- PYRAZOLE DERIVATIVES AS JAK INHIBITORS
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New pyrazole derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Page/Page column 137
(2011/09/19)
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- Novel orally bioavailable γ-secretase inhibitors with excellent in vivo activity
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The development of potent γ-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2′,3′,4′,5, 5′,6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methylpyrazol-3-yl) -5′-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11, 3′-[1,2,5]thiadiazole] 1′,1′-dioxide (16), which has excellent in vitro potency (0.06 nM) and which reduced amyloid-β in APP-YAC mice with an ED50 of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.
- Keown, Linda E.,Collins, Ian,Cooper, Laura C.,Harrison, Timothy,Madin, Andrew,Mistry, Jayesh,Reilly, Michael,Shaimi, Mohamed,Welch, Christopher J.,Clarke, Earl E.,Lewis, Huw D.,Wrigley, Jonathan D. J.,Best, Jonathan D.,Murray, Fraser,Shearman, Mark S.
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scheme or table
p. 3441 - 3444
(2010/03/30)
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- Discovery of novel heteroarylazoles that are metabotropic glutamate subtype 5 receptor antagonists with anxiolytic activity
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The highly potent, selective, and brain-penetrant metabotropic glutamate subtype 5 (mGlu5) receptor antagonists 3-(5-pyridin-2-yl-2H-tetrazol-2-yl) benzonitrile (47) and 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (48) are reported. Compound 47 is active in the rat fear-potentiated startle (FPS) model of anxiety with ED50 = 5.4 mg/kg (po) when dosed acutely. In this model the anxiolytic effects of 47 rapidly tolerate on repeated dosing.
- Roppe, Jeffrey,Smith, Nicholas D.,Huang, Dehua,Tehrani, Lida,Wang, Bowei,Anderson, Jeffrey,Brodkin, Jesse,Chung, Janice,Jiang, Xiaohui,King, Christopher,Munoz, Benito,Varney, Mark A.,Prasit, Petpiboon,Cosford, Nicholas D. P.
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p. 4645 - 4648
(2007/10/03)
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- HETEROARYL SUBSTITUTED SPIROCYCLIC SULFAMIDES FOR INHIBITION OF GAMMA SECRETASE
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Compounds of formula I are disclosed: in which X is a 5-membered heteroaryl ring and R is as defined herein. The compounds are inhibitors of the processing of APP by gamma-secretase, and hence are useful in the treatment or prevention of Alzheimer's disease.
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Page/Page column 120
(2008/06/13)
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- Micelle Activated Reactions I. Micelle Activated Iodination and Partial Dehalogenation of Pyrazoles and 1,2,4-Triazoles
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A method is described to iodinate pyrazole, substituted pyrazoles or 1,2,4-triazole with iodine or iodine chloride in aqueous alkaline in the presence of an anionic surfactant. 4-Iodo- (2a), 4-iodo-3(5)-methyl- (2b), 3(5),4-diiodo- (3a), 3(5),4-diiodo-5(3)-methyl- (3b), and 3,4,5-triiodo-pyrazole (3d) as soon as 4-iodo-pyrazole-3(5)-carboxylic acid (2c), and 3(5)-iodo-1,2,4-triazole (5) were prepared.Anhydrous hydrogen fluoride or triethylamine trishydrofluoride were found to be a suitable agent to effect a regioselective partial dehalogenation of 3b, 3d and 3,5-dibromo-1,2,4-triazole (7).We prepared 3(5)-iodo-5(3)-methyl-pyrazole (6b), 3,5-diiodo-pyrazole (6d) and 3(5)-bromo-1,2,4-triazole (8) on this way.
- Miethchen, R.,Randow, R.,Listemann, R.,Hildebrandt, J.,Kohlheim, K.
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p. 799 - 805
(2007/10/02)
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