- Pyrimidine derivatives as anti-diabetic agents
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The pyrimidine derivatives as anti-diabetic agents are chloropyrimidinyl derivatives having the general formula of compound 81, wherein R1 is —N(CH3)CH2CH2OH (compound 81c) or —N(H)CH2CH2OH (compound 81f) or the general formula of compound 82, wherein R2 is —N(CH3)CH2CH2OH (compound 82c) or —N(CH2CH2)2O (compound 82d), as follows: The derivatives may be used for treating diabetes in humans or animals and have demonstrated efficacy, specifically in treating type 2 diabetes. Two methods of synthesizing the pyrimidine derivatives are described herein. The method using microwaves (Method B) is a green method that can provide high yields in a short time and with high purity. The compounds act as GLP-1 receptor agonists and are more potent than conventional drugs. As such, the compounds may be used in lower doses, and, hence, have fewer side effects.
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Page/Page column 6
(2020/07/21)
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- Mycobacterium tuberculosis Decaprenylphosphoryl-β- d -ribose Oxidase Inhibitors: Expeditious Reconstruction of Suboptimal Hits into a Series with Potent in Vivo Activity
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Decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) is an essential enzyme in Mycobacterium tuberculosis and has recently been studied as a potential drug target, with inhibitors progressing to clinical studies. Here we describe the identification of a n
- Borthwick, Jennifer A.,Alemparte, Carlos,Wall, Ian,Whitehurst, Benjamin C.,Argyrou, Argyrides,Burley, Glenn,De Dios-Anton, Paco,Guijarro, Laura,Monteiro, Maria Candida,Ortega, Fatima,Suckling, Colin J,Pichel, Julia Castro,Cacho, Monica,Young, Robert J.
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p. 2557 - 2576
(2020/03/31)
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- O-GLYCOPROTEIN-2-ACETAMIDO-2-DEOXY-3-D-GLUCOPYRANOSIDASE INHIBITORS
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Described herein are compounds represented by formulas (IA) or (IB) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same and methods of preparing and using the same. The variables R1, R3, R4, Y1, Y2, Ar, Z and n are as defined herein.
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Paragraph 00223
(2020/04/25)
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- FUSED TETRAZOLES AS LRRK2 INHIBITORS
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The present invention is directed to fused tetrazoles of formula (IA) which are inhibitors of LRRK2 and are useful in the treatment of CNS disorders.
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Page/Page column 67-69
(2019/12/04)
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- Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia
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Small-molecule inhibitors of hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment options for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased erythropoietin (EPO) expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, structure–activity relationship (SAR), and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia. High-throughput screening of our corporate compound library identified BAY-908 as a promising hit. The lead optimization program then resulted in the identification of molidustat (BAY 85-3934), a novel small-molecule oral HIF-PH inhibitor. Molidustat is currently being investigated in clinical phase III trials as molidustat sodium for the treatment of anemia in patients with CKD.
- Beck, Hartmut,Jeske, Mario,Thede, Kai,Stoll, Friederike,Flamme, Ingo,Akbaba, Metin,Ergüden, Jens-Kerim,Karig, Gunter,Keldenich, J?rg,Oehme, Felix,Militzer, Hans-Christian,Hartung, Ingo V.,Thuss, Uwe
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p. 988 - 1003
(2018/04/19)
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- COMPOUNDS
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Disclosed are novel compounds that inhibit LRRK2 kinase activity, processes for their preparation, compositions containing them and their use in the treatment of or prevention of diseases characterized by LRRK2 kinase activity, for example Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis(ALS).
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Page/Page column 73
(2017/02/09)
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- Design and Discovery of N-(2-Methyl-5′-morpholino-6′-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3′-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers
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RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date
- Nishiguchi, Gisele A.,Rico, Alice,Tanner, Huw,Aversa, Robert J.,Taft, Benjamin R.,Subramanian, Sharadha,Setti, Lina,Burger, Matthew T.,Wan, Lifeng,Tamez, Victoriano,Smith, Aaron,Lou, Yan,Barsanti, Paul A.,Appleton, Brent A.,Mamo, Mulugeta,Tandeske, Laura,Dix, Ina,Tellew, John E.,Huang, Shenlin,Mathews Griner, Lesley A.,Cooke, Vesselina G.,Van Abbema, Anne,Merritt, Hanne,Ma, Sylvia,Gampa, Kalyani,Feng, Fei,Yuan, Jing,Wang, Yingyun,Haling, Jacob R.,Vaziri, Sepideh,Hekmat-Nejad, Mohammad,Jansen, Johanna M.,Polyakov, Valery,Zang, Richard,Sethuraman, Vijay,Amiri, Payman,Singh, Mallika,Lees, Emma,Shao, Wenlin,Stuart, Darrin D.,Dillon, Michael P.,Ramurthy, Savithri
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supporting information
p. 4869 - 4881
(2017/06/28)
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- Selective mono-amination of dichlorodiazines
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A mild, easy-to-perform, and versatile method for the formation of aminochlorodiazines from reaction of several types of dichlorodiazines (i.e., pyridazines, pyrimidines, and pyrazines) with primary or secondary amines in ethanol in the presence of trieth
- Sengmany, Stéphane,Lebre, Julie,Le Gall, Ewan,Léonel, Eric
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p. 4859 - 4867
(2015/08/03)
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- Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntingtons disease
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We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.
- Toledo-Sherman, Leticia M.,Prime, Michael E.,Mrzljak, Ladislav,Beconi, Maria G.,Beresford, Alan,Brookfield, Frederick A.,Brown, Christopher J.,Cardaun, Isabell,Courtney, Stephen M.,Dijkman, Ulrike,Hamelin-Flegg, Estelle,Johnson, Peter D.,Kempf, Valerie,Lyons, Kathy,Matthews, Kimberly,Mitchell, William L.,Oconnell, Catherine,Pena, Paula,Powell, Kendall,Rassoulpour, Arash,Reed, Laura,Reindl, Wolfgang,Selvaratnam, Suganathan,Friley, Weslyn Ward,Weddell, Derek A.,Went, Naomi E.,Wheelan, Patricia,Winkler, Christin,Winkler, Dirk,Wityak, John,Yarnold, Christopher J.,Yates, Dawn,Munoz-Sanjuan, Ignacio,Dominguez, Celia
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p. 1159 - 1183
(2015/03/04)
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- BIARYL AMIDE COMPOUNDS AS KINASE INHIBITORS
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The present invention provides compounds of Formula (I) as described herein, and salts thereof, and therapeutic uses of these compounds for treatment of disorders associated with Raf kinase activity. The invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds and a therapeutic co-agent.
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Paragraph 0250; 0251
(2014/09/29)
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- SUBSTITUTED DIHYDROPYRAZOLONES AND USE THEREOF AS HIF-PROLYL-4 -HYDROXYLASE INHIBITORS
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The present application relates to novel substituted dihydropyrazolone derivatives, processes for their preparation, their use for treatment and/or prophylaxis of diseases and their use for the preparation of medicaments for treatment and/or prophylaxis of diseases, in particular cardiovascular and hematological diseases and kidney diseases, and for promoting wound healing.
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Page/Page column 16
(2012/10/23)
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- Effect of substituent structure on pyrimidine electrophilic substitution: A rebuttal
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The report about a series of unexpected and obscure effects influencing the electrophilic nitrosation of activated pyrimidines (Tetrahedron 2007, 63, 5394) was shown to be erroneous. Instead of electrophilic substitution at position 5 of the pyrimidine ring, N-nitrosation of the secondary amino group in the 4-position of the pyrimidine ring took place. Moreover it was shown that the synthetic sequence for the preparation of purines is also incorrect.
- Jakubkiene, Virginija,?ikotiene, Inga
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scheme or table
p. 2294 - 2298
(2012/04/10)
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- SUBSTITUTED DIHYDROPYRAZOLONES FOR TREATING CARDIOVASCULAR AND HEMATOLOGICAL DISEASES
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The invention relates to dihydropyrazolon-derivatives of formula (I), to methods for their production, to their use for treating and/or for preventing diseases and their use for producing medicaments for treating and/or for preventing diseases, in particular cardiovascular and haematological diseases, kidney diseases and for promoting the healing of wounds.
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Page/Page column 20
(2010/12/29)
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- Effect of substituent structure on pyrimidine electrophilic substitution
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In an investigation into the electrophilic nitrosation reactions of a series of 4,6-disubstituted pyrimidine derivatives, a subtle interplay between the electronic nature of the C-4 and C-6 substituents and reactivity was found where these were chloro-, mono- or disubstituted amino groups. Effects such as the presence of an aryl group or two alkyl groups on the amino moiety impede the progress of the reaction despite the presence of a second activating group.
- van der Westhuyzen, Christiaan W.,Rousseau, Amanda L.,Parkinson, Christopher J.
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p. 5394 - 5405
(2008/01/07)
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