- Furo-3-carboxamide derivatives and methods of use
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Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein R1, Z1, Z2, and n are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by Tropomysin receptor kinases (Trk). Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.
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- A 2,4-piperidine dione synthetic method (by machine translation)
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The invention discloses a synthetic method of 2, 4-dioxopiperidine. The method comprises the following steps: by taking monomethyl malonate, 3-amino methyl propionate hydrochloride or 3-amino ethyl propionate hydrochloride as an initial raw material, dichloromethane as a solvent, dicyclohexylcarbodiimide (DDC) as a dehydrator and triethylamine as an acid-binding agent, carrying out a reaction; acidylating a condensation product methyl-3-((3-methoxyl-3-carbonyl propyl) amino)-3-carbonyl propionate, wherein in the acidylating condensation reaction process, onium salt is used as a catalyst which is good in selectivity, few in side reaction and higher in yield; then, circularly condensing to obtain 3-(carbomethoxy(methoxycarbonyl))-4-carbonyl-1, 4, 5, 6-tetrapyridine-2-alcoholic sodium under the effect of sodium methylate; and then, decarboxylating in a hydrochloric acid system to obtain 2, 4-dioxopiperidine. In the whole reaction, as methoxyl is easy to remove, so that the synthetic method is available in the raw materials, mild in reaction condition, safe to operate and high in conversion rate.
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Paragraph 0044
(2016/11/28)
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- FURO-3-CARBOXAMIDE DERIVATIVES AND METHODS OF USE
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Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein R1, Z1, Z2, and n are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by Tropomysin receptor kinases (Trk). Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.
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- 17a-HYDROXYLASE/C17,20-LYASE INHIBITORS
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The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, A and n are as defined herein. A deuteriated derivative of the compound of Formula (I) is also provided.
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- A multifaceted secondary structure mimic based on piperidine-piperidinones
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Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld-1-faf crystallized in a conformation that is estimated to be 0.91 kcal-mol-1 above the minimum energy solution state. Do we know, when designing a new peptidomimetic scaffold like the one shown, how it can resemble secondary structures? Design and modular synthesis of this elongated mimic is reported, and the structure is related to ideal and real structures at PPI interfaces.
- Xin, Dongyue,Perez, Lisa M.,Ioerger, Thomas R.,Burgess, Kevin
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supporting information
p. 3594 - 3598
(2014/04/17)
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- Metal-free, mild, nonepimerizing, chemo- and enantio- or diastereoselective N-alkylation of amines by alcohols via oxidation/imine-iminium formation/reductive amination: A pragmatic synthesis of octahydropyrazinopyridoindoles and higher ring analogues
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A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Bronsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Bronsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues.
- Khan, Imran A.,Saxena, Anil K.
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p. 11656 - 11669
(2014/01/06)
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- Extending the scope of the aza-Fischer synthesis of 4- and 6-azaindoles
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Fischer indole cyclization has recently been described as an efficient approach to the synthesis of azaindoles bearing electron-donating groups. We now show that this cascade reaction can be very efficient for the formation of a wider range of 4- and 6-azaindoles by using microwave irradiation. Fischer indole cyclization starting from aminopyridines is a very efficient cascade sequence leading to 4- and 6-azaindoles. The scope of the substituents on the pyridine ring was extended to include halogens and to weakly electron-donating substituents by using microwave irradiation. Copyright
- Thomae, David,Jeanty, Matthieu,Coste, Jerome,Guillaumet, Gerald,Suzenet, Franck
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p. 3328 - 3336
(2013/07/05)
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- 17α-HYDROXYLASE/C17,20-LYASE INHIBITORS
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The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, A and n are as defined herein. A deuteriated derivative of the compound of Formula (I) is also provided.
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- In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part II
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Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D-E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC50 50
- Revesz, Laszlo,Schlapbach, Achim,Aichholz, Reiner,Dawson, Janet,Feifel, Roland,Hawtin, Stuart,Littlewood-Evans, Amanda,Koch, Guido,Kroemer, Markus,Moebitz, Henrik,Scheufler, Clemens,Velcicky, Juraj,Huppertz, Christine
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scheme or table
p. 4719 - 4723
(2010/09/16)
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- INDOLONE MODULATORS OF 5-HT3 RECEPTOR
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The present invention relates to new indolone modulators of 5-HT3 receptor, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 12
(2010/05/13)
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- ISOQUINOLINOPYRROLOPYRIDINONES ACTIVE AS KINASE INHIBITORS
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Heteroarylpyridinone derivatives represented by formula (I) wherein R1, R2, R3, R4, R5, and X are as defined in the specification, compositions thereof, and methods of use thereof. Particularly, there are described isoquinolinoyrrolopyridinones, pharmaceutical compositions comprising them and their use as therapeutic agents in the treatment of cancer and cell proliferation disorders.
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- Preparation and intramolecular [2+2]-photocycloaddition of 1,5-dihydropyrrol-2-ones and 5,6-dihydro-1H-pyridin-2-ones with C-, N-, and O-linked alkenyl side chains at the 4-position
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(Chemical Equation Presented) The 1,5-dihydropyrrol-2-ones 2, 6, 9, and 11 were prepared from methyl tetramates (1a-c), N-Boc-protected tetramic acid (3), or N-Boc-protected tetramic acid bromide (7) in short reaction sequences and in very good overall yields. The homologous 5,6-dihydro-1H-pyridin-2-ones 16,18, 20, 21, 23, and 27 were prepared along analogous routes starting from piperidin-2,4-dione (19) or from its N-terf-butyl derivative 15. Optimized conditions for the [2+2]-photocycloaddition include the use of dichloromethane as the solvent and an irradiation with a mercury low-pressure lamp (λ = 254 nm). Upon applying these conditions at ambient temperature, the corresponding intramolecular photocycloaddition products 28-37 were obtained in good yields (52-79%) and with perfect diastereoselectivity. The constitution and configuration of the products was elucidated by NMR-spectroscopy. For the O-tethered substrates 2a and 20, a strong decrease of the photocycloaddition rate with temperature was observed. The effect was less pronounced for N- and C-tethered substrates 6, 9, 23, and 27. The use of a chiral complexing agent to achieve enantioselective reactions appears viable. Complexing agent (-)-38, however, is not suited because of its instability at λ = 254 nm.
- Albrecht, Dominik,Basler, Birte,Bach, Thorsten
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p. 2345 - 2356
(2008/09/19)
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- Cdc7 kinase inhibitors: Pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships
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Cdc7 kinase is an essential protein that promotes DNA replication in eukaryotic organisms. Genetic evidence indicates that Cdc7 inhibition can cause selective tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 small-molecule inhibitors for the treatment of cancers. In this paper, the synthesis and structure-activity relationships of 2-heteroaryl-pyrrolopyridinones, the first potent Cdc7 kinase inhibitors, are described. Starting from 2-pyridin-4-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c] pyridin-4-one, progress toward a simple scaffold, tailored for Cdc7 inhibition, is reported.
- Vanotti, Ermes,Amici, Raffaella,Bargiotti, Alberto,Berthelsen, Jens,Bosotti, Roberta,Ciavolella, Antonella,Cirla, Alessandra,Cristiani, Cinzia,D'Alessio, Roberto,Forte, Barbara,Isacchi, Antonella,Martina, Katia,Menichincheri, Maria,Molinari, Antonio,Montagnoli, Alessia,Orsini, Paolo,Pillan, Antonio,Roletto, Fulvia,Scolaro, Alessandra,Tibolla, Marcellino,Valsasina, Barbara,Varasi, Mario,Volpi, Daniele,Santocanale, Corrado
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p. 487 - 501
(2008/09/18)
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- N-substituted pyrrolopyridinones active as kinase inhibitors
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Compounds represented by formula (I) wherein A, R1, R2, R3, R4, R5, and R6 are as defined in the specification, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 16-17
(2010/11/27)
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- Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2)
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A new class of potent kinase inhibitors selective for mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2 or MK-2) for the treatment of rheumatoid arthritis has been prepared and evaluated. These inhibitors have IC50 values as low as 10 nM against the target and have good selectivity profiles against a number of kinases including CDK2, ERK, JNK, and p38. These MK-2 inhibitors have been shown to suppress TNFα production in U397 cells and to be efficacious in an acute inflammation model. The structure-activity relationships of this series, the selectivity for MK-2 and their activity in both in vitro and in vivo models are discussed. The observed selectivity is discussed with the aid of an MK-2/inhibitor crystal structure.
- Anderson, David R.,Meyers, Marvin J.,Vernier, William F.,Mahoney, Matthew W.,Kurumbail, Ravi G.,Caspers, Nicole,Poda, Gennadiy I.,Schindler, John F.,Reitz, David B.,Mourey, Robert J.
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p. 2647 - 2654
(2008/02/04)
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- Dihydronaphthyridine potassium channel openers
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Compounds of formula I are useful in treating diseases prevented by or ameliorated with potassium channel openers. Also disclosed are potassium channel opening compositions and a method of opening potassium channels in a mammal.
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- Process for preparing pyrazolopyridine compounds
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Compounds of the formula (I): STR1 wherein R4 is hydrogen, D is oxygen or NR6, R1, R3, R6, R7 and R8 have defined values, and n is 1 or 2 are produced by internally cyclizing a compound of the formula (XV): STR2 wherein R19 is a value of R1 or hydrogen and, if R19 is hydrogen, reacting the cyclization product with R1 --Br and a weak base such as potassium carbonate.
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- CNS-Depressant pyrazolopyridines
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Compounds of the formula (I): STR1 wherein R1, R3, R4, R7 and R8 are as described herein, D is oxygen or NR6, n is 1 or 2 and the physiologically acceptable salts thereof useful in reducing anxiety in an animal such as man. The compounds are potent anxiolytics having reduced side effects compared to known anxiolytics. Also pharmaceutical compositions, intermediates and methods of treatment and synthesis are described.
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