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Kinase inhibitors useful for the treatment of proliferative diseases

A sequential, CH2 technology, applied in the field of disease treatment, can solve problems such as out-of-control signal transduction pathways

Inactive Publication Date: 2009-08-26
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

[0536] Example A1: Acetic acid (10 mL, 174 mmol) was added to a mixture of Example C2 (10 g, 54.6 mmol) and 4-fluoro-3-nitroaniline (8.5 g, 54.6 mmol) in water (350 mL), and The mixture was stirred overnight at room temperature. The solid was collected by filtration and washed with MeOH (2 x 20 mL) to give 5-((4-fluoro-3-nitrophenylimino)methyl)-N-methyl-2-(methylthio)pyrimidine-4 - Amine (8.0 g, 46% yield) as a yellow solid. 1 H NMR (300MHz, DMSO-d 6 ): δ9.39(m, 1H), 8.71(s, 1H), 8.33(s, 1H), 8.18(m, 1H), 7.80(m, 1H), 7.61(t, J=6.9Hz, 1H) , 3.05 (d, J=3.6Hz, 3H), 2.48 (s, 3H); MS (ESI) m / z: 322.2 (M+H + ).

[0537] to LiAlH at 0°C 4 (1.3g, 34mmol) of anhydrous THF suspension was added in batches to the above 5-((4-fluoro-3-nitrophenylimino)methyl)-N-methyl-2-(methanol) over 20 minutes Thio)pyrimidin-4-amine. After the addition was complete, the mixture was stirred at 0°C for 30 minutes. Aqueous 10% NaOH (2 mL) was added and the resulting precipitate was removed by fil...

Embodiment A2

[0540] Example A2: CH to Example A1 (400mg, 1.3mmol) 2 Cl 2 (5 mL) solution was added 3-chloroperbenzoic acid (mCPBA) (430 mg, 2.5 mmol) in one portion. After stirring for 2 h, the reaction mixture was washed with NaHCO 3 Aqueous solution and NaHSO 3 The aqueous solution was quenched. The organic layer was separated, washed with brine, and dried (Na 2 SO 4 ), concentrated in vacuo. The crude product was dissolved in DMSO (2 mL) and treated with ammonia in dioxane (2M, 30 mL, 60 mmol). The mixture was stirred overnight at room temperature. The reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give 7-amino-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrimido[4 ,5-d]pyrimidin-2(1H)-one (276 mg, 77% yield) as a yellow solid. 1 H NMR (300MHz, DMSO-d 6 ): δ7.88(s, 1H), 6.96(dd, J=8.4, 6.6Hz, 1H), 6.68(dd, J=6.3, 2.1Hz, 1H), 6.52(br s, 2H), 6.44(m , 1H), 5.18(s, 2H), 4.48(s, 2H), 3.19(s, 3H); MS (ESI) m / z: 289....

Embodiment A3

[0541] Example A3: Example A1 (1.0 g, 3.1 mmol), mCPBA (1.1 g, 6.3 mmol) and methylamine were combined by the process of Example A2 to give 3-(3-amino-4-fluorophenyl)- 1-Methyl-7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (370 mg, 39% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ): δ7.93(s, 1H), 6.99-6.94(m, 2H), 6.69(d, J=8.4Hz, 1H), 6.44(m, 1H), 5.18(s, 2H), 4.50(s, 2H), 3.23(s, 3H), 2.78(d, J=4.0Hz, 3H); MS (ESI) m / z: (M+H + )303.2

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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 incorporated herein 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 such compounds, 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] Several 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, atherosclerosis and retino...

Claims

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Application Information

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IPC IPC(8): A61K31/54
Inventor D·L·弗林P·A·派提罗M·D·考夫曼W·C·派特
Owner DECIPHERA PHARMA LLC
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