Pyrrolo [2,3-c] pyridine derivatives as p38 kinease inhibiting agents

a technology of pyridine derivatives and kineases, applied in the field of heterocyclic compounds, can solve the problems of adaptive hypertrophic response and decidedly negative consequences

Inactive Publication Date: 2011-05-05
SAHOO SOUMYA P +6
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

are inhibitors of p38 and are useful in the treatment of inflammation such as in the treatment of asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.

Problems solved by technology

These are said to lead to an adaptive hypertrophic response, which, if not controlled, has decidedly negative consequences.
Further, to the extent that the α-isoform is toxic in other muscle cell types, α-selective inhibitors would be useful for conditions associated with cachexia attributed to TNF or other conditions such as cancer, infection, or autoimmune disease.

Method used

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  • Pyrrolo [2,3-c] pyridine derivatives as p38 kinease inhibiting agents
  • Pyrrolo [2,3-c] pyridine derivatives as p38 kinease inhibiting agents
  • Pyrrolo [2,3-c] pyridine derivatives as p38 kinease inhibiting agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

6-(1H-benzimidazol-2-ylmethyl)-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0277]

Step A: N-(1H-benzimidazol-2-ylmethyl)-2,2-dimethoxyethanamine

[0278]

[0279]To a MeOH 150 mL suspension of 1-(1H-benzimidazol-2-yl)methanamine dihydrochloride (4.0 g, 18.2 mmol) were added dimethoxyacetaldehyde (1.89 g, 18.2 mmol, 60 wt. % solution in water), sodium acetate (7.45 g, 91 mmol) and sodium cyanoborohydride (9.09 mL, 9.09 mmol, 1.0 M THF solution). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and reconstituted in DCM (150 mL). The resulting suspension was filtered. The filtrate was concentrated and chromatographed on silica gel with a gradient solvent mixture (5% MeOH-DCM to 15% MeOH-DCM over 15 CV) to give the title compound as oil (3.1 g). LC / MS: m / z 205 (M+-OMe). 1H-NMR (CDCl3, 500 MHz) δ 3.02 (d, 1H), 3.36 (s, 6H), 4.40 (s, 2H), 4.52 (t, 1H), 7.28-7.32 (m, 2H), 7.58-7.62 (m, 2H), 8.78-8.92 (br.s, 1H).

Step B: N-...

example 2

[0285]6-[(4-fluoro-1H-benzimidazol-2-yl)methyl]-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one LC / MS: m / z 441 (M+H). 1H-NMR (500 MHz, d6-DMSO): δ: 5.50 (s, 2H), 6.99-7.03 (m, 2H), 7.15 (m, 1H), 7.32-7.37 (m, 3H), 7.59 (d, 1H), 7.91 (d, 1H), 13.09 (s, 1H).

example 3

[0286]6-[(4,5-difluoro-1H-benzimidazol-2-yl)methyl]-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one LC / MS: m / z 459 (M+H). 1H-NMR (500 MHz, d4-CD3OD:d6-DMSO=3:1): δ 5.62 (s, 2H), 7.21-7.28 (m, 3H), 7.31-7.37 (m, 1H), 7.41 (dd, 1H), 7.65 (d, 1H), 7.88 (s, 1H).

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Abstract

Compounds described by the chemical formula (I) or pharmaceutically acceptable salts thereof: (A) are inhibitors N of p38 and are useful in the treatment of inflammation such as in the treatment of asthma, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.

Description

BACKGROUND OF THE INVENTION[0001]The present invention relates to heterobicyclic compounds that inhibit the action of the p38 mitogen-activated protein kinase, a mammalian protein kinase that is involved in cell proliferation, cell response to stimuli, and cell death. In particular, this invention relates to heterobicyclic compounds that are selective and potent inhibitors of the p38 mitogen-activated protein kinase. This invention also relates to pharmaceutical compositions containing such heterobicyclic compounds that inhibit the p38 mitogen-activated protein kinase.RELATED BACKGROUND[0002]The Mitogen-Activated Protein (MAP) kinases are a family of proline-directed serine / threonine kinases that are activated by dual phosphorylation, and in turn phosphorylate their substrates on either Threonine-Proline or Serine-Proline sites.[0003]MAP kinases are activated in response to a variety of signals including nutritional and osmotic stress, W light, growth factors, endotoxin and inflamma...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/437C07D471/04A61K31/519A61K31/5025A61K31/5377C07F7/10A61K31/695A61P29/00A61P19/02A61P11/06A61P11/00
CPCC07D519/00A61P11/00A61P11/06A61P19/00A61P19/02A61P19/06A61P25/00A61P29/00A61P37/08A61P43/00
Inventor SAHOO, SOUMYA P.CHEN, MENG-HSINDYKSTRA, KEVIN D.KOYAMA, HIROOMEINKE, PETER T.O'KEEFE, STEPHEN J.YANG, GINGER XU-QIANG
Owner SAHOO SOUMYA P
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