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C-fms kinase inhibitors

A technology of solvates and compounds, applied in the field of novel compounds

Inactive Publication Date: 2008-08-20
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Receptor binding leads to initiation of multiple intracellular tyrosine kinase-dependent phosphorylation processes that ultimately lead to oncogene transcription

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] 5-Cyano-furan-2-carboxylic acid [2-(4-acetylamino-piperidin-1-yl)-phenyl]-amide

[0094]

[0095] a) 5-cyano-furan-2-carboxylic acid

[0096]

[0097] To 2-formyl-5-furancarboxylic acid (2.8 g, 20 mmol) and hydroxylamine hydrochloride (2.7 g, 40 mmol) was added anhydrous pyridine (50 mL) under argon. The mixture was heated to 85°C, acetic anhydride (40 mL) was added, and the mixture was stirred for 3 hours. After cooling to 60°C, water (250 mL) was added, and the mixture was stirred at room temperature for 70 hours. The mixture was acidified to pH 2 with concentrated hydrochloric acid and extracted with 3:1 dichloromethane-isopropanol (8 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (1.26 g, 46%) as a tan solid.

[0098] 1 H-NMR (CD 3 OD; 400MHz): δ14.05(br s, 1H), 7.74(d, 1H, J=3.8Hz), 7.42(d, 1H, J=3.8Hz).

[0099] b) 4-acetyla...

Embodiment 2

[0115] 5-Cyano-1H-pyrrole-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide

[0116]

[0117] a) Ethyl 5-formyl-1H-pyrrole-2-carboxylate

[0118]

[0119] Phosphorus oxychloride (1.5 mL) was added dropwise in DMF (1.3 mL, 17 mmol) cooled to 5-10 °C, and the mixture was diluted with 1,2-dichloroethane (5 mL). The flask was then cooled to -10 °C, 1,2-dichloroethane (5 mL) containing ethyl pyrrole-2-carboxylate (2.00 g, 14.4 mmol) was added dropwise over 5 minutes, and the mixture was heated to reflux for 15 minutes, cooled to room temperature, and added ethyl acetate (15 mL), water (20 mL) and saturated aqueous sodium bicarbonate (70 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3 x 20 mL). The combined organic layers were washed with saturated sodium carbonate (50 mL), dried over sodium sulfate, the solvent was removed in vacuo and the resulting solid was purified by column chromatography on silica gel (300 g) eluting with 30% et...

Embodiment 3

[0137] 5-Cyano-furan-2-carboxylic acid (4-methoxy-2-piperidin-1-yl-phenyl)-amide

[0138]

[0139] a) 1-(5-Chloro-2-nitro-phenyl)-piperidine

[0140] To a cooled (0° C.) solution of 4-chloro-2-fluoronitrobenzene (1.75 g, 10.0 mmol) in EtOH (15 mL) was added piperidine (2.97 mL, 30.0 mmol) dropwise over 5 minutes. The solution was stirred at 0°C for 10 minutes, then at 23°C for 30 minutes. The mixture was poured into water (225 mL), extracted with EtOAc (2 x 30 mL). The combined extracts were washed with saturated aqueous sodium bicarbonate and brine (30 mL each) and dried (Na 2 SO 4 ). Concentration afforded 2.33 g (97%) of the title compound as an orange oil, which crystallized on standing.

[0141] Mass Spectrum (ESI, m / z): For C 11 h 13 ClN 2 o 2 The calculated value of 241.1 (M+H), the measured value: 241.1.

[0142] b) 1-(5-methoxy-2-nitro-phenyl)-piperidine

[0143] To a solution of 1-(5-chloro-2-nitro-phenyl)-piperidine (197 mg, 0.810 mmol) in DMF (1.5 mL)...

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PUM

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Abstract

The present invention relates to compounds of formula (I) and their solvates, hydrates, tautomers or pharmaceutically acceptable salts for inhibiting protein tyrosine kinases, especially c-fms kinases, wherein A, R1, R2 , R3, R4, X and W are set forth in the specification.

Description

[0001] Inventors: M.R. Pryor, N. Baindur, B.M. Brandt, N. Chadha, R.J. Page, D. Asgari, and T. George Diss. [0002] RELATIONSHIP TO OTHER APPLICATIONS AND PRIORITY CLAIM: This application is a continuation-in-part of USSN 10 / 831,216 filed April 26, 2004; Provisional Application No. 60 / 465,204 filed on . field of invention [0003] The present invention relates to novel compounds which act as inhibitors of protein tyrosine kinases. More specifically, the present invention relates to novel compounds that act as c-fms kinase inhibitors. Background of the invention [0004] Protein kinases are enzymes that serve as key components of signal transduction pathways, catalyzing the transfer of the terminal phosphate of ATP to the hydroxyl groups of tyrosine, serine, and threonine residues in proteins. Thus, protein kinase inhibitors and substrates are important tools for evaluating the physiological consequences of protein kinase activation. In mammals, overexpression or inapprop...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D207/40C07D307/68C07D233/90A61K31/4525A61P9/00A61P35/00A61K31/16A61K31/195A61K31/452A61K31/4545C07D223/12C07D265/30C07D279/12C07D409/12
CPCC07D207/416C07D233/90C07D307/68C07D405/12C07D409/12A61P13/12A61P17/06A61P19/02A61P25/18A61P25/28A61P29/00A61P35/00A61P43/00A61P9/00A61P9/10A61P3/10
Inventor M·R·普莱尔N·拜恩杜尔B·M·布兰德特N·查德哈R·J·佩奇D·阿斯加里T·乔治迪斯
Owner JANSSEN PHARMA NV
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