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Thieno[3,2-b]pyridine-6-carbonitriles as protein kinase inhibitors

一种-NHCH2-、化合物的技术，应用在3-取代的-噻吩并[3领域，能够解决变异等问题

Inactive Publication Date: 2007-04-18
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although mutations in the raf gene are rare in human cancers, c-raf is activated by the ras oncogene, which is mutated in many human tumors

Method used

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  • Thieno[3,2-b]pyridine-6-carbonitriles as protein kinase inhibitors
  • Thieno[3,2-b]pyridine-6-carbonitriles as protein kinase inhibitors
  • Thieno[3,2-b]pyridine-6-carbonitriles as protein kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] 3-Bromo-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile

[0114]

[0115]To a suspension of sodium hydride (438 mg of a 60% dispersion in mineral oil, 10.96 mmol) in 60 mL of tetrahydrofuran was added 2,4-dichloro-5-methoxyaniline (2.10 g, 10.96 mmol). The mixture was heated under reflux for 1 hour, then cooled to room temperature, and 1.50 g of 3-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile and 3,7-dibromothieno[ 3,2-b] A 1:2.4 mixture of pyridine-6-carbonitrile. The reaction mixture was heated at reflux for 2 hours, then cooled to room temperature and treated with saturated aqueous sodium chloride. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with a gradient of ethyl acetate in hexane to afford 1.78 g of 3-bromo-7-[(...

Embodiment 2

[0120] 7-[(2,4-dichloro-5-methoxyphenyl)amino]-3-(4-formylphenyl)thieno[3,2-b]pyridine-6-methyl

[0121] Nitrile

[0122]

[0123] 3-Bromo-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile (1.67g, 3.89mmol), 4 - A mixture of formylphenylboronic acid (1.17g, 7.78mmol) and tetrakis(triphenylphosphine)palladium (225mg, 0.20mmol) in 50mL of ethylene glycol dimethyl ether and 42mL of saturated aqueous sodium bicarbonate was heated under reflux 2 hours, then cooled to room temperature. The precipitate was collected by filtration, washed with ethyl acetate and ether to give 1.09 g of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-3-(4-formyl) as a brown solid Phenyl)thieno[3,2-b]pyridine-6-carbonitrile, mp 268°C; 1 HNMR (DMSO-d 6 )δ3.87(s, 3H), 7.44(s, 1H), 7.79(s, 1H), 8.01(d, J=8Hz, 2H), 8.23(d, J=8Hz, 2H), 8.55(s, 1H), 8.73 (s, 1H), 9.86 (s, 1H), 10.05 (s, 1H); MS 454.0, 456.0 (M+H)+; HRMS found: 454.01716 (M+H)+.

[0124] ...

Embodiment 3

[0128] 7-[(2,4-dichloro-5-methoxyphenyl)amino]-3-{4-[(dimethylamino)methyl]phenyl}thieno

[0129] [3,2-b]pyridine-6-carbonitrile

[0130]

[0131] 7-[(2,4-dichloro-5-methoxyphenyl)amino]-3-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (200mg , 0.44 mmol) and 1.1 mL of 2M dimethylamine in tetrahydrofuran (2.20 mmol) in 5 mL of dichloromethane and 1 mL of dimethylformamide were cooled to 0°C. Sodium triacetoxyborohydride (560 mg, 2.64 mmol) was added portionwise, followed by 3 drops of acetic acid. The resulting mixture was stirred at room temperature for 2.5 hours, then quenched by the addition of water. The mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of methanol in dichloromethane to aff...

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Abstract

This invention provides compounds of Formula II: wherein: R1, R2 and X are defined hereinbefore in the specification, which are useful in the treatment of cancer, stroke, myocardial infarction, neuropathic pain, osteoporosis, polycystic kidney disease, autoimmune disease, rheumatoid arthritis, and transplant rejection. The invention also provides processes for producing said compounds.

Description

[0001] The present application relates to thieno[3,2-b]pyridine-6-carbonitriles, more particularly to 3-substituted-thieno[3,2-b]pyridine-6-carbonitriles, the preparation of Their methods and pharmaceutical compositions comprising them. 3-Substituted-thieno[3,2-b]pyridine-6-carbonitriles as protein kinase inhibitors are useful, inter alia, in the treatment of cancer, stroke, myocardial infarction, neuropathic pain, osteoporosis, polycystic kidney disease, autologous Immunological diseases, rheumatoid arthritis and graft rejection. Background technique [0002] The present invention relates to compounds which inhibit the activity of protein kinases. Protein kinases are enzymes that catalyze the transfer of a phosphate group from ATP to an amino acid residue on a protein such as tyrosine, serine, threonine or histidine. Regulation of these protein kinases is important for the control of many cellular events including proliferation and migration. Specific protein kinases have ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04A61K31/4365
CPCA61K31/535C07D495/04A61K31/497A61K31/44A61P9/10A61P13/12A61P19/02A61P19/10A61P25/04A61P29/00A61P35/00A61P37/06A61P43/00A61K31/4365
Inventor D·H·博舍利N·张A·C·巴里奥斯索萨H·杜鲁特利克B·吴
Owner WYETH LLC