- Synthesis of 3-(Piperidin-4-yl)-6,7-dihydro-5H-pyrrolo-[2,1-c][1,2,4]triazole and Theoretical Study of the Hydrazone-Hydrazine Tautomerism of the Intermediate Hydrazonation Product
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3-(Piperidin-4-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole was synthesized through a four-step process including etherification, hydrazonation, cyclization, and reduction with an overall yield of 39%. The final product was characterized by 1/su
- Zhang,Wan,Ma, Yu,Qin,Ke,Pan,Zhang
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Read Online
- γ-Lactam-Based Antifungal Compounds against the Wheat Pathogen Zymoseptoria tritici
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As new environmentally friendly and effective antifungal agents are deeply needed, efficient ecofriendly strategies were designed to access two series of compounds inspired from natural γ-lactams. Designed compounds were fully characterized and evaluated as antifungal candidates against Zymoseptoria tritici, the main pathogen on wheat crops. The targeted derivatives were prepared from natural resources using green solvents, simple procedures, and limited purification steps. These bio-inspired compounds revealed as good candidates for further development of efficient crop protection products. Indeed, the HIT compounds exhibited IC50 around 1 μg/mL and were more active than the references tebuconazole and bixafen towards some multidrug-resistant strains. Two dozen of derivatives have been obtained for each series and allowed to establish early structure-activity relationships useful for the development of next generation of γ-lactam derivatives with improved efficacy.
- Damiens, Audrey,Dascalu, Anca-Elena,Taghi Alebrahim, Mohammad,Furman, Christophe,Lipka, Emmanuelle,Ghinet, Alina,Hilbert, Jean-Louis,Siah, Ali,Billamboz, Muriel
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- N-Heterocyclic carbene triazolium salts containing brominated aromatic motifs: Features and synthetic protocol
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In this work, we provide a brief overview of the role of N-aryl substituents on triazolium N-heterocyclic carbene (NHC) catalysis. This synopsis provides context for the disclosed synthetic protocol for new chiral N-heterocyclic carbene (NHC) triazolium salts with brominated aromatic motifs. Incorporating brominated aryl rings into NHC structures is challenging, probably due to the substantial steric and electronic influence these substituents exert throughout the synthetic protocol. However, these exact characteristics make it an interesting N-aryl substituent, because the electronic and steric diversity it offers could find broad use in organometallic- A nd organo-catalysis. Following the synthetic reaction by NMR guided the extensive modification of a known protocol to enable the preparation of these challenging NHC pre-catalysts.
- Raed, Anas Abo,Dhayalan, Vasudevan,Barkai, Shahar,Milo, Anat
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p. 878 - 882
(2020/12/25)
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- Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies
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A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.
- Barlaam, Bernard,Casella, Robert,Cidado, Justin,Cook, Calum,De Savi, Chris,Dishington, Allan,Donald, Craig S.,Drew, Lisa,Ferguson, Andrew D.,Ferguson, Douglas,Glossop, Steve,Grebe, Tyler,Gu, Chungang,Hande, Sudhir,Hawkins, Janet,Hird, Alexander W.,Holmes, Jane,Horstick, James,Jiang, Yun,Lamb, Michelle L.,McGuire, Thomas M.,Moore, Jane E.,O'Connell, Nichole,Pike, Andy,Pike, Kurt G.,Proia, Theresa,Roberts, Bryan,San Martin, Maryann,Sarkar, Ujjal,Shao, Wenlin,Stead, Darren,Sumner, Neil,Thakur, Kumar,Vasbinder, Melissa M.,Varnes, Jeffrey G.,Wang, Jianyan,Wang, Lei,Wu, Dedong,Wu, Liangwei,Yang, Bin,Yao, Tieguang
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supporting information
p. 15564 - 15590
(2021/01/09)
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- METALLOENZYME INHIBITOR COMPOUNDS
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Provided are compounds having HDAC6 modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by HDAC6.
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Page/Page column 332
(2018/09/28)
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- Propionic Acid Derivatives and Methods of Use Thereof
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Provided herein are compounds and pharmaceutical compositions of formula I where R1, R2, R3, R4, R5 and R6 are as described herein. Also provided pharmaceutically acceptable salts or stereoisomers of these compounds. In addition methods are provided for inhibiting the binding of an integrin to treat various pathophysiological conditions.
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Paragraph 1811; 1812
(2018/11/21)
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- Carboranes as Aryl Mimetics in Catalysis: A Highly Active Zwitterionic NHC-Precatalyst
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Modern catalysis takes advantage of aryl-based interactions to tune and control reactions. In the design of N-heterocyclic-carbene catalysts, both the electronic and steric nature of the nitrogen substituents play a crucial role. Although hydrocarbon-based systems and especially aryl residues have contributed considerably to overcome multifaceted catalytic challenges, the unique properties of carborane moieties, including delocalized charge, potential planar chirality, and well-known thermodynamic stability, offer unprecedented opportunities to develop new catalysts while being employed as aryl mimetics. We report a straightforward synthetic route to a novel zwitterionic triazolium-based N-heterocyclic carbene (NHC) precatalyst bearing a 7,8-dicarba-nido-undecaboranyl substituent. The catalyst's excellent activity and its broad applicability are demonstrated in a wide range of organocatalytic transformations. Comparison of the performance with known N-aryl NHC catalysts offers preliminary insights into the stereoelectronic nature of this nido-carboranyl substituent.
- Selg, Christoph,Neumann, Wilma,L?nnecke, Peter,Hey-Hawkins, Evamarie,Zeitler, Kirsten
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supporting information
p. 7932 - 7937
(2017/06/19)
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- Synthesis of [1,2-A]-fused tricyclic dihydroquinolines by palladiumcatalyzed intramolecular C-N cross-coupling of polarized heterocyclic enamines
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A simple methodology for [1,2-A]-fused tricyclic dihydroquinolines is established. The key ste of the methodology is an intramolecular Buchwald-Hartwig amination reaction of suitabl halogenated (both bromo and chloro) cyclic enaminoketones, enaminoesters and enaminonitrile with various ring size (from five-to seven-membered). Optimal reaction conditions (palladiu source, base, ligand) depend on the ring size of the starting enamine, giving 65-98% yield of th tricyclic product. A treatment of the products with perchloric acid gives respective quinoliniu perchlorates.
- Bro?, B?etislav,R??i?ková, Zdeňka,?im?nek, Petr
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supporting information
p. 118 - 141
(2016/10/22)
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- Chemical Compounds
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Provided are a series of novel pyridine or pyrimidine derivatives which inhibit CDK9 and may be useful for the treatment of hyperproliferative diseases. In particular the compounds are of use in the treatment of proliferative disease such as cancer including hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors such as breast cancer, lung cancer, neuroblastoma and colon cancer.
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Paragraph 0679
(2017/01/19)
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- NITROGENATED HETEROCYCLIC COMPOUND
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The present invention provides a compound having a PDE2A selective inhibitory action, which is useful as an agent for the prophylaxis or treatment of schizophrenia, Alzheimer's disease and the like. The present invention is a compound represented by the formula (1): wherein each symbol is as described in the specification, or a salt thereof.
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Paragraph 0895
(2015/03/28)
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- Highly β-regioselective Friedel-Crafts aminoalkylation of pyrroles with cyclic perfluoroalkylated imines
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A Friedel-Crafts-type alkylation reaction was studied between various pyrroles and α-polyfluoroalkylated cyclic imines that were activated by Lewis acids. The reaction proceeded under mild conditions and provided a high yielding synthesis of α-CF3-substituted pyrrolidines and piperidines as well as seven-membered analogues that contained a pyrrole ring. The unpredictably high β-selectivity for the aminoalkylation of both 1H-pyrrole and N-substituted pyrrole was observed as a result of a thermodynamically-controlled electrophilic substitution reaction. The computational data are in full agreement with the experimental results, which confirmed the observed regioselectivity as a result of the lower energy of the β-substituted pyrroles that contain α-trifluoromethyl-substituted pyrrolidine, piperidine, and azepane rings. Trifluoromethyl-substituted cyclic imines were activated by various Lewis acids and underwent a reaction with pyrrole derivatives. An unpredictable β-selectivity was observed. The regioselectivity of the aminoalkylation was explained by computation data, which also confirmed the isomerization of the α isomer into the β isomer. Copyright
- Shmatova, Olga I.,Shevchenko, Nikolay E.,Balenkova, Elisabeth S.,Roeschenthaler, Gerd-Volker,Nenajdenko, Valentine G.
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p. 3049 - 3058
(2013/06/27)
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- New pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines: Synthesis, 2D-QSAR, anti-inflammatory, analgesic and ulcerogenicity studies
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New pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines were synthesized. A series of ylidene carbohydrazides 14a-i, and hydrazonate 15, were obtained from the prepared 3-carbohydrazide derivative 13. Pyrazole derivatives 12, 16a,b, 18, 19, 20, were also prepared through different reactions. The anti-inflammatory and analgesic activities of all new compounds were evaluated and most of them exerted comparable activity to indomethacin and celecoxib. Ulcer indexes for the most active compounds were calculated and most of them showed less ulcerogenic effect than the reference drugs. The most potent anti-inflammatory compound 12 showed an IC50 of 6.00 μmol/kg and low ulcer index. COX-1/COX-2 activity ratio of compounds 12 and 16b showed almost equal inhibitory effect on both isoenzymes. 2D-QSAR studies revealed good predictive and statistically significant QSAR models.
- Hanna, Mona M.
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- 2,6-dimethoxyphenyl-substituted n-heterocyclic carbenes (NHCs): A family of highly electron-rich organocatalysts
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Based on our recent finding that 2,6-dimethoxyphenyl-substituted NHCs show superior reactivity in the hydroacylation reactions of electron-neutral olefins compared with known NHCs, we now report the syntheses and crystal structures of four highly electron
- Schedler, Michael,Froehlich, Roland,Daniliuc, Constantin-G.,Glorius, Frank
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experimental part
p. 4164 - 4171
(2012/09/22)
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- N-heterocyclic carbene-catalyzed annulation of α-cyano-1,4-diketones with ynals
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In this paper, the first stereoselective annulation reaction between r-cyano-1,4-diketones and ynals, mediated by catalytic amounts of a triazolium salt precatalyst and cocatalytic amounts of a weak carboxylate base, is disclosed. The title transformation proceeds smoothly under mild reaction conditions and generates three contiguous stereogenic centers, one of which is a quaternary acetal carbon. This reaction tolerates a wide variety of electronically distinct substituents on both reaction partners and affords privileged bicyclic scaffolds in 61-90% isolated yields and with up to 20:1 diastereomeric preference.
- Romanov-Michailidis, Fedor,Besnard, Celine,Alexakis, Alexandre
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supporting information
p. 4906 - 4909,4
(2012/12/12)
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- N-heterocyclic carbene-catalyzed annulation of α-cyano-1,4-diketones with ynals
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In this paper, the first stereoselective annulation reaction between r-cyano-1,4-diketones and ynals, mediated by catalytic amounts of a triazolium salt precatalyst and cocatalytic amounts of a weak carboxylate base, is disclosed. The title transformation proceeds smoothly under mild reaction conditions and generates three contiguous stereogenic centers, one of which is a quaternary acetal carbon. This reaction tolerates a wide variety of electronically distinct substituents on both reaction partners and affords privileged bicyclic scaffolds in 61-90% isolated yields and with up to 20:1 diastereomeric preference.
- Romanov-Michailidis, Fedor,Besnard, Céline,Alexakis, Alexandre
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supporting information
p. 4906 - 4909
(2013/01/15)
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- MEK INHIBITOR SALTS AND SOLVATES THEREOF
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The present invention relates to sodium salt forms of 7-(4-Bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-1,3,5-tetrahydro-indolizine-8-carboxylic acid (2- hydroxyethoxy)-amide and 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo- 1,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy-amide and their corresponding solvates and polymorphs, which are useful in the treatment of a disease, disorder or syndrome associated with MEK inhibition, such as cancer, in mammals.
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Page/Page column 26
(2011/06/25)
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- Heterocyclic Compounds as MEK Inhibitors
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The present invention relates to compounds of formula I and pharmaceutically acceptable salts. These compounds can act as potential MEK inhibitors in the treatment of hyperproliferative diseases, like cancer and inflammation. The present invention also reveals methods of preparation thereof.
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Page/Page column 17
(2009/12/02)
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- Potent antimalarial activity of 2-aminopyridinium salts, amidines, and guanidines
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We describe the design, synthesis, and antimalarial activity of 60 bis-tertiary amine, bis-2(1H)-imino-heterocycle, bis-amidine, and bis-guanidine series. Bis-tertiary amines with a linker from 12 to 16 methylene groups were active against the in vitro growth of Plasmodium falciparum within the 10 -6-10-7 M concentration range. IC50 decreased by 2 orders of magnitude for bis-2-aminopyridinium salts, bis-amidines, and bis-guanidines (27 compounds with IC50 a over 12.5. Maximal activity occurs for bis-2-aminopyridinium, two C-duplicated bis-amidines, and three bis-guanidines, with IC50 values lower than 1 nM. In comparison to similar quaternary ammonium salts, amidinium compounds have distinct structural requirements for antimalarial activity and likely additional binding opportunities on account of their hydrogen-bond-forming properties.
- Calas, Michèle,Ouattara, Mahama,Piquet, Gilles,Ziora, Zyta,Bordat,Ancelin, Marie L.,Escale, Roger,Vial, Henri
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p. 6307 - 6315
(2008/09/16)
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- THIOPHENE-SUBSTITUITED PYRAZOLINES
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The invention relates to the field of blood coagulation and, in particular, to the use of thiophene-substituted pyrazolines (1) as medicaments, novel thiophene-substituted pyrazolines and to a method for the production thereof and to the use thereof for p
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Page/Page column 25
(2008/06/13)
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- AZETIDINE-SUBSTITUTED PYRAZOLINES AS PAR-1 ANTAGONISTS
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The invention relates to blood clotting, and especially to the use of azetidine-substituted pyrazolines as medicaments, novel azetidine-substituted pyrazolines, methods for the production thereof, and the use of the same for producing medicaments for the treatment and/or prophylaxis of diseases, especially cardiovascular diseases, preferably thromboembolic diseases.
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Page/Page column 29
(2008/06/13)
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- PYRAZOLINES AS PAR-1 ANTAGONISTS FOR TREATMENT OF CARDIOVASCULAR DISEASES
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The invention relates to pyrazolines of formula (I), where E = methylene, NH, O or S and R2 = a group of formula (II), methods for the production and use thereof for the production of medicaments for the treatment and/or prophylaxis of diseases, in particular, cardiovascular diseases, such as thromboembolitic diseases.
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Page/Page column 39
(2010/02/10)
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- Adamantyl triazoles as selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1
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Adamantyl triazoles were identified as selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). They are active both in in vitro and in in vivo pharmacodynamic models. The synthesis and structure-activity relationships of these inhibitors are presented.
- Olson, Steven,Aster, Susan D.,Brown, Kai,Carbin, Linda,Graham, Donald W.,Hermanowski-Vosatka, Anne,LeGrand, Cheryl B.,Mundt, Steven S.,Robbins, Michael A.,Schaeffer, James M.,Slossberg, Llnon H.,Szymonifka, Michael J.,Thieringer, Rolf,Wright, Samuel D.,Balkovec, James M.
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p. 4359 - 4362
(2007/10/03)
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- Compounds with antiparasitic activity and medicines containing same
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The invention relates to compounds having an anti-parasitic, in particular antimalarial activity, characterized in that they correspond to general formula (I) Applications in particular as compounds with anti-parasitic activity.
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Page/Page column 7
(2008/06/13)
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- Treatment of bacterial induced diseases using DNA methyl transferase inhibitors
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Methods for treating and/or preventing disease conditions caused or induced or aggravated by microbes, especially bacteria, by inhibiting DNA methyltransferase activity, such as by administering to an animal a DNA methyltransferase inhibitor, are disclosed, along with methods of reducing or ablating virulence in bacteria by inhibiting DNA methyltransferase activity.
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Page/Page column 29
(2008/06/13)
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- THE R-ISOMER OF BETA AMINO ACID COMPOUNDS AS INTEGRIN RECEPTOR ANTAGONISTS DERIVATIVES
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The present invention relates to a class of compounds represented by the Formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising compounds of the Formula (I), and methods of selectively inhibiting or antagonizing the αVβ3 and/or the αV β5 integrin without significantly inhibiting the αV β6 integrin
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Page/Page column 95
(2010/02/07)
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- DNA Methyltransferase inhibitors
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A compound of the formula or a pharmaceutically acceptable salt thereof,whereinR1, R2, and R3 are the same or different and are independently hydrogen, lower alkyl, aryl or substituted aryl, lower alkoxy, lower alkoxyalkyl, or cycloalkyl or cycloalkyl alkoxy, where each cycloalkyl group has from 3-7 members, where up to two of the cycloalkyl members are optionally hetero atoms selected from oxygen and nitrogen, and where any member of the alkyl, aryl or cycloalkyl group is optionally substituted with halogen, lower alkyl or lower alkoxy, aryl or substituted aryl, andwhereR3 can be ribose, deoxyribose or phosphorylated derivatives thereof,whereinR1, R2, and R3 are not all hydrogen andwhereinwhen R3 is ribose, deoxyribose or phosphorylated derivatives thereof, one of R1 or R2 is not hydrogen.
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- N-acylpyrrolidin-2-ylalkylbenzamidine derivatives as inhibitors of factor Xa
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This invention is directed to N-acylpyrrolidin-2-ylalkylbenzamidine derivatives which useful for inhibiting the activity of Factor Xa, by contacting said derivatives with a composition containing Factor Xa. The present invention is also directed to compositions containing said derivatives, methods for their preparation, their use, such as in inhibiting the formation of thrombin or for treating a patient suffering from, or subject to, a disease state associated with a physiologically detrimental excess amount of thrombin.
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- N-acylpyrrolidin-2-ylalkylbenzamidine derivatives as inhibitors of factor Xa
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This invention is directed to N-acylpyrrolidin-2-ylalkylbenzamidine derivatives which useful for inhibiting the activity of Factor Xa, by contacting said derivatives with a composition containing Factor Xa. The present invention is also directed to compos
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- Synthesis and biological evaluation of pyrrolinic isosteres of rilmenidine. Discovery of cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)- amine (LNP 509), an I1 imidazoline receptor selective ligand with hypotensive activity
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To find new compounds selective for purported I1 imidazoline receptors (I1Rs), over I2 imidazoline binding sites (I2BS) and α2-adrenoceptors (α2ARs), a series of pyrrolinic isosteres of rilmenidine has been prepared and their biological activity at I1Rs, I2BS, and α2ARs evaluated. This isosteric replacement provided us with compounds which still bound to I1Rs but not to I2BS nor to α2-ARs. A limited structure-affinity relationship was generated around the heterocyclic moiety of these ligands. One compound in this series, LNP 509 (1e) [cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl) -amine], had no detectable affinity at α2ARs yet was capable of lowering blood pressure after central administration. These pyrrolinic analogues constitute a new chemical class of imidazoline related compounds with high selectivity for the I1Rs. They could be used as new tools in the study of I1Rs and in the conception of new centrally acting hypotensive drugs.
- Schann,Bruban,Pompermayer,Feldman,Pfeiffer,Renard,Scalbert,Bousquet,Ehrhardt
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p. 1588 - 1593
(2007/10/03)
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- Synthesis and antimuscarinic activity of some N-(4-dimethylaminomethyl- 2-phenyl-[1,3]dioxolan-2-ylmethyl)lactam methiodides
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A series of 1,3-dioxolane-based ligands, having a lactam function were synthesized and tested as potential muscarinic antagonists. The compounds display moderate affinity for the three receptor subtypes M1-M3, with significant selectivity for the M1-M3 over the M2 subtype.
- Malmusi, Luca,Franchini, Silvia,Mucci, Adele,Angeli, Piero,Gulini, Ugo,Marucci, Gabriella,Brasili, Livio
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p. 499 - 509
(2007/10/03)
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- Cyclic amidine analogs as inhibitors of nitric oxide synthase
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Disclosed herein are compounds of Formula I STR1 and pharmaceutically acceptable salts thereof which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders, including neurodegenerative disorders, disorders of gastrointestinal motility and inflammation. These disease and disorders include hypotension, septic shock, toxic shock syndrom, hemodialysis, IL-2 therapy such as in cancer patients, cachexia, immunosuppression such as in transplant therapy, autoimmune and/or inflammatory indications including sunburn or psoriasis and respiratory conditions such as bronchitis, asthma, and acure respiratory distress (ARDS), myocarditis, heart failure, atherosclerosis, arthritis, rheumatoid arthritis, chronic or inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE), ocular conditions such as ocular hypertension and uveitis, type 1 diabetes, insulin-dependent diabetes mellitus and cystic fibrosis. Compounds of Formula I are also usful in the treatment of hypoxia, hyperbaric oxygen convulsions and toxicity, dementia, Sydenham's chorea, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, mulitple sclerosis, Korsakoff's disease, imbecility related to cerebral vessel disorder, ischemic brain edema, sleeping disorders, schizophrenia, depression, PMS, anxiety, drug addiction, pain, migraine, immune complex disease, as immunosupressive agents and for preventing or reversing tolerance to opiates and diazepines.
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