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Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases

a technology of kinase inhibitors and proliferative diseases, applied in the field of kinase inhibitors and modulator compounds, can solve the problems of molecularly targeted small therapies that target c-kit mutations that remain elusiv

Inactive Publication Date: 2008-10-23
DECIPHERA PHARMA LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0012]Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, leukemias, papillary thyroid carcinoma, non small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, rheumatoid arthritis, asthma, chronic obstructive pulmonary disorder, a disease caused by c-Abl kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, or a disease caused by c-Kit, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof.

Problems solved by technology

GIST most often become Gleevec resistant and molecularly targeted small therapies that target c-KIT mutations remain elusive.

Method used

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  • Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases
  • Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases
  • Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases

Examples

Experimental program
Comparison scheme
Effect test

example a1

[0137]A suspension of 3-fluoro-4-aminophenol (8.0 g, 63.0 mmol) in dimethylacetamide (80 mL) was de-gassed in vacuo and treated with potassium tert-butoxide (7.3 g, 65 mmol). The resultant mixture was stirred at RT for 30 min. 2,4-Dichloropyridine (8 g, 54 mmol) was added and the mixture was heated to 80° C. for 12 h. The solvent was removed under reduced pressure to give a residue which was partitioned between water and EtOAc (3×100 mL). The organic layers were washed with saturated brine, dried (MgSO4), concentrated in vacuo and purified by silica gel column chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-phenylamine (11 g, 86% yield). 1H NMR (300 MHz, DMSO-d6), δ 8.24 (d, J=5.7 Hz, 1 H), 7.00 (dd, J=9.0, 2.7 Hz, 1 H), 6.89-6.73 (m, 4 H), 5.21 (br s, 2 H); MS (ESI) m / z: 239.2 (M+H+).

[0138]To a degassed solution of 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (0.801 g, 3.36 mmol) in DMF (2 mL) and TEA (2 mL) was added ethynyltrimethylsilane (0.929 ml, 6.71 mmol), tr...

example a2

[0141]To a solution of 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine from Example A1 (1.0 g, 4.2 mmol) in NMP (10 ml) was added DBU (0.94 mL, 6.3 mmol) and 1,2,4-triazol sodium salt (0.57 g, 6.3 mmol) and the mixture was heated overnight under argon atmosphere at 160° C. The reaction mixture cooled to RT, diluted with water (100 mL) and the solution was extracted with EtOAc (3×). The organics were combined and washed with LiCl solution and brine (2×), dried (Na2SO4) and concentrated in vacuo. The residue was slurried in EtOAc (5 mL), the solid was filtered and washed with EtOAc to obtain a mixture of product and SM. The filtrate was concentrated in vacuo, the residue was slurried in CH2Cl2, filtered and washed with CH2Cl2 to obtain 4-(2-(1H-1,2,4-triazol-1-yl)pyridin-4-yloxy)-2-fluorobenzenamine (0.35 g). MS (ESI) m / z: 272.2 (M+H+).

example a3

[0142]4-(2-Chloropyridin-4-yloxy)-2-fluorobenzenamine from Example A1 (150 mg, 0.629 mmol), 2-(tri-n-butylstannyl)oxazole (0.132 ml, 0.629 mmol) and PdCl2(dppf)-CH2Cl2 (51.3 mg, 0.063 mmol) were combined in DMF (3 ml) under Ar and stirred with heating at 90° C. After 3 h, the completed reaction was cooled to RT and treated with satd. aq. KF (5 ml; prepared from equal portions of KF.H2O and H2O) and stirred at RT for 1 h. The suspension was diluted with EtOAc and filtered through Celite®, rinsing forward with EtOAc. The filtrate was diluted with H2O and the layers were separated. The aqueous was extracted with EtOAc (2×). The combined organics were washed with brine (2×), dried (MgSO4), concentrated in vacuo and purified by flash column chromatography (EtOAc / hexanes) to afford 80 mg of 2-fluoro-4-(2-(oxazol-2-yl)pyridin-4-yloxy)benzenamine (0.295 mmol, 47% yield) as an oil that solidified on standing. 1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, J=5.8 Hz, 1H), 8.26 (s, 1H), 7.40 (d, J=2.3 H...

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Abstract

Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, leukemias, papillary thyroid carcinoma, non small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, mastocyctosis, mast cell leukemia, a disease caused by c-Abl kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, or a disease caused by c-Kit kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of Provisional Application 60 / 913,216 filed Apr. 20, 2007. This provisional application is incorporated by reference herein in its entirety.SEQUENCE LISTING[0002]This application contains a Sequence Listing in both paper and computer readable format in accordance with 37 C.F.R. 1.821 (c) and (e), the contents of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION[0003]The present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase / compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferably, the compounds are useful for the modulation of kinase activity of C-Abl, c-Kit, VEGFR, PDGFR kinases, Flt-3, c-Met, FGFR, the HER family and disease polymorphs thereof.BACKGROUND OF THE INVENTION[0004]Several ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4439C07D401/12C07D413/12C07D417/12A61K31/541A61P27/02A61P11/00A61P19/02A61P35/00A61K31/5377A61K31/496A61K31/4545
CPCC07D401/14C07D417/14C07D413/14A61P11/00A61P11/06A61P19/02A61P27/00A61P27/02A61P29/00A61P3/00A61P35/00A61P35/02A61P35/04A61P37/08A61P43/00A61P9/10C07D403/14A61K31/506
Inventor FLYNN, DANIEL L.PETILLO, PETER A.KAUFMAN, MICHAEL D.
Owner DECIPHERA PHARMA LLC
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