WO2007059202A2 - Derives de pyrazolyluree utilisables dans le traitement du cancer - Google Patents

Derives de pyrazolyluree utilisables dans le traitement du cancer Download PDF

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WO2007059202A2
WO2007059202A2 PCT/US2006/044322 US2006044322W WO2007059202A2 WO 2007059202 A2 WO2007059202 A2 WO 2007059202A2 US 2006044322 W US2006044322 W US 2006044322W WO 2007059202 A2 WO2007059202 A2 WO 2007059202A2
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cancer
fluorophenyl
acid
pyrazol
urea
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PCT/US2006/044322
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English (en)
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WO2007059202A3 (fr
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Louis-David Cantin
Roger Smith
Zhi Chen
Holia N. Hatoum-Mokdad
Eric Mull
Wendy Lee
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Bayer Healthcare Ag
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Priority to EP06837652A priority Critical patent/EP1960394A2/fr
Priority to CA002629468A priority patent/CA2629468A1/fr
Publication of WO2007059202A2 publication Critical patent/WO2007059202A2/fr
Publication of WO2007059202A3 publication Critical patent/WO2007059202A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to novel compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper- proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients, e.g., cytotoxic therapies.
  • tumor cells require a functional stroma, a support structure consisting of fibroblast, smooth muscle cells, endothelial cells, extracellular matrix proteins, and soluble factors (Folkman, J., Semin Oncol, 2002. 29(6 Suppl 16), 15-8).
  • Tumors induce the formation of stromal tissues through the secretion of soluble growth factors such as PDGF and transforming growth factor-beta (TGF-beta), which in turn stimulate the secretion of complimentary factors by host cells such as fibroblast growth factor (FGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF).
  • FGF fibroblast growth factor
  • EGF epidermal growth factor
  • VEGF vascular endothelial growth factor
  • an agent targeting a single pathway may have limited efficacy. It is desirable to provide treatment against a number of key signaling pathways utilized by tumors to induce angiogenesis in the host stroma. These include, for example, PDGF, a potent stimulator of stroma formation (Ostman, A. and CH. Heldin, Adv Cancer Res, 2001, 80, 1-38), FGF, a chemo-attractant and mitogen for fibroblasts and endothelial cells, and VEGF, a potent regulator of vascularization. HGF (hepatocyte growth factor) represents an additional signaling growth factor of interest.
  • PDGF is a key regulator of stromal formation, which is secreted by many tumors in a paracrine fashion and is believed to promote the growth of fibroblasts, smooth muscle and endothelial cells, promoting stroma formation and angiogenesis.
  • PDGF was originally identified as the v-sis oncogene product of the simian sarcoma virus (Heldin, C. H., et al., J Ce// Sci Suppl, 1985, 3, 65-76).
  • the growth factor is made up of two peptide chains, referred to as A or B chains which share 60% homology in their primary amino acid sequence.
  • the chains are disulfide cross linked to form the 30 kDa mature protein composed of either AA, BB or AB homo- or heterodimmers.
  • PDGF is found at high levels in platelets, and is expressed by endothelial cells and vascular smooth muscle cells. In addition, the production of PDGF is up regulated under low oxygen conditions such as those found in poorly vascularized tumor tissue (Kourembanas, S., et al., Kidney Int, 1997, 51(2), 438-43). PDGF binds with high affinity to the PDGF receptor, a 1106 amino acid 124 kDa transmembrane tyrosine kinase receptor (Heldin, C. H., A. Ostman, and L.
  • PDGFR is found as homo- or heterodimer chains which have 30% homology overall in their amino acid sequence and 64% homology between their kinase domains (Heldin, C. H., et al.. Embo J, 1988, 7(5), 1387-93).
  • PDGFR is a member of a family of tyrosine kinase receptors with split kinase domains that includes VEGFR2 (KDR), VEGFR3 (Flt4), c-Kit, and FLT3.
  • the PDGF receptor is expressed primarily on fibroblast, smooth muscle cells, and pericytes and to a lesser extent on neurons, kidney mesangial, Leydig, and Schwann cells of the central nervous system. Upon binding to the receptor, PDGF induces receptor dimerization and undergoes auto- and trans-phosphorylation of tyrosine residues which increase the receptors' kinase activity and promotes the recruitment of downstream effectors through the activation of SH2 protein binding domains.
  • a number of signaling molecules form complexes with activated PDGFR including PI-3-kinase, phospholipase C-gamma, src and GAP (GTPase activating protein for p21-ras) (Soskic, V., et al. Biochemistry, 1999, 38(6), 1757-64).
  • PI-3-kinase phospholipase C-gamma
  • src GAP
  • PDGF central nervous system
  • PDGF vascular endothelial growth factor
  • angiogenesis PDGF controls interstitial fluid pressure, regulating the permeability of vessels through its regulation of the interaction between connective tissue cells and the extracellular matrix. Inhibiting PDGFR activity can lower interstitial pressure and facilitate the influx of cytotoxics into tumors improving the anti-tumor efficacy of these agents (Pietras, K., et al. Cancer Res, 2002. 62(19), 5476-84; Pietras, K., et al. Cancer Res, 2001. 61(7), 2929-34).
  • PDGF can promote tumor growth through either the paracrine or autocrine stimulation of PDGFR receptors on stromal cells or tumor ceils directly, or through the amplification of the receptor or activation of the receptor by recombination.
  • Over expressed PDGF can transform human melanoma cells and keratinocytes (Forsberg, K., et al. Proc Natl Acad Sci U S A., 1993. 90(2), 393-7; Skobe, M. and N.E. Fusenig, Proc Natl Acad Sci U S A, 1998. 95(3), 1050-5), two cell types that do not express PDGF receptors, presumably by the direct effect of PDGF on stroma formation and induction of angiogenesis.
  • PDGFR inhibitors will interfere with tumor stromal development and are believed to inhibit tumor growth and metastasis.
  • VEGF vascular endothelial growth factor
  • VPF vascular permeability factor
  • VEGF expression is reported to be induced by hypoxia (Shweiki et al. Nature 1992, 359, 843), as well as by a variety of cytokines and growth factors, such as interleukin-1 , interleukin-6, epidermal growth factor and transforming growth factor. To date, VEGF and the VEGF family members have been reported to bind to one or more of three transmembrane receptor tyrosine kinases (Mustonen et al. J.
  • VEGF receptor-1 also known as flt-1 (fms-like tyrosine kinase-1)
  • VEGFR-2 also known as kinase insert domain containing receptor (KDR); the murine analogue of KDR is known as fetal liver kinase-1 (flk-1)), and VEGFR-3 (also known as flt-4).
  • KDR and flt-1 have been shown to have different signal transduction properties (Waltenberger et al. J. Biol. Chem. 1994, 269, 26988); Park et al. Oncogene 1995, 10, 135).
  • KDR undergoes strong ligand-dependant tyrosine phosphorylation in intact cells, whereas flt-1 displays a weak response.
  • binding to KDR is believed to be a critical requirement for induction of the full spectrum of VEGF-mediated biological responses.
  • VEGF plays a central role in vasculogenesis, and induces angiogenesis and permeabilization of blood vessels.
  • Deregulated VEGF expression contributes to the development of a number of diseases that are characterized by abnormal angiogenesis and/or hyperpermeability processes. It is believed regulation of the VEGF-mediated signal transduction cascade by some agents can provide a useful mode for control of abnormal angiogenesis and/or hyperpermeability processes.
  • VEGF, VEGF-C, VEGF-D vascular endothelial growth factors
  • VEGFR2, VEGFR3 lymphangiogenesis
  • VEGF, VEGF-C and VEGF-D are expressed in most tumors, primarily during periods of tumor growth and, often at substantially increased levels.
  • VEGF expression is stimulated by hypoxia, cytokines, oncogenes such as ras, or by inactivation of tumor suppressor genes (McMahon, G. Oncologist 2000, 5(Suppl. 1), 3- 10; McDonald, N. Q.; Hendrickson, W.A. Ce// 1993, 73, 421-424)
  • VEGFR3 also called Flt-4.
  • VEGFR3 function is needed for new lymphatic vessel formation, but not for maintenance of the pre-existing lymphatics.
  • VEGFR3 is also upregulated on blood vessel endothelium in tumors.
  • VEGF-C and VEGF-D ligands for VEGFR3, have been identified as regulators of lymphangiogenesis in mammals. Lymphangiogenesis induced by tumor-associated lymphangiogenic factors could promote the growth of new vessels into the tumor, providing tumor cells access to systemic circulation.
  • VEGF-C vascular endothelial growth factor
  • VEGF-D vascular endothelial growth factor
  • VEGFR3 vascular endothelial growth factor-D
  • clinicopathological factors that relate directly to the ability of primary tumors to spread (e.g., lymph node involvement, lymphatic invasion, secondary metastases, and disease-free survival).
  • these studies demonstrate a statistical correlation between the expression of lymphangiogenic factors and the ability of a primary solid tumor to metastasize (Skobe, M. et al. Nature Med. 2001, 7(2), 192- 198; Stacker, S.A. et al.. Nature Med. 2001 , 7(2), 186-191 ; Makinen, T.
  • hypoxia appears to be an important stimulus for VEGF production in malignant cells.
  • Activation of p38 MAP kinase is required for VEGF induction by tumor cells in response to hypoxia (Blaschke, F. et al. Biochem. Biophys. Res. Commun. 2002, 296, 890-896; Shemirani, B. et al. Oral Oncology 2002, 38, 251-257).
  • p38 MAP kinase promotes malignant cell invasion, and migration of different tumor types through regulation of collagenase activity and urokinase plasminogen activator expression (Laferriere, J. et al. J. Biol.
  • Trk-A The receptor tyrosine kinase Trk-A is another target of interest for the preparation of medicines directed at the treatment and prevention of cancer.
  • TrkA is the high affinity receptor of the nerve growth factor (NGF).
  • NGF nerve growth factor
  • the expression of TrkA and NGF in tumors is believed to be implicated in the proliferation and metastasis of tumors such as pancreatic, prostate and also breast, as well as in angiogenesis. TrkA expression is reported in pancreatic, breast, ovarian, and prostate tumors. Recent studies demonstrate that human prostate and pancreatic tumor cells can secrete NGF, which, along with its receptor, TrkA, creates an autocrine loop that promotes the growth and survival of these tumor cells (Ruggeri, B. A. et al, Curr. Med. Chem.
  • the proto-oncoogene c-Met encodes a heterodimeric complex consisting of a 140-kDa membrane-spanning Dchain and a 50-kDa extracellular O chain.
  • This heterodimeric complex acts as a high-affinity receptor for hepatocyte growth factor (HGF) or scatter factor (SF).
  • HGF hepatocyte growth factor
  • SF scatter factor
  • c-Met/HGF signaling is required for normal mammalian development and has been shown to be particularly important in cell growth, migration, morphogenic differentiation, and organization of three-dimensional tubular structures (e.g. renal tubular cells, gland formation, etc.).
  • c- Met and HGF are widely expressed in a variety of tissues, and their expression is normally confined to cells of epithelial and mesenchymal origin, respectively.
  • HGF/c-Met signaling has an important role in the development and malignant progression of tumors of various histological types.
  • Cell lines that ectopically overexpress c-Met or HGF become tumorigenic and metastatic in nude mice, whereas c-Met downregulation decreases their tumorigenic potential.
  • HGF-dependent autocrine loops are found associated with osteosarcomas, rhabdomyosarcomas and breast carcinomas (Trusolino and Comoglio, Nat Rev Cancer, 2002, 2, 289-300).
  • c-Met or HGF transgenic mice develop metastatic tumors (Wang, R. et al., J. Cell Biol. 2001 , 153, 1023-1034; Takayama et al., Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 701-706).
  • Over-expression of c-Met expression has been found in many kinds of solid tumors and correlates with poor prognosis (Birchmeier, et al. MoI. Cell Biol., 2003, 4, 915-925; Christensen, J. and Salgia, R., Can Lett, 2005, 225, 1-26).
  • HGF/SF-neutralizing antibodies Cao et al., Proc Natl Acad Sci USA 2001, 98, 7443-8
  • c-Met antisense oligonucleotides Kitamura et al., Br J Cancer 2000, 83: 668- 73
  • dominant-negative forms of the Met protein Firon et al., Oncogene 2000, 19, 2386- 97; Furge et al., Proc Natl Acad Sci USA 2001 , 98, 10722-7
  • ribozymes that target Met mRNA Abounader et al., J Natl Cancer Inst, 1999, 91, 1548-56; Abounader et al., FASEB J 2002, 16, 108 -10
  • small c-Met tyrosine kinase inhibitor small molecule c-Met tyrosine kinase inhibitor
  • Chronic myelogenous leukemia is caused by the oncogenic protein, Bcr- AbI (Groffen, J. et al., J Cell Physiol Suppl, 1984, 3, 179-191 , Sattler, M. and Griffin, J. D., Semin Hematol, 2003, 40, 4-10).
  • Bcr- AbI The Philadelphia chromosome, which is the hallmark of CML, is formed in CML patients due to a reciprocal translocation between chromosomes 9 and 22 (Rowley, J. D., Nature, 1973, 243, 290-293), and this translocation results in the formation of Bcr-Abl fusion protein (Groffen, J.
  • AbI protein is a nonreceptor tyrosine kinase whose activity is tightly regulated in the normal cells. However, the fusion protein is co ⁇ stitutively activated due to the presence of Bcr protein at the N- terminus. The constitutively active protein transforms at the myeloid the blast cell stage thus giving rise to CML (Kelliher, M. A., et al., Proc Natl Acad Sci U S A, 1990, 87, 6649-6653). Depending on the exact breakpoints at the chromosomes involved in the translocation, the size of the fusion protein varies from 185 to 230 kDa, although 210 kDa protein being the most commoon in CML.
  • BMS-354825 has been reported to be an inhibitor of Bcr-Abl and also Src family kinases.
  • BMS-354825 was reported to inhibit all the mutant forms of the protein except T315I (Shah, N. P., et al., Science, 2004, 305, 399-401).
  • the compound AMN-107 has been reported to inhibit Bcr-Abl kinase activity with 20-fold greater potency than Imatinib.
  • AMN-107 was reported to inhibit most lmanitib resistant mutations except for T315I. AMN-107 also shows weaker inhibition in a biochemical assay against E255K mutant (IC 50 of 40OnM) (Weisberg, E., et al., Cancer Cell, 2005, 7, 129-141). Therefore, there is a significant unmet medical need for new therapeutics to treat CML and Imatinib-resistant CML.
  • Certain diarylureas have been described as having activity as serine-threonine kinase and/or as tyrosine kinase inhibitors. The utility of these diarylureas as an active ingredient in pharmaceutical compositions for the treatment of cancer, angiogenesis disorders, and inflammatory disorders has been demonstrated.
  • the utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the in vitro tumor cell proliferation assay described below.
  • the link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been very well established in the art.
  • taxol Silvestrini et al. Stem Cells 1993, 11(6), 528-35
  • taxotere Bissery et al. Anti Cancer Drugs 1995, 6(3), 339
  • topoisomerase inhibitors Edelman et al. Cancer Chemother. Pharmacol. 1996, 37(5), 385-93 were demonstrated with the use of in vitro tumor proliferation assays.
  • compositions described herein exhibit antiproliferative activity and are thus useful to prevent or treat the disorders associated with hyper-proliferation.
  • the present invention pertains to: (i) novel compounds of examples 1-82 below, which are
  • a preferred embodiment of the present invention pertains to: (i) the novel compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1- (4-cyanophenyl)-1 H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
  • Another preferred embodiment of the present invention pertains to: (i) the novel compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1- (3-chloro-4-fluorophenyl)-1H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
  • An additional preferred embodiment of the present invention pertains to: (i) the novel compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1- (4-methylphenyl)-1 H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
  • a further preferred embodiment of the present invention pertains to: (i) the novel compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[1-(3- fluorophenyl)-3-isopropyl-1 H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
  • One additional preferred embodiment of the present invention pertains to: (i) the novel compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyI ⁇ -N'-[3-tert-butyl-1- (3-methoxyphenyl)-1 H-pyrazol-5-yl]urea salts thereof, metabolites thereof, solvates thereof, hydrates thereof, prodrugs thereof, polymorphs thereof and diastereoisomeric forms thereof (both isolated stereoisomers and mixtures of stereoisomers);
  • diseases e.g., hyper-proliferative and/
  • the compounds of this invention may contain one. or more asymmetric centers, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R) or (Sj configuration or (R, S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.
  • Preferred compounds are those which produce the more desirable biological activity.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallization.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivitization, are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, co-precipitates, metabolites, hydrates, solvates and prodrugs of all the compounds of examples 1-82, preferably:
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid.
  • Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts.
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate,
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides
  • Preferred salts include salts of: (i) salts of N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1-(4- cyanophenyl)-1 H-pyrazol-5-yl]urea and hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid or citric acid;
  • Preferred acid addition salts also include:
  • Certain compounds of this invention can be further modified with labile functional groups that are cleaved after in vivo administration to furnish the parent active agent and the pharmacologically inactive derivatizing (functional) group.
  • labile functional groups that are cleaved after in vivo administration to furnish the parent active agent and the pharmacologically inactive derivatizing (functional) group.
  • prodrugs can be used, for example, to alter the physicochemical properties of the active agent, to target the active agent to a specific tissue, to alter the pharmacokinetic and pharmacodynamic properties of the active agent, and to reduce undesirable side effects.
  • Prodrugs of the invention include, e.g., the esters of appropriate compounds of this invention, are well-tolerated, pharmaceutically acceptable amides such as alkyl amide including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl(Ci-C5)alkyl may be used, although methyl amide is preferred. Solvates for the purpose of this invention are those forms of the compounds of this invention, such as
  • the compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the compounds of the present invention, with more detailed particular examples being presented below in the experimental section describing the working examples.
  • the compounds of the invention can be made according to conventional chemical methods, and/or as disclosed below, from starting materials which are either commercially available or producible according to routine, conventional chemical methods.
  • General methods for the preparation of the compounds are given below, and the preparation of representative compounds is specifically illustrated in examples.
  • Specific preparations of diaryl ureas, including pyrazolyl ureas, are already described in the patent literature, and can be adapted to the compounds of the present invention.
  • Miller S. et al "Inhibition of p38 Kinase using Symmetrical and Unsymmetrical Diphenyl Ureas" PCT int. Appl. WO 99 32463, Miller, S et al.
  • Compounds of the present invention can be prepared according to General Method 1 (Reaction Scheme 1), where 5-aminopyrazoles of Formula 1.1 and amines of Formula 1.2 are coupled together to form a urea of Formula I.
  • This process occurs in the presence of a coupling agent such as carbonyldiimidazole, carbonylditriazole, phosgene, diphosgene, triphosgene, and the like.
  • the isocyanates may or may not be formed in situ.
  • the coupling step may be performed in an inert solvent such as dioxane, diethylether, dichloromethane, chloroform, tetrahydrofuran, toluene, and the like, at a temperature selected between 0 0 C and reflux.
  • an inert solvent such as dioxane, diethylether, dichloromethane, chloroform, tetrahydrofuran, toluene, and the like.
  • Aromatic amines of Formula (1.2) are generally employed in an amount of from 1 to 3 mole per mole of compounds of Formula (1.1); an equimolar amount or slight excess of compounds of Formula (1.2) is preferred.
  • Amines of Formula (1.2) are commercially available or can be synthesized according methods commonly known to those skilled in the art. In particular, a large variety of aromatic amines of Formula (1.2) has been described in the diaryl urea patent literature cited above. Reaction Scheme 10 (below) will also illustrate one of the synthetic methods than can be used to prepare compounds of Formula (1.2).
  • the reaction of the compounds of Formula (1.1) with amines of Formula (1.2) is generally carried out within a relatively wide temperature range. In general, they are carried out in a range of from -20 to 200 0 C, preferably from 0 to 100 0 C, and more preferably from 25 to 50 0 C.
  • the steps of this reaction are generally carried out under atmospheric pressure. However, it is also possible to carry them out under super- atmospheric pressure or at reduced pressure (for example, in a range of from 0.5 to 5 bar).
  • the reaction time can generally be varied within a relatively wide range. In general, the reaction is finished after a period of from 2 to 24 hours, preferably from 6 to 12 hours.
  • the compounds of the present invention can be synthesized according to the reaction sequence shown in the General Method 2 (Reaction Scheme 2). These compounds can be synthesized by reacting arylamines of Formula (1.2) with isocyanates of Formula (2.2).
  • Compounds of Formula (2.2) can be synthesized according to methods commonly known to those skilled in the art.
  • isocyanates of Formula (2.2) may be prepared in situ or isolated from treatment of amino-pyrazoles of Formula (1.1) with phosgene or a phosgene equivalent such as trichlor ⁇ methyl chloroformate (diphosgene), bis(trichloromethyl)carbonate (triphosgene), or ⁇ /,/V'-carbonyldiimidazole (CDI), or ⁇ /, ⁇ /'-carbonylditriazole (CDT).
  • compounds of Formula 2.2 can be obtained from the corresponding pyrazole-carboxylic acid derivatives via a Curtius-type rearrangement.
  • 5-Aminopyrazo!es of Formula (1.1) can be prepared by a variety of methods. Specific preparations are already described in the patent literature, and can be adapted to the compounds of the present invention. For example, Keerigan, F. et a/., "Preparation of piperazine derivatives as therapeutic agents” PCT Int. App/., WO 9703067, Dumas, J. et al., "Inhibition of p38 Kinase Activity using Aryl- and Heteroaryl- Substituted Heterocyclic Ureas" PCT Int. Appl., WO 99 32110, Regan, J. et al., J. Med, Chem. 2003, 46 4676-4686.
  • Reaction Scheme 6 illustrates the synthesis of compounds for Formula (1.1c) where R 2 is halo as defined in examples 80 and 81 and A is as defined in examples 1- 82 below.
  • AIk optionally substituted (C 0 -C 4 ) alkyl substituted (C 1 -C 6 ) alkyl *Suitable boronic acid esters include group, or two R' groups may form a ring
  • Reaction Scheme 6 illustrates how the aminopyrazole of Formula (1.1a) may be converted to other aminopyrazoles of Formula (1.1c) by halogenation followed by Suzuki or Stille coupling reactions to introduce an R 2 group other than H.
  • the product of the Stille reaction (1.1d) can also be reduced, for example by hydrogenation, to give the saturated compound of Formula (1.1c).
  • Hydrazines of Formula (4.3) are either commercially available or can be prepared as shown in Reaction Scheme 7.
  • a substituted amine of Formula (7.1) is converted into a diazonium salt intermediate by exposure to sodium nitrite in the presence of an acid, such as HCI.
  • the diazonium salt is subsequently reduced, for example by using tin(ll)chloride as the reductant, in the presence of an acid such as HCI.
  • Compounds of Formula (8.1) can be reacted with benzophenone hydrazone (8.2) in the presence of a catalyst and ligand to afford intermediate (8.3).
  • this reaction is performed using a palladium catalyst (e.g., Pd(ll)acetate) in the presence of a phosphine ligand such as 4,5-bis(diphenylphosphino)xanthene.
  • a palladium catalyst e.g., Pd(ll)acetate
  • a phosphine ligand such as 4,5-bis(diphenylphosphino)xanthene.
  • the addition of base is favorable, in particular when using sodium ferf-butoxide.
  • the reaction is best performed under anhydrous conditions in a suitable solvent such as toluene.
  • Intermediate (8.3) can be used in Reaction Schemes 4 and 5 as an in situ form of (4.3), or it can be converted to a compound of Formula (4.3) in the presence of acid, preferably
  • 5-Amino pyrazoles of Formula (1.1) can be further functionalized [by methods well know to one skilled in the Art] before being coupled with keto-nitriles of Formula (1.2, Reaction Schemes 1-3).
  • Reaction Scheme 9 illustrates the manipulation of an alkoxyl substituted 5-amino pyrazoles.
  • Aminopyrazoles of Formula (9.1 ) are de-methylated to the corresponding hydroxy compounds of Formula (9.2) (for example, with the use of boron tribromide, methylthiolate in DMF 1 lithium diphenylphosphide, or an equivalent reagent known in the art).
  • compounds of Formula (9.2) can be further elaborated by alkylation, for example with an alkyl halide such as Y-Br, Y-I, or Y-Cl or by a Mitsunobu reaction with an alkanol such as Y-OH, to afford aminopyrazoles of Formula (9.3).
  • Reaction Scheme 10 illustrates the synthesis of compounds of Formula (1.2) where B pyridyl.
  • Reaction of a 2-carboxy pyridine of Formula (10.1) can be treated with an halogenating agent, preferably SOCI 2 /SOBr 2 , with heating to produce acid chloride 10.2.
  • Conversion to intermediate (10.3) is achieved either through Hofmann (NH 3 ; KOH 1 Br 2 ) or Curtius (NaN 3 , heat) rearrangement performed in a suitable solvent.
  • the 2-amino functional group can be masked as a 2,5-dimethylpyrrole by treatment with acetonyl acetone in the presence of a catalytic amount of acid.
  • Condensation of fragment 10.5 with intermediate 10.4 can be achieved in the presence of base in a suitable solvent, for example using potassium terf-butoxide in DMSO.
  • Unmasking of the 2-amino group can the be achieved by using hydroxyl amine in a solvent such as an alcohol in the presence of water and a mild base to provide compounds of Formula (1.2)
  • Synthetic transformations that may be employed in the synthesis of compounds of this invention and in the synthesis of intermediates involved in the synthesis of compounds of this invention are known by or accessible to one skilled in the art. Collections of synthetic transformations may be found in compilations, such as: J. March. Advanced Organic Chemistry, 4th ed.; John Wiley: New York (1992) R. C. Larock. Comprehensive Organic Transformations, 2nd ed.; Wiley-VCH: New York
  • compositions of the compounds of this invention are provided.
  • compositions containing one or more compounds of the present invention preferably one or more of:
  • compositions can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention, preferably one or more of:
  • a pharmaceutically acceptable carrier is preferably a carrier that is relatively nontoxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated.
  • N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N l -[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea; can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
  • the compounds of this invention including:
  • N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1-(3- methoxyphenyl)-1 H-pyrazol-5-yl]urea can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compounds of this invention including:
  • N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1-(3- methoxyphenyl)-1H-pyrazol-5-yl]urea; may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities
  • Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing, or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil- in-water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p- hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • the compounds of this invention including:
  • N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1-(3- methoxyphenyl)-1H-pyrazol-5-yl]urea; may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethy!-1 ,1-dioxolane-4-methanol, ethers such as poly(
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty acid alkali metal, ammontum, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents, for example di
  • compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient, such as
  • compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17.
  • HLB hydrophile-lipophile balance
  • the quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • compositions of this invention may be in the form of sterile injectable aqueous suspensions.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcelluJose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • a pharmaceutical composition of the invention including those which comprise
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • a suitable non- irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non- irritation excipient are, for example, cocoa butter and polyethylene glycol.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion in controlled amounts of the compounds of the present invention, including:
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 11 , 1991 , incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
  • composition of this invention such as one which includes one or more of
  • compositions of the invention including those which comprise one or more of;
  • compositions comprising a solid dispersion of the active ingredient, wherein the matrix comprises a pharmaceutically acceptable polymer, such as polyvinylpyrrolidone, vinylpyrrolidone/vinylacetate copolymer, polyalkylene glycol (i.e. polyethylene glycol), hydroxyalkyl cellulose (i.e. hydroxypropyl cellulose), hydroxyalkyl methyl cellulose (i.e.
  • a pharmaceutically acceptable polymer such as polyvinylpyrrolidone, vinylpyrrolidone/vinylacetate copolymer, polyalkylene glycol (i.e. polyethylene glycol), hydroxyalkyl cellulose (i.e. hydroxypropyl cellulose), hydroxyalkyl methyl cellulose (i.e.
  • hydroxypropyl methyl cellulose carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polymethacrylates, polyvinyl alcohol, polyvinyl acetate, vinyl alcohol/vinyl acetate copolymer, polyglycolized glycerides, xanthan gum, carrageenan, chitosan, chitin, poyldextrin, dextrin, starch and proteins or a sugar and/or sugar alcohol and/or cyclodextrin, for example sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, inositol, trehalose, isomalt, inu ⁇ n, maltodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin or sulfobuty
  • Additional suitable carriers that are useful in the formation of the matrix of the solid dispersion include, but are not limited to alcohols, organic acids, organic bases, amino acids, phospholipids, waxes, salts, fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and urea.
  • the solid dispersion of the compounds of this invention in the matrix may contain certain additional pharmaceutical acceptable ingredients, such as surfactants, fillers, disintegrants, recrystallization inhibitors, plasticizers, defoamers, antioxidants, detackifier, pH-modifiers, glidants and lubricants.
  • additional pharmaceutical acceptable ingredients such as surfactants, fillers, disintegrants, recrystallization inhibitors, plasticizers, defoamers, antioxidants, detackifier, pH-modifiers, glidants and lubricants.
  • the solid dispersion of the invention is prepared according to methods known to the art for the manufacture of solid dispersions, such as fusion/melt technology, hot melt extrusion, solvent evaporation (i.e. freeze drying, spray drying or layering of powders of granules), coprecipitation, supercritical fluid technology and electrostatic spinning method.
  • compositions for its intended route of administration include:
  • acidifying agents include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid
  • alkalinizing agents include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine
  • adsorbents examples include but are not limited to powdered cellulose and activated charcoal
  • aerosol propellants examples include but are not limited to carbon dioxide, CCI2F2,
  • F 2 CIC-CCiF 2 and CCIF 3 air displacement agents
  • air displacement agents include but are not limited to nitrogen and argon
  • antifungal preservatives include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate
  • antimicrobial preservatives include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal
  • antioxidants include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisul
  • caramel and ferric oxide red examples include clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable
  • suspending agents examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum
  • sweetening agents examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose
  • tablet anti-adherents examples include but are not limited to magnesium stearate and talc
  • tablet binders examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-
  • tablet direct compression excipients examples include but are not limited to dibasic calcium phosphate
  • tablet disintegrants examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch
  • tablet glidants examples include but are not limited to colloidal silica, corn starch and talc
  • tablet lubricants examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate
  • tablet/capsule opaquants examples include but are not limited to titanium dioxide
  • tablet polishing agents examples include but are not limited to carnuba wax and
  • compositions according to the present invention including those which comprise one or more of:
  • Sterile IV Solution A 5 mg/mL solution of the desired compound of this invention, such as
  • the solution is diluted for administration to 1 — 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 minutes.
  • Lyophilized powder for IV administration A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention, such as
  • the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 — 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.
  • Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble compound of this invention, preferably one or more of:
  • Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, preferably one or more of
  • Soft Gelatin Capsules A mixture of active ingredient, preferably one or more of:
  • a digestible oil such as soybean oil, cottonseed oil or olive oil
  • a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient.
  • the capsules are washed and dried.
  • the active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, preferably one or more of: N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1-(4-cyanophenyl)-1 H- pyrazol-5-yl]urea,
  • aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • Immediate Release Tablets/Capsules are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the active ingredient preferably one or more of:
  • the drug compounds such as one or more of:
  • the present invention relates to a method for using the compounds of the present invention, preferably
  • compositions thereof to treat mammalian hyper-proliferative disorders.
  • the compounds of this invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
  • the methods of this invention comprise administering to a mammal in need thereof, including a human, an amount of a compound of this invention, (Compounds of examples 1-82 or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc.) which is effective to treat the disorder.
  • Preferred embodiments of the methods of this invention comprise administering to a mammal in need thereof, including a human, one or of:
  • Hyper-proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • BPH benign prostate hyperplasia
  • solid tumors such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • Those disorders also include lymphomas, sarcomas, and leukemias.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to small- cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • treating or “treatment” as stated throughout this discussed is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
  • the present invention also provides methods for the treatment of disorders associated with aberrant kinase activity (such as tyrosine kinase activity), including, but not limited Flk-1 (VEGFR2), Trk-A, c-MET, and/or AbI (such as Bcr-Abl), comprising administering an effective amount of a compound of the present invention.
  • disorders include cancers (such as those mentioned herein), disorders associated angiogenesis (see above), cell proliferation disorders, etc.
  • SF/HGF and/or c-MET over- expression and mutations have been found in many tumor types, including, e.g., carcinomas, sarcomas, hematopoitic cancers, and other neoplastic diseases (Table 1).
  • c-Met over-expression has been associated with the progression of the neoplastic disease.
  • the evaluation of Met levels/activity could itself be used in the identification of a subset of patients who may require an alternative treatment strategy (Cheng, H. et al., Journal of Clinical Oncology, 2002, 20, 1544-1550).
  • Trk-A expression and mutations have been reported in cancers, including, e.g., pancreatic, breast, ovarian, prostate carcinoma, papillary thyroid carcinoma, medullary thyroid carcinoma (including familial forms), and acute myeloid leukemia (AML), neuroblastoma, breast cancer, and prostate.
  • the only change leading to the transforming capacity of the TRK gene is the replacement of the extracellular domain of NTRK1 by sequences coding for the 221 amino-terminal residues of tropomyosin-3 (TPM3) (Coulier, F. et al., Molec. Cell. Biol., 1989, 9, 15-23).
  • TPM3 tropomyosin-3
  • TPM3 and NTRK1 genes Sequence rearrangements between the TPM3 and NTRK1 genes result in TRKA oncogenes and their gene products, which are associated with papillary thyroid carcinomas (Butti, M. et al., Genomics, 1995, 28, 15-24). Elevated activity or levels of Trk-A has been observed in primary tumors as well as metastatic tumors in patients with papillary thyroid carcinomas (Bongarzone, I. et al., Oncogene, 1989, 4, 1457-1462). Papillary thyroid carcinoma (PTC), the most frequent neoplasia originating from the thyroid epithelium, accounts for about 80% of all thyroid cancers.
  • PTC Papillary thyroid carcinoma
  • NTRK1 In human neuroblastoma, expression of NTRK1 is a good prognostic marker, most likely because Trk-A mediated signaling is important for growth arrest and/or differentiation of the neural crest derived cells from which these tumors originate (Brodeur, G. et al., J Pediatr. Hematol. Oncol., 1997, 19, 93-101). In both in vitro and in vivo it has been found that the product of the TRK protooncogene is sufficient to mediate signal transduction processes induced by nerve growth factor (NGF) and neurotrophin-3. TRK is expressed in monocytes, which suggests that NGF is an immunoregulatory cytokine acting on monocytes.
  • NGF nerve growth factor
  • Trk-A deletion constructs that had transforming potential have been screened in patients with acute myeloid leukemia (Reuther, G. et al., Molecular and Cellular Biology, 2000, 20, 8655-8666). Fusion products of Trk-C, a closely related homolog of Trk-A, have also been implicated in certain patients with AML (Eguchi, M. et al., Blood, 1999, 93, 1355- 63).
  • fusion product of Bcr and AbI has been observed with Chronic myeloid leukemia, aberrant translocation, Acute erythroleukemia (FAB type M6), Acute lymphoblastic leukemia/lymphoblastic lymphoma, Acute megakaryoblastic leukemia (FAB type M7), Acute myeloblasts leukemia with maturation (FAB type M2), Acute myeloblasts leukemia with minimal differentiation (FAB type MO), Acute myeloblasts leukemia without maturation (FAB type M1), Acute myeloid leukemia, NOS, Acute myelomonocytic leukemia (FAB type M4), Acute promyelocyte leukemia (FAB type M3),
  • one aspect of the instant invention is a method for treating cancer related to the elevated activity and/or levels of the above-identified genes and their gene-products.
  • Effective amounts of compounds of the present invention can be used to treat such disorders, including those diseases (e.g., cancer) mentioned in the Background section above. Nonetheless, such cancers and other diseases can be treated with compounds of the present invention, regardless of the mechanism of action and/or the relationship between the kinase and the disorder.
  • aberrant kinase activity or "aberrant tyrosine kinase activity,” includes any abnormal expression or activity of the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant activity, include, but are not limited to, over-expression of the gene or polypeptide; gene amplification; mutations which produce constitutively-active or hyperactive kinase activity; gene mutations, deletions, substitutions, additions, etc.
  • the present invention also provides for methods of inhibiting a kinase activity, especially of Flk-1 , Trk-A, and/or c-MET, comprising administering an effective amount of a compound of the present invention (compounds of examples 1-82, including salts, polymorphs, metabolites, hyrates, solvates, prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof).
  • a compound of the present invention compounds of examples 1-82, including salts, polymorphs, metabolites, hyrates, solvates, prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof.
  • Kinase activity can be inhibited in cells (e.g., in vitro), or in the cells of a mammalian subject, especially a human patient in need of treatment.
  • Compounds of the present invention can be used for any of the indications described in U.S. Pat. Nos.
  • the present invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
  • Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism.
  • a number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal- vein occlusion, and retinopathy of prematurity (Aiello et at. New Engl. J. Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638), age-related macular degeneration (AMD; see, Lopez et al. Invest. Opththalmol. Vis. Sci.
  • neovascular glaucoma neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc.
  • RA rheumatoid arthritis
  • restenosis in-stent restenosis
  • vascular graft restenosis etc.
  • the increased blood supply associated with cancerous and neoplastic tissue encourages growth, leading to rapid tumor enlargement and metastasis.
  • the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer.
  • compounds of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
  • Compound and compositions of the present invention can be tested routinely for angiogenic activity, e.g., by contacting a blood vessel-forming cell population with a compound of the present invention, and determining the effect of the compound on blood vessel formation. Any cell population capable of forming blood vessels can be utilized.
  • Useful models include, e.g., in vivo Matrigel-type assays; tumor neovascularization assays; CAM assays; BCE assays; cell migration assays; HUVEC growth inhibition assays; animal models (e.g., tumor growth in athymic mice, chronically ischemic lower limb in a rabbit model, cancer models, etc.); in vivo systems, such as a heart or limb present in a patient (e.g., angiogenic therapy to treat myocardial infarction); hosts in need of treatment, e.g., hosts suffering from angiogenesis related diseases, such as cancer, ischemic syndromes, arterial obstructive disease, to promote collateral circulation, to promote vessel growth into bioengineered tissues, etc.
  • angiogenesis related diseases such as cancer, ischemic syndromes, arterial obstructive disease, to promote collateral circulation, to promote vessel growth into bioengineered tissues, etc.
  • Cells can include, e.g., endothelial, epithelial, muscle, embryonic and adult stem cells, ectodermal, mesenchymal, endodermal, neoplastic, blood, bovine CPAE (CCL-209), bovine FBHE (CRL-1395), human HUV-EC-C (CRL-1730), mouse SVEC4-10EHR1 (CRL-2161), mouse MS1 (CRL-2279), mouse MS1 VEGF (CRL-2460), stem cells, etc.
  • the phrase "capable of forming blood vessels" does not indicate a particular cell-type, but simply that the cells in the population are able under appropriate conditions to form blood vessels. In some circumstances, the population may be heterogeneous, comprising more than one cell-type, only some which actually differentiate into blood vessels, but others which are necessary to initiate, maintain, etc., the process of vessel formation.
  • a useful model to determine the effect of compounds or compositions on angiogenesis is based on the observation that, when a reconstituted basement membrane matrix, such as Matrigel, supplemented with growth factor (e.g., FGF-1), is injected subcutaneously into a host animal, endothelial cells are recruited into the matrix, forming new blood vessels over a period of several days. See, e.g., Passaniti et al., Lab. Invest., 67:519-528, 1992.
  • the growth factor can be bound to heparin or another stabilizing agent.
  • the matrix can also be periodically re-infused with growth factor to enhance and extend the angiogenic process.
  • a Matrigel plug implant comprising FGF-1 can be implanted subcutaneously into a host mouse.
  • the initial bolus of FGF attracts endothelial cells into the implant, but does not result in new blood vessel formation.
  • the implant can be re-infused with FGF-1.
  • the FGF- 1 stimulates the endothelial cells already present in the implant, initiating the process of angiogenesis.
  • neovascularization of tumor explants e.g., U.S. Pat. Nos. 5,192,744; 6,024,688
  • CAM chicken chorioallantoic membrane
  • BCE bovine capillary endothelial
  • HUVEC human umbilical cord vascular endothelial cell growth inhibition assay
  • a cell population can be contacted with the compound or composition in any manner and under any conditions suitable for it to exert an effect on the cells.
  • the means by which compound is delivered to the cells may depend upon the type of test agent, e.g., its chemical nature, and the nature of the eel! population. Generally, a compound must have access to the cell population, so it must be delivered in a form (or pro-form) that the population can experience physiologically, i.e., to put in contact with the cells.
  • the intent is for the agent to enter the cell, if necessary, it can be associated with any means that facilitate or enhance cell penetrance, e.g., associated with antibodies or other reagents specific for cell-surface antigens, liposomes, lipids, chelating agents, targeting moieties, etc.
  • Cells can also be treated, manipulated, etc., to enhance delivery, e.g., by electroporation, pressure variation, etc.
  • the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • "drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compounds of this invention can be combined with known anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • the additional pharmaceutical agent can be aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid,
  • Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ.
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.
  • cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to:
  • u Combination means for the purposes of the invention not only a dosage form which contains all the components (so-called fixed combinations), and combination packs containing the components separate from one another, but also components which are administered simultaneously or sequentially, as long as they are employed for the prophylaxis or treatment of the same disease.
  • the active ingredients of the combination according to the invention can be converted in a known manner into the usual formulations, which may be liquid or solid formulations. Examples are tablets, coated tablets, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, solutions.
  • the combination according to the invention is well tolerated and in some cases is effective even in low dosages, a wide range of formulation variants is possible.
  • one possibility is to formulate the individual active ingredients of the combination according to the invention separately. In this case, it is not absolutely necessary for the individual active ingredients to be taken at the same time; on the contrary, sequential intake may be advantageous to achieve optimal effects.
  • the active ingredients are present in the primary packaging in each case in separate containers which may be, for example, tubes, bottles or blister packs.
  • Such separate packaging of the components in the joint primary packaging is also referred to as a kit.
  • compositions which are suitable and preferred for the combination according to the invention are also fixed combinations.
  • "Fixed combination” is intended here to mean pharmaceutical forms in which the components are present together in a fixed ratio of amounts.
  • Such fixed combinations may be, for example, in the form of oral solutions, but they are preferably solid oral pharmaceutical preparations, e.g. capsules or tablets.
  • Celite ® brand of diatomaceous earth filtering agent registered trademark of Celite Corporation d doublet dd doublet of doublet ddd doublet of doublet of doublet
  • Electron impact mass spectra (El-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 ⁇ M coating; 30 m x 0.25 mm). The ion source was maintained at 250 0 C and spectra were scanned from 50-800 amu at 2 sec per scan.
  • High pressure liquid chrornatography-electrospray mass spectra were obtained using either a: a) Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA 1 and B: 2% water in acetonitrile with 0.018% TFA.
  • ELSD Electrode ugw Scattering Detector
  • the eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% to 90% B over 3.5 minutes at a flow rate of 1.5 mL/min was used with an initial hold of 0.5 minutes and a final hold at 90% B of 0.5 minutes. Total run time was 4.8 minutes. An extra switching valve was used for column switching and regeneration.
  • Agilent 1100 HPLC system Agilent 1100 HPLC system.
  • the Agilent 1100 HPLC system was equipped with an Agilent 1100 autosampler, quaternary pump, and a diode array.
  • the HPLC column used was a Waters Sunfire (2.1 x 30 mm, 3.5 uM).
  • the HPLC eluent was directly coupled with a 1 :4 split to a Finnigan LTQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 50-1000 amu using a variable ion time according to the number of ions in the source in either positive or negative ion mode.
  • the eluents were A: water with 0.1 Formic acid and B: aceto ⁇ itrile with 0.1% Formic acid. Gradient elution from 10% B to 90% B over 3.0 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 2.0 minutes and a final hold at 95% B of 1.0 minutes. Total run time was 8.0 minutes.
  • Routine one-dimensional NMR spectroscopy was performed on 300/400 MHz Varian Mercury-plus spectrometers. The samples were dissolved in deuterated solvents obtained from Cambridge Isotope Labs, and transferred to 5mm ID Wilmad NMR tubes. The spectra were acquired at 293 K. The chemical shifts were recorded on the ppm scale and were referenced to the appropriate solvent signals, such as 2.05 ppm for acetone-de, 2.49 ppm for DMSOd 6 , 1-93 ppm for CD 3 CN, 3.30 ppm for CD 3 OD, 5.32 ppm for CD2CI2 and 7.26 ppm for CDCI 3 for 1 H spectra.
  • Preparative HPLC was carried out in reversed phase mode, eluting with aqueous acetonitrile containing 0.5% TFA, typically using a Gilson HPLC system equipped with two Gilson 322 pumps, a Gilson 215 Autosampler, a Gilson diode array detector, and a YMC Pro C-18 column (20 x 150 mm, 120 A). Gradient elution was used with Buffer A as water with 0.1% TFA and Buffer B as acetonitrile with 0.1 % TFA. Sample was dissolved in MeOH or MeOH/DMSO with concentration about 50 mg/mL. Injection volume was about 2-3 mL/injection.
  • Sample was typically eluted as follows: 10-90% B over 15 minutes with flow rate of 25 mL/min, hold 2 minutes, back to 10% B.
  • the desired fraction(s) were collected by UV monitoring at 254 or 220 nm and evaporated by using a GeneVac centrifugal vacuum instrument.
  • MPLC medium pressure liquid chromatography
  • Step 1 Preparation of ⁇ Benzhydrylidene-/V -(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1 > 4]- dioxin-6-yl)hydrazine
  • Step 2 Preparation of 5-fe/f-Butyl-2-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1 ,4]dioxin-6- yl)-2H-pyrazol-3-ylamine
  • the title compound was prepared in the same manner as described for 5-tert- butyl-2-(4-fluoro-phenyl)-2/-/-pyrazol-3-ylamine, replacing 4-fluorophenylhydrazine with ethyl (4-hydrazinophenyl)acetate hydrochloride (11.98 g, 51.9 mmol).
  • the title compound was obtained as a solid (HCI salt, 11.95 g) in 68% yield.
  • the reaction flask was charged with water (200 ml_) and potassium hydroxide (35.83 g, 638.68 mmol) and cooled to 5° C.
  • potassium hydroxide 35.83 g, 638.68 mmol
  • Step 1 Preparation of 1-[5-tert-butyl-2(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3- ⁇ 4-[2-(2,5- dimethyl-pyrrol-1-yl)-pyridin-4-yloxy]-phenyl ⁇ -urea
  • Step 2 Preparation of 1- ⁇ 4-(2-amino-pyridin-4-yloxy)-phenyl]-3-[5-te/t-butyl-2-(4-fluoro- phenyl)-2H-pyrazol-3-yl]-urea
  • Step 1 To a suspension of 5-te/t-butyl-2-(4-cyclobutoxy-phenyl)-2H-pyrazol-3-ylamine (Intermediate 11 , 1.05 g, 3.66 mmol) and potassium carbonate (2.02 g, 14.63 mmol) in THF (10 ml_) was added phenyl chloroformate (1.89 g, 12.07 mmol). The reaction was stirred at room temperature under nitrogen for 18 h. The mixture was then diluted with EtOAc, washed successively with NaHC ⁇ 3 (saturated aqueous solution) and brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure.
  • DCM/MeOH 99/1-95/5
  • Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the activity of the compounds of the present invention, the following assays may be used.
  • This assay was performed in 96-well opaque plates (Costar 3915) in the TR- FRET format. Reaction conditions are as follows: 10 ⁇ M ATP 1 25 nM poly GT-biotin, 2 nM Eu-labelled phospho-Tyr Ab (PY20 Perkin Elmer), 10 nM APC (Perkin Elmer), 7 nM Flk-1 (kinase domain), 1% DMSO, 50 mM HEPES pH 7.5, 10 mM MgCI 2 , 0.1 mM EDTA, 0.015% BRIJ, 0.1 mg/mL BSA, 0.1 % ⁇ -mercaptoethanol). Reaction is initiated upon addition of enzyme. Final reaction volume in each well is 100 ⁇ l_.
  • Plates are read at both 615 and 665 nM on a Perkin Elmer Victor V Multilabel counter at about 1.5- 2.0 hours after reaction initiation. Signal is calculated as a ratio: (665 nm / 615 nm) * 10000 for each well.
  • This assay uses the N-terminal HiS-tagged intracellular kinase domain of human recombinant Trk-A in 96-well plates. This involves a biotinylated-poly-GluTyr substrate and an Eu-labelled anti-phosphotyrosine antibody for detection of kinase activity in a homogeneous time-resolved FRET format.
  • the Trk-A biochemical FRET assay protocol is as follows: 10 mM stock solution of test compounds are diluted to 1 mM in 100% DMSO. These stocks are diluted with 100% DMSO by a factor of 5, in a total of 7 steps to create an 8-point IC 50 curve. The diluted compounds are combined 1 :4 with distilled water to form the 25x dilution plate for the assay.
  • a 2 ⁇ l_ aliquot of compound from the 25x dilution plate is added with 23 ⁇ l_ of assay buffer (50 mM HEPES pH 7.0, 5 mM MnCI 2 , 0.1% BSA, 0.5 mM vanadate, 0.1% ⁇ -mercaptoethanol) into a 96-well, half volume opaque (black) plate (Costar #3694).
  • ATP is added to all wells except the negative controls (5 microliters of 40 ⁇ M).
  • Five microliters of 2.2 ⁇ g/mL poly(GluTyr)-biotin (CIS US # 61 GTOBLB) and 15 ⁇ L of 6.66 nM Trk-A diluted in assay buffer are added to the plate to start the reaction.
  • the assay is stopped with addition of 5 ⁇ L of 0.5M EDTA.
  • 25 ⁇ L each of 340 ng/mL PY20 cryptate antibody (CIS US #61Y20KLA) and 40 nM streptavidin labelled APC (SA-XL - CIS US # 611 SAXLB) are added in development buffer (50 mM HEPES pH7.0, 0.8M KF, 0.1 % BSA).
  • development buffer 50 mM HEPES pH7.0, 0.8M KF, 0.1 % BSA.
  • the assay plate sits at room temperature for at least one hour, then is read on a Perkin Elmer Victor 2 instrument at 615 and 665 nM emission. A ratio of these two numbers is used in the calculations of the data.
  • the cMET LANCE assay is run in a 96-well black plate (Costar #3694) in a 60 ⁇ l volume.
  • the assay buffer contains 5OmM Hepes pH 7.3, 5mM MnCI 2 , 0.1 mM EDTA, 0.015% Brij-35, 0.01% BSA, and 5mM B-ME.
  • Assay buffer and compound are added to the plate.
  • Compound final concentration ranges from 10 ⁇ M to 128 pM in an 8-point IC 5 O curve.
  • Final DMSO concentration is 1%.
  • cMET is added to a final concentration of 160 pM.
  • Abl-T315l Kinase Filtermat Assay Inhibition of Abl-T315l kinase phosphorylation of myelin basic protein by compounds in a 33 P-ATP Filtermat Assay.
  • MBP Myelin Basic Protein
  • the compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1 -(4- methylphenyl)-1 H-pyrazol-5-yl]urea showed IC50 ⁇ 10 ⁇ M in one or more of the biochemical assays discussed above.
  • the compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-f Iuorophenyl ⁇ -N"-[1 -(3- fluorophenyl)-3-isopropyl-1 H-pyrazol-5-yl]urea showed IC 50 ⁇ 10 ⁇ M in one or more of the biochemical assays discussed above.
  • the cells are plated in full growth media (10,000 cells/well) in 96-well plates on day one.
  • MSD MSD recommended lysis buffer
  • non-specific antibody-binding sites on the MSD phospho-Met plates are blocked with MSD Blocking Solution A overnight at 4 0 C.
  • the adherent tumor cell proliferation assay used to test the compounds of the present invention involves a readout called Cell Titre-Glo developed by Promega (Cunningham, BA "A Growing Issue: Cell Proliferation Assays. Modern kits ease quantification of cell growth” The Scientist 2001 , 15(13), 26, and Crouch, SP et al., "The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity” Journal of Immunological Methods 1993, 160, 81-88).
  • H460 cells lung carcinoma, purchased from ATCC
  • H460 cells are plated in 96-well plates at 3000 cells/well in complete media with 10% Fetal Calf Serum and incubated 24 hours at 37 0 C.
  • test compounds are added over a final concentration range of 10 nM to 20 ⁇ M in serial dilutions at a final DMSO concentration of 0.2 %.
  • Cells are incubated for 72 hours at 37 0 C in complete growth media after addition of the test compound.
  • On day 4 using a Promega Cell Titer GIo Luminescent ® assay kit, the cells are lysed and 100 microliters of substrate/buffer mixture is added to each well, mixed and incubated at room temperature for 8 minutes.
  • the samples are read on a luminometer to measure the amount of ATP present in the cell lysates from each well, which corresponds to the number of viable cells in that well. Values read at 24-hour incubation are subtracted as Day 0.
  • a linear regression analysis can be used to determine drug concentration which results in a 50% inhibition of cell proliferation using this assay format. This protocol was applied to different cell lines of interest, which include, but not limited to, CAKI-1, MNK45, GTL-16, HCC2998, K562, H441 , K812, MEG01, SUP15 and HCT116.
  • Compounds of this invention showed antiproliferative properties (IC 50 ⁇ 10 ⁇ M) in one or more cell lines of interest.
  • the compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1- (4-methylphenyl)-1H-pyrazol-5-yl]urea showed antiproliferative properties (IC 50 ⁇ 10 ⁇ M) in one or more cell lines of interest.
  • the compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[1-(3- fluorophenyl)-3-isopropyl-1 H-pyrazol-5-yl]urea showed antiproliferative properties (IC50 ⁇ 10 ⁇ M) in one or more cell lines of interest.
  • the compound N- ⁇ 4-[(2-aminopyridin-4-yl)oxy]-2-fluorophenyl ⁇ -N'-[3-tert-butyl-1- (3-methoxyphenyl)-1H-pyrazol-5-yl]urea showed antiproliferative properties (IC 50 ⁇ 10 ⁇ M) in one or more cell lines of interest.
  • An additional cell proliferation assay used to test the compounds of the present invention involves a readout called Cell Titre-Glo developed by Promega (Cunningham, BA "A Growing Issue: Cell Proliferation Assays. Modern kits ease quantification of cell growth” The Scientist 2001 , 15(13), 26, and Crouch, SP et a!., "The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity” Journal of Immunological Methods 1993, 160, 81-88).
  • IL-3-independent BaF3 cells overexpressing the tpr-met oncogene (Cooper, CS. , et al., "Molecular cloning of a new transforming gene from a chemically- transformed human cell line” Nature (London) 1984, 311 , 29-33) are plated in 384-well plates at 1667 cells/well in complete RPMI media with 10% Fetal Bovine Serum and 1 mg/ml G418. Immediately after plating, test compounds are added over a final concentration range of 10 ⁇ M to 128 pM in serial dilutions at a final DMSO concentration of 0.1%. Cells are incubated for 72 hours at 37 0 C in complete growth media after addition of the test compound.

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Abstract

La présente invention concerne des composés de pyrazole urée, des compositions pharmaceutiques qui les contiennent et des procédés de traitement du cancer qui les utilisent.
PCT/US2006/044322 2005-11-15 2006-11-15 Derives de pyrazolyluree utilisables dans le traitement du cancer WO2007059202A2 (fr)

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WO2010038086A3 (fr) * 2008-10-02 2010-06-24 Respivert Limited Nouveaux composés
WO2010089773A3 (fr) * 2009-02-02 2010-10-21 Indoco Remedies Limited Procédé pour la préparation de dérivés de nitropyridine
WO2012003338A1 (fr) 2010-07-01 2012-01-05 Takeda Pharmaceutical Company Limited Combinaison d'un inhibiteur de cmet et d'un anticorps dirigé contre hgf et/ou cmet
US8293771B2 (en) 2008-10-02 2012-10-23 Respivert Ltd. p38 MAP kinase inhibitors
US8642773B2 (en) 2009-04-03 2014-02-04 Respivert Ltd. P38MAP kinase inhibitor
WO2014078322A1 (fr) * 2012-11-13 2014-05-22 Array Biopharma Inc. Composés de thiazolyl-urée, oxazolyl-urée, thio-urée, guanidine et cyanoguanidine en tant qu'inhibiteurs de la kinase trka
US9120789B2 (en) 2010-02-01 2015-09-01 Cancer Research Technology Limited 1-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy
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US9155737B2 (en) 2007-12-19 2015-10-13 Institute Of Cancer Research: Royal Cancer Hospital (The) Pyrido[2,3-B]pyrazin-8-substituted compounds and their use
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US9546156B2 (en) 2012-11-13 2017-01-17 Array Biopharma Inc. N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors
US9562055B2 (en) 2011-05-13 2017-02-07 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9708317B2 (en) 2013-11-25 2017-07-18 Cancer Research Technology Limited Process for the preparation of 8-(4-aminophenoxy)-4H-pyrido[2,3-B]pyrazin-3-one derivatives
US9725447B2 (en) 2013-11-25 2017-08-08 Cancer Research Technology Limited 1-(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido[2,3-b]pyrazin-8-yl)oxy]phenyl]urea derivatives as RAF inhibitors for the treatment of cancer
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US10835533B2 (en) 2014-05-15 2020-11-17 Array Biopharma Inc. 1 -((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea as a TrkA kinase inhibitor
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032455A1 (fr) * 1997-12-22 1999-07-01 Bayer Corporation Inhibition de raf kinase a l'aide d'urees heterocycliques aryle et heteroaryle substituees
WO1999032106A1 (fr) * 1997-12-22 1999-07-01 Bayer Corporation Inhibition de raf kinase au moyen d'urees heterocycliques substituees
WO2005110994A2 (fr) * 2004-04-30 2005-11-24 Bayer Pharmaceuticals Corporation Derives de pyrazolyl uree substitues utiles dans le traitement du cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032455A1 (fr) * 1997-12-22 1999-07-01 Bayer Corporation Inhibition de raf kinase a l'aide d'urees heterocycliques aryle et heteroaryle substituees
WO1999032106A1 (fr) * 1997-12-22 1999-07-01 Bayer Corporation Inhibition de raf kinase au moyen d'urees heterocycliques substituees
WO2005110994A2 (fr) * 2004-04-30 2005-11-24 Bayer Pharmaceuticals Corporation Derives de pyrazolyl uree substitues utiles dans le traitement du cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JACQUES DUMAS, HOLIA HATOUM-MOKDAD, ROBERT N. SIBLEY, ROGER A. SMITH, WILLIAM J. SCOTT, UDAY KHIRE, WENDY LEE ET AL.: "Synthesis and pharmacological characterization of a potent, orally active p38 kinase inhibitor" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 12, 2002, pages 1559-1562, XP002434053 *

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