combination, combination kit, use of a combination, and pharmaceutical composition

专利摘要:
COMBINATION, COMBINATION KIT, USE OF A COMBINATION, AND PHARMACEUTICAL COMPOSITION. A new combination comprising the MEK inhibitor N5 {3- [3-cyclopropyl-5- (2-fluoro-4-iodo-phenylamino) 6,8-dimethyl; -2,4,7-trioxo3,4,6,7- tetrahydro-2H-pyrido [4,3-d] pyrimidin-1-yl] phenyl} acetamide, or a pharmaceutically acceptable salt or solvate of this, with a B-Raf inhibitor, particularly N- {3- [5- (2- Amino-4-pyrimidinyl) -2- (1,1-dimethyl-ethyl) -1,3-thiazol-4-yl] -2-fluorophenyl} -2,6difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same methods of using such combinations and compositions in the treatment of conditions where inhibition of MEK and / or B-Raf is beneficial, for example, cancer.
公开号:BR112012008854B1
申请号:R112012008854-8
申请日:2010-10-15
公开日:2020-12-29
发明作者:Melissa Dumble；Rakesh Kumar；Sylvie Laquerre；Peter Lebowitz
申请人:Novartis Ag；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[0001] The present invention relates to a method of treating cancer in a mammal and the combinations useful in such treatment. In particular, the method relates to a new combination comprising the MEK inhibitor N- {3 [3-cyclopropyl-5- (2-fluoro-4-iodo-phenylamino) -6,8-dimethyl; -2,4 , 7trioxo-3,4,6,7-tetrahydro-2H-pyrido [4,3-d] pyrimidin-1-yl] phenyl} acetamide, or a pharmaceutically acceptable salt or solvate of this, with a BRaf inhibitor, particularly N- {3 [5- (2-amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3thiazol-4-yl] -2-fluorophenyl} -2,6-difluorobenzenesulfonamide or a pharmaceutically acceptable salt , pharmaceutical compositions comprising the same and methods of using such combinations and compositions in the treatment of conditions in which inhibition of MEK and / or B-Raf is beneficial, for example, cancer. BACKGROUND OF THE INVENTION
[0002] Effective treatment of hyperproliferative disorders including cancer is an ongoing goal in the field of oncology. In general, cancer results from the dysregulation of normal processes that control cell division, differentiation and apoptotic cell death and is characterized by the proliferation of malignant cells that have the potential to grow unlimited, local expansion and systemic metastasis. Deregulation of normal processes includes abnormalities in the signal transduction pathways and response to factors that differ from those found in normal cells.
[0003] An important large family of enzymes is the protein kinase enzyme family. Currently, there are about 500 different known protein kinases. Protein kinases serve to catalyze the phosphorylation of an amino acid side chain into various proteins by transferring the Y-phosphate from the ATP-Mg2 + complex to said amino acid side chain. These enzymes control most signaling processes within cells, thereby controlling cell function, growth, differentiation and destruction (apoptosis) through reversible phosphorylation of hydroxyl groups of serine, threonine and tyrosine residues in proteins. Studies have shown that protein kinases are key regulators of many cellular functions, including signal transduction, transcriptional regulation, cell mobility and cell division. Several oncogenes have also been shown to encode protein kinases, suggesting that kinases play a role in oncogenesis. These processes are highly regulated, often by complex interconnected pathways where each kinase alone will be regulated by one or more kinases. Consequently, aberrant or inadequate protein kinase activity can contribute to the promotion of disease states associated with such aberrant kinase activity including benign and malignant proliferative disorders as well as diseases that result from inadequate activation of the immune and nervous systems. Due to their physiological relevance, variety and ubiquity, protein kinases have become one of the most important and widely studied families of enzymes in biochemical and medical research.
[0004] The enzyme protein kinase family is typically classified into two main subfamilies: Protein Tyrosine Kinases and Protein Serine / Threonine Kinases, based on the amino acid residue they phosphorylate. Serine / threonine protein kinases (PSTK), include cyclic AMP and cyclic GMP-dependent protein kinases, calcium and phospholipid-dependent protein kinases, calcium and calmodulin-dependent protein kinases, casein kinases, split-cycle protein kinases cell phone and others. These kinases are usually cytoplasmic or associated with particulate cell fractions, possibly by anchoring proteins. Aberrant protein serine / threonine kinase activity has been implicated or is suspected in various pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers and other proliferative diseases. Consequently, serine / threonine kinases and the signal transduction pathways they take part in are important targets for drug planning. Tyrosine kinases phosphorylate tyrosine residues. Tyrosine kinases play an equally important role in cell regulation. These kinases include various receptors for molecules such as growth factors and hormones, including the epidermal growth factor receptor, insulin receptor, platelet-derived growth factor receptor and others. Studies have indicated that many tyrosine kinases are transmembrane proteins with their receptor domains located outside the cell and their kinase domains inside. Many works are also in progress to identify modulators of tyrosine kinases.
[0005] Receptor tyrosine kinases (RTKs) catalyze the phosphorylation of certain tyrosyl amino acid residues in various proteins, including themselves, which control cell growth, proliferation and differentiation.
[0006] Downstream of several RTKs there are several signaling paths, among them is the Ras-Raf-MEK-ERK kinase path. It is currently understood that the activation of Ras GTPase proteins in response to growth factors, hormones, cytokines, etc. stimulates phosphorylation and activation of Raf kinases. These kinases then phosphorylate and activate the intracellular protein kinases MEK1 and MEK2, which in turn phosphorylate and activate other protein kinases, ERK1 and 2. This signaling pathway, also known as the mitogen-activated protein kinase pathway (MAPK ) or cytoplasmic cascade, mediates cellular responses to growth signals. The latter function is to bind the receptor activity to the cell membrane with modification of cytoplasmic or nuclear targets that control cell proliferation, differentiation and survival.
[0007] The constitutive activation of this pathway is sufficient to induce cell transformation. The unregulated activation of the MAP kinase pathway due to the activation of aberrant receptor tyrosine kinase, Ras mutations or Raf mutations have often been found in human cancers and represent a major factor that determines abnormal growth control. In human malignancies, Ras mutations are common, having been identified in about 30% of cancers. The Ras family of GTPase proteins (proteins that convert guanosine triphosphate to guanosine diphosphate) restore signals from activated growth factor receptors to downstream intracellular partners. Prominent among the targets recruited by the active membrane-bound Ras are the Raf family of serine / threonine protein kinases. The Raf family is composed of three related kinases (A-, Be C-Raf) that act as effectors downstream of Ras. The activation of Ras-treated Raf in turn triggers the activation of MEK1 and MEK2 (MAP / ERK kinases 1 and 2) which in turn phosphorylates ERK1 and ERK2 (kinases 1 and 2 regulated by extracellular signal) in tyrosine-185 and threonine -183. Activated ERK1 and ERK2 translocate and accumulate in the nucleus, where they can phosphorylate a variety of substrates, including the transcription factors that control cell growth and survival. Given the importance of the Ras / Raf / MEK / ERK pathway in the development of human cancers, the kinase components of the signaling cascade are consolidating themselves as potentially important targets for modulating disease progression in cancer and other proliferative diseases.
[0008] MEK1 and MEK2 are members of a larger family of dual specificity kinases (MEK1-7) that phosphorylate the threonine and tyrosine residues of several MAP kinases. MEK1 and MEK2 are encoded by the distinct genes, but they share high homology (80%) both within the C-terminal catalytic kinase domains and in most of the N-terminal regulatory region. The MEK1 and MEK2 forms of oncogenesis were not found in human cancers, but the constitutive activation of MEK has been shown to result in cell transformation. In addition to Raf, MEK can also be activated by other oncogenes. So far, the only known substrates for MEK1 and MEK2 are ERK1 and ERK2. This unusual substrate specificity in addition to the unique ability to phosphorylate both tyrosine and threonine residues places MEK1 and MEK2 at a critical point in the signal transduction cascade that allows them to integrate many extracellular signals into the MAPK pathway.
[0009] Consequently, it has been recognized that an inhibitor of a MAPK kinase pathway protein (eg, MEK) should be of value as both an anti-proliferative, pre-apoptotic and anti-invasive agent for use in restraint and / or treatment of proliferative or invasive disease.
[0010] Furthermore, it is also known that a compound having MEK inhibitory activity effectively induces the inhibition of ERK1 / 2 activity and the 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 unwanted cell proliferation, such as tumor genesis and / or cancer.
[0011] Mutations in several Ras GTPases and B-Raf kinase have been identified that can lead to prolonged and constitutive activation of the MAPK pathway, ultimately resulting in increased cell division and survival. As a consequence of this, these mutations have been strongly linked with the establishment, development and progression of a wide range of human cancers. The biological role of Raf kinases, and specifically that of B-Raf, in signal transduction is described in Davies, H., et al., Nature (2002) 9: 1-6; Garnett, M. J. & Marais, R., Cancer Cell (2004) 6: 313-319; Zebisch, A. & Troppmair, J., Cell. Mol. Life Sci. (2006) 63: 1314-1330; Midgley, R. S. & Kerr, D. J., Crit. Rev. Onc / Hematol. (2002) 44: 109-120; Smith, R. A., et al., Curr. Top. Med. Chem. (2006) 6: 1071-1089; and Downward, J., Nat. Rev. Cancer (2003) 3: 11-22.
[0012] The naturally occurring mutations of B-Raf kinase that activate MAPK pathway signaling have been discovered in a large percentage of human melanomas (Davies (2002) supra) and thyroid cancers (Cohen et al J. Nat. Cancer Inst . (2003) 95 (8) 625-627 and Kimura et al Cancer Res. (2003) 63 (7) 1454-1457), as well as at lower, but still significant, frequencies in the following:
[0013] Barret's adenocarcinoma (Garnett et al., Cancer Cell (2004) 6 313-319 and Sommerer et al Oncogene (2004) 23 (2) 554-558), biliary tract carcinomas (Zebisch et al., Cell. Mol. Life Sci. (2006) 63 1314-1330), breast cancer (Davies (2002) supra), cervical cancer (Moreno-Bueno et al Clin. Cancer Res. (2006) 12 (12) 3865-3866), cholangiocarcinoma (Tannapfel et al Gut (2003) 52 (5) 706-712), tumors of the central nervous system including primary CNS tumors such as glioblastomas, astrocytomas and ependymomas (Knobbe et al Acta Neuropathol. (Berl.) (2004) 108 (6) 467470, Davies (2002) supra and Garnett et al., Cancer Cell (2004) supra) and secondary CNS tumors (ie, metastases to the central nervous system of tumors that originate outside the central nervous system), colorectal cancer, including carcinoma of the large intestinal colon (Yuen et al Cancer Res. (2002) 62 (22) 6451-6455, Davies (2002) supra and Zebisch et al., Cell. Mol. Life Sci. (2006), gastric cancer (Lee et al Onco gene (2003) 22 (44) 69426945), carcinoma of the head and neck including squamous cell carcinoma of the head and neck (Cohen et al J. Nat. Cancer Inst. (2003) 95 (8) 625-627 and Weber et al Oncogene (2003) 22 (30) 4757-4759), hematological cancers including leukemias (Garnett et al., Cancer Cell (2004) supra, particularly acute lymphoblastic leukemia (Garnett et al., Cancer Cell (2004) supra and Gustafsson et al Leukemia (2005) 19 (2) 310-312), acute myelogenous leukemia (AML) (Lee et al Leukemia (2004) 18 (1) 170-172 and Christiansen et al Leukemia (2005) 19 (12) 2232-2240), myelodysplastic syndromes (Christiansen et al Leukemia (2005) supra) and chronic myelogenous leukemia (Mizuchi et al Biochem. Biophys. Res. Commun. (2005) 326 (3) 645-651); Hodgkin's lymphoma (Figl et al Arch. Dermatol. (2007) 143 (4) 495-499), non-Hodgkin's lymphoma (Lee et al Br. J. Cancer (2003) 89 (10) 1958- 1960), megacarioblastic leukemia (Eychene et al Oncogene (1995) 10 (6) 1159-1165) and multiple myeloma (Ng et al Br. J. Haematol. (2003) 123 (4) 637-645), hepatocellular carcinoma (Garnett et al., Cancer Cell (2004), lung cancer (Brose et al Cancer Res. (2002) 62 (23) 69 97-7000, Cohen et al J. Nat. Cancer Inst. (2003) supra and Davies (2002) supra), including small cell lung cancer (Pardo et al EMBO J. (2006) 25 (13) 3078-3088) and non-small cell lung cancer (Davies (2002) supra ), ovarian cancer (Russell & McCluggage J. Pathol. (2004) 203 (2) 617619 and Davies (2002) supra), endometrial cancer (Garnett et al., Cancer Cell (2004) supra and Moreno-Bueno et al Clin. Cancer Res. (2006) supra), pancreatic cancer (Ishimura et al Cancer Lett. (2003) 199 (2) 169-173), pituitary adenoma (De Martino et al J. Endocrinol. Invest. (2007) 30 (1) RC1-3), prostate cancer (Cho et al Int. J. Cancer (2006) 119 (8) 1858-1862), kidney cancer (Nagy et al Int. J. Cancer (2003) 106 (6) 980-981 ), sarcoma (Davies (2002) supra) and skin cancers (Rodriguez-Viciana et al Science (2006) 311 (5765) 1287-1290 and Davies (2002) supra). Overexpression of c-Raf has been linked to AML (Zebisch et al., Cancer Res. (2006) 66 (7) 3401-3408 and Zebisch (Cell. Mol. Life Sci. (2006)) and erythroleukemia (Zebisch et al ., Cell. Mol. Life Sci. (2006).
[0014] Due to the role played by Raf family kinases in these cancers and exploratory studies with a range of pre-clinical and therapeutic agents, including those selectively targeted to inhibit B-Raf kinase activity (King AJ, et al., ( 2006) Cancer Res. 66: 11100-11105), it is generally accepted that inhibitors of one or more kinases of the Raf family will be useful for the treatment of such cancers or other conditions associated with Raf kinase.
[0015] B-Raf mutation has also been implicated in other conditions, including cardio-facio-cutaneous syndrome (Rodriguez-Viciana et al Science (2006) 311 (5765) 1287-1290) and polycystic kidney disease (Nagao et al Kidney Int. (2003) 63 (2) 427-437).
[0016] Although there have been many recent advances in cancer treatment with compounds such as MEK and B-Raf inhibitors, there remains a need for more effective and / or enhanced treatment for an individual suffering from the effects of cancer. SUMMARY OF THE INVENTION
[0017] The present inventors have identified a combination of chemotherapeutic agents that provides increased activity over monotherapy. In particular, the drug combination which includes the MEK inhibitor N- {3 [3-cyclopropyl-5- (2-fluoro-4-iodo-phenylamino) 6,8dimethyl-2,4,7-trioxo-3,4, 6,7-tetrahydro-2H-pyrido [4,3-d] pyrimidin-1-yl] phenyl} acetamide, or a pharmaceutically acceptable salt or solvate thereof, in combination with the B-Raf inhibitor N- {3 [5 - (2-amino-4pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl} -2,6difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof is described.
[0018] The MEK inhibitor of the invention is represented by the structure of formula (I):
or a pharmaceutically acceptable salt or solvate thereof (collectively referred to herein as "compound A").
[0019] The B-Raf inhibitor of the invention is represented by the structure of formula (II):
or a pharmaceutically acceptable salt thereof (collectively referred to herein as "compound B").
[0020] In a first aspect of the present invention, a combination is provided which comprises: (i) a compound of formula (I)):
or a pharmaceutically acceptable salt or solvate thereof; and (ii) a compound of the formula (II)
or a pharmaceutically acceptable salt thereof.
[0021] In another aspect of the invention, a combination comprising Dimethylsulfoxide N- {3 [3-cyclopropyl-5- (2-fluoro-4-iodo-phenylamino) -6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydro-2Hpirido [4,3-d] pyrimidin-1-yl] phenyl} acetamide (solvate) and N- {3 [5- (2-amino-4-pyrimidinyl) methanesulfonate ) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2fluorophenyl} -2,6-difluoro-benzenesulfonamide.
[0022] In another aspect of the present invention, a combination is provided, comprising: (i) a compound of formula (I):
or a pharmaceutically acceptable salt or solvate thereof; and (ii) a compound of the formula (II):
or a pharmaceutically acceptable salt thereof for use in therapy.
[0023] In another aspect of the present invention, a combination is provided, comprising: (i) a compound of formula (I):
or a pharmaceutically acceptable salt or solvate thereof; and (ii) a compound of the formula (II):
or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
[0024] In another aspect of the present invention, a pharmaceutical composition is provided, which comprises: (i) a compound of formula (I):
or a pharmaceutically acceptable salt or solvate thereof; and (ii) a compound of the formula (II):
or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.
[0025] In another aspect it is provided the use of a combination comprising i) a compound of the formula (I)
or a pharmaceutically acceptable salt or solvate thereof; and (ii) a compound of the formula (II):
or a pharmaceutically acceptable salt of this in the manufacture of a cancer treatment drug.
[0026] In another aspect, a method of treating cancer in a mammal is provided, which comprises administering to said mammal: (i) a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt or solvate thereof: and (ii) a compound of formula (II):
or a pharmaceutically acceptable salt thereof.
[0027] In another aspect, a method of treating cancer in a human in need thereof is provided which comprises administering a therapeutically effective amount of a combination of N- {3 [3cyclopropyl-5- (2-fluoro-4 -iodo-phenylamino) 6,8-dimethyl-2,4,7-trioxo-3,4,6,7tetrahydro-2H-pyrido [4,3-d] pyrimidin-1-yl] phenyl} -acetamide, or a pharmaceutically acceptable salt or solvate thereof and N- {3 [5- (2-Amino-4pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2-fluoro-phenyl} - 2,6difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof.
[0028] In another aspect, a method of treating cancer in a human in need is provided which comprises administering a therapeutically effective amount of a N- {3 [3-cyclopropyl-5- dimethyl sulfoxide solvate combination (2-fluoro-4-iodo-phenylamino) 6,8dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido [4,3-d] -pyrimidin-1yl] phenyl} N- {3 [5- (2-amino-4-pyrimidinyl) -2 (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl} -2,6- acetamide and methanesulfonate difluorobenzenesulfonamide.
[0029] In another aspect of this invention there is provided a method of treating cancer in a mammal in need thereof which comprises administering a therapeutically effective amount of a combination of the invention in which the combination is administered within a specific period and for a duration of time. BRIEF DESCRIPTION OF THE FIGURES
[0030] FIGURE 1 is a graph showing the inhibition of tumor growth due to the administration of Compound A MEK inhibitor, Compound B B-Raf inhibitor and the combination thereof.
[0031] FIGURE 2 is a graph showing the inhibition of tumor growth due to the administration of the MEK inhibitor of Compound A, the B-Raf inhibitor of Compound B and the combination thereof. DETAILED DESCRIPTION OF THE INVENTION
[0032] As used herein, the MEK inhibitor N- {3 [3-cyclopropyl-5 (2-fluoro-4-iodo-phenylamino) 6,8-dimethyl-2,4,7-trioxo-3,4, 6,7-tetrahydro-2Hpirido [4,3-d] pyrimidin-1-yl] phenyl} acetamide, or a pharmaceutically acceptable salt or solvate thereof, is represented by a compound of formula (I):
or pharmaceutically acceptable salt or solvate thereof. For convenience, the group of compound and possible salts or solvates is collectively referred to as Compound A, meaning that the reference to Compound A will refer to any of the pharmaceutically acceptable compounds or salt or solvate thereof in the alternative.
[0033] Depending on the naming convention, the compound of formula (I) can also be appropriately referred to as N- {3 [3-cyclopropyl-5 [(2-fluoro-4-iodophenyl) amino] -6,8-dimethyl -2,4,7-trioxo-3,4,6,7tetrahydropyrido [4,3-d] pyrimidin-1 (2H) -yl] phenyl} acetamide.
[0034] As used herein, the BRaf inhibitor N- {3 [5- (2-amino-4pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl } -2,6difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof, is represented by a compound formula (II):
or a pharmaceutically acceptable salt thereof. For convenience, the group of the compound and possible salts and salts are collectively referred to as Compound B, meaning that the reference to Compound B will refer to any of the pharmaceutically acceptable compounds or salt thereof in the alternative.
[0035] As used herein the term "combination of the invention" refers to a combination comprising Compound A and Compound B.
[0036] As used herein the term "neoplasm" refers to an abnormal growth of cells or tissue and is understood to include benign growths, that is, non-cancerous and malignant growths, that is, cancerous. The term "neoplastic" means of or related to a neoplasm.
[0037] As used herein the term "agent" is understood to mean a substance that produces a desired effect on a tissue, system, animal, mammal, human being, or other individual. Consequently, the term "antineoplastic agent" is understood to mean a substance that produces an antineoplastic effect on a tissue, system, animal, mammal, human being, or other individual. It should also be understood that an "agent" can be a single compound or a combination or composition of two or more compounds.
[0038] By the term "treat" and derivatives thereof as used herein, therapeutic therapy is intended. In reference to a particular condition, treating means: (1) improving the condition or one or more of the biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition (3) assessing one or more of the symptoms, effects or side effects associated with the condition or one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or ( 4) reduces the progression of the condition or one or more of the biological manifestations of the condition.
[0039] As used herein, "prevention" is understood to refer to the prophylactic administration of a drug to substantially decrease the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof. A qualified technician will assess that "prevention" is not an absolute term. Prophylactic therapy is appropriate, for example, when an individual is considered to be at high risk for developing cancer, such as when an individual has a strong family history of cancer or when an individual has been exposed to a carcinogen.
[0040] As used herein, the term "effective amount" means that the amount of a drug or pharmaceutical agent that will evoke the biological or medical response of a tissue, system, animal or human being being sought, for example, by a researcher or doctor. In addition, the term "therapeutically effective amount" means any amount that, when compared to a corresponding individual who has not received such amount, results in improved treatment, cure, prevention, or improvement of a disease, disorder, or side effect, or a decrease in the rate of progression of a disease or disorder. The term also includes within its scope effective amounts to enhance normal physiological function.
[0041] Compounds A and / or B may contain one or more chiral atoms, or may otherwise be able to exist as enantiomers. Consequently, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also, it is understood that all tautomers and mixtures of tautomers are included within the scope of Compound A and Compound B.
[0042] Also, it is understood that Compounds A and B can be present, separately or both, as solvates. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, the compounds of formula (I) or (II) or a salt thereof and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, dimethylsulforide, ethanol and acetic acid. In one embodiment, the solvent used is a pharmaceutically acceptable solvent Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid In another embodiment, the solvent used is water.
[0043] Compounds A and B may have the ability to crystallize in more than one form, a characteristic, which is known polymorphism and it is understood that such polymorphic forms ("polymorphs") are within the scope of The Compounds A and B Polymorphism in general can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallization process. Polymorphs can be distinguished by the various physical characteristics known in the art such as X-ray diffraction patterns, solubility and melting point.
[0044] Compound A is disclosed and claimed, together with its pharmaceutically acceptable salts and also as solvates thereof, as being useful as an inhibitor of MEK activity, particularly in the treatment of cancer, in WO 2005/121142. Compound A is the compound of example 4-1. Compound A can be prepared as described in WO 2005/121142.
[0045] Suitably, Compound A is in the form of a dimethylsulfoxide solvate. Suitably, Compound A is in the form of a sodium salt. Suitably, Compound A is in the form of a solvate selected from: hydrate, acetic acid, ethanol, nitromethane, chlorobenzene, 1-pentancol, isopropyl alcohol, ethylene glycol and 3-methyl-1-butanol. These solvates and salt forms can be prepared by a person of skill in the art from the description in WO 2005/121142.
[0046] Compound B is disclosed and claimed, along with its pharmaceutically acceptable salts, as being useful as an inhibitor of BRaf activity, particularly in the treatment of cancer, in PCT patent application PCT / US09 / 42682. Compound B is incorporated by Examples 58a through 58e of the application. The PCT application was published on November 12, 2009 as publication WO 2009/137391 and is incorporated herein by reference.
[0047] More particularly, Compound B can be prepared according to the methods below: Method 1: Compound B (first crystalline form) N- {3 [5- (2-Amino-4pyrimidinyl) -2- (1,1 -dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl} -2,6-difluorobenzenesulfonamide

[0048] A suspension of N- {3 [5- (2-chloro-4-pyrimidinyl) -2- (1,1dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl} -2,6 -difluorobenzene-sulfonamide (196 mg, 0.364 mmol) and 7 M ammonia in methanol (8 ml, 56.0 mmol) was heated in a sealed tube to 90 ° C for 24 hours. The reaction was diluted with DCM and added silica gel and concentrated. The crude product was subjected to chromatography on silica gel eluting with 100% 1: 1 DCM [DCM: (9: 1 EtOAc: MeOH)]. The light fractions were concentrated to produce the crude product. The crude product was repurified by reverse phase HPLC (a gradient of acetonitrile: water with 0.1% TFA in both). The combined light fractions were concentrated then partitioned between DCM and saturated NaHCO3. The DCM layer was separated and dried over Na2SO4. The title compound, N- {3 [5- (2-amino-4-pyrimidinyl) -2- (1,1-dimethyl-ethyl) -1,3thiazol-4-yl] -2-fluorophenyl} -2, 6-difluoro-benzenesulfonamide was obtained (94 mg, 47 yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.55 7.70 (m, 1H), 7 , 35 7.43 (m, 1H), 7.31 (t, J = 6.3Hz, 1H), 7.14 7.27 (m, 3H), 6.70 (s, 2 H), 5, 79 (d, J = 5.13 Hz, 1H), 1.35 (s, 9H). MS (ESI): 519.9 [M + H] +. Method 2: Compound B (alternative crystalline form) N- {3 [5- (2-Amino-4pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl} -2,6-difluorobenzenesulfonamide
[0049] 19.6 mg of N- {3 [5- (2-Amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl} -2,6-difluorobenzenesulfonamide (can be prepared according to example 58a) were combined with 500 L of ethyl acetate in a 2 ml bottle at room temperature. The slurry was cycled at a temperature between 0 to 40 ° C for 48 hours. The resulting slurry was allowed to cool to room temperature and was collected by vacuum filtration. The solids were analyzed by Raman, PXRD, DSC / TGA analyzes, which inhibit a crystalline form from the different crystalline form that results from Example 58a, above. Method 3: Compound B (alternative crystalline form, large batch) N- {3 [5 (2-amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] - 2-fluoro-phenyl} -2,6difluorobenzenesulfonamide

[0050] Step A: 3- {[(2,6-difluorophenyl) sulfonyl] amino} -2 methyl fluorobenzoate

[0051] Methyl 3-amino-2-fluorobenzoate (50 g, 1 eq) was charged to the reactor followed by dichloromethane (250 ml, 5 vol). The contents were stirred and collected to ~ 15 ° C and pyridine (26.2 ml, 1.1 eq) was added. After the addition of the pyridine, the contents of the reactor were adjusted to ~ 15 ° C and the addition of 2,6-difluorobenzenesulfonyl chloride (39.7 ml, 1.0 eq) was stirred through the addition funnel. The temperature during the addition was maintained <25 ° C. After complete addition, the reactor contents were heated to 20 to 25 ° C and maintained overnight. Ethyl acetate (150 ml) was added and dichloromethane was removed by distillation. Once the distillation was complete, the reaction mixture was then further diluted with ethyl acetate (5 vol) and concentrated. The reaction mixture was diluted with ethyl acetate (10 vol) and water (4 vol) and the contents heated to 50 to 55 ° C with stirring until all solids dissolve. The layers were shaken and separated. The organic layer was diluted with water (4 vol) and the contents heated from 50 to 55 ° for 20 to -30 minutes. The layers were stirred and then separated and the ethyl acetate layer was evaporated under reduced pressure of ~ 3 volumes. Ethyl acetate (5 vol.) Was added and again evaporated under reduced pressure of ~ 3 volumes. Cyclohexane (9 vol) was then added to the reactor and the contents were heated to reflux for 30 minutes and then cooled to 0 ° C. The solids were rinsed with cyclohexane (2 x 100 ml). The solids were air dried overnight to obtain methyl 3- {[(2,6-difluorophenyl) sulfonyl] amino} -2 (94.1 g, 91%) methyl fluorobenzoate.
[0052] Step B: N- {3 [(2-chloro-4-pyrimidinyl) acetyl] -2-fluorophenyl} 2,6-difluoro-benzenesulfonamide

[0053] Methyl 3- {[(2,6-difluorophenyl) sulfonyl] amino} -2-fluorobenzoate (490 g, 1 equiv.), Prepared in general according to Step A, above, was dissolved in THF ( 2.45 liters, 5 vols) and stirred and cooled to 0 to 3 ° C. 1M lithium bis (trimethylsilyl) amide in THF (5.25 liters, 3.7 equiv.) the solution was charged to the reaction mixture followed by the addition of 2-chloro-4methylpyrimidine (238 g, 1.3 equiv.) in THF (2.45 liters, 5 vols). The reaction was then stirred for 1 hour. The reaction was quenched with 4.5 M HCl (3.92 liters, 8 vols). the aqueous layer (bottom layer) was removed and discarded. The organic layer was concentrated under reduced pressure to ~ 2 liters. IPAC (isopropyl acetate) (2.45 liters) was added to the reaction mixture which was then concentrated to ~ 2 liters. IPAC (0.5 liter) and MTBE (2.45 liters) were added and stirred overnight under N2. The solids were filtered. The solids and the precursor filtrate added back together and stirred for several hours. The solids were filtered and washed with MTBE (~ 5 vol). The solids were placed in a vacuum oven at 50 ° C overnight. The solids were dried in a vacuum oven at 30 ° C over the weekend to obtain N- {3 [(2-chloro-4-pyrimidinyl) acetyl] -2-fluorophenyl} -2,6difluorobenzene-sulfonamide (479 g, 72%).
[0054] Step C: N- {3 [5- (2-chloro-4-pyrimidinyl) -2- (1,1-dimethylethyl) 1,3-thiazol-4-yl] -2-fluorophenyl} -2, 6-difluorobenzenesulfonamide

[0055] N- {3 [(2-chloro-4-pyrimidinyl) acetyl] -2-fluorophenyl} -2,6-difluorobenzenesulfonamide (30 g, 1 eq) was charged to a reactor vessel followed by dichloromethane (300 ml). The reaction fluid was cooled to ~ 10 ° C and N-bromosuccinimide (“NBS”) (12.09 g, 1 eq) was added in 3 approximately equal portions, stirred for 10 to 15 minutes between each addition. After the final addition of NBS, the reaction mixture was heated to ~ 20 ° C and stirred for 45 minutes. Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to ~ 120 ml. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to ~ 120 ml. Dimethylacetamide (270 ml) was then added to the reaction mixture and cooled to ~ 10 ° C. 2,2-Dimethylpropanothioamide (1.3 g, 0.5 eq) in two equal portions was added to the reactor contents with stirring for ~ 5 minutes between additions. The reaction was heated to 20 to 25 ° C. After 45 minutes, the contents of the vessel were heated to 75 ° C and maintained for 1.75 hours. The reaction mixture was then cooled to 5 ° C and water (270 ml) was slowly charged while maintaining the temperature below 30 ° C. The ethyl acetate (4 vol) was then loaded and the mixture was stirred and the layers separated. The ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. The ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20 to 25 ° C. The organic layers were then concentrated under heating and vacuum to 120 ml. The contents of the vessel were then heated to 50 ° C and heptanes (120 ml) were added slowly. After the addition of heptanes, the contents of the vessel were heated to reflux then cooled to 0 ° C and maintained for ~ 2 hours. The solids were rinsed with heptanes (2 x 2 vol). The solid product was then dried under vacuum at 30 ° C to obtain N- {3 [5- (2-chloro-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] - 2-fluorophenyl} -2,6difluorobenzene sulfonamide (28.8 g, 80%).
[0056] Step D: N- {3 [5- (2-amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) 1,3-thiazol-4-yl] -2-fluorophenyl} -2, 6-difluorobenzenesulfonamide
[0057] In a 1-gallon (3.8-liter) pressure reactor, a mixture of N- {3 [5- (2-chloro-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1, 3-thiazol-4-yl] -2fluorophenyl} -2,6-difluorobenzenesulfonamide (120 g) prepared according to Step C, above and ammonium hydroxide (28 to 30%, 2.4 liters, 20 vol) was heated in pressure reactor sealed up to 98 to 103 ° C and stirred at this temperature for 2 hours. The reaction was slowly cooled to room temperature (20 ° C) and stirred overnight. The solids were filtered and washed with minimal precursor liquid and dried under vacuum. The solids were added to an EtOAc (15 vol) / water (2 vol) mixture and heated until complete dissolution from 60 to 70 ° C and the aqueous layer was removed and discarded. The EtOAC layer was loaded with water (1 vol) and neutralized with aq. to ~ pH 5.4 to 5.5. and added water (1 vol). The aqueous layer was removed and discarded at 60 to 70 ° C. The organic layer was washed with water (1 vol) at 60 to 70 ° C and the aqueous layer was removed and discarded. The organic layer was filtered at 60 ° C and concentrated to 3 volumes. EtOAc (6 vol) was loaded into the mixture and heated and stirred at 72 ° C for 10 minutes, then cooled to 20 ° C and stirred overnight. EtOAc was removed by vacuum distillation to concentrate the reaction mixture to ~ 3 volumes. The reaction mixture was kept at ~ 65 to 70 ° C for ~ 30 minutes. The product crystals having the same crystalline form as that prepared in Example 58b (and preparable by the procedure of Example 58b), above, in heptane slurry were loaded. Heptane (9 vol) was slowly added at 65 to 70 ° C. The slurry was stirred at 65 to 70 ° C for 2 to 3 hours and then cooled slowly from 0 to 5 ° C. The product was filtered, washed with EtOAc / Heptane (3/1 v / v, 4 vol) and dried at 45 ° C under vacuum to obtain N- {3 [5- (2-amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3thiazol-4-yl] -2-fluorophenyl} -2,6-difluorobenzene-sulfonamide (102.3 g, 88%). Method 4: Compound B (mesylate salt) N- {3 [5- (2-amino-4-pyrimidinyl) -2 (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl } -2,6-difluorobenzenesulfonamide methanesulfonate

[0058] To a solution of N- {3 [5- (2-amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl} - 2,6-difluorobenzene sulfonamide (204 mg, 0.393 mmol) in isopropanol (2 ml), methanesulfonic acid (0.131 ml, 0.393 mmol) was added and the solution was allowed to stir at room temperature for 3 hours. A white precipitate formed and the slurry was filtered and rinsed with diethyl ether to give the title product as a white crystalline solid (210 mg, 83 yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1H) 7.92 8.05 (m, 1H) 7.56 7.72 (m, 1H) 6.91 7.50 (m , 7 H) 5.83 5.98 (m, 1H) 2.18 2.32 (m, 3H) 1.36 (s, 9H). MS (ESI): 520.0 [M + H] +. Method 5: Compound B (alternative salt of the mesylate embodiment) N- {3 [5- (2-amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3thiazole-4- methanesulfonate il] -2-fluorophenyl} -2,6-difluorobenzene-sulfonamide
[0059] N- {3 [5- (2-amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol 4-yl] -2-fluorophenyl} -2,6-difluorobenzenesulfonamide (as can be prepared according to example 58a) (2.37 g, 4.56 mmol) was combined with prefiltered acetonitrile (5.25 vol, 12.4 ml). A pre-filtered solution of meic acid (1.1 eq., 5.02 mmol, 0.48 g) in H2O (0.75 eq., 1.78 ml) was added at 20 ° C. The temperature of the resulting mixture was raised from 50 to 60 ° C while maintaining a low stirring speed. Once the temperature of the mixture reached 50 to 60 ° C, a N- {3 [5- (2-amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1 methanesulfonate seed slurry , 3-thiazol-4-yl] -2-fluorophenyl} -2,6-difluoro-benzenesulfonamide (1.0 wt% pasted in 0.2 vol of pre-filtered acetonitrile) was added and the mixture was aged under agitation at a speed fast enough to prevent solids from settling at 50 to 60 ° C for 2 hours. The mixture was then cooled from 0 to 5 ° C to 0.25 ° C / minutes and maintained at 0 to 5 ° C for up to 6 hours. The mixture was filtered and the wet cake was washed twice with pre-filtered acetonitrile. The first wash consisted of 14.2 ml (6 vol) pre-filtered acetonitrile and the second wash consisted of 9.5 ml (4 vol) pre-filtered acetonitrile. The wet solid was dried at 50 ° C under vacuum, yielding 2.39 g (85.1 yield) of the product.
[0060] Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts within the term "pharmaceutically acceptable salts" refer to the non-toxic salts of the compounds of this invention. The salts of the compounds of the present invention can comprise acid addition salts derived from a nitrogen in a substituent on a compound of the present invention. Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromate, calcium edetate, cansylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, stolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylsanilate, hexylressorcinate, hydrabamine, hydro-bromate, hydrochloride, hydroxinaftoate, iodine, isethionate, lactate, lacto-bionate, laurate, malate, maleate, mandelate, mesylate, methylbromate, methylate, methylate, monohydrate, methylate mucate, napsylate, nitrate, N-methylglucamine, oxalate, pomoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, trioxide, tetraylate and valerate. Other salts, which are not pharmaceutically acceptable, can be useful in the preparation of the Compounds of this invention and these form another aspect of the invention. Salts can be easily prepared by a person skilled in the art.
[0061] Although it is possible that, for use in therapy, Compounds A and B, can be administered as raw chemicals, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which include a Compound A and / or a compound B and one or more carriers, diluents, pharmaceutically acceptable excipients. Compounds A and B are as described above. The carrier (s), diluent (s) or excipient (s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of the chemical formulation and not harmful to your receiver. According to another aspect of the invention there is also provided a process for the preparation of a pharmaceutical composition including mixing Compound A and / or Compound B, with one or more pharmaceutically acceptable carriers, diluents or excipients. Such elements of the pharmaceutical compositions used can be present in pharmaceutical combinations separated or formulated together in a pharmaceutical composition. Accordingly, the invention further provides a combination of pharmaceutical compositions, one of which includes Compound A and one or more carriers, diluents, pharmaceutically acceptable excipients and a pharmaceutical composition containing Compound B and one or more carriers, diluents, pharmaceutically acceptable excipients.
[0062] Compound A and Compound B are as described above and can be used in any of the compositions described above.
[0063] The pharmaceutical compositions can be present in unit dose forms containing a predetermined amount of the active ingredient per unit dose. As those skilled in the art are known, the amount of active ingredient per dose will depend on the condition to be evaluated, the route of administration and the age, weight and condition of the patient. Preferred unit dosage compositions are those that contain a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. In addition, such pharmaceutical compositions can be prepared by any of the methods well known in the art of pharmacy.
[0064] Compounds A and B can be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). It will be appreciated that the preferred route may vary, for example, with the condition of the recipient of the combination and the cancer being treated. It will also be assessed that each of the agents administered can be administered by the same or different routes and that Compounds A and B can be combined together in a pharmaceutical composition.
[0065] Pharmaceutical compositions adapted for oral administration may be present as separate units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible whipped foams or creams; or liquid oil-in-water emulsions or liquid water-in-oil emulsions.
[0066] For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, pharmaceutically inert non-toxic inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, such as, for example, starch or mannitol. Flavoring, preserving, dispersing and coloring agent may also be present.
[0067] The capsules are manufactured by preparing a mixture as described above and filling formed gelatin sheaths. Gelatins and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or sodium polyethylene glycol can be added to the powder mixture before the filled operation. A disintegrating or solubilizing agent such as agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the drug when the capsule is ingested.
[0068] In addition, when desired or necessary, suitable binders, lubricating disintegrating agents and coloring agents can also be granulated, powder mixtures can be conducted through the tablet machine and the result is imperfectly formed tablets broken into granules. The granules can be lubricated and incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, wax and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a mixture, granulation or tabletting, adding a lubricant and disintegrant and pressing on Tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a retardant solution such as paraffins, a resorption accelerator such as a quaternary salt and / or an absorption agent such as betonite, kaolin or dicalcium phosphate. Powder mixtures can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of polymeric cellulosic materials and forcing through a sieve. As an alternative to prevent it from sticking to the matrix that forms the tablet by adding stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with an inert carrier with free flow and compressed into the Tablets directly without going through the granulation and tabletting steps. A clear or opaque protective coating consists of a shellac sealing coating, a sugar coating or polymeric material and a wax polishing coating can be provided. Dyes can be added to these coatings to distinguish different unit dosages.
[0069] Oral fluids as a solution, syrups and elixirs can be prepared in unit dosage form so that a given amount contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a properly flavored aqueous solution, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyethylene ethylene sorbitol esters, preservatives, flavor additives such as mint oil or natural sweeteners or saccharin or other artificial sweeteners and the like can also be added.
[0070] Where appropriate, compositions for oral administration can be microecapsulated. The composition can also be prepared to prolong or sustain release, for example by coating or embedding particulate material in polymers, wax or the like.
[0071] The agents for use according to the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
[0072] The agents for use according to the present invention can also be released by the use of monoclonal antibodies as individual carriers to which the molecules of the compound are attached. The compounds can also be linked with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethylene oxopolylysine substituted with palmitoyl residues. In addition, the compounds can be linked to a class of biodegradable polymers useful in obtaining the controlled release of a drug, for example, lactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyiortoesters, polyacetals, polyhydropyranes, polyacrylates and copolymers of reticulated or amphipathic blocks of hydrogels.
[0073] Pharmaceutical compositions adapted for transdermal administration may be present as separate patches intended to remain in close contact with the epidermis of the recipient for an extended period of time. For example, the active ingredient can be released from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
[0074] Pharmaceutical compositions adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
[0075] For eye treatments or other external tissues, for example mouth and skin, the compositions are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient can be used with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream with a creamy oil-in-water base or a water-in-oil base.
[0076] Pharmaceutical compositions adapted for topical administration to the eye include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
[0077] Pharmaceutical compositions adapted for topical administration in the mouth include tablets, lozenges and mouthwashes.
[0078] Pharmaceutical compositions adapted for rectal administration may be present as suppositories or as enemas.
[0079] Pharmaceutical compositions adapted for nasal administration in which the carrier is a solid include a coarse powder having a particle size for example in the range of 20 to 500 microns which is administered in a manner in which inspiration is taken, i.e. by rapid inhalation through the nasal passage of a powder container held close to the nose. Suitable compositions in which the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
[0080] Pharmaceutical compositions adapted for administration by inhalation include fine particle dust or mists that can be generated by various types of metered dose aerosols, nebulizers or pressurized insufflators.
[0081] Pharmaceutical compositions adapted for vaginal administration may be present as pessaries, tampons, creams, gels, pastes, foams or spray compositions.
[0082] Pharmaceutical compositions adapted for parenteral administration include sterile aqueous and non-aqueous injection solutions that may contain antioxidants, buffers, bacteriostats and solutes that make the formulation isotonic with the blood of the intended container; and sterile aqueous and non-aqueous suspensions which may include suspending agents and thickening agents. The compositions can be present in single dose or multiple dose containers, for example ampoules and sealed vials and can be stored in a freeze-dried (lyophilized) condition that requires only the addition of the sterile liquid carrier, for example water for injections, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.
[0083] It should be understood that in addition to the ingredients particularly mentioned above, the compositions may include other agents conventional in the art considering the type of the formulation in question, for example those suitable for oral administration may include flavoring agents.
[0084] Unless otherwise defined, in all dosing protocols described here, the administered Compounds regimen does not have to start with the start of treatment and end with the type of treatment, it is only required that the number of days consecutive days in which both compounds are administered and the optional number of consecutive days in which only one of the component compounds is administered, or indicated dosing protocol including the amount of Compound administered, occurs at some point during the course of treatment.
[0085] Compounds A and B can be used in combination according to the invention by simultaneous administration in a unitary pharmaceutical composition including both compounds. Alternatively, the combination can be administered separately in separate pharmaceutical compositions, each including one of compounds A and B in a sequential manner in which, for example, Compound A or Compound B are administered first and another second. Such an administration sequence can be close in time (for example, simultaneously) or remote in time. Furthermore, in addition it does not matter whether the compounds are administered in the same dosage form, for example one compound can be administered topically and the other compound can be administered orally. Suitably, both compounds are administered orally.
[0086] Thus in one embodiment, one or more doses of Compound A are administered simultaneously or separately with one or more doses of Compound B.
[0087] Unless otherwise defined, in all dosage protocols described here, the regimen of compounds administered does not have to start with the start of treatment and end with the type of treatment, it is only required that the number of days consecutive days in which both compounds are administered and the optional number of consecutive days in which only one of the component compounds is administered, or indicated dosing protocol including the amount of Compound administered, occurs at some point during the course of treatment.
[0088] In one embodiment, multiple doses of Compound A are administered simultaneously or separately with multiple doses of Compound B.
[0089] In one embodiment, multiple doses of Compound A are administered simultaneously or separately with a dose of Compound B.
[0090] In one embodiment, one dose of Compound A is administered simultaneously or separately with multiple doses of Compound B.
[0091] In one embodiment a dose of Compound A is administered simultaneously or separately with a dose of Compound B.
[0092] In all embodiments, Compound A can be administered first or Compound B can be administered first.
[0093] Combinations can be present as a combination kit. By the terms "combination kit" "or kit of parts" as used herein is intended the composition or pharmaceutical compositions that are used to administer Compound A and Compound B according to the invention. When both compounds are administered simultaneously, the combination kit can contain Compound A and Compound B in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions. When Compounds A and B are not administered simultaneously, the combination kit will contain Compound A and Compound B in separate pharmaceutical compositions in a single package or Compound A and Compound B in separate pharmaceutical compositions in separate packages.
[0094] In one aspect a kit of parts is provided which comprise the components: Compound A in combination with a pharmaceutically acceptable excipient, diluent or carrier; and Compound B in combination with a pharmaceutically acceptable excipient, diluent or carrier.
[0095] In an embodiment of the invention the kit of parts comprising the following components: Compound A in association with a pharmaceutically acceptable excipient, diluent or carrier; and Compound B in combination with a pharmaceutically acceptable excipient, diluent or carrier, wherein the components are provided in a form that is suitable for sequential, separate and / or simultaneous administration.
[0096] In one embodiment the kit of parts comprises: a first container comprising Compound A in association with a pharmaceutically acceptable excipient, diluent or carrier; and a second container comprising Compound B in association with a pharmaceutically acceptable excipient, diluent or carrier and a container means for containing said first and second containers.
[0097] The combination kit can also be provided by the instruction, such as dosing and administration instructions. Such dosage and administration instructions may be of the types that are provided to a physician, for example by a drug product label, or they may be of the type that are provided by a physician, such as instructions to a patient.
[0098] The term "loading dose" as used herein will be understood to mean a single dose or short duration regimen of Compound A or Compound B having a higher dosage than the maintenance dose administered to the individual for, for example, rapidly increase the level of concentration in the blood of the drug. Suitably, a short duration regime for use will be here: 1 to 14 days; adequately from 1 to 7 days; adequately from 1 to 3 days; properly for three days; properly for two days; properly for a day. In another embodiment, the "loading dose" can increase the blood concentration of the drug to a therapeutically effective level. In another embodiment, the "loading dose" can increase the blood concentration of the drug to a therapeutically effective level in conjunction with a maintenance dose of the drug. The “loading dose” can be administered once a day, or more than once a day (for example, up to 4 times a day). Suitably, the “loading dose” will be administered once a day. Suitably, the loading dose will be an amount of 2 to 100 times the maintenance dose; adequately 2 to 10 times; adequately 2 to 5 times; properly 2 times; properly 3 times; properly 4 times; properly 5 times. Suitably, the loading dose will be administered for 1 to 7 days; adequately from 1 to 5 days; adequately from 1 to 3 days; properly for 1 day; properly for 2 days; properly for 3 days, followed by a maintenance dosing protocol.
[0099] The term "maintenance dose" as used herein will be understood to mean a dose that is administered in series (for example; at least twice) and which is intended to slowly increase the blood concentration levels of the compound to a level therapeutically effective, or to maintain such a therapeutically effective level. The maintenance dose is generally administered once a day and the daily maintenance dose is lower than the total daily dose of the loading dose.
[00100] Suitably the combinations of this invention are administered within a "specific period".
[00101] By the terms "specific period" and derivatives thereof, as used herein, the time interval between the administration of a Compound A and Compound B and the other of Compound A and Compound B is intended. Unless otherwise defined period, the specific period may include simultaneous administration. When both compounds of the invention are administered once a day, the specific period refers to the administration of Compound A and Compound B during a single day. When one or both of the compounds of the invention are administered more than once a day, the specific period is calculated based on the first administration of each compound on a specific day. All administrations of a compound of the invention that are subsequent to the first during a specific day are not considered when calculating the specific period.
[00102] Suitably, if the compounds are administered within a "specific period" and not administered simultaneously, they are both administered within about 24 hours of each other in this case, the specific period will be approximately 24 hours; adequately both can be administered within about 12 hours of each other in this case, the specific period will be approximately 12 hours; adequately both can be administered within about 11 hours of each other in this case, the specific period will be about 11 hours; adequately both can be administered within about 10 hours of each other in this case, the specific period will be approximately 10 hours; adequately both can be administered within about 9 hours of each other in this case, the specific period will be approximately 9 hours; adequately both can be administered within about 8 hours of each other in this case, the specific period will be approximately 8 hours; adequately both can be administered within about 7 hours of each other in this case, the specific period will be about 7 hours; adequately both can be administered within about 6 hours of each other in this case, the specific period will be approximately 6 hours; adequately both can be administered within about 5 hours of each other in this case, the specific period will be approximately 5 hours; adequately both can be administered within about 4 hours of each other in this case, the specific period will be approximately 4 hours; adequately both can be administered within about 3 hours of each other in this case, the specific period will be approximately 3 hours; properly they will be administered within about 2 hours of each other in this case, the specific period will be approximately 2 hours; adequately both can be administered within about 1 hour of each other in this case, the specific period will be approximately 1 hour. As used herein, administration of Compound A and Compound B in less than about 45 minutes separately is considered simultaneous administration.
[00103] Suitably, when the combination of the invention is administered for a "specific period", the compounds will be co-administered for a duration of time ".
[00104] By the term "time duration" and derivatives thereof, as used herein it is intended that both compounds of the invention are administered for an indicated number of consecutive days.
[00105] With respect to the administration in “specific period”:
[00106] Suitably, both compounds will be administered within a specific period for at least one day in this case, the length of time will be at least one day; suitably, during the course of treatment, both compounds will be administered within a specific period for at least 3 consecutive days in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specific period for at least 5 consecutive days in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specific period for at least 7 consecutive days in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specific period for at least 14 consecutive days in this case, the duration of time will be at least 14 days; suitably, during the course of treatment, both compounds will be administered within a specific period for at least 30 consecutive days; in this case, the duration will be at least 30 days.
[00107] Still with respect to the administration in “specific period”:
[00108] Suitably, during the course of treatment, Compound A and Compound B will be administered within a specific period for 1 to 4 days over a period of 7 days or other days within the period of 7 days Compound A will be administered alone . Suitably, this 7-day protocol is represented by 2 cycles or by 14 days; adequately for 4 cycles or 28 days; adequately for continuous administration.
[00109] Suitably, during the course of treatment, Compound A and Compound B will be administered within a specific period for 1 to 4 days over a period of 7 days or other days within the period of 7 days Compound B will be administered alone . Suitably, this 7-day protocol is represented by 2 cycles or by 14 days; adequately for 4 cycles or 28 days; adequately for continuous administration. Suitably, Compound B is administered for consecutive days over the 7 day period. Suitably, Compound B is administered in a day-to-day pattern during each 7-day period.
[00110] Suitably, during the course of treatment, Compound A and Compound B will be administered within a specific period for 3 days over a period of 7 days or other days within the period of 7 days Compound B will be administered alone. Suitably, this 7-day protocol is represented by 2 cycles or by 14 days; adequately for 4 cycles or 28 days; adequately for continuous administration. Suitably, Compound A will be administered for 3 consecutive days over the 7-day period.
[00111] Suitably, during the course of treatment, Compound A and Compound B will be administered within a specific period for 2 days over a period of 7 days or other days within the period of 7 days Compound B will be administered alone. Suitably, this 7-day protocol is represented by 2 cycles or by 14 days; adequately for 4 cycles or 28 days; adequately for continuous administration. Suitably, Compound A will be administered 2 consecutive days over the 7 day period.
[00112] Suitably, during the course of treatment, Compound A and Compound B will be administered within a specific period for 1 day over a period of 7 days and during or other days of the period of 7 days Compound B will be administered alone . Suitably, this 7-day protocol is represented by 2 cycles or by 14 days; adequately for 4 cycles or 28 days; adequately for continuous administration.
[00113] Suitably, if the compounds are not administered during a "specific period", they are administered sequentially. By the term "sequential administration" and its derivatives, as used herein, it is intended that one of Compound A and Compound B is administered for two or more consecutive days and the other of Compound A and Compound B is subsequently administered for two or more days consecutive. Also, a recess of the drug used between the sequential administration of Compound A and Compound B and the other of Compound A and Compound B is considered here. As used herein, a recess of the drug is a period of days after sequential administration of a Compound A and Compound B and prior to the administration of the other Compound A and Compound B where no Compound A and no Compound B are administered. Appropriately, the withdrawal of the medication will be a period of selected days: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days and 14 days.
[00114] With respect to sequential administration:
[00115] Suitably, one of Compound A and Compound B is administered for 1 to 30 consecutive days, followed by an optional drug withdrawal, followed by the administration of the other Compound A and Compound B for 1 to 30 consecutive days. Suitably, one of Compound A and Compound B is administered for 2 to 21 consecutive days, followed by an optional drug withdrawal, followed by the administration of the other Compound A and Compound B for 2 to 21 consecutive days. Suitably, a Compound A and Compound B are administered for 2 to 14 consecutive days, followed by a recess of the drug for 1 to 14 days, followed by the administration of the other Compound A and Compound B for 2 to 14 consecutive days. Suitably, a Compound A and Compound B are administered for 3 to 7 consecutive days, followed by a recess of the drug for 3 to 10 days, followed by the administration of the other Compound A and Compound B for 3 to 7 consecutive days.
[00116] Suitably, Compound B will be administered first in the sequence, followed by an optional drug recess, followed by the administration of Compound A. Suitably, Compound B is administered for 1 to 21 consecutive days, followed by an optional drug recess. , followed by the administration of Compound A for 1 to 2 consecutive days. Suitably, Compound B is administered for 3 to 21 consecutive days, followed by a withdrawal of the drug from 1 to 14 days, followed by the administration of Compound A for 3 to 21 consecutive days. Suitably, Compound B is administered for 3 to 21 consecutive days, followed by a withdrawal of the drug for 3 to 14 days, followed by administration of Compound A for 3 to 21 consecutive days. Suitably, Compound B is administered for 21 consecutive days, followed by an optional drug withdrawal, followed by administration of Compound A for 14 consecutive days. Suitably, Compound B is administered for 14 consecutive days, followed by a withdrawal of the drug from 1 to 14 days, followed by administration of Compound A for 14 consecutive days. Suitably, Compound B is administered for 7 consecutive days, followed by a withdrawal of the drug for 3 to 10 days, followed by administration of Compound A for 7 consecutive days. Suitably, Compound B is administered for 3 consecutive days, followed by a withdrawal of the drug for 3 to 14 days, followed by administration of Compound A for 7 consecutive days. Suitably, Compound B is administered for 3 consecutive days, followed by a withdrawal of the drug for 3 to 10 days, followed by administration of Compound A for 3 consecutive days.
[00117] Suitably, Compound A will be administered first in the sequence, followed by an optional drug recess, followed by administration of Compound B. Suitably, Compound A is administered for 1 to 2 consecutive days, followed by an optional drug recess. , followed by the administration of Compound B for 1 to 2 consecutive days. Suitably, Compound A is administered for 3 to 21 consecutive days, followed by a withdrawal of the drug from 1 to 14 days, followed by the administration of Compound B for 3 to 21 consecutive days. Suitably, Compound A is administered for 3 to 21 consecutive days, followed by a withdrawal of the drug for 3 to 14 days, followed by administration of Compound B for 3 to 21 consecutive days. Suitably, Compound A is administered for 21 consecutive days, followed by an optional drug withdrawal, followed by administration of Compound B for 14 consecutive days. Suitably, Compound A is administered for 14 consecutive days, followed by a withdrawal of the drug from 1 to 14 days, followed by administration of Compound B for 14 consecutive days. Suitably, Compound A is administered for 7 consecutive days, followed by a withdrawal of the drug for 3 to 10 days, followed by administration of Compound B for 7 consecutive days. Suitably, Compound A is administered for 3 consecutive days, followed by a withdrawal of the drug for 3 to 14 days, followed by administration of Compound B for 7 consecutive days. Suitably, Compound A is administered for 3 consecutive days, followed by a withdrawal of the drug for 3 to 10 days, followed by administration of Compound B for 3 consecutive days.
[00118] It is understood that an administration in “specific period” and an “sequential” administration can be followed by repeated dosages or can be followed by an alternate dosing protocol and a medication recess can precede the repeated dosing or alternating dosing protocol .
[00119] Suitably, the amount of Compound A (based on the weight of the unsalted / unsolvated amount) administered as part of the combination according to the present invention will be a selected amount of about 0.125 mg to about 10 mg; suitably, the amount will be selected from about 0.25 mg to about 9 mg; suitably, the amount will be selected from about 0.25 mg to about 8 mg; accordingly, the amount will be selected from about 0.5mg to about 8mg; accordingly, the amount will be selected from about 0.5mg to about 7mg; accordingly, the amount will be selected from about 1mg to about 7mg; properly, the amount will be around 5mg. Accordingly, the amount of Compound A administered as part of the combination according to the present invention will be a selected amount of about 0.125mg to about 10mg. For example, the amount of Compound A administered as part of the combination according to the present invention can be 0.125mg, 0.25mg, 0.5mg, 0.75mg, 1mg, 1.5mg, 2mg, 2.5mg, 3mg , 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg.
[00120] Suitably, the amount of Compound B (based on the weight of the unsalted / unsolvated amount) administered as part of the combination according to the present invention will be a selected amount of about 10mg to about 600mg. Suitably, the amount will be selected from about 30mg to about 300mg; accordingly, the amount will be selected from about 30mg to about 280mg; accordingly, the amount will be selected from about 40mg to about 260mg; accordingly, the amount will be selected from about 60mg to about 240mg; accordingly, the amount will be selected from about 80mg to about 220mg; accordingly, the amount will be selected from about 90mg to about 210mg; appropriately, the amount will be selected from about 100mg to about 200mg, appropriately, the amount will be selected from about 110mg to about 190mg, appropriately, the amount will be selected from about 120mg to about 180mg, appropriately, the amount will be selected from about 130mg to about 170mg, accordingly, the amount will be selected from about 140mg to about 160mg, accordingly, the amount will be 150mg. Consequently, the amount of Compound B administered as part of the combination according to the present invention will be a selected amount of about 10mg to about 300mg. For example, the amount of Compound B administered as part of the combination according to the present invention is suitably selected from 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg , 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg , 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg and 300mg. Suitably, the selected amount of Compound B is administered 1 to 4 times a day. Suitably, the selected amount of Compound B is administered twice daily. Suitably, Compound B is administered in an amount of 150mg twice a day. Suitably, the selected amount of Compound B is administered once daily.
[00121] As used herein, all amounts specified for Compound A and Compound B are indicated as the amount of the free or unsalted compound. TREATMENT METHOD
[00122] Combinations of the invention are believed to be useful in disorders in which inhibition of MEK and / or B-Raf is beneficial.
The present invention thus also provides a combination of the invention, for use in therapy, particularly in the treatment of disorders in which the inhibiting activity of MEK and / or B-Raf is beneficial, particularly cancer.
[00124] Another aspect of the invention provides a method of treating a disorder in which inhibition of MEK and / or B-Raf is beneficial, which comprises administering a combination of the invention.
[00125] Another aspect of the present invention provides the use of a combination of the invention in the manufacture of a medicament for the treatment of a disorder in which inhibition of MEK and / or B-Raf is beneficial.
[00126] Typically, the disorder is a cancer such that inhibition of MEK and / or B-Raf has a beneficial effect. Examples of cancers that are suitable for treatment with the combination of the invention include, but are not limited to, both primary and metastatic forms of head and neck, breast, lung, colon, ovarian and prostate cancers. Appropriately cancer is selected from: cerebral (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, breast, inflammatory breast disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant bone cell tumor, thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia , chronic lymphocytic leukemia, hair cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, AML, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, myocardial myocardial myeloma , multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, Hodgkins lymphoma, lymphoma non-Hodgkins, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, oral cancer, mouth cancer, GIST (gastrointestinal stromal tumor) and testicular cancer.
[00127] Additionally, examples of a cancer to be treated include Barret's adenocarcinoma; biliary tract carcinomas; breast cancer; cervical cancer; collagiocarcinoma; tumors of the central nervous system including primary CNS tumors such as glioblastomas, astrocytomas (eg glioblastoma multiforme) and secondary CNS ependymomas and tumors (ie, metastases of the central nervous system of tumors originating outside the central nervous system) ; colorectal cancer including carcinoma of the large intestinal colon; gastric cancer; head and neck carcinoma including head and neck squamous cell carcinoma; hematological cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, myeloma and multiple myeloma; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; kidney cancer; sarcoma; skin cancers including melanomas; and thyroid cancers.
[00128] Suitably, the present invention relates to a method for treating or decreasing the severity of a cancer selected from: cerebral (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.
[00129] Suitably, the present invention relates to a method for treating or decreasing the severity of a cancer selected from ovarian, breast, pancreatic and prostate.
[00130] The combination of the invention can be used alone or in combination with one or more other therapeutic agents. The invention thus provides in another aspect another combination comprising a combination of the invention with another therapeutic agent or agents, compositions and medicaments comprising the combination and use of the other combination, compositions and medicaments in therapy, in particular in the treatment of diseases susceptible to inhibition of MEK and / or kinase B.
[00131] In the embodiment, the combination of the invention can be used with other therapeutic cancer treatment drugs. In particular, in antineoplastic therapy, combination therapy with other chemotherapeutic agents, hormones, antibodies as well as surgical treatments and / or radiation other than those mentioned above are considered. Combination therapies according to the present invention thus include the administration of Compound A and Compound B as well as the optional use of other therapeutic agents including other antineoplastic agents. Such a combination of agents can be administered together or separately and, when administered separately it can occur simultaneously or separately in any order, both near and remote in time. In one embodiment, the pharmaceutical combination includes Compound A and Compound B and optionally at least one additional antineoplastic agent.
[00132] As indicated, the therapeutically effective amounts of Compound A and Compound B are discussed above. The therapeutically effective amount of the other therapeutic agents of the present invention will depend on a number of factors including, for example, the age and weight of the mammal, the treatment that requires the precise condition, the severity of the condition, the nature of the formulation and the route of administration. Ultimately, the therapeutically effective amount will be at the discretion of the attending physician or veterinarian. The relative timing of administration will be selected in order to obtain the desired combined therapeutic effect.
[00133] In one embodiment, the other anticancer therapy is surgical and / or radiation therapy.
[00134] In one embodiment, the other anticancer therapy is at least one additional antineoplastic agent.
[00135] Any antineoplastic agent that has activity versus a susceptible tumor being treated can be used in combination. Typical useful antineoplastic agents include, but are not limited to, antimicrotubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogenous, oxazaphosphorins, alkylsulfonates, nitrosoureas and triazenes; antibiotic agents such as anthracyclines, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogs and antifoliate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine angiogenesis inhibitors; immunotherapeutic agents; proapoptic agents; and cell cycle signaling inhibitors.
[00136] Anti-microtubule or antimitotic agents: Anti-microtubule or antimitotic agents are specific phase agents active against tumor cell microtubules during M or the cell cycle mitosis phase. Examples of antimicrotubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
[00137] Diterpenoids, which are derived from natural sources, are phase-specific anticancer agents that operate in the G2 / M phases of the cell cycle. Diterpenoids are believed to stabilize the β tubulin subunit of microtubules by binding to this protein. The disassembly of the protein then appears to be inhibited with mitosis being disrupted and resulting in cell death. Examples of diterpenoids include, but are not limited to, paclitaxel and its analogue docetaxel.
[00138] Paclitaxel, 5β, 20-ep0xi-1,2α, 4,7β, 10β, 13α-hexahydr0xitax-11-en-9-one 4,10-diacetate 2-benzoate with 13-ester (2R , 3S) -Nbenzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as a TAXOL® solution for injection. It is a member of the taxane family of terpenes. Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64: 583, 1991; McGuire et al., Ann. Intem. Med., 111: 273, 1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83: 1797, 1991.) It is a potential candidate for the treatment of skin neoplasms (Einzig et. Al ., Proc. Am. Soc. Clin. Oncol., 20: 46) and head and neck carcinomas (Forastire et. Al., Sem. Oncol., 20: 56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et. Al., Nature, 368: 750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lines, Ignoff, RJ et. Al, Cancer Chemoterapy Pocket Guide, 1998) related to the duration of dosing above a threshold concentration (50 nM) (Kearns, CM et al., Seminars in Oncology, 3 (6) p, 16-23, 1995).
[00139] Docetaxel, (2R, 3S) -N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5β-20-ep0xi-1,2α, 4,7β, 10β, 13α-hexaidr0xi-tax11 -en-9-one 4-acetate 2-benzoate, trihydrate; it is commercially available as a solution for injection like TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semi-synthetic derivative of paclitaxel q.v., prepared using a natural precursor precursor, 10-deacetylbacatin III, extracted from the needle of the European yew tree.
[00140] Vinca alkaloids are phase-specific antineoplastic agents derived from a myrtle plant. Vinca alkaloids act in the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the binding of the tubulin molecule is unable to polymerize in microtubes. Mitosis is believed to be disrupted in metaphase resulting in cell death. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine and vinorelbine.
[00141] Vinblastine, vincaleucoblastine sulfate, is commercially available as VELBAN® as a solution for injection. Although, it has a possible indication as a second-line therapy for several solid tumors, it is primarily indicated for the treatment of testicular cancer and various lymphomas including Hodgkin's disease; and lymphocytic and histocytic lymphomas. Myelosuppression is the dose-limiting side effect of vinblastine.
[00142] Vincristine, vincaleucoblastine, 22-oxo-, sulfate, is commercially available as ONCOVIN® as a solution for injection. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for malignant Hodgkin's and non-Hodgkin's lymphomas. Alopecia and neurological effects are the most common side effects of vincristine and to a lesser extent myelosuppression and gastrointestinal mucositis effects occur.
[00143] Vinorelbine, 3 ', 4'-dideshydro-4'-deoxy-C'-norvincaleucoblastine [R- (R *, R *) - 2,3-dihydroxybutanedioate (1: 2) (salt)], commercially available as a vinorelbine tartrate solution for injection (NAVELBINE®), it is a semi-synthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly cancers of small lung cell, advanced breast and hormone refractory prostate. Myelosuppression is the most common dose that limits the side effect of vinorelbine.
[00144] Platinum coordination complexes: Platinum coordination complexes are specific non-phase anti-cancer agents that are interactive with DNA. The platinum complexes enter the tumor cells, undergo, warm up and form cross-links and DNA interlining to cause different biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, oxaliplatin, cisplatin and carboplatin.
[00145] Cisplatin, cis-diaminodichloroplatin, is commercially available as PLATINOL® as a solution for injection. Cisplatin is primarily indicated for the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
[00146] Carboplatin, platinum, diamino [1,1-cyclobutane-dicarboxylate (2 -) - O, O '] and commercially available as PARAPLATIN® as a solution for injection. Carboplatin is primarily indicated as the first and second line treatment of advanced ovarian carcinoma.
[00147] Alkylating agents: Alkylating agents are specific non-phase anti-cancer agents and strong electrophiles. Typically, alkylating agents form covalent bonds, through alkylation, to DNA through nucleophilic portions of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl and imidazole groups. Such alkylation disrupts the function of the nucleic acid leading to cell death. Examples of the alkylating agents include, but are not limited to, nitrogenous compounds such as cyclophosphamide, melphalan and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
[00148] Cyclophosphamide, 2 [bis (2-chloroethyl) amino] tetrahydro-2H-1,3,2oxazaphosphorin 2-oxide monohydrate, is commercially available as a solution for injection or tablets such as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma and leukemia.
[00149] Melphalan, 4 [bis (2-chloroethyl) amino] -L-phenylalanine, is commercially available as a solution for injection or tablets like ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable ovarian carcinoma of the ovary. Bone marrow suppression is the most common dose that limits the side effect of melphalan.
[00150] Chlorambucil, 4 [bis (2-chloroethyl) amino] benzenobutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma and Hodgkin's disease.
[00151] Busulfan, 1,4-butanediol dimethanesulfonate, is commercially available as MILERAN® TABLETES. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia.
[00152] Carmustine, 1,3 [bis (2-chloroethyl) -1-nitrosourea, is commercially available as single vials of lyophilized material such as BiCNU®. Carmustine is indicated for palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease and non-Hodgkin's lymphomas.
[00153] Dacarbazine, 5- (3,3-dimethyl-1-triazene) -imidazole-4carboxamide, is commercially available as single vials of material such as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second-line treatment of Hodgkin's disease.
[00154] Antineoplastic antibiotics: Antineoplastic antibiotics are specific non-phase agents that bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand disruption, which disrupts the common function of nucleic acids that lead to cell death. Examples of antibiotic antineoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclines such as daunorubicin and doxorubicin; and bleomycins.
[00155] Dactinomycin, also known as Actinomycin D, is commercially available in an injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma.
[00156] Daunorubicin, (8S-cis -) - 8-acetyl-10 [(3 amino-2,3,6- tri-deoxy-L-waste- hexopyranosyl) oxy] -7,8,9,10 hydrochloride -tetrahydro-6,8,11trihydroxy-1-methoxy-5,12 naphthopenedione, is commercially available as a liposomal injectable form like DAUNOXOME® or as an injectable like CERUBIDINE®. Dunorubicin is indicated to induce remission in the treatment of acute non-lymphocytic leukemia and advanced HIV associated with Kaposi's sarcoma.
[00157] Doxorubicin, (8S, 10S) -10 [(3-amino-2,3,6-tridesoxy-a-Llixo-hexopyranosyl) oxy] -8-glycoloyl, 7,8,9,10- hydrochloride tetrahydro-6,8,11 trihydroxy-1-methoxy-5,12 naphthopenedione, is commercially available as an injectable form like RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but it is also a useful component in the treatment of some solid tumors and lymphomas.
[00158] Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas and testicular carcinomas.
[00159] Topoisomerase II inhibitors: Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
[00160] Epipodophyllotoxins are phase-specific antineoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The filament ruptures accumulate and cell death ensues. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
[00161] Ethoposide, 4'-desmethyl-epipodophyllotoxin 9 [4,6-0- (R) ethylidene-eD-glycopyranoside], is commercially available as a solution for injection or capsules like VePESID® and is commonly known as VP-16 . Ethoposide is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of non-small cell testicular and lung cancers.
[00162] Teniposide, 4'-desmethyl-epipodophyllotoxin 9 [4,6-0- (R) tenylidene-β-D-glycopyranoside], is commercially available as an injectable solution like VUMON® and is commonly known as VM-26 . Teniposide is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of acute leukemia in children.
[00163] Neoplastic antimetabolite agents: Neoplastic antimetabolite agents are phase-specific antineoplastic agents that act in the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting the synthesis of the purine or pyrimidine base and this thereby limiting DNA synthesis. Consequently, the S phase did not proceed and cell death follows. Examples of antimetabolite antineoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine and gemcitabine.
[00164] 5-fluorouracil, 5-fluoro-2,4- (1H, 3H) pyrimidinedione, is commercially available as fluorouracil. The administration of 5fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result is typically cell death. 5-fluorouracil is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine monophosphate (floxuridine) and 5-fluorodeoxyuridine.
[00165] Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2 (1H) pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. Cytarabine is believed to exhibit cell phase specificity in the S phase by inhibiting the elongation of the DNA strand by incorporating the cytarabine terminal into the growing DNA strand. Cytarabine is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacitidine and 2 ', 2'difluorodeoxycytidine (gemcitabine).
[00166] Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETOL®. Mercaptopurine exhibits cell phase specificity in the S phase by inhibiting DNA synthesis by a mechanism until now unspecified. Mercaptopurine is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of acute leukemia. A useful mercaptopurine analogue is azathioprine.
[00167] Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits cell-phase specificity in the S-phase by inhibiting DNA synthesis by a mechanism so far unspecified. Thioguanine is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of acute leukemia. Other purine analogs include pentostatin, erythroidroxynonyladenine, fludarabine phosphate and cladribine.
[00168] Gemcitabine, 2'-deoxy-2 ', 2'-difluorocytidine (β isomer) monohydrochloride, is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity in the S phase and by blocking cell progression across the G1 / S border. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer.
[00169] Methotrexate, N [4 [(2,4-diamino-6-pteridinyl) methyl] methylamino] benzoyl] -L-glutamic acid, is commercially available as sodium methotrexate. Methotrexate exhibits cell phase effects specifically in the S phase by inhibiting, repairing and / or replicating DNA synthesis through the inhibition of dihydrofolic acid reductase that is required for the synthesis of purine and thymidylate nucleotides. Methotrexate is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma and carcinomas of the breast, head, neck, ovary and bladder.
[00170] Topoisomerase I inhibitors: Camptothecins, including camptothecin and camptothecin derivatives are available or under development as topoisomerase I inhibitors. The cytotoxic activity of camptothecins is believed to be related to their Topoisomerase I inhibitory activity. Camptothecins include, but are not limited to, irinotecan, topotecan and the various optical forms of 7- (4-methylpiperazine-methylene) -10,11-ethylenedioxy-20-camptothecin described below.
[00171] Irinotecan HCl, (4S) -4,11-diethyl-4-hydroxy-9 [(4piperidinopiperidine) carbonyloxy] -1H-pyran [3 ', 4', 6,7] indolizine [1,2- b] quinoline-3.14 (4H, 12H) -dione, is commercially available as the CAMPTOSAR® solution for injection. Irinotecan is a camptothecin derivative that binds, together with its active metabolite SN-38, to the topoisomerase I DNA complex. Cytotoxicity is believed to occur as a result of irreparable double strand breaks caused by the interaction of the ternary topoisomerase I: DNA: irinotecan or SN-38 complex with replication enzymes. Irinotecan is indicated for the treatment of metastatic cancer of the colon or rectum.
[00172] Topotecan HCl, (S) -10 [(dimethylamino) methyl] -4-ethyl-4,9-dihydroxy-1H-pyran [3 ', 4', 6.7] indolizine [1,2- b] -quinoline3,14- (4H, 12H) -dione, is commercially available as the HYCAMTIN® solution for injection. Topotecan is a camptotecan derivative that binds to the topoisomerase I DNA complex and prevents rewiring of single-strand breaks caused by Topoisomerase I in response to the torsional strain of the DNA molecule. Topotecan is indicated for second-line treatment of metastatic ovarian carcinoma and small cell lung cancer.
[00173] Hormones and hormonal analogues: Hormones and hormonal analogues are useful compounds to treat cancers in which there is a relationship between the hormone (s) and growth and / or the lack of growth of the cancer. Examples of hormones and hormonal analogs useful in the treatment of cancer include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutetimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole and exemestane useful in the treatment of adrenocortical carcinoma and hormone-dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone-dependent breast cancer and endometrial carcinoma; estrogens, androgens and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5αreductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, as well as selective estrogen receptor modulators (SERMS) such as those described in US Patent Nos. 5,681,835, 5,877,219 and 6,207,716, useful in the treatment of hormone-dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and its analogs that stimulate the release of lutenizing hormone (LH) and / or follicle stimulating hormone (FSH) for the treatment of prostatic carcinoma, for example, LHRH agonists and antagonists such as acetate goserelin and luprolide.
[00174] Inhibitors of the signal transduction path: Inhibitors of the signal transduction path are those inhibitors, which block or inhibit a chemical process that evokes an intracellular change. As used here, this change is cell proliferation or differentiation. Signal transduction inhibitors useful in the present invention include receptor tyrosine kinase inhibitors, non-receptor tyrosine kinases, SH2 / SH3 domain blockers, serine / threonine kinases, phosphotidyl inositol-3 kinases, myo-inositol signaling and Ras oncogenes.
[00175] Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in regulating cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
[00176] Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain and a tyrosine kinase domain. Receptor tyrosine kinases are involved in regulating cell growth and are generally called growth factor receptors. Inadequate or uncontrolled activation of many of these kinases, ie receptor activity of aberrant kinase growth factor, for example by overexpression or mutation, has been shown to result in uncontrolled cell growth. Consequently, the aberrant activity of such kinases has been linked to the growth of malignant tissue. Consequently, inhibitors of such kinases may provide methods of treating cancers. Growth factor receptors include, for example, epidermal growth factor (EGFr) receptor, platelet-derived growth factor receptor (PDGFr), erbB2, erbB4, ret, vascular endothelial growth factor (VEGFr) receptor, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (TIE-2), insulin growth factor I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, receptors fibroblast growth factor (FGF), Trk receptors (TrkA, TrkB and TrkC), ephrin receptors (eph) and the RET protooncogene. Several growth receptor inhibitors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and antisense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for example, in Kath, John C., Exp. Opin. The R. Patents (2000) 10 (6): 803-818; Shawver et al DDT Vol 2, No 2 February 1997; and Lofts, F. J. et al, “Growth factor receptors as targets”, New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
[00177] Tyrosine kinases, which are not growth factor receptor kinases are called non-receptor tyrosine kinases. Non-receptor tyrosine kinases useful in the present invention, which are potential targets or targets of anticancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Brutons tyrosine kinase and Bcr-Abl. Such non-receptor kinases and agents that inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S. J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 80; and Bolen, J. B., Brugge, J. S., (1997) Annual review of Immunology. 15: 371-404.
[00178] SH2 / SH3 domain blockers are agents that disrupt the binding of the SH2 or SH3 domain in a variety of enzymes or adapter proteins including, the PI85-K p85 subunit, Src family kinases, adapter molecules (Shc, Crk , Nck, Grb2) and Ras-GAP. The SH2 / SH3 domains as targets for anticancer drugs are discussed in Smithgall, T. E. (1995), Journal of Pharmacological and Toxicological Methods. 34 (3) 125-32.
[00179] Serine / Threonine Kinase inhibitors including MAP kinase cascade blockers that include Raf kinase (rafk) blockers, Mitogen or Extracellular Regulated Kinase (MEKs) and Extracellular Regulated Kinases (ERKs); and blockers members of the protein C kinase family including PKC blockers (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). The IkB kinase family (IKKa, IKKb), PKB family kinases, members of the akt kinase family and TGF beta receptor kinases. Such Serine / Threonine kinases and their inhibitors are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A. and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27: 41-64; Philip, P. A. and Harris, A. L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No. 6,268,391; and Martinez-Iacaci, L., et al, Int. J. Cancer (2000), 88 (1), 44-52.
[00180] Inhibitors of the members of the phosphotidyl kinase family inositol-3 including PI3-kinase blockers, ATM, DNA-PK and Ku are also useful in the present invention. Such kinases are discussed in Abraham, R. T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C. E., Lim, D. S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S. P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7): 935-8; and Zhong, H. et al, Cancer Res., (2000) 60 (6), 1541-1545.
[00181] Also useful in the present invention are myo-inositol signaling inhibitors such as phospholipase C blockers and myoinositol analogs. Such signal inhibitors are described in Powis, G. and Kozikowski A., (1994) New Molecular Targets for Cancer Chemoterapy ed., Paul Workman and David Kerr, CRC press 1994, London.
[00182] Another group of inhibitors of the signal transduction pathway are Oncogene Ras inhibitors. Such inhibitors include farnesyltransferase, geranyl-geranyl transferase and CAAX proteases as well as antisense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block the activation of ras in cells containing wild-type ras mutants, thus acting as antiproliferation agents. The inhibition of the Ras oncogene is discussed in Scharovsky, O. G., Rozados, V. R., Gervasoni, S. I. Matar, P. (2000), Journal of Biomedical Science. 7 (4) 292-8; Ashby, M. N. (1998), Current Opinion in Lipidology. 9 (2) 99 102; and BioChim. Biophys. Acta, (19899) 1423 (3): 19-30.
[00183] As mentioned above, antibody antagonists for binding the receptor kinase ligand may also serve as inhibitors of signal transduction. This group of inhibitors of the signal transduction pathway includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example EGFR specific antibody Imclone C225 (see Green, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26 (4), 269286); Herceptin ® erbB2 antibody (see Tyrosine Kinase Signalling in Breast Cancer: erbB Family Receptor Tyrosine Kinases, Breast Cancer Res., 2000, 2 (3), 176-183); and VEGFR2 specific antibody 2CB (see Brekken, R. A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal AntiVEGF antibody blocks gowth in mice, Cancer Res. (2000) 60, 5117-5124).
[00184] Anti-angiogenic agents: Anti-angiogenic agents including non-receptor MEK angiogenesis inhibitors may also be useful. Anti-angiogenic agents such as those that inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin®] and compounds that work by other mechanisms (for example linomide , inhibitors of αvβ3 integrin function, endostatin and angiostatin);
[00185] Immunotherapeutic agents: Agents used in immunotherapeutic regimes can also be useful in combination with the compounds of the formula (I). immunotherapy methods, including for example ex vivo and in vivo methods to increase the immunogenicity of the patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, methods to decrease the T cell energy, methods using transfected immune cells such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cell lines and methods using anti-idiotypic antibodies.
[00186] Pro-apoptotic agents: Agents used in pro-apoptotic regimens (e.g., bcl-2 antisense oligonucleotides) can also be used in the combination of the present invention.
[00187] Cell cycle signaling inhibitors: Cell cycle signaling inhibitors inhibit molecules involved in cell cycle control. A family of protein kinases called cyclin-dependent kinases (CDKs) and their interaction with a family of proteins called cyclins controls progression through the eukaryotic cell cycle. Coordinated activation and inactivation of different cyclin / CDK complexes are necessary for normal progression through the cell cycle. Several cell cycle signaling inhibitors are under development. For example, examples of cyclin-dependent kinases, including CDK2, CDK4 and CDK6 and inhibitors for them are described, for example, in Rosania et al, Exp. Opin. The R. Patents (2000) 10 (2): 215-230.
[00188] In one embodiment, the combination of the present invention comprises a compound of formula I or a salt or solvate thereof and at least one antineoplastic agent selected from antimicrotubule agents, platinum coordination complexes, alkylating agents, agents antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogs, signal transduction pathway inhibitors, non-receptor tyrosine MEK angiogenesis inhibitors, immunotherapeutic agents, pro-apoptic agents and signaling inhibitors cell cycle.
[00189] In one embodiment, the combination of the present invention comprises a compound of formula I or a salt or solvate thereof and at least one anti-neoplastic agent which is an anti-microtubule agent selected from diterpenoids and vinca alkaloids.
[00190] In another embodiment, the at least one antineoplastic agent is a diterpenoid.
[00191] In another embodiment, the at least one anti-neoplastic agent is a vinca alkaloid.
[00192] In one embodiment, the combination of the present invention comprises a compound of formula I or a salt or solvate thereof and at least one anti-neoplastic agent, which is a complex of platinum coordination.
[00193] In another embodiment, the at least one anti-neoplastic agent is paclitaxel, carboplatin, or vinorelbine.
[00194] In another embodiment, the at least one anti-neoplastic agent is carboplatin.
[00195] In another embodiment, the at least one anti-neoplastic agent is vinorelbine.
[00196] In another embodiment, the at least one anti-neoplastic agent is paclitaxel.
[00197] In one embodiment, the combination of the present invention comprises a compound of formula I and salts or solvates thereof and at least one anti-neoplastic agent which is an inhibitor of the signal transduction pathway.
[00198] In another embodiment the inhibitor of the signal transduction pathway is an inhibitor of a growth factor kinase receptor VEGFR2, TIE2, PDGFR, BTK, erbB2, EGFr, IGFR-1, TrkA, TrkB, TrkC, or c-fms.
[00199] In another embodiment the inhibitor of the signal transduction pathway is an inhibitor of a serine / threonine kinase rafk, akt, or PKC-zeta.
[00200] In another embodiment the signal transduction pathway inhibitor is an inhibitor of a non-receptor tyrosine kinase selected from the src family of kinases.
[00201] In another embodiment the signal transduction pathway inhibitor is a c-src inhibitor.
[00202] In another embodiment the inhibitor of the signal transduction pathway is an inhibitor of the Ras oncogene selected from inhibitors of farnesyl transferase and geranylgeranyl transferase.
[00203] In another embodiment the inhibitor of the signal transduction pathway is an inhibitor of a serine / threonine kinase selected from the group consisting of PI3K.
[00204] In another embodiment the signal transduction pathway inhibitor is a dual EGFr / erbB2 inhibitor, for example N- {3Cloro-4 [(3-fluorobenzyl) oxy] phenyl} -6 [5- ( {[2- (methanesulfonyl) ethyl] amino} methyl) -2-furyl] -4-quinazolinamine (structure below):

[00205] In one embodiment, the combination of the present invention comprises a compound of formula I or a salt or solvate thereof and at least one anti-neoplastic agent which is an inhibitor of cell cycle signaling.
[00206] In another embodiment, the cell cycle signaling inhibitor is a CDK2, CDK4 or CDK6 inhibitor.
[00207] In one embodiment the mammal in the methods and uses of the present invention is a human being.
[00208] Suitably, the present invention relates to a method of treating or decreasing the severity of a cancer that is wild-type or mutant for each of Raf, Ras, MEK and PI3K / Pten. This includes but is not limited to patients having cancers that are mutants for RAF, wild type for RAS, wild type for MEK and wild type for PI3K / PTEN; mutant for RAF, mutant for RAS, wild type for MEK and wild type for PI3K / PTEN; mutant for RAF, mutant for RAS, mutant for MEK and wild type for PI3K / PTEN; and RAF mutant, wild type for RAS, mutant for MEK and wild type for PI3K / PTEN.
[00209] The term "wild type" as understood in the art refers to a sequence of polypeptide or polynucleotide that occurs in a native population without genetic modification. As is also understood in the art, a "mutant" includes a polypeptide or polynucleotide sequence having at least one modification to an amino acid or nucleic acid compared to the corresponding amino acid or nucleic acid found in a wild-type polypeptide or polynucleotide, respectively. Included in the mutant term is the Single Nucleotide Polymorphism (SNP) where a single base pair distinction exists in the sequence of a nucleic acid strand compared to the most prevalent (wild type) nucleic acid filament.
[00210] Cancers that are wild-type or mutant for Raf, Ras, MEK, or mutant for PI3K / Pten are identified by known methods. For example, wild-type or mutant tumor cells can be identified by DNA amplification and sequencing techniques, DNA and RNA detection techniques, including, but not limited to Northern and Southern blot, respectively, and / or various biochip technologies. and arrangement. Wild-type and mutant polypeptides can be detected by a variety of techniques including, but not limited to, immunodiagnostic techniques such as ELISA, Western blot or immunocytochemistry. Suitably, pyrophosphorolysis (PAP) activated polymerization and / or PCR methods can be used. Liu, Q et al; Human Mutation 23: 426436 (2004).
[00211] The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. EXAMPLES Example 1 Capsule Composition
[00212] An oral dosage form for administering a combination of the present invention is produced by filling a standard two-part hard gelatin capsule with the ingredients in the proportions shown in Table A, below. Table A

[00213] Although the preferred embodiments of the invention are illustrated by the above, it should be understood that the invention is not limited to the precise instructions disclosed herein and that the right to all modifications that fall within the scope of the claims that follow is reserved. ESSAY
[00214] In vitro combination studies of BRAF and MEK inhibitors on cancer cell lines of multiple origins encoding different mutations A. Concentration ranges A
[00215] The drug combination experiments were performed on plates of 384 reservoirs. The cells were plated in plates of 384 wells to 500 cells / well in appropriate culture medium for each cell type, supplemented with 10% FBS and 1% penicillin / streptomycin and incubated overnight at 37 ° C, 5% of CO2. Sixteen 2-fold dilution concentrations of each drug were tested in the matrix for inhibition of cell growth. The concentrations tested for Compound A (free form) were from 1 μM to 0.03 nM and for compound B (solvate in DMSO) was 10 μM to 0.3 nM. The cells were treated with compound combination and incubated at 37 ° C for 72 hours. Cell growth was measured using the CellTiter-Glo® reagent according to the manufacturer's protocol and signals were read on a PerkinElmer EnVision® reader set to luminescence mode with a 0.5 second reading. The results are expressed as a percentage inhibition compared to cells treated with DMSO and the background correction was done by subtracting values from the reservoirs that do not contain any cells.
[00216] The response (percentage inhibition compared to untreated and normalized samples for only half) of Compound "A" at concentration "a" (Ra) and that of Compound "B" at concentration "b" (Rb) are compared with the response of the mixture of Compounds "A" and "B" in the concentrations "a" and "b" respectively (Rab). Using these values, the Excess Over the Highest Single Agent (EOHSA) was calculated for each concentration of each of the tested cell lines:
[00217] Rab> 10% of the highest value between Ra and Rb = more than additive
[00218] Rab <-10% of the highest value between Ra and Rb = antagonism
[00219] Using this formula, if Rab is 10% or more greater than the highest value between Ra and Rb, the drug combination is considered more than additive. If Rab is less than 10% or more than the highest value between Ra and Rb, the drug combination is antagonistic.
[00220] For each of the cell lines tested, the number of combinations in the 16 X 16 matrix with more than additive response (those where Rab is greater than 10% higher than the highest value between Ra and Rb ) have been listed. The number of more than additive combinations (of the 264 tested) are summarized in Table 1. In this table, the concentration combinations in a given cell line were found to be particularly beneficial (gray square) if more than 20% (51 combinations) of the 256 tested) of tested combinations showed> 10% EOHSA. Table 1: Effect of combination of MEK and BRAF inhibitors in multiple cancer cell line.

[00221] These data demonstrate that the combination of Compound A and Compound B is favorable in multiple cancer cell lines of multiple origin independent of the mutational status of key oncogenes within the MAPK or AKT / PI3K / PTEN pathways. B. Concentration bands B
[00222] Evaluation similar to Section A above the combination of Compound A and Compound B was performed using the data generated in Section A, but only for drug concentrations that were judged to be clinically relevant (100 nM to 3 nM). These concentrations were chosen as those that tended to be effective but non-toxic in preclinical mouse xenograft models. Using these concentrations, a total of 25 drug combinations were evaluated for each cell line and the results are summarized in Table 2.
[00223] The number of combinations having Rab> 10% of the highest value between Ra and Rb of the 25 clinically relevant combinations tested were calculated and expressed as a percentage in Table 2. Table 2: In vitro combination of MEK and BRAF inhibitors using concentrations of clinically relevant medication


[00224] The data demonstrate that the combination of Compound A and Compound B is favorable in most cell lines tested at the relevant clinical drug concentrations and highly favorable in all BRAFV600E and KRAS mutant cell lines, regardless of the mutational situation of the PI3K / PTEN path. Inhibition of cell growth in vitro in tumor cell lines Methods:
[00225] Cell line and growth conditions Human colon tumor lines, Colo-205, DLD-1, HCT-8, HT-29, LS-1034, NCI-H508, RKO, SW1417, SW1463, SW480 and SW837 and A375 human melanoma strain were from the ATCC. A375PF11 was derived from A375. 12R5-1, 12R5-3, 12R8-1, 12R8-3, 16R5-2, 16R6-3 and 16R6-4 are single cell clones of mixed populations of A375PF11 cells that were selected to grow on Compound A at concentrations of 1200 and 1600 nM, thereby exhibiting acquired resistance to Compound B. All strains were cultured in RPMI 1640 medium containing 10% fetal bovine serum (FBS).
[00226] Cell growth inhibition assay and combination data analysis All cells were cultured for a minimum of 72 hours before plating the cell. The cells were assayed in a 96 well tissue culture plate (NUNC 136102) of RPMI medium containing 10% FBS for all cells at 1,000 cells per well. Approximately 24 hours after plating, cells were exposed to ten three-fold serial dilutions of Compound or the combination of the two agents at a constant 1:10 molar to molar ratio of Compound A (solvate in DMSO) to Compound B (free form) in RPMI medium containing 10% FBS. The tested concentrations for Compound A were 1 μM to 0.05 nM and for Compound B were 10 μM to 0.5 nM. The cells were incubated in the presence of the Compounds for 3 days. ATP levels were determined by adding Cell Titer Glo® (Promega) according to the manufacturer's protocol. In summary, Cell Titer Glo® was added to each plate, incubated for 30 minutes after the luminescent signal was read on the SpectraMax L plate reader with an integration time of 0.5 s.
[00227] The inhibition of cell growth was estimated after treatment with compound or combination of Compounds for three days and comparing the signal to cells treated with vehicle (DMSO). Cell growth was calculated in relation to vehicle-treated control reservoirs (DMSO). The concentration of the Compound that inhibits the growth of 50% of the control cells (IC50) was interpolated when y = 50% of the vehicle control using non-linear regression with the equation, y = (A + (BA) / (1+ ( C / x) AD))), where A is the minimum response (ymin), B is the maximum response (ymax), C is the inflection point of the curve (EC50) and D is the Hill coefficient.
[00228] The effect of combinations on power was assessed using the Combination Index (CI) which was calculated with the IC50 values retrointerpolated and the mutually non-exclusive equation derived by Chou and Talalay (1): CI = Da / IC50 ( a) + Db / IC50 (b) + (Da x Db) / (IC50 (a) x IC50 (b)) where IC50 (a) is the IC50 of Compound A; IC50 (b) is the IC50 for Compound B; Da is the concentration of Compound A in combination with Compound B that inhibited 50% of cell growth; and Db is the concentration of Compound B in combination with Compound A that inhibited 50% of cell growth. In general, a CI value <0.9, between 0.9 and 1.1, or> 1.1 indicates synergy, additivity and antagonism, respectively. In general, the lower the CI number, the greater the synergy strength.
[00229] The combination effects on the response scale were quantified by the Excess Regarding the Highest Single Agent (EOHSA) based on the concept of non-linear combination as described in detail by Peterson and Novick (2007) and Peterson (2010) [ (2; 3) [Peterson and Novick, 2007; Peterson, 2010]. EOHSA values are defined as increases in the improvement (here, in difference of 'percentage points' (ppts)) produced by the combination in relation to the best single agent in its component dose level for the combination. For single agent and combination treatments, cells were exposed to compounds in a fixed dose ratio and dose response curves were fitted to the experimental data and analyzed using regression models. At the specified dose levels the total IC50 dose levels along the dose-response curve, the dose combination (which corresponds to the IC50) was determined to make statistical inferences of EOHSA. More specifically, for a combination drug experiment involving drug 1 at dose d1 and drug 2 at dose d2, (ie, the total dose is equal to d1 + d2) it is said to have a positive EOHSA if the average response in combination is better than the average response to drug 1 at dose d1 or drug 2 at dose d2. Results:
[00230] The effect of inhibiting cell growth by an inhibitor of MEK Compound A, an inhibitor of BRAF Compound B and their combination was determined in a panel of human tumor cell lines. The mean IC50s (from at least two independent experiments) and the combination effects in IC50s are summarized in Table 3 with the status of the BRAF and KRAS mutation.
[00231] Referring to Table 3, the four colon cell lines with the BRAF V600E mutation demonstrated sensitivity for Compound A with IC50 values between 0.001 μM and 0.025 μM and for Compound B with IC50 values between 0.018 μM and 5.654 μM. The combination of Compound A and Compound B was synergistic with CI values between 0.25 and 0.73 and / or enhanced cell growth inhibition with EOHSA values between 7 and 26 ppts in these four strains with BRAF V600E mutation. The seven colon lines without BRAF V600E mutation (with BRAF G596R or KRAS mutations) were insensitive to Compound B (IC50> 10 μM), however highly sensitive to the inhibition of cell growth by Compound A with IC50s ranging from 0.001 to 0.093 μM in six of the seven strains. The combination of Compound A and Compound B showed enhanced cell growth inhibition in the colon tumor line DLD1 and minimal to no added benefit over treatment with Compound A single compound in the other six colon cell lines.
[00232] For the melanoma cell lines listed in Table 3, A375PF11 cells with the BRAF V600E mutation were highly sensitive to either the single agent of Compound A (IC50 = 0.001 μM) or Compound B (IC50 = 0.012 μM). The combination of Compound A and Compound B were synergistic with a CI value of 0.3 in A375PF11 cells. The melanoma strains 12R8-3, 12R8-1, 12R5-3 and 16R6-3 were resistant to Compound B (IC50> 10 μM), moderately sensitive to Compound A with IC50s ranging from 0.058 μM to 0.109 and responded to the combination of Compound A and Compound B with IC50s ranging from 0.018 to 0.023 μM for Compound A and 0.178 to 0.234 μM for Compound B. The melanoma strains 16R5-2, 16R6-4 and 12R5-1 were resistant or insensitive to Compound A or Compound B alone, however, became sensitive to the combination of Compound A and Compound B with IC50s ranging from 0.018 to 0.039 μM for Compound A and from 0.177 to 0.386 μM for Compound B. The combination of Compound A and Compound B also showed enhancement of cell growth inhibition in all these melanoma strains. Note, CI values could not be calculated therefore not applicable where single agent values were outside the tested range.
[00233] Of interest, the combined administration of Compound A and Compound B in the colon cell lines and mutant BRAFV600E melanoma showed a synergistic effect demonstrated by CI values <0.9, or resulted in a reduced IC 50 value compared to that of Compound A or Compound B, administered alone, where at least one of the unique agents does not result in 50% inhibition within the tested range.
[00234] Table 3. Inhibition of cell growth by Compound A, Compound B and their combination in human tumor cell lines.
Table 3 Key: IC50: the concentration of Compound as a single agent, or the concentration of Compounds A or B in combination when Compound A and Compound B = 1:10 molar ratio that reduces cell growth by 50%; CI; Combination Index; N / A = not applicable EOHSA: Excess in relation to the Highest Single Agent, measured as a percentage. List of references (1) Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984; 22: 27-55. (2) Peterson JJ, Novick SJ. Nonlinear blending: a useful general concept for the assessment of combination drug synergy. J Recept Signal Transduct Res 2007; 27 (2-3): 125-46. (3) Peterson J. A Review of Synergy Concepts of Nonlinear Blending and Dose-Reduction Profiles. Frontiers of Bioscience S2, 483-503. 2010. Mouse xenograft model A
[00235] A xenograft model using A375P F11 cells (human melanoma cell line encoding the BRafV600E mutation) was established from culturing cells in tissue culture and aseptically harvested using trypsin digestion. Tumor cells were injected subcutaneously into female athymic mice (nu / nu strain) with between 5 x 106 and 107 cells in 50% hammerhead. The tumors were allowed to settle. Dosing started on day 24 after implantation, which corresponds to an average tumor volume of ~ 200 mm3.
[00236] This human xenograft tumor model used 4 groups of mice, with 8 mice per group. The animals were identified using a subcutaneous microchip (sc) or tattoos.
[00237] A first group of control animals carrying untreated or placebo-treated tumors acted as controls. A second group was dosed once daily orally with N- {3 [5- (2-Amino4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl } -2,6difluorobenzenesulfonamide (forms the crystalline free base) (Compound B). A third group was dosed once daily orally with N- {3 [3-cyclopropyl-5- (2-fluoro-4-iodo-phenylamino) -6,8-dimethyl-2,4,7-trioxo3 solvate, 4,6,7-tetrahydro-2H-pyrido [4,3-d] pyrimidin-1-yl] phenyl} -acetamide in dimethylsulfoxide (Compound A). A fourth group was dosed once daily with a combination of N- {3 [5- (2-Amino-4-pyrimidinyl) -2- (1,1dimethylethyl) -1,3-thiazol-4-yl] - 2-fluoro-phenyl} -2,6-difluorobenzenesulfonamide (crystalline free base form) and N- {3 [3-cyclopropyl-5- (2-fluoro-4-iodophenylamino) -6,8-dimethyl-2,4 , 7-trioxo-3,4,6,7-tetrahydro-2H-pyrido [4,3d] pyrimidin-1-yl] phenyl} acetamide solvate in dimethylsulfoxide. Each drug was supplied in a suspension of 0.5% HPMC / 0.2% TWEEN 80.
[00238] Tumor sizes were measured twice a week using Vernier gauges. The tumor volume was calculated from two-dimensional measurements using an equation that approximates the volume of an ellipsoid elongated in the direction of the poles: Tumor Volume in cubic mm = (length x width2) x 0.5
[00239] The measurements are reported in Figure 1 after 36 days of treatment. The data showed that the combination of the MEK inhibitor and BRafs is advantageous compared to each agent administered individually. Models of mouse xenograft B
[00240] A375P cells were harvested from the culture flasks by exposure to 0.25% trypsin / EDTA for 5 min at 37 ° C. The detached cells were collected, centrifuged (1500 rpm, 5 minutes, 4 ° C) and rinsed to remove the trypsin solution. The cells were resuspended in PBS without magnesium or calcium and counted. The cells were spun as before to remove PBS and a single cell suspension was created in 50% Matrigel: 50% PBS (v: v) or 100% PBS so that a subcutaneous injection of 100 μl would release the required number of cells per mouse. The A375P melanoma strain was injected with Matrigel to 1.75 million cells per mouse subcutaneously in 8-10 week old mice, female CD-1 nu / nu. Tumors were established (~ 150-300 mm3) for all cell lines within 2 to 4 weeks after injection.
[00241] Compound A (solvate in DMSO) and Compound B (free form) were administered orally to the mice at the doses indicated in 0.2 ml / 20 grams of body weight in 0.5% HPMC (hydroxypropylmethylcellulose, Sigma cat # H7509) and 0.2% Tween 80 (Sigma cat # P1754) in distilled water, pH 7.0 to 8.0.
[00242] Mice with tumors of similar size (150 to 200 mm3) were identified. The length and width of the tumors were measured by manual gauges and the body weights of the mice were measured using a bench weighing scale. The mice were placed in groups of eight or seven appropriately and dosed orally with vehicle, individual compound or compound combination. The mice were weighed and the tumors measured twice a week for the duration of the study. The data presented in Figure 2 demonstrates that the combination of Compound A (0.1mg / kg) and Compound B (30mg / kg) daily for 33 days (days 24 to 56 after implantation) is more effective than each agent alone .

权利要求:
Claims (12)
[0001]
1. Combination, characterized by the fact that it comprises: (i) a compound of the formula (I)
[0002]
2. Combination according to claim 1, characterized in that the compound (i) is in the form of the dimethylsulfoxide solvate and the compound (ii) is in the form of the methanesulfonate salt.
[0003]
3. Combination kit, characterized by the fact that it comprises: (i) a compound of the formula (I)
[0004]
4. Use of a combination, as defined in claim 1 or 2, characterized by the fact that it is in the manufacture of a drug for the treatment of cancer.
[0005]
5. Combination according to claim 1 or 2, characterized by the fact that it is for use in therapy.
[0006]
6. Combination according to claim 1 or 2, characterized by the fact that it is for use in the treatment of cancer.
[0007]
7. Pharmaceutical composition, characterized by the fact that it comprises a combination, as defined in claim 1 or 2, together with a pharmaceutically acceptable diluent or carrier.
[0008]
8. Use of (i) a compound of formula (I)
[0009]
9. Use according to claim 8, characterized by the fact that the cancer is selected from head and neck cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, prostate cancer, gliomas, glioblastoma, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, LhermitteDuclos disease, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, kidney cancer, liver cancer, melanoma, pancreatic cancer, sarcoma, osteosarcoma , giant bone cell tumor, thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, AML, chronic leutrophilic leukemia, acute lymphoblastic T cell leukemia , plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Megacarioblastic leukemia, multiple myeloma, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, cervical cancer, cancer, vulval cancer endometrial, kidney cancer, mesothelioma, spongeal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, oral cancer, mouth cancer, GIST (stromal gastric tumor), and testicular cancer.
[0010]
10. Use according to claim 8 or 9, characterized by the fact that the cancer is melanoma.
[0011]
11. Use according to claim 8 or 9, characterized by the fact that the cancer is lung cancer.
[0012]
Use according to any one of claims 8 to 11, characterized in that the compound (i) is in the form of the dimethylsulfoxide solvate and the compound (ii) is in the form of the methanesulfonate salt.

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-02-20| B25A| Requested transfer of rights approved|Owner name: GLAXO GROUP LIMITED (GB) |

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2018-03-06| B25A| Requested transfer of rights approved|Owner name: NOVARTIS PHARMA AG (CH) |

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2018-03-20| B25A| Requested transfer of rights approved|Owner name: NOVARTIS AG (CH) |

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2019-05-28| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-10-29| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-07-28| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2020-11-10| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-12-29| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 10 (DEZ) ANOS CONTADOS A PARTIR DE 29/12/2020, OBSERVADAS AS CONDICOES LEGAIS. |

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2021-05-25| B16C| Correction of notification of the grant [chapter 16.3 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/10/2010 OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |

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2021-09-08| B15V| Prolongation of time limit allowed|

优先权:

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申请号 | 申请日 | 专利标题

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US25221309P| true| 2009-10-16|2009-10-16|

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US61/252,213|2009-10-16|

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PCT/US2010/052808|WO2011047238A1|2009-10-16|2010-10-15|Combination|

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