Kinase inhibitors useful for the treatment of proliferative diseases

A technology selected from, pyrimidinyl, applied in the field of kinase inhibitors for the treatment of proliferative diseases, which can solve the problem of uncontrolled signal transduction pathways

Inactive Publication Date: 2009-10-07
DECIPHERA PHARMA LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This single-site mutation is sufficient to confer constitutive activity on the mutant BRAF kinase, leading to deregulated signaling pathways and human cancer

Method used

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  • Kinase inhibitors useful for the treatment of proliferative diseases
  • Kinase inhibitors useful for the treatment of proliferative diseases
  • Kinase inhibitors useful for the treatment of proliferative diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A1

[0509] Example A1: To the CH of Example A3 (6.0g, 19mmol) 2 Cl 2 (50 mL) was added m-chloroperbenzoic acid (mCPBA, 6.5 g, 38 mmol) in one portion. After stirring at room temperature for 2 h, saturated NaHCO 3 Aqueous solution and NaHSO 3 aqueous solution and continued stirring for a few minutes. The combined organic layers were washed with brine, dried and concentrated in vacuo. The residue was dissolved in DMSO (5 mL) and ammonia in dioxane (2M, 200 mL, 400 mmol) was added. The resulting reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was purified by reverse phase prep-HPLC to give 2-amino-6-(3-amino-4-fluorophenyl)-8-methylpyrido[2,3-d]pyrimidine- 7(8H)-Kone (1.9 g, 35% yield). 1 H NMR (300MHz, DMSO-d 6 ), δ8.63(s, 1H), 7.80(s, 1H), 7.39(br s, 2H), 7.12(d, J=6.0Hz, 1H), 7.03(t, J=12.0Hz, 1H), 6.80 (m, 1H), 3.53 (s, 3H); MS (ESI) m / z: 286.2 (M+H + ).

Embodiment A2

[0510] Example A2: Using a method similar to Example A1, Example A9 (3.50g, 10.6mmol) was oxidized with mCPBA (2.87g, 11.7mmol, 70%wt) to obtain intermediate 6-(3-amino-4-fluorophenyl )-8-Ethyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (2.35 g, 61% yield). The intermediate (1.40 g, 3.86 mmol) and 0.5 M ammonia in dioxane (15.5 mL, 2 equiv) were combined and purified by silica gel column chromatography to give 2-amino-6-(3-amino-4-fluorobenzene yl)-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one (0.65 g, 56% yield). 1 H NMR (400MHz, DMSO-d 6 ): δ8.63(s, 1H), 7.79(s, 1H), 7.27(s, 1H), 7.10(dd, J=2.4, 8.8Hz, 1H), 7.00(dd, J=8.8, 11.6Hz, 1H), 6.75(m, 1H), 5.14(s, 2H), 4.31(q, J=6.8Hz, 2H), 1.18(t, J=6.8Hz, 3H); LC-MS(EI) m / z : 300.0(M+H + ).

Embodiment A3

[0511] Example A3 : Example C1 (15g, 82mmol), ethyl 2-(3-amino-4-fluorophenyl)acetate (19.4g, 98mmol; described by Kuse et al. Tetrahedron (2005), 61,5754-5762 method) and K 2 CO 3 (34.0 g, 246 mmol) in DMF (100 mL) was heated at 110 °C overnight. The mixture was poured into water and the product was extracted with ethyl acetate (3 x 200 mL). The combined organics were washed with brine, dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by silica gel chromatography gave 6-(3-amino-4-fluorophenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (13.0 g, 50% yield). 1 H NMR (300MHz, DMSO-d 6 ), δ8.91(s, 1H), 7.99(s, 1H), 7.15(dd, J=8.7, 2.1Hz, 1H), 7.04(dd, J=11.4, 8.4, 1H), 6.80(m, 1H ), 5.21 (br s, 2H), 3.65 (s, 3H), 2.60 (s, 3H); MS (ESI) m / z: 317.2 (M+H + ).

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Abstract

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 Raf kinases and disease polymorphs thereof. Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant melanoma, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, non small cell lung cancer, and mesothelioma. Compounds of the present invention also find utility in the treatment of rheumatoid arthritis and retinopathies including diabetic retinal neuropathy and macular degeneration.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of provisional application 60 / 844552 filed September 14,2006. This application is hereby incorporated by reference. field of invention [0003] The present invention relates to novel kinase inhibitor and modulator compounds useful in the treatment of various diseases. More specifically, the present invention relates to the compounds, kinase / compound adducts, methods of treating diseases and methods of synthesizing the compounds. Preferably such compounds are useful for modulating the kinase activity of Raf kinases and disease polymorphs thereof. Background of the invention [0004] Many members of the protein kinase family have been clearly implicated in the pathogenesis of various proliferative diseases and thus represent important therapeutic targets for these diseases. Some proliferative diseases of relevance to the present invention include cancer, rheumatoid arthritis, athero...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/54A61K39/395
Inventor D·L·弗林M·D·考夫曼W·C·派特P·A·派提罗
Owner DECIPHERA PHARMA LLC
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