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Inhibitors of C-FMS kinase

A CH3, solvate technology, applied in the field of compounds with c-fms kinase inhibitor function

Active Publication Date: 2009-07-01
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The present invention addresses the current need for selective and active protein tyrosine kinase inhibitors by providing active c-fms kinase inhibitors

Method used

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  • Inhibitors of C-FMS kinase
  • Inhibitors of C-FMS kinase
  • Inhibitors of C-FMS kinase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0315] N-[2-(4,4-Dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-5-cyano- 1H-imidazole-2-carboxamide

[0316]

[0317] a) 1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazole-4-carbonitrile

[0318]

[0319] Imidazole-4-carbonitrile (0.50g, 5.2mmol) (Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMC1) (0.95mL, 5.3mmol), K 2 CO 3 (1.40g, 10.4mmol) and acetone (5mL) were added to the flask and stirred at room temperature for 10h. The mixture was diluted with EtOAc (20 mL), washed with water (20 mL), brine (20 mL), and the organic layer was washed over MgSO 4 dry. The crude product was eluted on a 20-g SPE cartridge (silica gel) with 30% EtOAc / hexanes to afford 0.80 g (70%) of the title compound as a colorless oil. Mass spectrometry (CI(CH 4 ), m / z): C10 h 17 N 3 Theoretical value of OSi, 224.1 (M+H), found value 224.1.

[0320] b) 2-bromo-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazole-4-carbonitrile

[0321]

[0322] To 1-(2-...

Embodiment 2

[0341] N-[4-[4-(2-Dimethylamino-ethoxy)-tetrahydro-pyran-4-yl]-2-(4,4-dimethyl-cyclohex-1-enyl )-phenyl]-5-cyano-1H-imidazole-2-carboxamide trifluoroacetate

[0342]

[0343]To N-[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-5-cyano -1H-imidazole-2-carboxamide (48.0 mg, 0.114 mmol) (the product of step (h) of Example 1) in 1 mL of DCM suspension was added 2-dimethylaminoethanol (0.114 mL, 1.14 mmol), TFA (0.130 mL, 1.17 mmol). The mixture was heated to 50 °C for 8 h. The mixture was concentrated and the title compound was purified by RP-HPLC on a C18 column with a linear gradient of 30-50% CH 3 CN / 0.1% TFA / H 2 O was eluted for 12 min to afford 14 mg (20%) of a white solid. 1 H-NMR (400MHz, CD 3 OD δ 8.21(d, J=8.6Hz, 1H), 7.91(s, 1H), 7.35(dd, J=8.6, 2.2Hz, 1H), 7.21(d, J=2.2Hz, 1H), 5.67(m , 1H), 3.83-3.66(m, 4H), 3.30-3.15(m, 4H), 2.76(s, 6H), 2.26-2.20(m, 2H), 2.12-1.94(m, 6H), 1.51(t , J=6.3Hz, 2H), 1.00 (s, 6H). Mass Spectrum (ESI...

Embodiment 3

[0345] {4-[4-[(5-cyano-1H-imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-tetra Hydrogen-pyran-4-yloxy}-acetic acid

[0346]

[0347] To N-[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-5-cyano -1H-Imidazole-2-carboxamide (48.0 mg, 0.114 mmol) (the product of step (h) of Example 1) in 1 mL of DCM was added methyl glycolate (0.215 mL, 2.78 mmol), TFA (0.036 mL, 0.464 mmol). The mixture was stirred at room temperature for 8 h. The mixture was concentrated and the methyl ester of the title compound was eluted on a 10-g SPE cartridge with 50% EtOAc / hexanes. The obtained ester was dissolved in 1 mL MeOH, 2N KOH (0.30 mL, 0.60 mmol) was added, the mixture was stirred at room temperature for 8 h, the title compound was purified by RP-HPLC on a C18 column with a linear gradient of 30-60% CH 3 CN / 0.1%TFA / H 2 O was eluted for 12 min to afford 13 mg (30%) of a white solid. 1 H-NMR (400MHz, CD 3 OD δ 8.34(d, J=8.6Hz, 1H), 7.85...

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Abstract

The invention relates to compounds of Formula I: wherein Z, X, J, R<2> and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including rheumatoid arthritis, and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.

Description

[0001] Related Application Cross Reference [0002] This application claims priority to US Patent Provisional Application Serial No. 60 / 793,667, filed April 20, 2006, the contents of which are hereby incorporated by reference in their entirety. Background of the invention [0003] The present invention relates to novel compounds having the function of protein tyrosine kinase inhibitors. More particularly, the present invention relates to novel compounds that function as c-fms kinase inhibitors. [0004] Protein kinases are enzymes that serve as key components of signal transduction pathways, they are catalysts for the translocation of the terminal phosphate of 5'-adenosine triphosphate (ATP) to hydroxyl groups in tyrosine, serine and threonine residues of proteins. Thus, protein kinase inhibitors and substrates are valuable tools for evaluating the physiological consequences of protein kinase activation. Overexpression or inappropriate expression of normal or mutant pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D233/90C07D405/12C07D405/14C07D409/12C07D493/08A61K31/4178A61K31/5355A61K31/496A61K31/382A61K31/41A61K31/4418A61P13/00A61P11/00A61P35/00
CPCC07D207/34C07D413/14C07D409/12C07D493/08C07D401/12C07D405/14C07D413/12C07D405/12C07D401/14C07D233/90C07D403/12C12N9/99A61P1/02A61P1/04A61P1/18A61P11/00A61P11/06A61P13/00A61P13/12A61P17/06A61P19/02A61P19/08A61P19/10A61P25/00A61P25/04A61P25/18A61P25/28A61P27/02A61P29/00A61P31/04A61P31/18A61P35/00A61P35/02A61P35/04A61P37/00A61P37/02A61P37/06A61P43/00A61P7/00A61P9/00A61P9/10A61P9/14A61P3/10A61K31/4178
Inventor C·R·伊利S·K·巴伦泰恩J·陈雷尼·L·德斯贾莱斯S·K·米加拉B·E·汤楚克M·沃尔K·威尔逊
Owner JANSSEN PHARMA NV
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