- COPPER COMPLEXES FOR TREATMENT OF NEURODEGENERATIVE DISORDERS
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The present disclosure relates to copper complexes, pharmaceutical compositions comprising these complexes, chemical processes for preparing these complexes, and their use in the treatment of neurodegenerative disease, e.g., amyotrophic lateral sclerosis (ALS).
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Page/Page column 121; 158
(2022/03/22)
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- SUBSTITUTED [1,2,4] TRIAZOLO [1,5-A] PYRIMIDIN-7-YL COMPOUNDS AS PDE2 INHIBITORS
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The invention provides a chemical entity of Formula (I): wherein R1, R2, X, Y and Z have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of
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Page/Page column 48
(2015/11/10)
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- "Nanorust"-catalyzed benign oxidation of amines for selective synthesis of nitriles
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Organic nitriles constitute key precursors and central intermediates in organic synthesis. In addition, nitriles represent a versatile motif found in numerous medicinally and biologically important compounds. Generally, these nitriles are synthesized by traditional cyanation procedures using toxic cyanides. Herein, we report the selective and environmentally benign oxidative conversion of primary amines for the synthesis of structurally diverse aromatic, aliphatic and heterocyclic nitriles using a reusable "nanorust" (nanoscale Fe2O3)-based catalysts applying molecular oxygen.
- Jagadeesh, Rajenahally V.,Junge, Henrik,Beller, Matthias
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- Synthesis and evaluation of fluorinated analogues of monoamine reuptake inhibitors
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The synthesis of two series of fluorinated analogues of monoamines reuptake inhibitors based on tertiary alcohols 2-substituted morpholines scaffold has been achieved through the incorporation of fluorinated substituent into 2-substituted morpholino ketones. Their binding affinities have been measured on different monoamine transporters.
- Philippe, Christine,Kaffy, Julia,Milcent, Thierry,Bonnet-Delpon, Danile
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experimental part
p. 136 - 145
(2012/03/08)
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- A COMPOUND FOR INHIBITING HUMAN 11-β-HYDROXY STEROID DEHYDROGENASE TYPE 1, AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to a novel compound, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for human-11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) comprising the same. The invention provides a compound, which has excellent activity and solubility and is more efficiently formulated and delivered, and a pharmaceutical composition for human-11-beta-hydroxysteroid dehydrogenase type 1 comprising the same.
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Page/Page column 27-28
(2012/10/08)
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- Discovery of triazolopyrimidine-based PDE8B inhibitors: Exceptionally ligand-efficient and lipophilic ligand-efficient compounds for the treatment of diabetes
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PDE8B is a cAMP-specific isoform of the broader class of phosphodiesterases (PDEs). As no selective PDE8B inhibitors had been reported, a high throughput screen was run with the goal of identifying selective tools for exploring the potential therapeutic utility of PDE8B inhibition. Of the numerous hits, one was particularly attractive since it was amenable to rapid deconstruction leading to inhibitors with very high ligand efficiency (LE) and lipophilic ligand efficiency (LLE). These triazolopyrimidines were optimized for potency, selectivity and ADME properties ultimately leading to compound 42. This compound was highly potent and selective with good bioavailability and advanced into pre-clinical development.
- Deninno, Michael P.,Wright, Stephen W.,Etienne, John B.,Olson, Thanh V.,Rocke, Benjamin N.,Corbett, Jeffrey W.,Kung, Daniel W.,Dirico, Kenneth J.,Andrews, Kim M.,Millham, Michele L.,Parker, Janice C.,Esler, William,Van Volkenburg, Maria,Boyer, David D.,Houseknecht, Karen L.,Doran, Shawn D.
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scheme or table
p. 5721 - 5726
(2012/09/22)
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- DIHYDROPTERIDINONE DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF
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Dihydroperidinone derivatives, preparation process and pharmaceutical use thereof are disclosed. Specially, new dihydroperidinone derivatives represented by general formula (I), wherein each substituent of the general formula (I) is defined as in the description, their preparation process, pharmaceutical compositions comprising said derivatives and their use as therapeutical agents, especially as Plk kinase inhibitors are disclosed.
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- DIHYDROPTERIDINONE DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF
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Dihydroperidinone derivatives, preparation process and pharmaceutical use thereof are disclosed. Specially, new dihydroperidinone derivatives represented by general formula (I), wherein each substituent of the general formula (I) is defined as in the description, their preparation process, pharmaceutical compositions comprising said derivatives and their use as therapeutical agents, especially as Plk kinase inhibitors are disclosed.
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- CHEMICAL COMPOUNDS
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The invention is directed to 6-(4-pyι?midinyl)-1 H-indazole derivatives. Specifically, the invention is directed to compounds according to Formula (I) wherein R1 - R4 are defined herein. The compounds of the invention are inhibitors of PDK1 and can be useful in the treatment of immune and metabolic diseases and disorders characterized by constitutively activated ACG kinases such as cancer and more specifically cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 224-225
(2010/07/10)
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- Practical synthesis of chiral 2-morpholine: (4-Benzylmorpholin-2-(s)-yl)- (tetrahydropyran-4-yl) Methanone mesylate, a useful pharmaceutical intermediate
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A commercial synthesis was developed for the production of (4-benzylmorpholin-2-(S)-yl)-(tetrahydropyran-4-yl) methanone mesylate, la, a key starting material for a phase 2, new investigational drug candidate at Eli Lilly and Company. The target compound was produced in the clinical pilot plant by the combination of two key steps: resolution of a morpholine amide intermediate to install the S-morpholino stereocenter in 35% yield and a high-yielding (89%) Grignard reaction to generate the title compound la, isolated as a mesylate salt. The Grignard reaction was found to proceed optimally when using a combination of I2 and DIBAL-H for the initiation. In addition, the Grignard reagent formation was monitored by ReactMax calorimetry, and proof-of-concept studies were completed, demonstrating that the Grignard step could potentially be run as a continuous process with magnesium recycling.
- Kopach, Michael E.,Singh, Utpal K.,Kobierski, Michael E.,Trankle, William G.,Murray, Michael M.,Pietz, Mark A.,Forst, Mindy B.,Stephenson, Gregory A.,Mancuso, Vincent,Giard, Thierry,Vanmarsenille, Michel,De France, Thierry
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experimental part
p. 209 - 224
(2010/04/22)
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- 3-METHYL-2- ( (2S) -2- (4- (3-METHYL-L, 2, 4-0XADIAZ0L-5-YL) PHENYL) MORPHOLINO) -6- (PYRIMIDIN-4-YL) PYRIMIDIN-4 (3H) -ONE AS TAU PROTEIN KINASE INHIBITOR
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A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof: which is used for preventive and/or therapeutic treatment of a disease caused by abnormal activity of tau protein kinase 1 such as a neurodegenerative diseases (e.g.
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Page/Page column 25
(2009/04/25)
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- 6-PYRIMIDINYL-PYRIMID-2-ONE DERIVATIVE
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A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof: which is used for preventive and/or therapeutic treatment of a disease caused by abnormal activity of tau protein kinase 1 such as a neurodegenerative diseases (e.g.
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Page/Page column 25-26
(2009/04/25)
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- Enantioselective synthesis of (R)- and (S)-N-Boc-morpholine-2-carboxylic acids by enzyme-catalyzed kinetic resolution: application to the synthesis of reboxetine analogs
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The (R)- and (S)-N-Boc-morpholine-2-carboxylic acids 9 and 10 were prepared using an enantioselective synthesis employing a highly selective enzyme-catalyzed kinetic resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (11) as the key step. Acids 9 and 10 were then converted efficiently and stereoselectively to reboxetine analogs 3 and 4.
- Fish, Paul V.,Mackenny, Malcolm,Bish, Gerwyn,Buxton, Timothy,Cave, Russell,Drouard, David,Hoople, David,Jessiman, Alan,Miller, Duncan,Pasquinet, Christelle,Patel, Bhairavi,Reeves, Keith,Ryckmans, Thomas,Skerten, Melanie,Wakenhut, Florian
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scheme or table
p. 389 - 391
(2009/05/11)
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- Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition
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Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.
- Fish, Paul V.,Deur, Christopher,Gan, Xinmin,Greene, Keri,Hoople, David,Mackenny, Malcolm,Para, Kimberly S.,Reeves, Keith,Ryckmans, Thomas,Stiff, Cory,Stobie, Alan,Wakenhut, Florian,Whitlock, Gavin A.
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p. 2562 - 2566
(2008/12/21)
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- Discovery of novel and selective tertiary alcohol containing inhibitors of the norepinephrine transporter
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A novel series of tertiary alcohol containing 2-substituted benzyl morpholines have been discovered as potent and selective inhibitors of the norepinephrine transporter. Efficient synthetic routes were developed featuring a highly diastereoselective nucleophilic addition of benzyl Grignard reagents to enantiopure (4-benzylmorpholin-2-yl)phenylmethanone (11) as the key synthetic step. In vitro binding affinity for the norepinephrine, dopamine and serotonin transporters and in vivo examination of a select compound (16) in a pharmacodynamic animal model for norepinephrine reuptake inhibition are presented.
- Cases-Thomas, Manuel J.,Masters, John J.,Walter, Magnus W.,Campbell, Gordon,Haughton, Louise,Gallagher, Peter T.,Dobson, David R.,Mancuso, Vincent,Bonnier, Benjamin,Giard, Thierry,Defrance, Thierry,Vanmarsenille, Michel,Ledgard, Andrew,White, Craig,Ouwerkerk-Mahadevan, Sivi,Brunelle, Francoise J.,Dezutter, Nancy A.,Herbots, Camy A.,Lienard, Joel Y.,Findlay, Jeremy,Hayhurst, Lorna,Boot, John,Thompson, Linda K.,Hemrick-Luecke, Susan
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p. 2022 - 2025
(2007/10/03)
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- MORPHOLINE DERIVATIVES AS NOREPINEPHRINE REUPTAKE INHIBITORS
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Compounds of the general formula (I) are inhibitors of the reuptake of norepinephrine. As such, they may be useful for the treatment of disorders of the central and/or peripheral nervous system.
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Page/Page column 47-48
(2010/02/11)
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- TREATMENT OF HOT FLASHES, IMPULSE CONTROL DISORDERS AND PERSONALITY CHANGE DUE TO A GENERAL MEDICAL CONDITION
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Selective norepinephrine reuptake inhibitors are useful for the prevention or treatment of hot flashes, vasomotor symptoms, impulse control disorders or personality change due to a general medical condition.
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Page/Page column 275
(2010/02/12)
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- PYRIDINYLMORPHOLINE DERIVATIVES
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The invention relates to compounds of formula (I); wherein R, R1, R2 and X are as defined herein, their preparation and their use as pharmaceuticals.
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Page/Page column 31-32
(2008/06/13)
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- MORPHOLINE DERIVATIVES AS NOREPINEPHRINE REUPTAKE INHIBITORS
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Compounds of the general formula (I) are inhibitors of the reuptake of norepinephrine. As such, they may be useful for the treatment of disorders of the central and/or peripheral nervous system.
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Page/Page column 36
(2008/06/13)
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- TREATMENT OF LEARNING DISABILITIES AND MOTOR SKILLS DISORDER WITH NOREPINEPHRINE REUPTAKE INHIBITORS
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Provided are methods and medicaments for treating a learning disability or a Motor Skills Disorder, comprising administering to a patient in need of such treatment an effective amount of a selective norepinephrine reuptake inhibitor.
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Page/Page column 124
(2010/02/11)
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- TREATMENT OF PERVASIVE DEVELOPMENTAL DISORDERS WITH NOREPINEPHRINE REUPTAKE INHIBITORS
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Provided are methods and medicaments for treating a Pervasive Developmental Disorder, comprising administering to a patient in need of such treatment an effective amount of a selective norepinephrine reuptake inhibitor.
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Page/Page column 126-128
(2010/02/11)
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- BENZYL MORPHOLINE DERIVATIVES
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A compound of formula (I) (I)wherein R is H; Ar is an aromatic group selected from phenyl; X is a phenyl group; R' is H or C1-C4 alkyl; each R1 is independently H or C1-C4 alkyl; and pharmaceutically acceptable salts thereof.
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- ARYL AND HETEROARYL MORPHOLINE DERIVATIVES
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Compounds of formula (I) are selective inhibitors of the reuptake of norepinephrine, wherein Rx is H; Ry is H or C1-C4 alkyl; each Rz is independently H or C1-C4 alkyl; X represents O; Y represents OH or OR; R is C1-C4 alkyl; and Ar1 and Ar2 are optionall
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- MORPHOLINE DERIVATIVES
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Compounds of formula (I), wherein: A is S or O; R is H; Ar is an optionally substituted phenyl group; X is an optionally substituted phenyl group, a C1-C4 alkyl, a C3-C6 cycloalkyl group or a CH2(C3-C6 cycloalkyl) group; R' is H or C1-C4 alkyl; and each R
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- Substituted Benzamides with Conformationally Restricted Side Chains. 5. Azabicyclo Derivatives as 5-HT4 Receptor Agonists and Gastric Motility Stimulants
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The syntheses of benzamides containing azabicyclo side chains and their 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties are described.These compounds were designed to mimic higher energy conformations of quinol
- King, Frank D.,Hadley, Michael S.,Joiner, Karen T.,Martin, Roger T.,Sanger, Gareth J.,et al.
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p. 683 - 689
(2007/10/02)
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- The synthesis of 2-morpholine carboxylic acid derivatives and their elaboration to 1-aza-4-oxabicyclo[3.3.1]nonan-6-one
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Two syntheses of novel 2-morpholine carboxylic acid derivatives are described. The esters were converted into 1-aza-4-oxabicyclo[3.3.1]nonan-6-one, the first example of this ring system, which was further elaborated to the ortho-methoxy benzamide derivative (2).
- King,Martin
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p. 2281 - 2284
(2007/10/19)
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