell surface to the nucleus (Crews and Erikson, Cell, 74:215-17, 1993).
  • MEK Mitogen-activated protein
  • MAP Mitogen-activated protein
  • ERK extracellular signal-regulated kinase
  • MEK Mitogen-activated protein
  • the Raf family (B-Raf, C-Raf etc.) activates the MEK family (MEK-1 , MEK-2 etc.) and the MEK family activates the ERK family (ERK-1 and ERK-2).
  • the signaling activity of the RAF/MEK/ERK pathway controls mRNA translation. This includes genes related to the cell cycle. Hence, hyperactivation of this pathway can lead to uncontrolled cell proliferation.
  • RAF/MEK/ERK pathway by ERK hyperactivation is seen in approximately 30% of all human malignancies (Allen, LF, et al. Semin. Oncol. 2003. 30(5 Suppl 16): 105-16).
  • RAS which can signal through both the PI3K/AKT and RAF/MEK/ERK, has a mutated oncogenic protein in 15% of all cancers (Davies, H. et al. Nature. 2002. 417:949-54).
  • activating BRAF mutations have been identified at a high frequency in specific tumor types (e.g., melanomas) (Davies, H. et al. Nature. 2002. 417:949-54).
  • MEK inhibitory activity effectively induces inhibition of ERK1/2 activity and suppression of cell proliferation (The Journal of Biological Chemistry, vol. 276, No. 4, pp. 2686-2692, 2001), and the compound is expected to show effects on diseases caused by undesirable cell proliferation, such as tumor genesis and/or cancer.
  • Compound B is a compound which is disclosed and claimed, along with pharmaceutically acceptable salts and solvates thereof, as being useful as an inhibitor of MEK activity, particularly in treatment of cancer, in International Application No.
  • Compound B is the compound of Example 4-1.
  • Compound B can be prepared as described in International Application No. PCT/JP2005/011082.
  • Compound B can be prepared as described in United States Patent Publication No. US 2006/0014768, Published January 19, 2006, the entire disclosure of which is hereby incorporated by reference.
  • Compound B is the compound of Example 4-1.
  • Compound B is in the form of a dimethyl sulfoxide solvate, or Compound A as defined herein.
  • Compound B is in the form of a solvate selected from:
  • Solvates and salt forms can be prepared by one of skill in the art, for example from the description in International Application No.
  • Compound A is prepared in Example 4-149 of United States Patent Publication No. US 2006/0014768. It would be advantageous to provide an improved method of treating cancer .
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, which method takes into account adverse reactions of the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, which method takes into account the toxicology of the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, which method takes into account the risk for Retinal Vein Occlusion caused by the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, which method takes into account use in specific populations for the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, which method takes into account Skin Toxicity caused by the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, which method takes into account Retinal Pigment Epithelial Detachment caused by the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, which method takes into account Cardiomyopathy caused by the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, which method takes into account Interstitial Lung Disease and/or pneumonitis caused by the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, which method takes into account the clinical pharmacology of the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, which method takes into account Drug Interactions of the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, which method takes into account contra-indications and limitations on using the compound.
  • This invention comprises a method of treating cancer with a V600K mutation, suitably unresectable or metastatic melanoma with a V600K mutation, which method comprises administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof.
  • Figure - 1 depicts Kaplan-Meier Curves of Investigator- Assessed
  • MEKINIST is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA- approved test.
  • MEKINIST Limitation of use: MEKINIST is not indicated for the treatment of patients who have received a prior BRAF inhibitor therapy.
  • Cardiomyopathy Re-assess after one month of treatment, and evaluate LVEF
  • RPED Retinal Pigment Epithelial Detachment
  • RVO Retinal Vein Occlusion
  • Embryo-Fetal Toxicity Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus. (5.6, 8.1) ADVERSE REACTIONS
  • MEKINIST TM is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test [see Clinical Studies (14. 1)].
  • MEKINIST Limitation of use: MEKINIST is not indicated for treatment of patients who have received a prior BRAF-inhibitor therapy [see Clinical Studies (14.2)].
  • the recommended dose is 2 mg orally once daily until disease progression or unacceptable toxicity. Take at least 1 hour before or 2 hours after a meal. Do not take a missed dose within 12 hours of the next dose.
  • Tablets Yellow, modified oval, biconvex, film-coated tablets with 'GS' debossed on one face and TFC on the opposing face.
  • Tablets White, round, biconvex, film-coated tablets with 'GS' debossed on one face and 'LHE' on the opposing face.
  • Tablets Pink, round, biconvex, film-coated tablets with 'GS' debossed on one face and 'HMJ' on the opposing face.
  • cardiomyopathy defined as cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction (LVEF)] occurred in 7% (14/21 1) of patients treated with MEKINIST; no chemotherapy-treated patient in Trial 1 developed
  • cardiomyopathy The median time to onset of cardiomyopathy in patients treated with MEKINIST was 63 days (range 16 to 156 days); cardiomyopathy was identified within the first month of treatment with MEKINIST in 5 of these 14 patients. Four percent of patients in Trial 1 required discontinuation (4/21 1) and/or dose reduction (7/21 1) of MEKINIST. Cardiomyopathy resolved in 10 of these 14 (71 %) patients.
  • Retinal pigment epithelial detachments can occur with treatment with MEKINIST.
  • RPED Retinal pigment epithelial detachments
  • Trial 1 where ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment, one patient (0.5%) receiving MEKINIST developed RPED and no cases of RPED were identified in chemotherapy- treated patients. Across all clinical trials of MEKINIST, the incidence of RPED was 0.8% (14/1749).
  • Retinal detachments were often bilateral and multifocal, occurring in the macular region of the retina.
  • RPED led to reduction in visual acuity that resolved after a median of 11.5 days (range 3 to 71 days) following the interruption of dosing with MEKINIST, although Ocular Coherence Tomography (OCT) abnormalities persisted beyond a month in at least several cases.
  • OCT Ocular Coherence Tomography
  • RVO retinal glaucoma
  • Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented retinal vein occlusion [see Dosage and Administration (2.3)].
  • the median time to first presentation of ILD or pneumonitis was 160 days (range 60 to 172 days).
  • the median time to onset of skin toxicity in patients treated with MEKINIST was 15 days (range 1 to 221 days) and median time to resolution of skin toxicity was 48 days (range 1 to 282 days). Reductions in the dose of MEKINIST were required in 12% and permanent discontinuation of MEKINIST was required in 1 % of patients with skin toxicity. Monitor patients receiving MEKINST for skin toxicities and for secondary infections [see Dosage and Administration (2.3)].
  • MEKINIST can cause fetal harm when administered to a pregnant woman.
  • MEKINIST was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. [See Use in Specific Populations (8.1).]
  • the data described in the Warnings and Precautions section and below reflect exposure to MEKINIST in 329 patients including 107 (33%) exposed for greater than or equal to 6 months and 30 (9%) exposed for greater than or equal to one year.
  • stomatitis a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation.
  • abdominal pain abdominal pain lower, abdominal pain upper, and abdominal tenderness.
  • lymphedema edema
  • peripheral edema edema
  • e Includes the following terms: epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage.
  • e Events included are higher in the trametinib arm compared to chemotherapy by ⁇ 5% in overall incidence or by >2% Grade 3-4 adverse reactions >2% higher in trametinib arm compared to chemotherapy.
  • Nervous System Disorders Dizziness, dysgeusia.
  • Ocular Disorders Vision blurred, dry eye.
  • Cardiac Disorders Bradycardia.
  • Gastrointestinal Disorders Xerostomia.
  • trametinib is not a substrate, inhibitor or inducer of human cytochrome P450 (CYP) enzymes; therefore, no formal clinical studies have been conducted to evaluate CYP enzyme-mediated drug interactions with trametinib [see Clinical Pharmacology (12.3)]..
  • CYP cytochrome P450
  • Pregnancy Category D Risk Summary MEKINIST can cause fetal harm when administered to a pregnant woman.
  • Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.6)].
  • trametinib In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared to control animals.
  • MEKINIST can cause fetal harm when administered during pregnancy.
  • Trametinib may impair fertility in female patients [Nonclinical Toxicology (13. 1)].
  • Trametinib dimethyl sulfoxide is a.
  • the chemical name is acetamide, N-[3-[3-cyclopropyl- 5-[(2-fluoro-4- iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl- 2,4,7-trioxopyrido[4,3- d]pyrimidin-1 (2H)-yl]phenyl]-, compound with 1 ,1 '-sulfinylbis[methane] (1 :1). It has a molecular formula C2 6 H2 3 FI N5O4.C2H 13 OS with a molecular mass of 693.53.
  • Trametinib dimethyl sulfoxide has the following chemical structure.
  • Trametinib dimethyl sulfoxide is a white to almost white powder. It is practically insoluble in the pH range of 2 to 8 in aqueous media.
  • MEKINIST (trametinib) Tablets are supplied as 0.5 mg, 1 mg, and 2 mg tablets for oral administration. Each 0.5 mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib non-solvated parent. Each 1 mg tablet contains
  • trametinib dimethyl sulfoxide equivalent to 1 mg of trametinib non-solvated parent 1.127 mg trametinib dimethyl sulfoxide equivalent to 1 mg of trametinib non-solvated parent. Each 2 mg tablet contains 2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib non-solvated parent.
  • the inactive ingredients of MEKINIST Tablets are: Tablet Core: mannitol, microcrystalline cellulose, hypromellose, croscarmellose sodium, magnesium stearate (vegetable source), sodium lauryl sulfate, colloidal silicon dioxide. Coating: hypromellose, titanium dioxide, polyethylene glycol, polysorbate 80 (2 mg tablets), iron oxide yellow (0.5 mg tablets), iron oxide red (2 mg tablets).
  • Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity.
  • MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.
  • ERK extracellular signal-related kinase
  • V600E BRAF mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2.
  • Trametinib inhibits BRAF V600 mutation positive melanoma cell growth in vitro and in vivo.
  • PK pharmacokinetics
  • T maX concentrations
  • Trametinib is 97.4% bound to human plasma proteins.
  • the apparent volume of distribution (V c /F) is 214 L.
  • Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases.
  • Elimination The estimated elimination half-life based on the population PK model is 3.9 to 4.8 days. The apparent clearance is 4.9 L/hr.
  • Hepatic Impairment Based on a population pharmacokinetic analysis in 64 patients with mild hepatic impairment (total bilirubin ⁇ ULN and AST >ULN or total bilirubin >1.0-1.5 x ULN and any AST), mild hepatic impairment has no clinically important effect on the systemic exposure of trametinib. The pharmacokinetics of trametinib have not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations (8.7)].
  • Renal Impairment As renal excretion of trametinib is low ( ⁇ 20%), renal impairment is unlikely to have a clinically important effect on the exposure of trametinib. Based on a population PK analysis in 223 patients with mild renal impairment (GFR 60 to 89 mL/min/1.73 m 2 ) and 35 patients with moderate renal impairment (GFR 30 to 59 mL/min/1.73 m 2 ), mild and moderate renal impairment have no clinically important effect on the systemic exposure of trametinib. The PK of trametinib have not been studied in patients with severe renal impairment [see Use in Specific Populations (8.8)].
  • Trametinib is not a substrate of CYP enzymes or efflux transporters P-gp or BCRP in vitro.
  • trametinib is not an inhibitor of CYP450 including CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 or of transporters including OATP1 B1 , OATP1 B3, P-gp, and BCRP at a clinically relevant systemic concentration of 0.04 ⁇ .
  • Trametinib is an inhibitor of CYP2C8 in vitro.
  • Trametinib is an inducer of CYP3A4 in vitro. Based on cross-study comparisons, oral administration of trametinib 2 mg once daily with everolimus (sensitive CYP3A4 substrate) 5 mg once daily, had no clinically important effect on the AUC and C max of everolimus.
  • Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells and micronuclei in the bone marrow of rats.
  • Trametinib may impair fertility in humans. In female rats given trametinib for up to
  • the safety and efficacy of MEKINIST were evaluated in an international, multi-center, randomized (2: 1), open label, active-controlled trial (Trial 1) in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted.
  • the primary efficacy outcome measure was progression-free survival (PFS).
  • Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes versus no) and lactate dehydrogenase level (normal versus greater than upper limit of normal). Tumor tissue was evaluated for BRAF mutations at a central testing site using a clinical trial assay. Tumor samples from 295 patients (200 patients treated with MEKINST and 95 patients from chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion diagnostic test, THxlDTM-BRAF assay.
  • the median age for randomized patients was 54 years, 54% were male, >99% were white, and all patients had baseline ECOG performance status of 0 or 1. Most patients had metastatic disease (94%), were Stage M 1c (64%), had elevated LDH (36%), no history of brain metastasis (97%), and received no prior chemotherapy for advanced or metastatic disease (66%).
  • the distribution of BRAF V600 mutations was BRAF V600E (87%), V600K (12%), or both ( ⁇ 1 %).
  • the median duration of follow-up was approximately 5 months in both treatment arms (range: 0 to 10 months). Fifty-one (47%) patients crossed over from the chemotherapy arm at the time of disease progression to receive MEKINIST.
  • Trial 1 demonstrated a statistically significant increase in progression-free survival in the patients treated with MEKINIST.
  • Table 4 and Figure 1 summarize the PFS results.
  • CI confidence interval
  • CR complete response
  • HR Hazard Ratio
  • NR Not reached
  • PFS Progression-free Survival
  • PR partial response.
  • MEKINIST The clinical activity of MEKINIST was evaluated in a single-arm, multicenter, international trial (Trial 2) in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor. All patients received MEKINIST at a dose of 2 mg orally once daily until disease progression or unacceptable toxicity.
  • Tablets Yellow, modified oval, biconvex, film-coated tablets with 'GS' debossed on one face and TFC on the opposing face and are available in bottles of 30 (NDC 0173- 0849-13).
  • Tablets White, round, biconvex, film-coated tablets with 'GS' debossed on one face and 'LHE' on the opposing face and are available in bottles of 30 (NDC 0173-0858-13).
  • Tablets Pink, round, biconvex, film-coated tablets with 'GS' debossed on one face and 'HMJ' on the opposing face and are available in bottles of 30 (NDC 0173-0848-13).
  • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their health care provider as soon as possible if they experience dyspnea. [See Warnings and Precautions (5.4).]
  • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their health care provider if they develop symptoms of hypertension.
  • MEKINIST should be taken at least 1 hour before or 2hours after a meal.
  • MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use highly effective contraception during treatment and for 4 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1), (8.6)].
  • MEKINIST is a trademark of GlaxoSmithKline. Patient Information
  • MEKINIST is a prescription medicine used to treat people with a type of skin cancer called melanoma:
  • MEKINIST should not be used to treat people who have received a BRAF inhibitor for treatment of their melanoma.
  • MEKINIST may cause serious side effects, including:
  • heart problems including heart failure. Your healthcare provider should check your heart function before you start taking MEKINIST and during treatment. Signs and symptoms of heart problems may include:
  • MEKINIST can cause new or worsening high blood pressure (hypertension). Your healthcare provider should check your blood pressure during treatment with MEKINST. Tell your healthcare provider if you develop high blood pressure, your blood pressure worsens, or you have severe headache, lightheadedness, or dizziness. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
  • the MEKINIST bottle contains a desiccant packet to help keep your medicine dry. Do not throw away the desiccant packet.
  • Tablet Core mannitol, microcrystalline cellulose, hypromellose, croscarmellose sodium, magnesium stearate (vegetable source), sodium lauryl sulfate, colloidal silicon dioxide.
  • Tablet Coating hypromellose, titanium dioxide, polyethylene glycol, polysorbate 80 (2 mg tablets), iron oxide yellow (0.5 mg tablets), iron oxide red (2 mg tablets).
  • the amount of Compound A required to achieve the label claim of Compound B (the free or un-solvated compound) is calculated utilizing the molecular conversion factor of 0.8873 for the ratio of Compound B (un-solvated) to compound A (the DMSO solvate), and based on the purity value from the certificate of analysis. The amount of Mannitol is adjusted accordingly.
  • NP not present in formulation.
  • micronized drug substance sodium lauryl sulfate, silicon dioxide,
  • croscarmellose sodium, microcrystalline cellulose and hypromellose are screened, if required, and transferred into a suitable bin blender and blended.
  • the magnesium stearate is screened, if required, transferred to the bin blender and blended for an additional time.

Abstract

L'invention concerne des méthodes de traitement du cancer chez un être humain en ayant besoin qui comprend l'administration d'une quantité thérapeutiquement efficace de N-{3-[3-cyclopropyl- 5-(2-fluoro-4-iodo-phénylamino)-6,8-diméthyl-2,4,7-trioxo-3,4,6,7-tétrahydro-2H- pyrido[4,3-d]pyrimidin-1-yl]phényl}acétamide ou d'un sel ou solvate de celui-ci à un cet être humain. L'invention concerne également des méthodes de traitement du cancer chez un être humain en ayant besoin qui comprend l'administration d'une quantité thérapeutiquement efficace de N-{3-[3-cyclopropyl-5-(2-fluoro- 4-iodo-phénylamino)-6,8-diméthyl-2,4,7-trioxo-3,4,6,7-tétrahydro-2H-pyrido[4,3- d]pyrimidin-1-yl]phényl}acétamide diméthyl sulfoxyde à cet être humain.
PCT/IB2014/061757 2013-05-28 2014-05-27 N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2hp yrido[4,3-d]pyrimidin-1 -yl]phenyl}acetamide en vue d'une utilisation dans le traitement du cancer WO2014191920A1 (fr)

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TW (1) TW201536292A (fr)
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