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WO2007057397A1 - Traitement du cancer - Google Patents

Traitement du cancer Download PDF

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Publication number
WO2007057397A1
WO2007057397A1 PCT/EP2006/068459 EP2006068459W WO2007057397A1 WO 2007057397 A1 WO2007057397 A1 WO 2007057397A1 EP 2006068459 W EP2006068459 W EP 2006068459W WO 2007057397 A1 WO2007057397 A1 WO 2007057397A1
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Prior art keywords
indolinone
phenyl
anilino
methyl
methylene
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PCT/EP2006/068459
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English (en)
Inventor
Wolfgang Sommergruber
Norbert Kraut
Norbert Schweifer
Wolfgang Rettig
Frank Hilberg
Flavio Solca
Martin Steegmaier
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Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Application filed by Boehringer Ingelheim International Gmbh, Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim International Gmbh
Publication of WO2007057397A1 publication Critical patent/WO2007057397A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the field of cancer therapy, particularly to the use of compounds for the treatment of cancers associated with certain tyrosine kinases.
  • Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. Tyrosine kinases play critical roles in signal transduction for a number of cell functions via substrate phosphorylation.
  • Tyrosine kinases fall within the categories of receptor type or non-receptor type kinases.
  • Receptor type tyrosine kinases have an extracellular, a transmembrane, and an intracellular portion, while non-receptor type tyrosine kinases are intracellular.
  • the protein kinase family includes kinases such as, for example, the Abelson tyrosine kinase (ABL), fibroblast growth factor receptor 3 (FGFR3), FMS-related tyrosine kinase 1 and 3 (FLTl and FLT3) and receptor tyrosine kinase RET, and the like.
  • ABL Abelson tyrosine kinase
  • FGFR3 fibroblast growth factor receptor 3
  • FMS-related tyrosine kinase 1 and 3 FMS-related tyrosine kinase 1 and 3
  • FLT3 FMS-related tyrosine kinase 1 and 3
  • RET receptor tyrosine kinase
  • the receptor type tyrosine kinases are transmembrane receptors with diverse biological activity.
  • Members of the HER subfamily are EGFR, HER2, HER3, and HER4.
  • Ligands of this subfamily of receptors include epithelial growth factor, TGF- ⁇ , amphiregulin, HB- EGF, betacellulin and heregulin.
  • Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, and IR-R.
  • the PDGF subfamily includes the PDGF- ⁇ and ⁇ receptors, CSFlR, c-KIT and FLK-II.
  • the FLK family is comprised of the kinase insert domain receptor (KDR), fetal liver kinase- 1 (FLK-I), fetal liver kinase-4 (FLK-4) and the fins-like tyrosine kinase- 1 (FLT-I).
  • KDR kinase insert domain receptor
  • FLK-I fetal liver kinase- 1
  • FLK-4 fetal liver kinase-4
  • FLT-I fins-like tyrosine kinase- 1
  • Other receptor tyrosine kinase families are RET and AXL (AXL, MER, Tyro3).
  • the non-receptor type of tyrosine kinases also comprises numerous subfamilies, including SRC, FRK, BTK, CSK, ABL, ZAP70, FES/FPS, FAK, JAK, ACK, and LIMK.
  • SRC subfamily is one of the largest and includes SRC, YES, FYN, LYN, LCK, BLK, HCK, FGR, and YRK.
  • SRC subfamily of enzymes has been linked to oncogenesis.
  • Certain mutations in the genes of receptor protein tyrosine kinases result in activation of the receptor in a manner that is independent of the presence of a ligand. Such ligand- independent, or constitutive, receptor protein tyrosine kinase activation results in increased receptor activity.
  • the clinical manifestations of certain mutations are skeletal and proliferative disorders and diseases, including achondroplasia and various cancers.
  • tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation.
  • Compounds that regulate and/or modulate tyrosine kinase signal transduction and compositions containing such compounds are useful for treating tyrosine kinase-dependent diseases and conditions, such as angiogenesis and cancer and inflammatory diseases.
  • the ABL (ABLl) protooncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that is involved in a variety of different biological processes such as cell differentiation, cell division, cell adhesion, and stress response. Alterations of ABL by chromosomal rearrangement or viral transduction lead to malignant transformation, as in CML.
  • Activity of c-ABL protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABLl into an oncogene.
  • the t(9;22) translocation occurs in more than 90% of CML, 25 to 30% of adult and 2 to 10% of childhood acute lymphoblastic leukemia (ALL), and rare cases of AML.
  • CML CML-ABL oncogene
  • This fusion gene encodes a chimeric BCR-ABL protein, in which the tyrosine kinase activity of ABL is constitutively activated.
  • CML patients express the 210 kDa BCR-ABL, whereas patients with Ph+ ALL usually express a 190 kDa BCR- ABL protein arising from a different breakpoint in the BCR gene (MeIo et al., 1994, Leukemia 8:208-211; Ravandi et al., 1999, Br. J. Haematol. 107).
  • the ubiquitously expressed ABL tyrosine kinase is localized to the nucleus and binds to DNA.
  • the DNA-binding activity is regulated by CDC2-mediated phosphorylation.
  • Welch and Wang showed that the tyrosine kinase activity of nuclear ABL is regulated in the cell cycle through a specific interaction with the retinoblastoma (RBl) protein (Welch and Wang, 1993, Cell 75: 779-790).
  • Alternative splicing leads also to a 145-kD ABL protein classified as a "nonreceptor tyrosine kinase" (Chissoe et al., 1995, Genomics 27: 67-82).
  • a domain in the C-terminus of RB binds to the ATP-binding lobe of the ABL tyrosine kinase, resulting in kinase inhibition.
  • Hyperphosphorylation of RB correlates with release of ABL and activation of the tyrosine kinase in S phase cells.
  • the nuclear ABL tyrosine kinase can enhance transcription, and this activity is inhibited by RB.
  • nuclear ABL is an S phase-activated tyrosine kinase that might participate directly in the regulation of transcription.
  • Imatinib mesylate (Gleevec, STI571; Novartis Pharma AG) is a drug targeting the tyrosine kinase activity of BCR-ABL (Buchdunger et al., 2001, Biochim. Biophys. Acta 1551: Ml 1-M18) and is an effective therapy for CML.
  • BCR-ABL Buchdunger et al., 2001, Biochim. Biophys. Acta 1551: Ml 1-M18
  • response rates to imatinib therapy are significantly decreased and, of those who initially respond to treatment, many relapse within 12 months.
  • tyrosine kinase receptor FGFR3 fibroblast growth factor receptor 3
  • FGFR3 fibroblast growth factor receptor 3
  • Activating point mutations in the FGFR3 gene occur most frequently in low-grade and low-stage bladder carcinomas, whereas they are rare in high-grade carcinomas (van Rhijn et al., 2002, J. Pathol. 198: 245-251).
  • FLT3 FMS-related tyrosine kinase 3
  • STKl stem cell tyrosine kinase 1
  • FLT3 is a member of the type III receptor tyrosine kinase family that includes KIT, FMS, and PDGFR. FLT3 expression is restricted in human blood and marrow to CD34 + cells, a population greatly enriched by stem/progenitor cells. FLT3 functions as a growth factor receptor on hematopoietic stem and/or progenitor cells and plays an essential role in acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • the most common fusion partner is promyelocytic leukemia protein (PML), which is fused to RARA in the balanced reciprocal chromosomal translocation, t(15;17)(q22;ql 1).
  • PML/RARA promyelocytic leukemia protein
  • a candidate target gene for a second mutation is FLT3, because it is mutated in approximately 40% of human APL cases.
  • Activating mutations in FLT3 include e. g. ITD.
  • FLT3(ITD) expression transforms hematopoietic cell lines to factor independent growth and also induces a myeloproliferative disease in a murine bone marrow transplant model, but are not sufficient to cause AML; for this a cooperation of FLT3(ITD) and PML/RARA is necessary.
  • D835 Single point mutations mainly found in the activation loop domain (hotspot region for activating) e. g. D835 (similar to position D816 in the KIT oncogene).
  • the D835 mutation occurs independently of the FLT3 ITD mutation.
  • the FLT3 ITD mutation is found in 20% of patients with AML and is strongly associated with leukocytosis and a poor prognosis.
  • Yamamoto et al. 2001, Blood 97: 2434-2439
  • Activating mutations of the FLT3 receptor tyrosine kinase are common in AML but are rare in adult ALL. Armstrong et al.
  • PKC 412 a third FLT3 inhibitor, which also inhibits c-kit, vascular endothelial growth factor receptor (VEGFR), and protein kinase C, was associated with responses in mutant FLT3 patients and a more modest level of response in AML patients with wild-type FLT3 (Estey et al., 2003, Blood 102: 614a. Abstract 2270).
  • GTP14564 another tyrosine kinase inhibitor active against FLT3, was shown to inhibit not only mutated FLT3 in RS4;11 cells but also FLT3 amplified wild-type cells such as SEMK2-M1. Responses to GTP14564 in all cell types were directly related to the level of STAT5 phosphorylation in the cells (Yao et al., 2005, Leukemia 19: 1605-1612).
  • the RET receptor tyrosine kinase protooncogene undergoes oncogenic activation in vivo and in vitro by cytogenetic rearrangement (Grieco et al., 1990, Cell 60: 557-563). Mutations in the RET gene are associated with multiple endocrine neoplasia, type HA, multiple endocrine neoplasia, type HB, Hirschsprung disease (HSCR), aganglionic megacolon, and medullary thyroid carcinoma (MTC). Salvatore et al. (2000, J. Clin. Endocr. Metab.
  • oncogenic mutations cause constitutive activation of the kinase function of RET, which in turn results in the autophosphorylation of RET tyrosine residues critical for signaling.
  • the concomitant phosphorylation of Y1015 and Y 1062 cause multiple endocrine neoplasia type 2A (MEN2A), type 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC).
  • MEN2A multiple endocrine neoplasia type 2A
  • MEN2B type 2B
  • FMTC familial medullary thyroid carcinoma
  • FMTC-associated RET mutations affect the tyrosine kinase domain of the receptor; FMTC mutants are monomeric receptors which are autophosphorylated and activated independently of glial cell line-derived neurotrophic factor (GDNF; ligand of RET, normally expressed during lung development).
  • GDNF glial cell line-derived neurotrophic factor
  • the mutations lead to constitutive activation of signal transducers and activators of transcription 3 (STAT3).
  • STAT3 activation is mediated by a signaling pathway involving SRC, JAKl, and JAK2, differing from STAT3 activation promoted by REJ C634R which was previously found to be independent of SRC and JAKs (Menacho et al, 2005, Cancer Res. 65: 1729-1737).
  • Giordano et al. (2005, Oncogene 24: 6646-6656) performed transcriptional profiling for more than 50 papillary thyroid carcinomas.
  • the tumors were genotyped for their common activating mutations: BRAF V600E point mutation, RET/PTC 1 and 3 rearrangement and point mutations of KRAS, HRAS and NRAS.
  • BRAF V600E point mutation BRAF V600E point mutation
  • RET/PTC 1 and 3 rearrangement and point mutations of KRAS, HRAS and NRAS By combining expression profiles with mutational status, they defined distinct expression profiles for the BRAF, RET/PTC and RAS mutation groups.
  • By this one tumor without an obvious detectable mutation was predicted by the classifier to have a RET/PTC rearrangement and indeed was shown to contain one by fluorescence in situ hybridization analysis.
  • RET oncoproteins expressed in thyroid carcinomas have been considered as targets for therapeutic intervention.
  • Oncogenic activation of the receptor tyrosine kinase encoding RET gene occurs, in addition to gene rearrangement in papillary thyroid carcinomas (PTC), by missense mutation in medullary thyroid carcinomas (MTC).
  • PTC papillary thyroid carcinomas
  • MTC medullary thyroid carcinomas
  • RPI-I arylidene 2-indolinone RET inhibitor
  • TPC-I which spontaneously harbors the RET/PTC 1 oncogene
  • ZD6474 an anilinoquinazoline, blocked in vivo phosphorylation and signaling of oncogenic RET kinases.
  • ZD6474 blocked in vivo phosphorylation and signaling of the RET/PTC3 and RET/MEN2B oncoproteins and of an epidermal growth factor (EGF)-activated EGF-receptor/RET chimeric receptor.
  • ZD6474 prevented the growth of two human PTC cell lines that carry spontaneous RET/PTC 1 rearrangements, FB2 and TPCl (papillary carcinomas harboring the RET/PTC 1 rearrangement) whereas ARO harboring a wtRET did not respond.
  • ZD6474 blocked anchorage-independent growth of RET/PTC3- transformed NIH3T3 fibroblasts and the formation of tumors after injection of NIH- RET/PTC3 cells into nude mice.
  • SCLC small cell lung cancer
  • an object of this invention to provide compounds for the manufacture of a medicament useful in the treatment or prevention or amelioration of such diseases and disorders comprising administering to a patient in need of such treatment an effective amount of a pharmaceutical composition comprising a compound of formula (I).
  • the invention is based on the finding that indolinones are useful for the therapy of diseases which result from aberrant activity of certain tyrosine kinases.
  • Indolinones their preparation as well as the pharmacological activity of these compounds based on inhibition of kinases, e. g. VEGFR-2, suitable for therapy of cancer, are disclosed in WO 01/27081 and WO2004/13099.
  • the cited documents are herewith incorporated by reference with respect to any aspects relating to these specific compounds.
  • IC50 values are based on the Upstate Kinase Selectivity Screening Service. A detailed description of substrates used, of buffer composition and assay conditions for each of the analysed kinases is given in Kinase ProfilerTM Assay Protocols, Upstate Group, Inc. Oct.
  • HL 60 and THPl exhibit a normal chromosomal status (listed as 2-fold) n.a. indicates that no chromosomal data are yet available for these cell lines.
  • wtFLT3 wilde-type FLT3
  • FLT3-ITD FLT3 internal tandem duplications
  • IC50 values are listed in the nM concentration range.
  • Doxorubicin is used as a positive control for the proliferation assay (Alamar Blue).
  • FIGURE 1 Cluster analysis of transcription levels of selected genes versus 49 cell lines. Expression data were extracted from the BioExpress database (GeneLogic) and hierachical clustered using the Spotfire DecisionSite 8.1TM. Expression levels: Black boxes indicate high, bright grey low or no expression. For methodologic details see FIGURE 2 and 4.
  • ABL expression profile (GeneLogic BioExpress data base) in various human normal and tumor tissues.
  • box-and-whisker plots were generated as described (Shen-Ong et al, 2003, Cancer Res. 63: 3296 - 3301; Dolznig et al, 2005, Cancer Immun. 5: 10).
  • the center line indicates the median, the box itself represents the interquartile range (IQR) between the first and third quartiles. Whiskers extend to 1.5 times the IQR.
  • the human sample collection has been described by the originator of the BioExpress database (Shen- Ong et al., 2003, Cancer Res. 63: 3296 - 3301).
  • the respective hybridizations were performed on Affymetrix HG-Ul 33A/B oligonucleotide chips (Affymetrix Inc., Santa Clara, CA, USA).
  • Chip data were normalized with the statistical algorithm implemented in the Microarray Suite version 5.0 (Affymetrix Inc.). Briefly, the raw expression intensity for a given chip experiment is multiplied by a global scaling factor to allow comparisons between chips. This factor is calculated by removing the highest 2% and the lowest 2% of the values of the non-normalized expression values, and calculating the mean for the remaining values, as trimmed mean. One hundred divided by the trimmed mean gives the scaling factor, where 100 is the standard value used by GeneLogic. Numbers in brackets indicate the sample numbers.
  • the Affymetrix identification code for ABL is 202123_s_at_HG-U133A.
  • Ki N normal kidney
  • Ki RCC renal cell carcinoma
  • Ki CCC kidney clear cell carcinoma
  • Ki_WT Kidney Wilm's tumor
  • LN_N normal lymph node
  • LN_ACMet lymph node adeno carcinoma metastases
  • LN SCCMet lymph node squamous cell carcinoma metastases
  • Br N normal breast
  • LN IDCMet metastatic infiltrating ductal carcinoma in lymph node
  • So N normal soft tissue
  • So Os soft tissue osteosarcoma
  • So_S soft tissue sarcoma
  • So_MFH soft tissue malignant fibrous histocytoma
  • CC_N normal cerebral cortex
  • Bn GMF glioblastoma multiforme.
  • ABL expression in various cell lines (GeneLogic BioExpress data base).
  • the Affymetrix identification code for ABL is 202123_s_at_HG-U133A. Methodologic description see FIGURE 2 and 4.
  • FLT3 expression in various cell lines are derived from the BioExpress database (GeneLogic) and have been generated using the Affymetrix GeneChip Human Genome U133 (HG-U133) Set (Affymetrix Inc., Santa Clara, CA, USA) as described in Figure 6.
  • the Affymetrix identification code for FLT3 is 206674_at_HG133A.
  • the bold vertical lines indicate present (informative) calls as defined by Affymetrix Microarray Suit 5.0 (MAS5.0) the faint vertical lines indicate absent (non-informative) calls.
  • Methodologic description see FIGURE 2.
  • HL60 promyelocytic leukemia
  • THP-I acute monocytic leukemia
  • RET expression in various cell lines are derived from the BioExpress database (GeneLogic) as described in Figure 2 and Figure 4.
  • the Affymetrix identification code for RET is 205879_x_at_HG-U133A
  • BT-549 breast adenocarcinoma
  • COLO 205 colon adenocarcinoma
  • HL-60 acute promyelocytic leukaemia
  • MCF7 breast adenocarcinoma
  • MDA-MB-231 breast adenocarcinoma
  • NCI-H522 lung large cell carcinoma
  • SR anaplastic large cell lymphoma
  • THP-I acute monocytic leukaemia.
  • RET expression profile (GeneLogic BioExpress data base) in human normal and tumor tissues. Methodologic description see FIGURE 2 and 4.
  • the Affymetrix identification code for RET is 205879_x_at_HG-U133A.
  • Br N normal breast
  • Br IDC breast infiltrating ductal carcinoma
  • Co N normal colon
  • Co AC colon adenocarcinoma
  • Lu N normal lung
  • Lu AC lung adenocarcinoma
  • Lu SCC lung squamous cell carcinoma
  • Pr N normal prostate
  • Pr AC prostate adenocarcinoma.
  • the invention is based on the finding that indolinones are useful for the therapy of diseases which result from aberrant activity of a tyrosine kinase selected from the group comprising ABL, FGFR3, FLT3, and RET.
  • the present invention relates therefore to the use of a compound of formula (I)
  • R 1 is hydrogen, amino, methyl or ethyl
  • R 2 is -(CH 2 ) P NR C R C , substituted or unsubstituted piperidinyl-lylmethyl, substituted or unsubstituted imidazolyl, and
  • R c is independently from each other hydrogen, methyl, ethyl, -C(O)R a , -(CH 2 ) p NR a R a , -
  • R a is hydrogen, methyl or ethyl and p is 0, 1 or 2 or its tautomers, enantiomers, diastereomers, mixtures and salts thereof for the manufacture of a medicament for the treatment or prevention or amelioration of diseases or disorders associated with at least one tyrosine kinase selected from the group comprising
  • Another aspect of the invention is the use of a compound selected from the group consisting of
  • 6-methoxycarbonyl-2-indolinone (s) 3 -Z- [ 1 -(4-methylaminomethyl-anilino)- 1 -phenyl-methylene] -6-methoxycarbonyl-2- indolinone and (t) 3 -Z- [ 1 -(4-(iV-((4-methyl-piperazin- 1 -yl)-methylcarbonyl)- ⁇ f-methyl-amino)-anilino)- 1 - phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or a tautomer or salt thereof for the manufacture of a medicament for the treatment or prevention or amelioration of diseases or disorders associated with at least one tyrosine kinase selected from the group comprising ABL, FGFR3, FLT3, and RET.
  • a further aspect of the invention is the use 3-Z-[l-(4-(N-((4-methyl-piperazin-l-yl)- methylcarbonyl)-N-methyl-amino)-anilino)-l-phenyl-methylene]-6-methoxycarbonyl-2- indolinone or a salt thereof for the manufacture of a medicament for the treatment or prevention or amelioration of diseases or disorders associated with at least one tyrosine kinase selected from the group comprising ABL, FGFR3, FLT3, and RET.
  • a further aspect of the invention is the use 3-Z-[l-(4-(N-((4-methyl-piperazin-l-yl)- methylcarbonyl)-N-methyl-amino)-anilino)-l-phenyl-methylene]-6-methoxycarbonyl-2- indolinone monoethanesulfonate for the manufacture of a medicament for the treatment or prevention or amelioration of diseases or disorders associated with at least one tyrosine kinase selected from the group comprising ABL, FGFR3, FLT3, and RET.
  • a further aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention or amelioration of diseases or disorders associated the tyrosine kinase ABL.
  • a further aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention or amelioration of diseases or disorders associated the tyrosine kinase FGFR3.
  • a further aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention or amelioration of diseases or disorders associated the tyrosine kinase FLT3.
  • a further aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention or amelioration of diseases or disorders associated the tyrosine kinase RET.
  • Such diseases are characterized by aberrant activity of the above-mentioned tyrosine kinases that results from aberrant expression, e. g. overexpression of the wildtype protein, or from expression of a mutated version leading to a constitutive signaling.
  • ABL is found overexpressed in Kidney WiIm 's tumor, soft tissue osteosarcoma, and glioblastoma multiforme. Mutated versions of ABL are predominantly detected in Ph+ leukemias such as chronic myelogeneous leukemia (CML) or acute lymphocytic leukemia (ALL).
  • CML chronic myelogeneous leukemia
  • ALL acute lymphocytic leukemia
  • FGFR3 has been shown to be also involved in skeletal abnormalities, including achondroplasia and hypochondraplasia (WO02/102972).
  • Diseases involving deregulated FLT3 receptor tyrosine kinase activity include, but are not limited to, leukemias including acute myeloid leukemia (AML), AML with trilineage myelodysplasia (AML/TMDS), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). This term also, specifically includes diseases resulting from FLT3 receptor mutation. Modulation of c-RET activity may also be useful in treating cancers of the nerve tissue, such as neuroblastoma, even if an abnormality is not found in the signaling pathway.
  • AML acute myeloid leukemia
  • AML/TMDS AML with trilineage myelodysplasia
  • ALL acute lymphoblastic leukemia
  • MDS myelodysplastic syndrome
  • This term also, specifically includes diseases resulting from FLT3 receptor mutation. Modulation of c-RET activity may also be useful in treating cancers of the nerve tissue, such as neuroblastoma, even if an
  • Hereditary and spontaneous mutations that activate the RET kinase lead to several types of cancers, including multiple endocrine neoplasias type 2A and 2B (MEN2A and MEN2B), familial medullary thyroid carcinomas (FMTC), and papillary thyroid carcinomas (PTC). Subsets of mutations associate with each of these cancer types. Missense mutations in one of five cysteines of the RET extracellular domain are present in nearly all cases of MEN2A and FMTC, and presumably constitutively activate RET's tyrosine kinase activity by mimicking the effects of ligand binding to the extracellular domain. Most patients with MEN2B harbor mutations in codon 918 (Met-> Thr) in the ATP binding pocket of intracellular tyrosine kinase domain. This mutation presumably activates the kinase and alters its substrate specificity.
  • codon 918 Met-> Thr
  • breast cancer cell lines show an upregulation of RET (see FIGURE 5).
  • the importance of this observation is supported by the upregulation of RET detected in infiltrating ductal breast cancer samples (see FIGURE 6).
  • the compounds can be used for the prevention or short-term or long-term treatment of the above mentioned diseases including, where appropriate, in combination with other state-of- the-art compounds such as other anti-tumour substances, cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.
  • other state-of- the-art compounds such as other anti-tumour substances, cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.
  • Chemotherapeutic agents which can be administered in combination with the compounds according to the invention include, without being restricted thereto, hormones, hormone analogs and antihormones (e. g.
  • tamoxifen toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone and octreotide), aromatase inhibitors (e. g. anastrozole, letrozole, liarozole, vorozole, exemestane and atamestane), LHRH agonists and antagonists (e. g.
  • goserelin acetate and luprolide inhibitors of growth factors (growth factors such as platelet-derived growth factor and hepatocyte growth factor, examples of inhibitors are growth factor antibodies, growth factor receptor antibodies and tyrosine kinase inhibitors, such as gefitinib, imatinib, lapatinib and trastuzumab); antimetabolites (e. g.
  • antifolates such as methotrexate and raltitrexed, pyrimidine analogs such as 5-fluorouracil, capecitabine and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine and fludarabine); antitumor antibiotics (e. g. anthracyclines, such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin and streptozocin); platinum derivatives (e. g.
  • alkylating agents e. g. estramustine, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazine, cyclophosphamide, ifosfamide and temozolomide, nitrosoureas such as carmustine and lomustine and thiotepa
  • antimitotic agents e. g. vinca alkaloids such as vinblastine, vindesine, vinorelbine and vincristine; and taxans such as paclitaxel and docetaxel
  • topoisomerase inhibitors e. g.
  • epipodophyllotoxins such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan and mitoxantrone) and various other chemotherapeutic agents such as amifostin, anagrelide, clodronate, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotan, pamidronate and porfimer.
  • epipodophyllotoxins such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan and mitoxantrone
  • various other chemotherapeutic agents such as amifostin, anagrelide, clodronate, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole
  • the compounds may be administered by oral, transdermal or parenteral route or by inhalation.
  • the compounds are present as active ingredients in conventional preparations, e. g. in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance, such as for example plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal systems, etc.
  • An effective dose of the compounds according to the invention is between 1 and 100, preferably between 1 and 50, most preferably between 5-30 mg/dose, for oral administration, and between 0.001 and 50, preferably between 0.1 and 10 mg/dose for intravenous or intramuscular administration.
  • solutions containing 0.01 to 1, preferably 0.1 to 0.5 % of active substance are suitable according to the invention.
  • the use of powders is preferred.
  • the compounds according to the invention as a solution for infusion, preferably in physiological saline or nutrient salt solution.
  • the compounds may be used on their own or in conjunction with other active substances, optionally also in conjunction with other pharmacologically active substances.
  • suitable preparations include for example tablets, capsules, suppositories, solutions, elixirs, emulsions or dispersible powders.
  • Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example inert dilu
  • Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core may also consist of a number of layers.
  • the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
  • Syrups or elixirs containing the active substances or combinations thereof may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e. g. such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
  • a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e. g. such as vanillin or orange extract.
  • a flavour enhancer e. g. such as vanillin or orange extract.
  • They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
  • Solutions for injection and infusion are prepared in the usual way, e. g. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetra-acetic acid, and transferred into injection vials or ampoules.
  • Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
  • Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
  • a therapeutically effective daily dose is between 1 and 800 mg, preferably 10 - 300 mg, in adults.
  • cell lines overexpressing wild type and mutant ABL as described are used. Also included are cell lines which are identified to overexpress ABL such as NCI-H520 (see FIGURE 1). Additional cell lines are selected from the list in FIGURE 3 (preferentially cell lines derived from leukemias such as JURKAT and K-562).
  • Lysates of treated cell lines are subjected to Western Blot analysis for the inhibition of the autophosphorylation of BCR-ABL and BCR-ABL mutants antibodies useful in such assays have been described Weisberg et al., 2005, Cancer Cell 7: 129-141 (supplemental data) and O'Hare et al, 2005, Cancer Res. 65: 4500- 4505).
  • the tumor- inhibiting activity of the compounds of formula (I) can also be demonstrated in vivo.
  • a systemic 320 BCR-ABL leukemia model in mice and a bioluminescent BCR-ABL model of CML as described Weisberg et al., 2005, Cancer Cell 7: 129-141; Armstrong et al., 2003, Cancer Cell, 3: 173-183) can be used.
  • the tumor-inhibiting activity of the compound is determined using female Balb/c nude or NMRI nude mice in which cell lines, such as of human adeno or squamous cell carcinoma origin, or human tumor tissue are transplanted.
  • cell lines such as of human adeno or squamous cell carcinoma origin, or human tumor tissue are transplanted.
  • a ca. 25 mg piece of solid tumor is transplanted subcutaneously under inhaled isofiuorane narcosis on the left flank and the small incision wound is closed with a suture clip.
  • human tumor cells grown in tissue culture can be injected subcutaneously into one flank of the animal at a concentration of 1-2 x 10 per ml in PBS containing 5% FCS.
  • mice On day 6 after the tumor transplantation or when the tumor has reached a median size of 100-200 mm 3 , the mice are randomized in groups of 10 animals and treatment is commenced. The treatment is carded out for 15 days or until the control treated tumors have reached a median size of 1250 mm 3 by administering a compound of formula (I), e. g. suspension in 0.5% Natrosol or dimethyl sulfoxide/Tween 80/sodium chloride solution in the different doses perorally or intraperitoneally once daily. The tumors are measured twice weekly with a sliding caliper and the tumor volume determined. In this assay, the peroral or intraperitoneal administration of a compound of formula (I) effects a marked reduction in the average tumor volume compared with the untreated controls.
  • a compound of formula (I) e. g. suspension in 0.5% Natrosol or dimethyl sulfoxide/Tween 80/sodium chloride solution
  • Osteopontin (OPN) expression has been shown to be involved in the progression and increased aggression and invasiveness of many solid tumors. It recently has been demonstrated that OPN expression is also induced in CML.
  • the specific signaling pathway required for the induction of OPN expression by p210 BCR-ABL is driven via the sequential activation of RAS, phosphatidylinositol-3 kinase, atypical protein kinase C, RAF-I, and mitogen-activated protein kinase kinase.
  • RAS phosphatidylinositol-3 kinase
  • RAF-I atypical protein kinase C
  • mitogen-activated protein kinase kinase The data strongly suggest that these molecules represent a single pathway and also that there is no redundancy in this pathway, as inhibition of any individual component results in a block in the induction of OPN (Hickey et al, 2005, J.
  • Kidney WiIm 's tumor
  • soft tissue osteosarcoma a tumor that is overexpressed
  • glioblastoma multiforme a tumor that is overexpressed
  • these tumors may be regarded as indications for ABL targeting as well.
  • the compounds are further analyzed in conventional proliferation studies such as Alamar Blue assays or in apoptosis assays such as the Annexin-V-Fluos Staining kit (Boehringer Mannheim, Indianapolis, IN).
  • tyrosine kinase receptor FGFR3 fibroblast growth factor receptor 3
  • FGFR3 fibroblast growth factor receptor 3
  • Activating point mutations in the FGFR3 gene occur most frequently in low-grade and low-stage bladder carcinomas, whereas they are rare in high-grade carcinomas (van Rhijn et al., 2002, J. Pathol. 198: 245-251).
  • 3-Z-[l-(4-( ⁇ (4-methyl-piperazin-l-yl)-methylcarbonyl)-iV- methyl-amino)-anilino)-l-phenyl-methylen]-6-methoxycarbonyl-2-indolinone is tested in myeloid cell lines such as HL-60, Kasumi-1, K-562, and Mono-Mac- 1.
  • the compounds are further analyzed in conventional proliferation studies such as Alamar Blue assays or in apoptosis assays such as the Annexin-V-Fluos Staining kit (Boehringer Mannheim, Indianapolis, IN).
  • wtFLT3 such as RS4;11 (B cell precursor leukemia) or FLT3 ITD such as MV4;11 (AML; both alleles are mutated) or MOLM- 13 (AML) with one wt and one mutated allele
  • wtFLT3 such as RS4;11 (B cell precursor leukemia)
  • FLT3 ITD such as MV4;11 (AML; both alleles are mutated
  • MOLM- 13 AML
  • Expression of FLT3 seems to be highly restricted to leukemia cell lines as shown in FIGURE 4; e.g. cell lines HL60 and THP-I show the most prominent present (informative) calls for the FLT3 transcript.
  • Cells are seeded into 96-well plates and incubated for 3 days in the presence of various concentrations of 3 -Z- [ 1 -(4-(iV-((4-methyl-piperazin- 1 -yl)-methylcarbonyl)-iV- methyl-amino)-anilino)-l-phenyl-methylen]-6-methoxycarbonyl-2-indolinone or doxorubicin, respectively. After this period 20 ⁇ l of Alamar Blue dye (Biosource DALlOO) are added to each well (96-well plate) and exposed for the indicated time (TABLE 3). The 96-well plate is shaken carefully after each hour. Fluorescence is measured at Ex: 544 nm / Em: 590 nm.
  • 3 -Z- [ 1 -(4-(iV-((4-methyl-piperazin- 1 -yl)-methylcarbonyl)-iV- methyl-amino)-anilino)-
  • 3-Z-[ 1 -(4-(iV-((4-methyl-piperazin- 1 -yl)-methylcarbonyl)- ⁇ f-methyl-amino)- anilino)-l-phenyl-methylen]-6-methoxycarbonyl-2-indolinone is an efficient compound in targeting tumors expressing mutated FLT3.
  • RET mutated RET
  • breast cancer cell lines show an upregulation of RET (see FIGURE 5).
  • HTB- 107 thyroid squamous cell carcinoma
  • TT thyroid medulla carcinoma
  • the TT cell line was used in a xenograft model and shown to be sensitive for Irinotecan treatment resulting in complete remission in 100% of xenografts treated.
  • the duration of remission is further enhanced by combination with the kinase inhibitor, CEP-751 (Strock et al., 2005, J.
  • the cell line TT is used as an excellent xenograft model to test the efficacy of 3-Z-[l-(4-(iV-((4-methyl-piperazin-l-yl)- methylcarbonyl)- ⁇ f-methyl-amino)-anilino)- 1 -phenyl-methylen]-6-methoxycarbonyl-2- indolinone in a thyroid medulla carcinoma preclinical model.
  • the finely ground active substance, lactose and some of the corn starch are mixed together.
  • the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
  • the granules, the remaining corn starch and the magnesium stearate are screened and mixed together.
  • the mixture is compressed to produce tablets of suitable shape and size.
  • the finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened.
  • the sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
  • the active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water.
  • the moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45 0 C and the granules are then passed through the same screen.
  • convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine.
  • the tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc.
  • the finished coated tablets are polished with wax.
  • the substance and corn starch are mixed and moistened with water.
  • the moist mass is screened and dried.
  • the dry granules are screened and mixed with magnesium stearate.
  • the finished mixture is packed into size 1 hard gelatine capsules.
  • the active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic.
  • the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
  • the ampoules contain 5 mg, 25 mg and 50 mg of active substance.
  • the hard fat is melted.
  • the ground active substance is homogeneously dispersed. It is cooled to 38 0 C and poured into slightly chilled suppository moulds.

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Abstract

L'invention concerne l'utilisation des indolinones dans le traitement thérapeutique de maladies causées par une activité aberrante de certaines tyrosine kinases sélectionnées dans le groupe comprenant ABL, FGFR3, FLT3, and RET.
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