- SUBSTITUTED OXAZINES AS GLUCOCORTICOID RECEPTOR MODULATORS
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The present invention is directed to compounds of formula (I), wherein R1 represents a C3-6cycloalkyl group; or a physiologically functional derivative thereof, pharmaceutical compositions comprising the compounds, the use of the compounds for the manufacture of medicaments particularly for the treatment of inflammatory and/or allergic conditions, processes for the preparation of the compounds, and chemical intermediates in the processes for the manufacture of the compounds.
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Page/Page column 36
(2010/02/15)
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- Dissociated nonsteroidal glucocorticoid receptor modulators; discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series
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The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC50 = 8.92 (105%) and 8.69 (92%) and MMTV pEC50 = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.
- Barker, Mike,Clackers, Margaret,Copley, Royston,Demaine, Derek A.,Humphreys, Davina,Inglis, Graham G. A.,Johnston, Michael J.,Jones, Haydn T.,Haase, Michael V.,House, David,Loiseau, Richard,Nisbet, Lesley,Pacquet, Francois,Skone, Philip A.,Shanahan, Stephen E.,Tape, Dan,Vinader, Victoria M.,Washington, Melanie,Uings, Iain,Upton, Richard,McLay, Iain M.,Macdonald, Simon J. F.
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p. 4216 - 4231
(2007/10/03)
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- Process for producing quinolonecarboxlic acids and intermediates thereof
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This invention relates to methods for the efficient production of quinolonecarboxylic acid based synthetic antibacterial agents which are expected for applications such as excellent medicaments and agricultural chemicals and to intermediate compounds to be used therein. According to the present invention, an amine substituent as the 7-position substituent of the quinolonecarboxylic acid derivative can be efficiently introduced.
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- Cycloalkyl-substituted aminomethylpyrrolidine derivatives
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This invention provides a quinolone derivative which exerts strong antibacterial action upon various bacteria and has high safety, and it relates to a compound having a structure of formula (I), its salts and hydrates thereof: {R1and R2/s
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- Anti acid-fast bacterial agent containing pyridonecarboxylic acids as active ingredient
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Anti-acid-fast bacterial agents containing as the active ingredient compounds represented by the general formula (1), salts thereof or hydrates of the same. Namely, pyridonecarboxylic acid derivatives having an excellent antibacterial activity on tubercle
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- β-Trichlorostannyl Ketones and Aldehydes. Preparation and Facile Amine-Induced Dehydrostannation Leading to α-Methylene Ketones and Aldehydes
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Ring-opening reactions of siloxycyclopropanes 1 with SnCl4 take place under mild reaction conditions and site-selectively to give β-trichlorostannyl ketones and aldehydes 3 in high yields.The β-trichlorostannyl ketones and aldehydes thus obtained readily undergo base-induced dehydrotrichlorostannation at room temperature to give the corresponding α-methylene ketones and aldehydes 4.The reactions are quite general for amines, such as pyridine, triethylamine, N,N,N',N',-tetramethylethylenediamine (TMEDA), and 1,4-diazabicyclooctane (DABCO), and the yields are good to high.One-pot conversion from siloxycyclopropanes 1 to α-methylene ketones or aldehydes 4 by consecutive treatment of 1 with SnCl4 and TMEDA is also successful.The 1H NMR, 13C NMR, 119Sn NMR, and IR spectral properties of β-stannyl ketones and aldehydes are also reported.
- Nakahira, Hiroyuki,Ryu, Ilhyong,Ikebe, Masanobu,Oku, Yoshiaki,Ogawa, Akiya,et al.
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- The Friedel-Crafts reaction of acid chlorides with ethene; di-addition and molecular rearrangement
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Acid chlorides, complexed with excess aluminium chloride, reacted with ethene to form 3-methyl-2-buten-1-ones, i.e. rearranged di-addition products having a terminal isoprenoid skeleton, together with the usual β-chloropropanones. The latter were the sole products in the absence of excess catalyst. Acid chlorides containing a suitably situated π-system underwent intramolecular cyclization, e.g. 2-phenylcyclopropanecarbonyl chloride (10) cyclized to 3,4-benzobicyclo[3.1.0]hexan-2-one (11).
- Bates,Donnelly,Keegan
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p. 4991 - 5000
(2007/10/02)
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