- 5-(PYRIDIN-2-YL-AMINO)-PYRAZINE-2-CARBONITRILE COMPOUNDS AND THEIR THERAPEUTIC USE
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The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain pyridyl-amino-pyrazine carbonitrile compounds that, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) aDNA damaging agent; (c) an antimetabolite or thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; and (e) ionisin g radiation.
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Page/Page column 66; 67
(2013/05/23)
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- Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing
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Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b] azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice. (Figure presented)
- Reader, John C.,Matthews, Thomas P.,Klair, Suki,Cheung, Kwai-Ming J.,Scanlon, Jane,Proisy, Nicolas,Addison, Glynn,Ellard, John,Piton, Nelly,Taylor, Suzanne,Cherry, Michael,Fisher, Martin,Boxall, Kathy,Burns, Samantha,Walton, Michael I.,Westwood, Isaac M.,Hayes, Angela,Eve, Paul,Valenti, Melanie,De Haven Brandon, Alexis,Box, Gary,Van Montfort, Rob L. M.,Williams, David H.,Aherne, G. Wynne,Raynaud, Florence I.,Eccles, Suzanne A.,Garrett, Michelle D.,Collins, Ian
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experimental part
p. 8328 - 8342
(2012/02/06)
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- Simple one-pot process for the bioresolution of tertiary amino ester protic ionic liquids using subtilisin
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An efficient hydrolase-catalyzed bioresolution of tertiary amino ester protic ionic liquids has been demonstrated. Protic ionic liquids have been prepared in one step from the corresponding tertiary amino alcohols by treatment with butyric anhydride. Afte
- Brossat, Maude,Moody, Thomas S.,Taylor, Stephen J.C.,Wiffen, Jonathan W.
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experimental part
p. 2112 - 2116
(2010/02/28)
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- COMPOSITIONS CONTAINING (S)-BETHANECHOL AND THEIR USE IN THE TREATMENT OF INSULIN RESISTANCE, TYPE 2 DIABETES, GLUCOSE INTOLERANCE AND RELATED DISORDERS
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The present invention provides pharmaceutical compositions comprising (S)-bethanechol or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier and optionally at least one diabetes drug. The use of said composition in the treatment of insulin resistance, type 2 diabetes, impaired glucose tolerance and related disorders is also provided. The invention also provides for a kit comprising the pharmaceutical compositions and instructions for its use.
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Page/Page column 22
(2008/06/13)
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- Electroreductive generation of (S)-(+)-N,N-dimethyl-2-(hydroxymethyl)- pyrrolidinium mercury compound for enantioselective synthesis of 2-amino-1-alkyl/aryl ethanols
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(S)-(+)-N, N - Dimethyl-2-(hydroxymethyl)-pyrrolidinium (DMHP +)-mercury compound mediated enantioselective reduction of aminomethyl alkyl/aryl ketones in dimethylformamide-2-propanol (9:1) has been carried out using tetrabutylammonium tetrafluoroborate as a supporting electrolyte. The products viz. 2-amino-1-alkyl/aryl ethanols have been obtained in good yield (68-92%) with 35-91% optical purity and have been assigned (S)-configuration. The pinacol (racemic/meso) derivatives are also isolated as minor products (yield 5-20%) via dimerization of radical anion followed by protonation.
- Yadav, Ashok K.,Manju, Meera
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p. 2770 - 2772
(2008/04/18)
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- Stereoselective process for the preparation of Clopidogrel
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Preparation of (2-halophenyl)(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl) compounds (Ia) or their salts comprises converting benzene derivatives (II) with an optically active amino alcohol to form a first mixture of diastereomers. Preparation of (2-halophenyl)(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl) compounds of formula (Ia) or its salt comprises converting benzene derivatives of formula (II) with an optically active amino alcohol to a first mixture of diastereomers. X : halo; and Y, Z : leaving groups. Independent claims are also included for the following: (1) a mixture of benzene diastereomers of formulae (IVa) and (IVb); (2) a compound (IVa); (3) a mixture of thiazo piperidine diastereomers of formulae (VIa) and (VIb); (4) compound (VIa); (5) a mixture of thiophene diastereomers of formulae (VIIIa) and (VIIIb); (6) a compound (VIIIa); and (7) preparation of 1-dimethylamino-propan-2-ol compound of formula (a) comprising reacting a diastereomeric mixtures of 1-dimethylamino-propan-2-ol of formulae (b) and (c) with L-(-)-di-O-benzoyl-L-(-)-tartaric acid (L-(-)-DBTA) and separating the L-(-)-DBTA salts of the compounds. A* : 1-30C hydrocarbon (containing 5 heteroatoms of S, O, N or halo and substituted with 5 substituents of OH, oxo, CN or nitro group) or one or more optically active units; and either R 1>, R 2>H, 1-20C hydrocarbon containing 4 heteroatoms of S, O, N or halo and substituted with 5 substituents of OH, oxo, CN or nitro groups); or C+R 1>+R 2> or R 1>+R 2>+heteroatom of A* : 5-10 membered ring (optionally saturated and optionally containing further 1-3 heteroatoms of N, O or S adjacent to the N, then a ring member is substituted with up to 5 substituents of 1-6C alkyl, 1-6C alkenyl, 1-6C alkoxy, 5-10C (hetero)aryl, 3-8C cycloalkyl, 2-8C heterocycloalkyl, halo, OH, oxo, CN or nitro (especially 1-6C alkyl, 5-10C hetero(aryl), 3-8C cycloalkyl or 2-8C heterocycloalkyl or N+R 1>+R 2> forms 3-8C saturated or unsaturated ring optionally with 1-6C alkyl or halo substituted and adjacent to N 1-2 further heteroatom of S, N or O). [Image] [Image] [Image] ACTIVITY : Anticoagulant; Thrombolytic. MECHANISM OF ACTION : Thrombocyte aggregation inhibitor.
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Page/Page column 40
(2008/06/13)
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- Synthesis of optically active methadones, LAAM and bufuralol by lipase-catalysed acylations
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(R)- and (S)-Methadones and levo-α-acetylmethadol (LAAM) have been synthesised starting from lipase-catalysed acylation of dimethylaminopropan-2-ol. An approach to the synthesis of (R)-bufuralol is also presented.
- Hull, Jonathan D.,Scheinmann, Feodor,Turner, Nicholas J.
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p. 567 - 576
(2007/10/03)
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- Diphenyloxazaborolidine a new catalyst for enantioselective reduction of ketones
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A variety of ketones can be reduced in high enantioselectivity with the oxazaborolidines derived from commercially available erythro aminodiphenylethanol.
- Quallich, George J.,Woodall, Teresa M.
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p. 4145 - 4148
(2007/10/02)
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- Stereoisomeric lactoyl β methylcholine iodides. Interaction with cholinesterase and acetylcholinesterase
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The preparation and absolute configuration of the stereoisomeric forms of lactoyl β methylcholine iodide with the 2 racemic forms of the molecule are reported. None of the stereoisomers were substrates for the enzyme acetylcholinesterase, whereas two stereoisomers (L lactoyl β methylcholine and D lactoyl L β methylcholine iodide) were poor substrates for cholinesterase. Results are analyzed in the light of previous studies of the chiral requirements of these 2 enzymes and an attempt is made to define the rate limiting or prohibited step in the enzyme catalyzed reaction with these compounds.
- Chan,Robinson
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p. 1057 - 1060
(2007/10/05)
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