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2-pyridyl substituted imidazoles as therapeutic alk5 and/or alk4 inhibitors

a technology of imidazoles and pyridyl substitutes, which is applied in the direction of drug compositions, metabolism disorders, extracellular fluid disorders, etc., and can solve problems such as complicated organ transplantation

Active Publication Date: 2011-12-29
EWHA UNIV IND COLLABORATION FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0020]Surprisingly, it has now been discovered that a class of 2-pyridyl substituted imidazoles function as potent and selective inhibitors of ALK5 and / or ALK4 and, therefore, have utility in the treatment and prevention of various disease states mediated by ALK5 and / or ALK4, such as glomerulonephritis, diabetic nephropathy, lupus nephritis, hypertension-induced nephropathy, renal interstitial fibrosis, renal fibrosis resulting from complications of drug exposure, HIV-associated nephropathy, transplant nephropathy, liver fibrosis due to all etiologies, hepatic dysfunction attributable to infections, alcohol-induced hepatitis, disorders of the biliary tree, pulmonary fibrosis, acute lung injury, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, pulmonary disease due to infectious or toxic agents, post-infarction cardiac fibrosis, congestive heart failure, dilated cardiomyopathy, myocarditis, vascular stenosis, hypertension-induced vascular remodeling, pulmonary arterial hypertension, coronary restenosis, peripheral restenosis, carotid restenosis, stent-induced restenosis, atherosclerosis, ocular scarring, corneal scarring, proliferative vitreoretinopathy, excessive or hypertrophic scar or keloid formation in the dermis occurring during wound healing resulting from trauma or surgical wounds, peritoneal and sub-dermal adhesion, scleroderma, fibrosclerosis, progressive systemic sclerosis, dermatomyositis, polymyositis, arthritis, osteoporosis, ulcers, impaired neurological function, male erectile dysfunction, Peyronie's disease, Dupuytren's contracture, Alzheimer's disease, Raynaud's syndrome, fibrotic cancers, tumor metastasis growth, radiation-induced fibrosis, and thrombosis.

Problems solved by technology

Organ transplantation is complicated in many instances by chronic rejection and for some organs such as the kidney, it is the major forms of graft loss.

Method used

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  • 2-pyridyl substituted imidazoles as therapeutic alk5 and/or alk4 inhibitors
  • 2-pyridyl substituted imidazoles as therapeutic alk5 and/or alk4 inhibitors
  • 2-pyridyl substituted imidazoles as therapeutic alk5 and/or alk4 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 8

Preparative Example 8

Preparation of 6-(2-(dimethoxymethyl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (a Compound of the Formula (VI) wherein Ra═CH2CH3)

[0194]The titled compound was prepared as described in Preparative Example 7 by using 1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-ethylpyridin-2-yl)ethane-1,2-dione in place of 1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-methylpyridin-2-yl)ethane-1,2-dione. Yield: 68%; 1H NMR (400 MHz, CDCl3): δ 10.67 (br s, 1H), 8.97 (br s, 1H), 8.35 (s, 1H), 7.83 (dd, 1H, J=9.2, 1.6 Hz), 7.76 (dd, 1H, J=9.2, 0.8 Hz), 7.50 (t, 1H, J=7.8 Hz), 7.25 (br d, 1H, J=7.6 Hz), 7.05 (d, 1H, J=8.0 Hz), 5.56 (s, 1H), 3.46 (s, 6H), 2.83 (q, 2H, J=7.6 Hz), 1.31 (t, 3H, J=7.6 Hz).

example 9

Preparative Example 9

Preparation of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazole-2-carbaldehyde (a Compound of the Formula (VII) wherein Ra═CH3)

[0195]6-(2-(Dimethoxymethyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (6.00 g, 17.12 mmol) was dissolved in 1 N HCl (120 mL), and the mixture was heated at 70° C. for 3 h. The reaction mixture was allowed to cool to 0° C., and then it was neutralized with saturated aqueous NaHCO3 solution. The mixture was extracted with 10% MeOH in CHCl3 (3×200 mL), and the organic phase was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure to give the titled compound (4.69 g, 90%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.82 (s, 1H), 9.01 (br s, 1H), 8.41 (s, 1H), 7.85 (dd, 1H, J=9.2, 0.8 Hz), 7.82 (dd, 1H, J=9.2, 1.6 Hz), 7.55 (t, 1H, J=7.8 Hz), 7.33 (br s, 1H), 7.16 (d, 1H, J=8. 0 Hz), 2.60 (s, 3H).

example 10

Preparative Example 10

Preparation of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-ethylpyridin-2-yl)-1H-imidazole-2-carbaldehyde (a Compound of the Formula (VII) wherein Ra═CH2CH3)

[0196]The titled compound was prepared as described in Preparative Example 9 by using 6-(2-(dimethoxymethyl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine in place of 6-(2-(dimethoxymethyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine. Yield: 99%; 1H NMR (400 MHz, DMSO-d6) δ 9.86 (t, 1H, J=1.2 Hz), 9.59 (s, 1H), 8.43 (s, 1H), 8.21 (dd, 1H, J=9.2, 1.6 Hz), 7.82 (br d, 1H, J=8.0 Hz), 7.73 (dd, 1H, J=9.2, 0.8 Hz), 7.69 (t, 1H, J=7.8 Hz), 7.08 (br d, 1H, J=7.6 Hz), 2.71 (q, 2H, J=7.6 Hz), 1.16 (t, 3H, J=7.6 Hz).

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Abstract

This invention relates to 2-pyridyl substituted imidazoles which are inhibitors of the transforming growth factor-β (TGF-β) type I receptor (ALK5) and / or the activin type I receptor (ALK4), methods for their preparation, and their use in medicine, specifically in the treatment and prevention of a disease state mediated by these receptors.

Description

[0001]This work was supported by National Research Foundation grant funded by the Korean government (M10870050001-08N7005-00110).TECHNICAL FIELD OF THE INVENTION[0002]This invention relates to 2-pyridyl substituted imidazoles which are inhibitors of the transforming growth factor-β (TGF-β) type I receptor (ALK5) and / or the activin type I receptor (ALK4), methods for their preparation, and their use in medicine, specifically in the treatment and prevention of a disease state mediated by these receptors.BACKGROUND OF THE INVENTION[0003]TGF-β denotes a family of proteins, TGF-β1, TGF-β2 and TGF-β3, which are pleiotropic modulators of cell proliferation and differentiation, wound healing, extracellular matrix production and immunosuppression. Other members of this superfamily include activins, inhibins, bone morphogenetic proteins, growth and differentiation factors and Müllerian inhibiting substance.[0004]TGF-β1 transduces signals through two highly conserved single transmembrane serin...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/444A61P11/00A61P35/04A61P25/00C07D471/04A61K31/5377
CPCC07D471/04A61P1/04A61P1/16A61P1/18A61P11/00A61P13/08A61P13/12A61P15/00A61P15/10A61P17/00A61P17/02A61P19/02A61P19/10A61P21/00A61P25/00A61P25/28A61P27/02A61P27/06A61P31/18A61P35/00A61P35/02A61P35/04A61P43/00A61P7/02A61P9/00A61P9/04A61P9/08A61P9/10A61P9/12A61P3/10C07D401/14A61K31/437
Inventor KIM, DAE-KEESHEEN, YHUN YHONGJIN, CHENGHUAPARK, CHUL-YONGSREENU, DOMALAPALLYRAO, KOTA SUDHAKARKRISHNAIAH, MADDEBOINASUBRAHMANYAM, VURA BALA
Owner EWHA UNIV IND COLLABORATION FOUND
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