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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: 2008-10-30
DECIPHERA PHARMA LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to compounds that can be used to treat various types of cancer in humans, including but not limited to malignant melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinoma, mycloproliferative 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

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Experimental program
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examples

General Method A

[0108]To a stirring solution of the carboxylic acid (0.24 mmol) and TEA (1.2 mmol) in 1,4-dioxane (4.5 mL) at RT was added DPPA (0.29 mmol). After stirring for 0.5 h at RT, the appropriate amine (0.71 mmol) was added and the reaction was stirred with heating at 100° C. for 2 h. The reaction was cooled to RT, diluted with brine (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography to afford the target compound.

example a1

[0109]4-Fluoro-2-methyl-phenol (25 g, 0.2 mol) was added to a solution of sodium hydroxide (9.7 g, 0.24 mol) in water (160 mL) and the resultant solution was cooled to 0° C. Methyl chloroformate (24.2 g, 0.26 mol) was added dropwise at 0° C. At the completion of the reaction, the pH was adjusted to pH 8 with saturated aqueous Na2CO3 and then mixture was extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water and brine, dried (MgSO4) and were concentrated under reduced pressure to provide carbonic acid 4-fluoro-2-methyl-phenyl ester methyl ester (30 g, 82% yield). 1 H NMR (300 MHz, DMSO-d6): δ 7.22-7.13 (m, 2 H), 7.05 (m, 1H), 3.81 (s, 1H), 2.12 (s, 3H).

[0110]To a solution of carbonic acid 4-fluoro-2-methyl-phenyl ester methyl ester (15 g, 81.5 mmol) in conc. sulfuric acid (100 mL) at 0° C. was added powdered KNO3 (8.3 g, 82.2 mmol) in several portions. The reaction mixture was stirred for 1 hour at 0° C. and was then poured into ice water and ex...

example a2

[0114]Methyl chloroformate (77.3 g, 0.82 mol) was added dropwise to a −10° C. solution of 2-chloro-4-fluorophenol (100 g, 0.68 mol) and sodium hydroxide (32.8 g, 0.82 mol) in water (550 mL). After complete addition, the precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluorophenyl methyl carbonate (110 g, 79% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.62 (dd, J=8.1, 2.7 Hz, 1H), 7.50 (dd, J=9.0, 5.4 Hz, 1H), 7.30 (td, J=8.1, 3.0 Hz, 1H), 3.86 (s, 3H); MS (ESI) m / z: 205.2 (M+H+).

[0115]To a suspension of 2-chloro-4-fluorophenyl methyl carbonate (110 g, 0.54 mol) in conc. H2SO4 (50 mL) was slowly added a mixture comprised of conc. H2SO4 (40 mL) and fuming HNO3 (40.8 mL, 0.89 mol). The resultant mixture was stirred for 30 min at 0° C. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration and washed with water to rive 2-chloro-4-fluoro-5-nitrophenyl methyl carbonate (120 g, 90% yield). 1H NMR (400 MHz, DM...

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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. Preferrably, 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 causing polymorphs thereof.BACKGROUND OF THE INVENTION[0004...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/506C07D403/14A61P35/04A61P3/00A61P11/00A61P27/00C07D413/14
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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