WO2003020698A2 - Inhibiteurs de la tyrosine kinase - Google Patents

Inhibiteurs de la tyrosine kinase Download PDF

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Publication number
WO2003020698A2
WO2003020698A2 PCT/IL2002/000740 IL0200740W WO03020698A2 WO 2003020698 A2 WO2003020698 A2 WO 2003020698A2 IL 0200740 W IL0200740 W IL 0200740W WO 03020698 A2 WO03020698 A2 WO 03020698A2
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WIPO (PCT)
Prior art keywords
hydrocarbyl
nr7r8
independently selected
conr7r8
pharmaceutical composition
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PCT/IL2002/000740
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English (en)
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WO2003020698A3 (fr
Inventor
Doron Eren
Andrea Zaliani
David Pe'er
Oren Bogin
Avner Yayon
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Prochon Biotech Ltd.
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Priority claimed from IL14532901A external-priority patent/IL145329A0/xx
Application filed by Prochon Biotech Ltd. filed Critical Prochon Biotech Ltd.
Priority to AU2002334355A priority Critical patent/AU2002334355A1/en
Publication of WO2003020698A2 publication Critical patent/WO2003020698A2/fr
Publication of WO2003020698A3 publication Critical patent/WO2003020698A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • 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
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to inhibition of abnormal protein tyrosine kinase (PTK) activity, particularly to the use of certain heterocychc compounds as protein tyrosine kinase inhibitors, and to some novel heterocychc compounds.
  • PTK protein tyrosine kinase
  • Growth factors exert pleiotropic effects and play important roles in the development of multicellular organisms regulating cell growth, differentiation and migration as well in oncogenesis. Many of these factors mediate their effects by binding to specific cell surface receptors that trigger an enzymatic signal transduction cascade from the cell membrane to the cell nucleus, resulting in specific gene regulation, leading to diverse cellular responses.
  • PKs Protein kinases
  • PKs Protein kinases
  • PKs are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine and threonine residues of proteins.
  • Abnormal PK activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma.
  • These kinases largely fall into two groups: serine/threonine kinases, which are specific for phosphorylation of serine and threonine residues, and tyrosine kinases (PTK), specific for phosphorylation of tyrosine residues.
  • PTK tyrosine kinases
  • Protein kinases are also characterized by their location within the cell. Some kinases are transmembrane receptor proteins capable of binding ligand(s) external to tlie cell membrane. Ligand binding alters the receptor protein kinase 's catalytic activity. Others are non-receptor proteins lacking a transmembrane domain. Non-receptor protein kinases can be found in a variety of cellular compartments from the inner-surface ofthe cell membrane to the nucleus. Still others are ectokinases that have their catalytic domain on the extracellular (ecto) portion ofthe transmembrane protein or which are secreted as soluble extracellular proteins.
  • kinases are involved in regulatory cascades in which their substrates may include other kinases whose activities are regulated by their phosphorylation state. Ultimately the activity of a downstream effector is modulated by its phosphorylation resulting from the activation of such a pathway.
  • Kinases regulate all aspects of cellular function including cell growth, migration, differentiation, apoptosis, gene expression, muscle contraction, glucose metabolism, cellular protein synthesis, and regulation ofthe cell cycle.
  • RPTKs Receptor protein tyrosine kinases
  • RPTKs are a subclass of transmembrane-spanning receptors endowed with intrinsic, ligand-stimulatable tyrosine kinase activity. When mutated or altered structurally, RPTKs can become potent oncoproteins, causing cellular transformation. Conversely, RPTK activity in resting, untransformed cells is normally tightly controlled. In principle, oncogenic deregulation of all RPTKs involved in cancer, results from a relief or a perturbation of one or several of the auto-control mechanisms that ensure the normal repression ofthe catalytic domains.
  • RPTK RPTK overexpression leads to constitutive kinase activation by increasing the concentration of dimers.
  • EGFR epidermal growth factor receptor
  • Fibroblast growth factors constitute a family of over twenty structurally related polypeptides that are developmentally regulated and expressed in a wide variety of tissues. FGFs stimulate proliferation, migration and differentiation of cells of mesenchymal and neuroectodermal origin and play a major role in skeletal and limb development, wound healing, hematopoiesis, angiogenesis, and tissue repair as well as in tumorigenesis. The biological action of FGFs is mediated by specific cell surface receptors (FGFRs) that possess intrinsic tyrosine kinase activity and are phosphorylated upon binding of FGF. These proteins consist of an extracellular ligand binding domain, a single transmembrane domain and an intracellular tyrosine kinase domain.
  • FGFRs specific cell surface receptors
  • the FGFR extracellular region contains three immunoglobulin-like (Ig-like) loops or domains (Dl, D2 and D3), an acidic box, and a heparin-binding domain.
  • Ig-like immunoglobulin-like loops or domains
  • Dl, D2 and D3 immunoglobulin-like loops or domains
  • FGFR5 immunoglobulin-like loops or domains
  • FGFR5 lacking an intracellular domain has recently been identified (Sleeman et al, 2001).
  • the multiple alternatively spliced variants of FGFRs are designated as -, ⁇ -, or ⁇ -type.
  • Heparan sulfate proteoglycans HSPGs
  • Tissue-specific expression of heparan sulfate structural variants confers ligand-receptor specificity and activity of FGFs.
  • FGFs and their receptors play a key role during growth, development and repair ofthe human skeleton and are also implicated in chemotaxis, angiogenesis, apoptosis, and spatial patterning (Burgess and Maciag, 1989; Martin et al, 1998; Martin, 1998).
  • a growing number of skeletal abnormalities have been shown to result from mutations in FGFRs.
  • Specific point mutations in different domains of FGFR3 are associated with autosomal dominant human skeletal disorders, such as achondroplasia - the most common form of human dwarfism, hypochondroplasia, severe achondroplasia with developmental delay, acanthosis nigricans (SADDAN), and thanatophoric dysplasia.
  • FGFR3 mutations have also been described in Muenke coronal craniosynostosis and Crouzon syndrome with acanthosis nigricans (reviewed in Webster and Donoghue, 1997 and Vajo, et al, 2000). Certain mutations in FGFRs result in overactivation, i.e., constitutive activation, ofthe mutated receptors and increased RPTK activity, rendering cells and tissue unable to differentiate. Specifically, the achondroplasia mutations result in enhanced stabilization of the mutated receptor, dissociating receptor activation from down-regulation, leading to restrained chondrocyte maturation and aberrant bone formation (Monsonego-O nan, et al. 2000).
  • FGFR3 currently appears to be the most frequently mutated oncogene in bladder cancer where it is mutated in almost 50% ofthe cases and in about 70% of cases having recurrent superficial bladder tumors (Cappeln, et al, 1999; van Rhijn, et al, 2001; Billerey, et l, 2001).
  • FGFR3 signaling appear to be cell type-specific. In chondrocytes, FGFR3 hyperactivation results in growth inhibition (reviewed in Ornitz, 2001), whereas in the myeloma cell it contributes to tumor progression (Chesi et al., 2001).
  • Tyrosine Kinase Inhibitors In view ofthe apparent link between PK-related cellular acti ⁇ dties and a number of human diseases and disorders, a great deal of effort has been invested to identify ways to modulate PK activity (Cohen, 2002). Some of these attempts have involved biomimetic approaches using large molecules patterned on those involved in the actual cellular processes, e.g., mutant ligands (US 4,966,849) and soluble receptors and antibodies (WO 94/10202). In addition, small molecules have been described as tyrosine kinase inhibitors and said to be useful in the treatment of cancer.
  • aminopyrazole derivatives (US 5,916,908), pyrazolopyrimidine derivatives (US 5,593,997), pyrrolopyrimidine derivatives (Traxler and Furet, 1999; Traxler et al, 1997; Traxler et al, 1996); US 5,639,757), anilinopurine derivatives (WO 00/49018), anilinopyridopyrimidine derivatives (US 6,169,091), anilinopyrimidine derivatives (US 5,958,935), benzoquinazoline derivatives (WO 97/13760), benzothiazole derivatives (WO 99/24035), benzylidene-1,3- dihydro-indol-2-one derivatives (US 6,268,391), benzylphosphonic acid compounds (WO 91/15495, EP 0526488), bis-monocylic, bicyclic and heterocychc aryl compounds (WO 92/20642), l-cyclopropyl compounds (
  • the inventors have now found that the said known compounds, as well as some novel compounds are also effective tyrosine kinase inhibitors useful for the treatment of protein tyrosine kinase related disorders and diseases including angiogenesis, particularly tumor angiogenesis, malignant and non-malignant proliferative diseases and FGFR-related skeletal diseases and disorders.
  • heterocychc compounds more particularly certain substituted 2-aryl benzimidazole and benzofuro [3,2- c] quinoline compounds inhibit abnormal protein tyrosine kinase activity and thus can be useful in the treatment of diseases and disorders associated with abnormal protein tyrosine kinase activity.
  • the present invention thus relates, in one aspect, to a compound selected from the heterocychc compounds of structural formulae (I) and (II), disclosed below.
  • the invention provides novel compounds having the general formula (I):
  • X is N or O; Rl and R2 are at each occurrence independently selected from halogen, nitro, cyano, trifluoromethyl, hydrocarbyl, OR4, SR4, SOR5, SO 2 R5, COOH, COR6, SONR7R8,
  • R3 is selected from H or Rl , and is absent when X is O;
  • R9 and RIO are independently selected from H and Rl;
  • R4 is selected from H, hydrocarbyl, COR6, and CONR7R8;
  • R5 is hydrocarbyl
  • R6 is selected from H, hydrocarbyl, OR5 and NR7R8;
  • R7 and R8 are each independently selected from H or hydrocarbyl, or one of R7 or R8 is H or hydrocarbyl and the other is COR5, COOR5 or CONR7R8, or R7 and R8 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocychc ring optionally containing 1-2 further heteroatoms selected from oxygen, nitrogen and sulfur; m is 0 to 3 and n is 0 to 5; with the proviso that a) when m is 0, at least one of R3, R9 or R10 is other than H; and b) when X is O, at least one of R9 or Rl 0 is other than H.
  • the invention further provides novel compounds of the general formula (II):
  • Rl and R2 are at each occurrence independently selected from halogen, nitro, cyano, trifluoromethyl, hydrocarbyl, OR4, SR4, SOR5, SO 2 R5, COOH, COR6, SONR7R8, SO 2 NR7R8 andNR7R8; R3 is H or Rl;
  • R4 is selected from H, hydrocarbyl, COR6, and CONR7R8;
  • R5 is hydrocarbyl;
  • R6 is selected from H, hydrocarbyl, OR5 and NR7R8;
  • R7 and R8 are each independently selected from H or hydrocarbyl, or one of R7 or R8 is H or hydrocarbyl and the other is COR5, COOR5 or CONR7R8, or R7 and R8 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocychc ring optionally containing 1-2 further heteroatoms selected from oxygen, nitrogen and sulfur; m and n independently are an integer from 0 to 4; with the proviso that when R3 is H and m is 0, 1 or 2 and n is 0 or 1, Rl is other than, Ci-Cio alkyloxy, COOH, CONH 2) CO(CH2) 2-7 OH, OR4, N-mono-alkylcarbamoyl, N,N-di- alkylcarbamoyl, alkylsulfonyl or CHO.
  • One currently preferred embodiment of the present invention is a compound of general formula (I), wherein X is N, m is 1, Rl at position 5 is radical NHCOCH3, R9 and R10 are H, R3 is CH 2 -CH 2 -COOH, CH 2 -CH 2 -COOR5, or CH 2 -CH 2 -CONR7R8, wherein R5 is d- C 8 alkyl, preferably methyl, and R7 and R8 are each independently selected from H or hydrocarbyl or R7 and R8 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocychc ring optionally containing 1-2 further heteroatoms selected from oxygen, nitrogen and sulfur, n is 2 and R2 is C ⁇ -C 8 alkoxy, preferably methoxy, most preferably at positions 3 and 5 ofthe phenyl radical, denoted herein 3-(5- acetylamino-4-carbamoyl-2-(3,5-dimethoxyphenyl)-benzimid
  • One currently more preferred embodiment ofthe present invention is a compound of general formula (II) denoted herein 3-hydroxy 9-nitro-5H-benzofuro[3,2-c) quinoline-6- one (compound 6).
  • One currently most preferred embodiment ofthe present invention is a compound of general formula (II) denoted herein 3-methylcarbamoyloxy 9-amino-5H- benzofuro[3,2-c) quinoline-6-one (Compound 8).
  • Position 5 is marked on general formula (I)-
  • compositions which inhibit protein tyrosine kinase activity, are provided. These compositions are useful in preventing or treating disorders and diseases associated with protein tyrosine kinase activation.
  • the protein tyrosine kinase is a receptor protein tyrosine kinase.
  • One aspect ofthe present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active agent at least one heterocychc compound selected from the heterocychc compounds of general formulae (I) and (II) as described above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • Another aspect ofthe present invention provides methods for treating or inhibiting the protein tyrosine kinase related diseases and disorders by administering a therapeutically effective amount of a pharmaceutical composition comprising at least one heterocychc compound selected from the heterocychc compounds of general formulae (I) and (II) as described above, to a subject in need thereof.
  • certain known compounds according to general formulae (la) and (IIa) are provided for the use in the preparation of a medicament for the prevention or treatment of tyrosine kinase related disorders and diseases.
  • the present invention provides the use of a compound of general formula (la):
  • X is N or O;
  • Rl and R2 at each occurrence are independently selected from halogen, nitro, cyano, trifluoromethyl, hydrocarbyl, OR4, COOH, COR6 andNR7R8;
  • R3 is H or Rl, and is absent when X is O;
  • R4 is selected from H, hydrocarbyl, COR6, and CONR7R8;
  • R5 is hydrocarbyl
  • R6 is selected from H, hydrocarbyl, OR5 and NR7R8;
  • R7 and R8 are each independently selected from H or hydrocarbyl, or one of R7 or R8 is H or hydrocarbyl and the other is COR5, COOR5 or CONR7R8, or R7 and R8 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocychc ring optionally containing 1-2 further heteroatoms selected from oxygen, nitrogen and sulfur; and m is 0 to 3 and n is 0 to 5; for the preparation of a medicament for treating or preventing protein tyrosine kinase related diseases and disorders.
  • the present invention further provides the use of a compound of general formula (Ha):
  • Rl and R2 are each independently selected from halogen, hydrocarbyl, OR4, SR4, SOR5, SO 2 R5, COOH, COR6, SONR7R8, S0 2 NR7R8 and NR7R8;
  • R4 is selected from H, hydrocarbyl, COR6, and CONR7R8;
  • R5 is hydrocarbyl
  • R6 is selected from H, hydrocarbyl, OR5 and NR7R8;
  • R7 and R8 are each independently selected from H or hydrocarbyl, or one of R7 or R8 is H or hydrocarbyl and the other is COR5, COOR5 or CONR7R8, or R7 and R8 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocychc ring optionally containing 1-2 further heteroatoms selected from oxygen, nitrogen and sulfur; and m and n are independently selected from an integer of 0 to 4; for the preparation of a medicament for treating or preventing protein tyrosine kinase related diseases and disorders.
  • certain known compounds according to general formulae (la) and (Ila) are provided for the use in the preparation of a medicament for inhibiting abnormal protein kinase activity.
  • the present invention provides a method for inhibiting abnormal protein tyrosine kinase (PTK) activity, particularly receptor protein tyrosine kinase (RPTK) activity, which comprises administering to an individual in need thereof a PTK inhibitor selected from at least one heterocychc compound selected from the heterocychc compounds of structural formulae I and II, (la) and (Ila) wherein said compound is administered in an amount sufficient to inhibit said PTK, e.g. RPTK, activity.
  • PTK protein tyrosine kinase
  • RPTK receptor protein tyrosine kinase
  • the present invention provides novel conjugates ofthe compounds ofthe structural formulae I, II, (la) and (Ila) above with targeting moieties such as peptides, antibodies, growth factors or any other moiety capable of specifically targeting said compound to the protein tyrosine kinase of interest.
  • targeting moieties such as peptides, antibodies, growth factors or any other moiety capable of specifically targeting said compound to the protein tyrosine kinase of interest.
  • the pharmaceutical compositions ofthe present invention may be used for treating or preventing diseases and disorders associated with aberrant protein tyrosine kinase activity, including angiogenesis, proliferative disorders including benign and malignant tumors, and FGFR related skeletal diseases.
  • EGFR/ErbBl is associated with fibrosarcomas, mammary carcinoma, glioblastoma multiforme, ovarian, non-small-cell lung and other cancers;
  • ErbB2/HER2/Neu is associated with mammary, ovarian, gastric, non-small-cell lung and colon cancers;
  • ErbB3/HER3 is associated with mammary cancer;
  • ErbB4/HER4 is associated with mammary carcinoma and granulose cell tumors;
  • IGF-IR is associated with cervical and other cancers;
  • Flk2/FLT3 is associated with hematopoietic malignancies;
  • Flk/VEGFRl , Flkl/VEGFR2 and Flt4/NEGFR3 are associated with tumor angiogenesis;
  • FGFR1 is associated with acute myelogenous leukemia (AML) and with various tumors, and point mutations thereof are associated with autosomal skeletal disorders/dysplasias;
  • Figure 1 is a graph showing the effect ofthe compound 2 on the proliferation of FDCP cells transfected with human wild type FGFR3 (R3 cells) or FGFR1 (Rl cells) grown in the presence of either FGF9 (F9) or IL-3.
  • Figure 2 is a Western blot showing the inhibition of FGFR3 and JNK phosphorylation by Compound 2.
  • Figure 3 is a graph showing the effect of Compound 2 on G369C achondroplasia heterozygote mice femora growth in organ culture.
  • Figure 4 is a graph showing the effect of Compound 2 on the growth rate of G369C achondroplasia heterozygote mice femora bones.
  • Figure 5 presents a table ofthe results of an in vivo proliferation assay using certain compounds ofthe present invention.
  • Figures 6 and 7 show the synthetic pathways of certain embodiments ofthe present invention.
  • the present invention provides novel heterocychc compounds and pharmaceutical compositions comprising at least one said compound useful as protein tyrosine kinase inhibitors.
  • novel compounds ofthe present invention are compounds of general formulae I and II.
  • certain known compounds having the general formulae (la) and (IIa) may be used to prepare medicaments effective in the treatment of tyrosine kinase related diseases and disorders.
  • the invention provides a novel compound having the general formula (I):
  • X is N or O
  • Rl and R2 are at each occurrence independently selected from halogen, nitro, cyano, trifluoromethyl, hydrocarbyl, OR4, SR4, SOR5, SO 2 R5, COOH, COR6, SONR7R8,
  • R3 is selected from H or Rl , and is absent when X is O;
  • R9 and RIO are independently selected from H and Rl;
  • R4 is selected from H, hydrocarbyl, COR6, and CONR7R8;
  • R5 is hydrocarbyl
  • R6 is selected from H, hydrocarbyl, OR5 and NR7R8;
  • R7 and R8 are each independently selected from H or hydrocarbyl, or one of R7 or R8 is H or hydrocarbyl and the other is COR5, COOR5 or CONR7R8, or R7 and R8 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocychc ring optionally containing 1-2 further heteroatoms selected from oxygen, nitrogen and sulfur;
  • m is 0 to 3 and n is 0 to 5; with the proviso that a) when m is 0, at least one of R3, R9 or RIO is other than H; and b) when X is O, least one of R3, R9 or RIO is other than H.
  • the invention further provides novel compounds of the general formula (II):
  • Rl and R2 are at each occurrence independently selected from halogen, nitro, cyano, trifluoromethyl, hydrocarbyl, OR4, SR4, SOR5, SO 2 R5, COOH, COR6, SONR7R8,
  • R3 is H or Rl;
  • R4 is selected from H, hydrocarbyl, COR6, and CONR7R8;
  • R5 is hydrocarbyl
  • R6 is selected from H, hydrocarbyl, OR5 and NR7R8;
  • R7 and R8 are each independently selected from H or hydrocarbyl, or one of R7 or R8 is H or hydrocarbyl and the other is COR5, COOR5 or CONR7R8, or R7 and R8 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocychc ring optionally containing 1-2 further heteroatoms selected from oxygen, nitrogen and sulfur; m and n independently are an integer from 0 to 4; with the proviso that when R3 is H and m is 0, 1 or 2 and n is 0 or 1, Rl is other than Ci-Cio alkyloxy, COOH, CONH 2 , CO(CH2) 2-7 OH, OR4, N-mono-alkylcarbamoyl, N,N-di- alkylcarbamoyl, alkylsulfonyl or CHO.
  • One aspect ofthe present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active agent at least one heterocychc compound selected from the heterocychc compounds of general formulae (I) and (II) as described above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • Another aspect ofthe present invention provides methods for treating or inhibiting the protein tyrosine kinase related diseases and disorders by administering a therapeutically effective amount of a pharmaceutical composition comprising at least one heterocychc compound selected from the heterocychc compounds of general formulae (I) and (II) as described above, to a subject in need thereof.
  • certain known compounds according to general formulae (la) and (IIa) are now disclosed to be inhibitors of protein tyrosine kinase and are useful in the preparation of a medicament for inhibiting abnormal protein kinase activity.
  • the present invention provides the use of a compound of general formula (la):
  • X is N or O
  • Rl and R2 at each occurrence are independently selected from halogen, nitro, cyano, trifluoromethyl, hydrocarbyl, OR4, COOH, COR6 and R7R8;
  • R3 is H or Rl, and is absent when X is O;
  • R4 is selected from H, hydrocarbyl, COR6, and CONR7R8;
  • R5 is hydrocarbyl;
  • R6 is selected from H, hydrocarbyl, OR5 and NR7R8;
  • R7 and R8 are each independently selected from H or hydrocarbyl, or one of R7 or R8 is H or hydrocarbyl and the other is COR5, COOR5 or CONR7R8, or R7 and R8 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocychc ring optionally containing 1-2 further heteroatoms selected from oxygen, nitrogen and sulfur; and m is 0 to 3 and n is 0 to 5; for the preparation of a medicament for treating or preventing protein tyrosine kinase related diseases and disorders.
  • the present invention further provides the use of a compound of general formula (Ila):
  • Rl and R2 are each independently selected from halogen, hydrocarbyl, OR4, SR4, SOR5, SO 2 R5, COOH, COR6, SONR7R8, S0 2 NR7R8 and NR7R8;
  • R4 is selected from H, hydrocarbyl, COR6, and CONR7R8;
  • R5 is hydrocarbyl
  • R6 is selected from H, hydrocarbyl, OR5 and NR7R8;
  • R7 and R8 are each independently selected from H or hydrocarbyl, or one of R7 or R8 is H or hydrocarbyl and the other is COR5, COOR5 or CONR7R8, or R7 and R8 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocychc ring optionally containing 1-2 further heteroatoms selected from oxygen, nitrogen and sulfur; and m and n are independently selected from an integer of 0 to 4; for the preparation of a medicament for treating or preventing protein tyrosine kinase related diseases and disorders.
  • Axl a Tyro3 PTK
  • bFGF basic fibroblast growth factor
  • CSF1-R colony-stimulating factor- 1 receptor
  • EGF epidermal growth factor
  • EGFR epidermal growth factor receptor
  • EphR ephrin receptor
  • erbB2,3,4 members ofthe EGFR family
  • FGF fibroblast growth factor
  • FGFR FGF receptor
  • HB-EGF heparin-binding EGF-like growth factor
  • HGFR hepatocyte growth factor receptor
  • IGF-IR insulin growth factor 1 receptor
  • InsR insulin receptor
  • LTK leukocyte tyrosine kinase
  • NGFR nerve growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • PK protein kinase
  • PTK protein tyrosine kinase
  • RET resety
  • halo or halogen includes fluoro, chloro, bromo and iodo.
  • hydrocarbyl in any ofthe definitions ofthe different radicals R1-R8 includes any radical containing carbon and hydrogen including saturated or unsaturated, aromatic, straight or branched chain or cyclic including polycyclic, such as, but not being limited to, C ⁇ -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, aryl such as phenyl and naphthyl, ar(C ⁇ -C 8 )alkyl such as benzyl, and any such hydrocarbyl radical substituted by one or more radicals Rl as defined above.
  • C 2 -C 8 alkenyl and “C 2 -C 8 alkynyl” typically mean straight and branched hydrocarbon radicals having 2-8 carbon atoms and 1 double or triple bond, respectively, and include ethenyl, 3-buten-l-yl, 2-ethenylbutyl, 3-octen-l-yl, and the like, and propynyl, 2-butyn-l-yl, 3-pentyn-l-yl, and the like.
  • C 2 -C 6 alkenyl radicals are preferred.
  • C 3 -C 10 cycloalkyl means a cyclic or bicyclic hydrocarbyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, bicyclo[3.2.1]octyl, bicyclo[2.2.1]heptyl, and the like.
  • Ci -C 8 alkyl typically means a straight or branched hydrocarbon radical having 1-8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • Rl, R2, R3 or R6 is an alkoxy radical
  • the term means preferably a "Ci -C 8 alkoxy" radical including methoxy, ethoxy, isopropoxy, tert-butoxy, n-octyloxy, and the like.
  • Ci -C 6 alkoxy groups also denoted herein "lower alkoxy” are preferred.
  • Typical " -C 8 alkanoyl” groups formed by COR6 radicals include formyl, acetyl, propionyl, butyryl, and isobutyryl, and typical "C ⁇ -C 8 alkanoyloxy" groups formed by OCOR6 radicals include acetoxy, tert-butanoyloxy, pentanoyloxy, and the like. Similar radicals are contemplated for the corresponding groups having an S atom such as SR4, SOR5, and SO 2 R5.
  • R7 and R8 are each H or hydrocarbyl as defined above or form together with the N atom to which they are attached a saturated or unsaturated, preferably a 5- or 6-membered, heterocychc ring, optionally containing 1 or 2 further heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Such rings may be substituted, for example with one or two C ⁇ -C 6 alkyl groups.
  • radicals NR7R8 include, without being limited to, amino, dimethylamino, diethylamino, ethylmethylamino, dimethylaminomethyl, phenylmethylamino, pyrrolidino, piperidino, tetrahydropyridino, piperazino, morpholino, thiazolino, and the like, and examples of radicals hydrocarbyl substituted by NR7R8 include 4-diethylamino-3-buten-l-yl, 5- ethylmethylamino-3-pentyn-l-yl, 4-morpholinobutyl, 4-(4-methylpiperazin-l-yl)butyl, 4- tetrahydropyridinylbutyl-, 2-methyltetrahydropyridinomethyl-, 3 -imidazolidin- 1 -yl-propyl, 4-tetrahydrothiazol-3-yl-butyl, and the like
  • N-mono-alkylcarbamoyl and “N,N-di-alkylcarbamoyl” as used herein refer to -OCONHR and -OCONR 2 respectively, wherein R represents a C1-C6 alkyl group.
  • the compound is a substituted 2-aryl-benzimidazole-4- carboxamide compound ofthe structural formula I.
  • the compound is ofthe structural formula I wherein X is N, namely a substituted 2-aryl-benzimidazole-4-carboxamide derivative, wherein: Rl is each independently selected from Ci -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C ⁇ -C 8 alkanoyl, OR4, NR7R8, NHCONR7R8, NHCOOR5, NR5CONR7R8, NR5COOR5, OCONR7R8, OCOOR5, wherein R4, R5, R7 and R8 are each independently selected from hydrogen or C ⁇ -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, and C ⁇ -C 8 alkanoyl optionally substituted by OR4, COOH, COOR5, or NR7R8, wherein R7 and R8 may also together with the nitrogen atom to which they are attached form a 5-
  • R3, R9 and RIO are each independently selected from hydrogen, C ⁇ -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, NHCONR7R8, NHCOOR5, NR5CONR7R8, NR5COOR5, OR4, OCONR7R8, C ⁇ -C 8 alkanoyl, C ⁇ -C 8 alkylamino or di-C ⁇ -C 8 alkylamino; and wherein the alkyl, alkenyl, alkynyl and alkanoyl groups may be substituted by COOH, COOR5, CONR7R8 or NR7R8, where R4, R5, R7 and R8 are as defined above.
  • the compound is of formula (I) wherein X is N, m is 1, Rl at position 5 is a radical NHCOCH3, R9 and R10 are H, R3 is CH 2 -CH 2 -COOH, CH 2 -CH 2 - COOR5, or CH 2 -CH 2 -CONR7R8, wherein R5 is C ⁇ -C 8 alkyl, preferably methyl, and R7 and R8 are each independently selected from H or hydrocarbyl or R7 and R8 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocychc ring optionally containing 1-2 further heteroatoms selected from oxygen, nitrogen and sulfur, n is 2 and R2 is C ⁇ -C 8 alkoxy, preferably methoxy, most preferably at positions 3 and 5 of the phenyl radical.
  • a currently more preferred embodiment of the present invention is denoted herein 3-(5-acetylamino-4-carbamoyl-2-(3,5-dimethoxyphenyl)- benzimidazol-lyl)-propionic acid.
  • the compound is a substituted benzofuro[3,2-c]quinoline compound ofthe structural formula (II).
  • said composition comprises a compound of formula (II), wherein:
  • Rl is each independently selected from Ci -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C ⁇ -C 8 alkanoyl, OR4, NR7R8, NHCONR7R8, NHCOOR5, NR5CONR7R8, NR5COOR5, OCONR7R8, OCOOR5, wherein R4, R5, R7 and R8 are each independently selected from hydrogen or C ⁇ -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, and C ⁇ -C 8 alkanoyl optionally substituted by OR4, COOH, COOR5, or NR7R8, wherein R7 and R8 may also together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocychc ring optionally containing 1 or 2 further heteroatoms selected from nitrogen, oxygen, and sulfur; and m is 0 to 4;
  • R2 is each independently selected from halo, nitro, trifluoromethyl, optionally substituted phenyl, cyano, COOH, COOR5, COR6, SO 2 R5, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, OH, C ⁇ -C 8 alkoxy, SH, S-C ⁇ -C 8 alkyl, C ⁇ -C 8 alkanoyl, C ⁇ -C 8 alkanoyloxy, or NR7R8 and wherein the alkyl, alkenyl, alkynyl, alkoxy and alkanoyl groups may be substituted by NR7R8, where R7 and R8 are as defined above, and n is 0 to 4; and
  • R3 is selected from hydrogen, C ⁇ -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, NHCONR7R8, NHCOOR5, NR5CONR7R8, NR5COOR5, OR4, OCONR7R8, C ⁇ -C 8 alkanoyl, C ⁇ -C 8 alkylamino or di-C ⁇ -C 8 alkylamino; and wherein the alkyl, alkenyl, alkynyl and alkanoyl groups may be substituted by COOH, COOR5, CONR7R8 or NR7R8, wherein R4, R5, R7 and R8 are as defined above.
  • R3 is H, m is 1, Rl is OH, n is 1, R2 is NO 2 , herein denoted 3-hydroxy 9-nitro-5H-benzofuro[3,2-c) quinoline-6-one (compound 6).
  • R3 is H, m is 1, Rl is dimethyl carbamoyl, n is 1, R2 is NH 2 , herein denoted 3-methylcarbamoyloxy 9-amino-5H- benzofuro [3,2-c) quinoline-6-one (compound 8).
  • the pharmaceutical composition comprises as an active ingredient the compound of general formula (I) denoted 3-(5- acetylamino-4-carbamoyl-2-(3 , 5-dimethoxyphenyl)-benzimidazol- 1 yl)-propionic acid, and a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition comprises as an active ingredient the compound of general formula (II) denoted 3-hydroxy 9-nitro-5H-benzofuro [3,2-c) quinoline-6-one, and a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition comprises as an active ingredient the compound of general formula (II) denoted3- methylcarbamoyloxy 9-amino-5H-benzofuro[3,2-c) quinoline-6-one, and a pharmaceutically acceptable carrier or diluent.
  • a benzofuro[3,2-c]quinoline compound ofthe structural formula (II) wherein R3 is hydrogen is useful for the preparation of a medicament.
  • a compound of formula (II) wherein Rl and R2 are OR4, R4 is hydrogen or OCONR7R8, R7 and R8 are each C1-C3 alkyl, R3 is H, and each of m and n is 1 is disclosed
  • a compound according to formula la for the preparation of a medicament for inhibiting abnormal PTK wherein R3 is hydrogen, Rl and R2 are OR4, wherein R4 is hydrogen or OCONR7R8 wherein R7 and R8 are each C1-C 3 alkyl, and each of m and n is 1.
  • a currently preferred embodiment ofthe present invention is the use of a compound according to formula la for the preparation of a medicament for inhibiting abnormal PTK, wherein R3 is H and n is 1 and Rl and R2 are OH or OCON(CH 3 ) 2 .
  • the compounds of formula (I) may be prepared by the methods described in the above- mentioned US 6,100, 283 and US 6,015,827, or by the syntheses outlined herein, which describes a typical method for the preparation of 3-(5-acetylamino-4-carbarnoyl-2-phenyl- benzoimidazol-l-yl)-propionic acid from commercially available dinitrophthalic anhydride (modified from (White, 2000)).
  • Typical protecting groups, and methods for attaching and cleaving them are described fully by Greene and Wuts in Protective Groups in Organic Synthesis, John Wiley and Sons, New York, (2nd Ed, 1991), and McOmie, Protective Groups in Organic Chemistry, Plenum Press, New York, 1973.
  • the compounds of the present invention can exist both in unsolvated and solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope ofthe present invention.
  • compositions comprising the compounds of structural formulae (I) and (I ⁇ )above are for use as active ingredients of pharmaceutical compositions useful for inhibiting abnormal tyrosine kinase activity.
  • compositions I and II are also contemplated by the present invention, both salts formed by any carboxy group present in the molecule and a base as well as acid addition and/or base salts.
  • Pharmaceutically acceptable acid addition salts ofthe compounds include salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacruronate (see, for example, Berge S. M., et al., "Pharmaceutical Salts," J. of Pharmaceutical Science, 66:1-19 (1977)).
  • the acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount ofthe desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, andprocaine (see, for example, Berge S. M., et al., "Pharmaceutical Salts," J. of Pharmaceutical Science, 66:1-19 (1977)).
  • the base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount ofthe desired base to produce the salt in the conventional manner.
  • the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner.
  • the free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
  • the present invention further provides pharmaceutical formulations comprising at least one compound of (I) or (II) together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.
  • the formulations of this invention preferably contain from about 5% to about 70% ofthe active compound.
  • composition of this invention may be administered by any suitable means, such as orally, intranasally, subcutaneously (SC), intramuscularly (IM), intravenously (IN), intra-arterially, intralesionally or parenterally. Ordinarily, intravenous or oral administration will be preferred.
  • dosage forms may comprise as an active component either a compound of Formula (I) or (II) or a corresponding pharmaceutically acceptable salt or solvate thereof
  • pharmaceutically acceptable carriers can be either solid or liquid (Pillai and Panchagnula, 2001). Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid such as talc or starch which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • a preferred form for oral use is capsules, which include the formulation ofthe active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution, isotonic saline, 5% aqueous glucose, and the like.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • the pharmaceutical formulations ofthe invention may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. Waxes, polymers, and the like can be utilized to prepare sustained-release dosage forms. In addition, osmotic pumps can be employed to deliver the active compound uniformly over a prolonged period.
  • the pharmaceutical preparations ofthe invention are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities ofthe active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the therapeutically effective amount ofthe molecule according to the present invention will depend, inter alia upon the administration schedule, the unit dose of molecule administered, whether the molecule is administered in combination with other therapeutic agents, the immune status and health of the patient, the therapeutic activity ofthe molecule administered and the judgment ofthe treating physician.
  • a "therapeutically effective amount” refers to the amount of a compound required to alleviate one or more symptoms associated with a disorder being treated over a period of time.
  • the present invention further relates to a method for inhibiting abnormal PTK activity, particularly RPTK activity, which comprises administering to an individual in need thereof a PTK activity inhibitor selected from at least one heterocychc compound selected from the heterocychc compounds of structural formulae I and II.
  • a PTK activity inhibitor selected from at least one heterocychc compound selected from the heterocychc compounds of structural formulae I and II.
  • RPTKs are a subclass of transmembrane- spanning receptors endowed with intrinsic, ligand-stimulatable PTK activity. When mutated, overexpressed or altered structurally, RPTKs can become potent oncoproteins, causing cellular transformation. More than 90 PTK genes are known in the human genome: 58 encode transmembrane RPTKs distributed into 20 subfamilies, and 32 encode cytoplasmic, non-receptor PTKs in 10 subfamilies. Ofthe about 30 tumor-suppressor genes and more than 100 dominant oncogenes known to date, protein kinases, in particular PTKs, comprise a large fraction.
  • RPTKs and cytoplasmic PTKs are described in Blume-Jensen and Hunter, 2001, and inhibition of abnormal activity of all of them are encompassed by the present invention.
  • Table 1 of said publication discloses human RPTKs: the prototypic receptor for each family is indicated above the receptor, and the known members are listed below.
  • EGFR/ErbBl, ErbB2/HER2/Neu, ErbB3/HER3 and ErbB4/HER4 are members ofthe EGFR family
  • IGF-IR is a member ofthe insulin receptor (InsR) family
  • PDGFR- ⁇ , PDGFR- ⁇ , CSF-1R, kit/SCFR and Flk2/FLT3 are members ofthe PDGFR family
  • Flk/VEGFRl, Flkl/VEGFR2 and Flt4/VEGFR3 are members ofthe VEGFR family
  • FGFR1, FGFR2/K-SAM, FGFR3, FGFR4 and FGFR5 are members ofthe FGFR family
  • TrkA and TrkC are members ofthe NGFR family
  • RON is a member ofthe HGFR family
  • EphA2, EphB2 and EphB4 are members ofthe EphR family
  • Axl is a member ofthe AXL family
  • TIE/TIE 1 and Tek/TIE2 are members
  • cytoplasmic PTKs in Fig. 2 therein, from which the following are involved in human malignancies: Fgr, Src, Yesl, Lck -members ofthe SRC family; Abll, Arg - members of the ABL family; Jakl, Jak2 , Jak3 - members ofthe JAK family; Fak, Pyk2 - members of the FAK family; Fes - member ofthe FES family; Brk - member ofthe FRK family; and Syk - member ofthe SYK family.
  • EGFR/ErbBl is associated with f ⁇ brosarcomas, mammary carcinoma, glioblastoma multiforme, ovarian, non-small-cell lung and other cancers
  • ErbB2/HER2/Neu is associated with mammary, ovarian, gastric, non-small-cell lung and colon cancers
  • ErbB3/HER3 is associated with mammary cancer
  • ErbB4/HER4 is associated with mammary carcinoma and granulose cell tumors
  • IGF-IR is associated with cervical and other cancers
  • Flk2/FLT3 is associated with hematopoietic malignancies
  • Flk/VEGFRl, Flkl/VEGFR2 and Flt4/VEGFR3 are associated with tumor angiogenesis
  • FGFR1 is associated with acute myelogenous leukemia (AML) and with various tumors, and point mutations thereof are associated with autosomal skeletal disorders/dysplasias
  • FGFR2/K-S AM is associated
  • the heterocychc compounds of structural formulae (I) and (II ) are useful for inhibition of abnormal PTK activity, particularly inhibition of abnormal activity of a RPTK selected from the group consisting of EGFR ErbB 1 , ErbB2/HER2/Neu, ErbB/HER3 , ErbB4/HER4, IGF-IR, PDGFR- ⁇ , PDGFR- ⁇ , CSF-1R, kit/SCFR, Flk2/FLT3, Flk/VEGFRl, Flkl/VEGFR2, Flt4/VEGFR3, FGFR1, FGFR2/K-SAM, FGFR3, FGFR4, TrkA, TrkC, HGFR, RON, EphA2, EphB2, EphB4, Axl, TIE/TIE1, Tek/TIE2, Ret, ROS and Alk, as well as for inhibition of abnormal activity of a cytoplasmic PTK selected from the group consisting of Src, Fgr, Yes, Lck, Abl, Arg, Jak
  • the compounds of general formulae (I) and (II) , (la) and (Ila) are useful for the preparation of a medicament for inhibiting tyrosine kinase associated diseases or disorders including angiogenesis, particularly tumor angiogenesis and tumor progression.
  • the compounds are useful for preventing, treating or inhibiting a malignant cell proliferative disease or disorder caused by abnormal PTK activity.
  • the compounds are useful for the treatment or prevention of non-solid cancers, e.g. hematopoietic malignancies such as, but not being limited to, all types of leukemia, e.g.
  • CML chronic myelogenous leukemia
  • AML acute myelogenous leukemia
  • mast cell leukemia chronic lymphocytic leukemia and acute lymphocytic leukemia, lymphomas, and multiple myeloma
  • solid tumors such as, but not being limited to, mammary, ovarian, prostate, colon, cervical, gastric, esophageal, papillary thyroid, pancreatic, bladder, colorectal, melanoma, small-cell lung and non-small-cell lung cancers, granulosa cell carcinoma, transitional cell carcinoma, vascular tumors, all types of sarcomas, e.g.
  • osteosarcoma chondrosarcoma, Kaposi's sarcoma, myosarcoma, hemangiosarcoma, and glioblastomas. It is to be understood that whenever the terms “treating or inhibiting a malignant cell proliferative disease or disorder”, “treating or inhibiting a non-solid cancer”, “treating or inhibiting a tumor” are used herein in the description and in the claims, they are intended to encompass tumor formation, primary tumors, tumor progression or tumor metastasis.
  • the compounds of general formulae (I) and (II), (la) and (Ha) ofthe present invention are used for the preparation of a medicament for the treatment of bone and cartilage related disorders such as a skeletal dysplasia or a craniosynostosis disorder associated with abnormal activation of a receptor protein tyrosine kinase.
  • bone and cartilage related disorders such as a skeletal dysplasia or a craniosynostosis disorder associated with abnormal activation of a receptor protein tyrosine kinase.
  • craniosynostosis disorders are Muenke coronal craniosynostosis or Crouzon syndrome with acanthosis nigricans.
  • the skeletal dysplasia may be achondroplasia, thanatophoric dysplasia (TD), hypochondroplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) dysplasia.
  • the compounds are used for treatment of achondroplasia.
  • the compounds of general formulae (I) and (TI), (la) and (Ila) can be used for the preparation of a medicament useful for treating or inhibiting nonmalignant tumors such as benign prostate hypertrophy.
  • the compounds of general formulae (I) and (II), (la) and (Ila) are useful for inhibiting vascular smooth muscle cell proliferation and are thus useful in the treatment of disorders such as atherosclerosis, hyperthrophic heart failure and post surgical restenosis.
  • the compounds of general formulae (I) and (II), (la) and (Ila) are useful for treatment of autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease, of vision disorders such as diabetic retinopathy and macular degeneration, of metabolic disorders, of other cell proliferative diseases or disorders such as psoriasis, hypertrophic scars, acne and sclerosis/scleroderma, and of other diseases or disorders such as polyps, multiple exostosis, hereditary exostosis, retrolental fibroplasia, hemangioma, and arteriovenous malformation.
  • autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease
  • vision disorders such as diabetic retinopathy and macular degeneration
  • metabolic disorders of other cell proliferative diseases or disorders
  • other cell proliferative diseases or disorders such as psoriasis, hypertrophic scars, acne and sclerosis/scleroderma
  • conjugates ofthe compounds of general formulae (I) and (II), (la) and (Ila) with peptides, antibodies, growth factors or any other entity that can specifically target the compound to the protein kinase of interest are used.
  • the targeting moiety may be linked covalently to the compounds of general formulae (I) and (II), (la) and (Ila) either directly or through a linker.
  • tyrosine kinase inhibitor of general formulae (I) and (II), (la) and (Ila) is linked to EGF, as described in US 5,911,995, the conjugate will bind to EGFRs present on the surface of a cell and will inhibit tyrosine kinases associated with the EGFR, thereby inducing apoptosis and clonogenic cell death.
  • the compounds ofthe present invention may be delivered conjugated to a polymer (Kratz, et al, 1999).
  • the compounds ofthe invention are tested and evaluated in standard assays used to determine inhibition of PTK activity such as described herein in the examples for inhibition of FGFR3 activated by its ligand FGF9 or as described, for example, in US 5,733,913, herein inco ⁇ orated by reference in its entirety as if fully disclosed herein.
  • the therapeutically effective dose of a compound ofthe invention to be administered to an individual in need thereof will be sufficient to achieve the desired inhibition and will typically be from about 1 mg to about 100 mg/kg of body weight per day. Typical adult doses will be about 50 to about 800 mg per day, either in single or in multiple doses.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 500 mg, preferably about 0.5 mg to 100 mg according to the particular application and the potency ofthe active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • Dimethylcarbamylchloride (6 equiv., 0.434g) was dissolved in 2 ml DMF and added to the solution of Compound 1 obtained in Example 1 above (1 equiv., 0.90 g), triethylamine (4 equiv., 136 mg) and dimethylaminopyridine (0.1 equiv., 4.1 mg.) in 2 ml DMF. The resulting mixture was stirred at room temperature for 20 hours. After that, the solution was poured in water (20 ml) and extracted with ether (3 x 25 ml). The ether layer was washed with brine and dried with sodium sulfate.
  • Compound 3 was prepared by the same procedure as for Compound 2 in Example 2 above, but using diethylcarbamyl chloride instead of dimethylcarbamyl chloride.
  • Step 1 Synthesis of diethyl 2-(2 methoxy. 4 nitropheny ⁇ malonate.
  • ⁇ -NMR-Spectrum 500 MHz, CDC1 3 ): 1,25 (t, 6 H, C ⁇ CHs) ppm; 3,97 (s, 3 H, OCH 3 ) ppm; 4,22 (q, 4 H, CH 2 ) ppm; 5,19 (s, 1 H, CH) ppm; 7,52 (d, 1 H, Ar-H) ppm; 7,69 (dd, 1 H, Ar-H) ppm; 7,89 (dd, 1 H, Ar-H) ppm.
  • Step 2 Synthesis of 3-(2-methoxy. 4-nitro phenylV4-hydroxy-7-methoxy-lH-quinolin-2- 25 one (compound 5
  • Step 5 Synthesis of 3 -methylcarbamoyloxy 9-amino-5H-benzofuro[3,2-c) quinoline-6-one (Compound 8 " )
  • the FDCP cell line (ATCC no. CRL-12103) is a murine immortalized IL-3 -dependent cell line of myelocytic bone marrow origin, which does not express endogenous FGF receptors (FGFRs).
  • FDC-P1 (FDCP) cells were cultured at 37 °C in a humidified atmosphere containing 5% CO2.
  • the cells were grown in Iscove's modified Dulbeccos's medium (IMDM) supplemented with 10% fetal calf serum (FCS), 2mM L-glutamine, lOOU/ml penicillin, and lOO ⁇ g/ml streptomycin, and with 1% X-63-0 supernatant containing IL-3 (or with 0.1 ng/ml IL-3 from Pepro Tech).
  • IMDM Iscove's modified Dulbeccos's medium
  • FCS fetal calf serum
  • FCS fetal calf serum
  • 2mM L-glutamine 2mM L-glutamine
  • lOOU/ml penicillin lOO ⁇ g/ml streptomycin
  • X-63-0 supernatant containing IL-3 (or with 0.1 ng/ml IL-3 from Pepro Tech).
  • FDCP cells were transfected with either the human wild-type FGF receptor 3 (FGFR3; FDCP-FR3), or with the human wild-type FGF receptor 1 (FGFRl; FDCP-FR1).
  • PAW- FGFRl construct (from Dr. M. Mohammadi, see Mohammadi et al., 1997) was used for stable transfection of FDCP cells. Twenty million (20x10 6 ) cells were used for each transfection. The cells were washed and resuspended in 800 ⁇ l of IMDM without FCS. 50 ⁇ g DNA was added to the cells prior to electroporation (315v, 97 ⁇ F).
  • the cells were cooled on ice for 10 minutes and resuspended in IMDM-FCS medium supplemented with 1% X-63-0 supernatant. 48 hours later medium was exchanged and lmg/ml G418 (GibcoBRL) was added.
  • FGFR3 was constructed in a viral expression system using pLXSN (Clonetech).
  • FDCP cells were infected by MuLV containing pLXSN-FGFR constructs.
  • 0.5xl0 6 FDCP cells were incubated for 3 hours with 0.5 ml viral supernatant (and polybrene 4 ⁇ g/ml).
  • the infected cells were cultured with IMDM-FCS medium containing IL-3.
  • G418 (1 mg/ml) was added 24h post infection. 6b) Stimulation of cells by growth factors
  • FDCP transfected /infected cells were grown in medium containing IL-3 washed with medium without IL-3 prior to FGF stimulation. Stimulation ofthe cells by growth factors was performed by addition of 10 ng/ml FGF9 and 5 ⁇ g/ml heparin to the medium (without IL-3). Cells were grown with FGF+ heparin with media replaced every two days.
  • FGF Upon transfection with a FGFR cDNA, FGF induces a dose-dependent proliferation ofthe FDCP cell line, and this proliferative effect of FGF can replace the IL-3 growth dependence ofthe FDCP cells.
  • FDCP cell lines transfected with FGFR cDNA can, therefore, be used for screening of specific inhibitors or activators of FGFs, or for studying mutant FGFRs and FGFR signaling.
  • the effect of various ligands on FDCP cell proliferation is determined by a cell proliferation assay using XTT reagent according to the manufacturer's instructions (Cell Proliferation Kit, Biological Industries Co., Beit Haemek, Israel). The method is indicative of cell viability, and it is based on the capability of mitochondrial enzymes to reduce tetrazolium salts into soluble colored formazan compounds, which can be then quantitated.
  • FDCP cells were grown in Iscove's medium containing 2 mM glutamine, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 12.5 ⁇ g/ml nystatin, 10% FBS (Iscove's+++), 10 ng/ml FGF9, and 5 ⁇ g/ml heparin.
  • the medium containing heparin and FGF was prepared every 7-10 days. Under these culture conditions, the cells exhibited a "pearl-like" appearance, i.e., they were round and shiny.
  • the cells were split 1 :3 with fresh Iscove's+-H- medium containing 5 ⁇ g/ml heparin and 10 ng/ml FGF9. Twenty four hours later the cells were washed twice in Iscove's-t-H- medium, and resuspended at a final concentration of 4x10 5 cells/ml in Iscove's+++ medium containing 5 ⁇ g/ml heparin. Fifty ⁇ l of cell suspension well were seeded in a 96-well plate (2xl0 4 cells/well).
  • the tested compounds were usually prepared at a concentration of 10 mM in 100% DMSO (stock solution), from which serial dilutions were made in DDW (a final concentration of no more than 0.125% DMSO per well was added). At the final dilution the compounds were prepared in Iscove's-H-+ medium containing 5 ⁇ g/ml heparin and 2.5 ng/ml FGF9 or IL-3. Fifty ⁇ l were added to each well and the plate was incubated at 37 C. After 48 hrs of incubation, 50 ⁇ l ofthe XTT mixture was added to each well. The absorbance (O.D.) at 490 nm at this time point gave the baseline reading. Cells were then incubated for additional 4 hours at 37°C, and the proliferation was measured by absorbance at 490 nm. It should be noted that addition of DMSO alone did not affect cell proliferation.
  • the compounds are further tested to determine the level of inhibition and specificity of 5 inhibition by performing in vivo assays to a variety of cell types expressing different receptor tyrosine kinase proteins and by in vitro kinase assays known in the art.
  • Receptor specificity denotes the fact that a certain compound inhibits a biological response (e.g. proliferation) elicited by a particular receptor at an IC 50 that is at least half of that required to inhibit the response elicited by other receptors. 10 Biological responses and receptor affinity are measured by methods known in the art.
  • the receptor tyrosine kinase inhibitory activity of Compound 2 was assayed using the FDCP proliferation assay described in Example 5b above. Increasing concentrations of Compound 2 were added either to FDCP-FR3 cells or to FDCP-FR1 cells that were grown
  • the table in figure 5 presents the IC50 of compounds (compounds 5-8) synthesized according to Example 5 above. The compounds were tested in the in vivo FDCP cell assay for inhibition of FGFR3 activity in FGFR3 transfected FDCP cells. The IC 50 was determined by calculating the concentration of compound required to inhibit 50% proliferation.
  • Compound 6 3-hydroxy
  • RCJ cells fetal rat calvaria-derived mesenchymal cells, RCJ 3.1C5.18; Grigoriadis et al, 30 1988
  • FGF Receptors an inducible manner, in the absence of tetracycline, as described (Monsonego-Oman et al, 2000).
  • the cells were incubated in medium containing a low serum concentration and FGF was added to stimulate receptor activity and signaling.
  • the cells were lysed and the receptor (FGFR3) level, the receptor activation and signaling were assessed by Western blotting using anti- FGFR3, anti-phosphotyrosine, or anti-active JUN kinase (JNK) antibodies, respectively.
  • RCJ-W11 cells (RCJ cells stably transfected to overexpress wild type FGFR3) were grown to subconfluence in ⁇ -MEM containing 2 mM glutamine, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 12.5 ⁇ g/ml nystatin (medium A) and supplemented with 600 ⁇ g/ml neomycin, 2 ⁇ g/ml tetracycline, 50 ⁇ g/ml hygromycin B and 15% fetal calf serum (FCS).
  • FCS fetal calf serum
  • the cells were trypsinized and seeded (6x10 5 cells/well in a 6-well plate) in the aforementioned medium, excluding the hygromycin B. Twenty four hours later the cells were washed and then incubated with medium A supplemented with 15% FCS for 16 hours. Cells were washed and allowed to grow for 4 additional hours in 1 ml of medium A containing
  • test compounds were usually prepared at a concentration of 10 mM in 100% DMSO (stock solution), from which serial dilutions were made in DDW (a final concentration of no more than 0.125% DMSO per well was added).
  • RCJ-W11 cells were incubated in the presence ofthe test compounds for 20 min prior to FGF9 stimulation (5 min at a concentration of 100 ng/ml). Thereafter, the cells were placed on ice, washed twice with ice-cold PBS, and then lysed with lysis buffer (0.5 ml; EGTA 1 mM, EDTA 1 mM, Tris 25 mM, Hepes 50 mM, NaF 25 mM, ⁇ -glycerophosphate 50 mM, NaCl 50 mM, glycerol 10%, NP40 1%, pH 7.5, protease inhibitor mixture).
  • lysis buffer 0.5 ml; EGTA 1 mM, EDTA 1 mM, Tris 25 mM, Hepes 50 mM, NaF 25 mM, ⁇ -glycerophosphate 50 mM, NaCl 50 mM, glycerol 10%, NP40 1%, pH 7.5, protea
  • the lysate was then microcentrifuged (10 minutes at 4°C), and the cleared lysate was collected. The protein concentration was measured and the samples were prepared for 7.5% SDS-PAGE using Laemmli sample buffer.
  • 10 ⁇ l anti-FGFR3 antibodies Anti- FGFR3, SantaCruz #123
  • 10 ⁇ l anti-FGFR3 antibodies were added to the lysate (0.5 ml) and incubated for 4 hours at 4 C.
  • Forty ⁇ l protein A-SepharoseTM were added and incubated for an additional 1 hour at 4 C with continuous shaking.
  • the mixture was then microcentrifuged (15 seconds), and the supernatant was aspirated.
  • the beads were washed with lysis buffer and the samples were prepared for 7.5% SDS-PAGE using Laemmli sample buffer.
  • Fig. 2 shows a Western blot ofthe immunoprecipitated FGFR3 probed with antibodies against either FGFR3 (R3) or against phosphotyrosine antibodies ( ⁇ R3).
  • FGFR3 FGFR3
  • ⁇ R3 phosphotyrosine antibodies
  • cell lysates ofthe above treated cells were analyzed by Western blot using anti-P-JNK antibodies (JNK).
  • JNK anti-P-JNK antibodies
  • Femoral bone cultures were prepared by excising the hind limbs of heterozygous mice for the achondroplasia G369C mutation (age P0) (Gly369Cys mutation in mouse FGFR3 which causes achondroplasia, equivalent to the G380C mutation in humans; see Chen et al, 1999).
  • the limbs were carefully cleaned from the sunounding tissue (skin and muscles), the femora removed, and further cleared from tissue remains and ligaments.
  • the femora were measured for their initial length using a binocular equipped with an eyepiece micrometer ruler.
  • the bones were grown in 1 ml of medium ( ⁇ -MEM supplemented with 100 U/ml penicillin, 0.1 mg/ml streptomycin, 12.5 units/ml nystatin, 0.2% BSA, 1 mM ⁇ - glycerophosphate, and 50 ⁇ g/ml freshly prepared ascorbic acid) in a 24-well tissue culture plate.
  • a stock solution ofthe tested compound was usually prepared at a concentration of 10 mM in 100% DMSO.
  • the final dilution ofthe compound was made directly into the well such that a final concentration of no more than 0.125% DMSO per well was added.
  • the bones were cultured for 9 days. Measurements of bone length, medium replacement, and compound replacement were performed every three days. At the end ofthe experiment, the growth rate ofthe bones was calculated based on the length measurements obtained during day 3 to day 9.
  • Scheme 2 presents the pathway for the synthesis of compound II and derivatives having structural formula II.

Abstract

L'invention porte sur des composés hétérocycliques inhibiteurs de la tyrosine kinase dont les préférés sont l'aryl benzimidazole substitué en 2 et la benzofuro [3,2-c ] quinoline, tous deux étant nouveaux et connus. L'invention porte également sur des procédés d'utilisation desdits composés préférés pour la préparation de médicaments traitant les maladies et troubles prolifératifs, du squelette et du métabolisme associés à une activité anormale de la tyrosine kinase, dont le cancer et la dysplasie du squelette.
PCT/IL2002/000740 2001-09-06 2002-09-05 Inhibiteurs de la tyrosine kinase WO2003020698A2 (fr)

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