- Pyridine analogues of spirocyclic σ1 receptor ligands
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Spirocyclic benzopyrans 2 interact with high affinity and selectivity with σ1 receptors. Bioisosteric replacement of the benzene ring of the benzopyran substructure with the electron rich thiophene ring (3) led to increased σ1 affinity. Herein the synthesis and pharmacological evaluation of electron deficient pyridine bioisosteres 4 are reported. Homologation of the aldehyde 6 to afford the pyridylacetaldehyde derivative 8 was performed by a Wittig reaction. Bromine lithium exchange of the bromopyridine 8, addition to 1-benzylpiperidin-4-one and cyclization led to the spirocyclic pyrranopyridine 10. Hydrogenolytic removal of the N-benzyl moiety of 10 provided the secondary amine 11, which allowed the introduction of various N-substituents (12a-d). Cyclization of the hydroxy acetal 9 with HCl led to various modifications of the substituent in 3′-position. Generally the σ1 affinity of the pyridine derivatives is reduced compared with those of the benzene and thiophene derivatives 2 and 3. However, the relationships between the structure and the σ1 affinity follow the same rules as for the benzene and thiophene derivatives. The most promising σ1 ligand within this class of compounds is the pyranopyridine 15 with a double bond in the pyran ring revealing a Ki-value of 4.6 nM and a very high selectivity (>217-fold) over the σ2 subtype.
- Miyata, Kengo,Moeller, Guido,Schepmann, Dirk,Wuensch, Bernhard
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Read Online
- Synthesis of a new series of potent inhibitors of thromboxane A2 biosynthesis
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The pyridino prostanoids 9, 12 and 14 have been synthesized (in racemic form) and have been found to be effective inhibitors of the biosynthesis of thromboxane A2 in human platelets (IC50 1-3 μM).
- Corey,Pyne,Schafer
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Read Online
- One-pot homo- and cross-coupling of diazanaphthalenes via C-H substitution: Synthesis of Bis- and Tris-diazanaphthalenes
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The transition metal-free coupling reactions of unactivated diazanaphthalenes were studied using only lithium tetramethylpiperidine (LiTMP) reagent. Symmetrical and nonsymmetrical bis-diazanaphthalenes were synthesized in moderate to high yield by homo- and cross-coupling of related monomers. In addition, the single-step synthesis of diquinoxalino [2,3-a: 2', 3'c] phenazine and 2,2': 3', 2″ - terquinoxaline using the appropriate equivalent amount of LiTMP was performed. The products were characterized by means of NMR spectroscopy and HRMS spectrometry.
- Ucar, Sefa,Dastan, Arif
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supporting information
p. 4013 - 4022
(2020/09/21)
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- Transition-Metal-Free Oxidation of Benzylic C-H Bonds of Six-Membered N-Heteroaromatic Compounds
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A novel oxidation of benzylic C-H bonds for the synthesis of diverse six-membered N-heteroaromatic aldehydes and ketones has been developed. The obvious advantages of this approach are the simple operation, mild reaction conditions, and without use of toxic reagent and transition metal. The present method should provide a useful access for the synthesis and modification of N-heterocycles.
- Gao, Xianying,Han, Shuaijun,Zheng, Maolin,Liang, Apeng,Zou, Dapeng,Wu, Yusheng,Wu, Yangjie,Li, Jingya
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p. 4040 - 4049
(2019/04/30)
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- PRMT5 INHIBITORS AND USES THEREOF
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Described herein are compounds of Formula (A), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof:wherein Y1 is of formula (?) or formula (y):Ring Y is a 5- to 6-membered heteroaryl ring; and V4, V5, Rx, x, y, and n are as defined herein. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.
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Paragraph 00504; 00505
(2016/04/20)
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- THIENO[3,2-D]PYRIMIDINE-6-CARBOXAMIDES AND ANALOGUES AS SIRTUIN MODULATORS
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Provided herein are novel substituted thieno[3,2-d]pyrimidine-6-carboxamide sirtuin inhibitors and methods of use thereof. The sirtuin inhibitors may be used for inhibiting a sirtuin-mediated biological process, and, e.g. for treating and/or preventing diseases and disorders including, but not limited to cancer, neurodegenerative disease and inflammation. Also provided herein are pharmaceutical compositions comprising these sirtuin inhibitors and compositions comprising a sirtuin inhibitor in combination with another therapeutic agent.
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- Synthesis and σ receptor affinity of regioisomeric spirocyclic furopyridines
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In order to investigate systematically the effect of the position of the pyridine N-atom on the σ1 receptor affinity four regioisomeric furopyridines 2a-d were synthesized and pharmacologically evaluated. The key steps of the synthesis comprise bromine/lithium exchange at regioisomeric bromopyridinecarbaldehyde acetals 7a-d, subsequent addition to 1-benzylpiperidin-4-one and cyclization. The regioisomeric acetals 7a-d were obtained either by o-metalation of bromopyridines 5b and 5c or by oxidation of bromopicolines 3a and 3d. In radioligand binding studies the regioisomeric furopyridines 2a-d showed 7- to 12-fold lower σ1 affinity than the benzofuran analog 1. The reduced σ1 affinity of the furopyridines 2a-d is explained with the reduced electron density of the pyridine ring. Since the four regioisomeric furopyridines show almost the same σ1 affinity (Ki = 4.9-10 nM), a directed interaction of the pyridine N-atom with the receptor protein can be excluded.
- Miyata, Kengo,Schepmann, Dirk,Wünsch, Bernhard
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p. 709 - 716
(2014/07/22)
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- Copper(I) salt/PEG-400 catalysis in one-pot direct synthesis of 1-aryl-1H-indazoles from 2-bromobenzaldehydes and arylhydrazines
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2-Bromobenzaldehydes are condensed and cyclized with arylhydrazines (or their hydrochlorides) in PEG-400 at 110 °C in the presence of a catalytic amount of a copper(I) salt along with a base to give 1-aryl-1H-indazoles in high yields. Copyright 2013 John Wiley & Sons, Ltd. Condensation of 2-bromobenzaldehydes with arylhydrazines (or their hydrochlorides) followed by C-N bond formation in PEG-400 in the presence of a copper(I) salt along with a base affords 1-aryl-1H-indazoles. Copyright
- Bae, Yeon Kyu,Cho, Chan Sik
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p. 224 - 227
(2013/05/23)
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- Expeditious synthesis of cis-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo- [3,2h]isoquinoline/[2,3-f]quinoline via azomethine ylide-alkene [3+2] cycloaddition
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Expeditious syntheses of cis-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo- [3,2h]isoquinoline/[2,3-f]quinoline have been developed. The syntheses started with commercially available materials and afforded excellent overall yields in straightforward steps. Intramolecular azomethine ylide-alkene [3+2] cycloaddition is the key step in the construction of these pyrroloisoquinoline and pyrroloquinoline scaffolds. This route is much more atom-economic than those reported in the literature and is appropriate for scale-up synthesis.
- Zhang, Zhenfa,Dwoskin, Linda P.,Crooks, Peter A.
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supporting information; experimental part
p. 2667 - 2669
(2011/06/10)
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- Synthesis of 1-phenyl- and 1-pyridyl-3-pyridoazepines by reductive cyclization of diarylacetonitriles
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Several pyrido[2,3-d]azepines and pyrido[3,4-d]azepines, novel aza analogs of the pharmacologically relevant 1-aryl-3-benzazepines, were synthesized by assembling the azepine ring by reductive cyclization of (2-methoxyvinyl)pyridinyl(aryl)acetonitrile derivatives, which were easily derived from contiguously substituted bromo(2-methoxyvinyl)pyridines and the corresponding arylacetonitriles.
- de la Fuente, M. Carmen,Domínguez, Domingo
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scheme or table
p. 3653 - 3658
(2009/09/08)
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- AZA-BETA-CARBOLINES AND METHODS OF USING SAME
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Provided are compounds having the general structure according to Formula (I): Further provided are pharmaceutical compositions comprising these compounds. The invention still further provides methods of treating alcoholism, methods of reducing alcohol intake, methods of treating anhedonia, and methods of treating anxiety using theses compounds or the compositions containing them.
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Page/Page column 12; sheet 14
(2009/12/24)
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- Synthesis of isoquinolines through the coupling of Fischer carbene complexes with o-alkynylpyridine carbonyl derivatives
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The reaction of Fischer carbene complex with o-alkynylpyridine carbonyl derivatives has been investigated. This involves the generation of furo[3,4-c]pyridine as transient intermediates through the coupling of o-alkynylpyridine carbonyl derivatives with carbene complex and subsequent Diels-Alder trapping with suitable dienophiles resulted in the formation of isoquinoline derivatives and the entire sequence can be run in one pot. When an olefinic tether was present, intramolecular Diels-Alder cycloaddition occurred followed by ring opening to yield tricyclic alcohols.
- Mukherjee, Soumita,Jana, Gouranga P.,Ghorai, Binay K.
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body text
p. 4100 - 4106
(2010/03/04)
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- Palladium-catalyzed cyclization of 3-bromopyridine-4-carbaldehyde with carbon monoxide and carboxylic acids
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(Chemical Equation Presented) 3-Bromopyridine-4-carbaldehyde is cyclized with carboxylic acids in acetonitrile at 100° under carbon monoxide pressure in the presence of a catalytic amount of a palladium catalyst along with a base to afford the corresponding 3-oxo-1,3-dihydrofuro[3,4-c]pyridine-1-yl alkanoates in moderate to good yields.
- Chan, Sik Cho,Jun, Uk Kim
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scheme or table
p. 1397 - 1399
(2009/04/06)
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- β-Substituted cyclohexanecarboxamide cathepsin K inhibitors: Modification of the 1,2-disubstituted aromatic core
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Further SAR study around the central 1,2-disubstituted phenyl of the previously disclosed Cat K inhibitor (-)-1 has demonstrated that the solvent exposed P2-P3 linker can be replaced by various 5- or 6-membered heteroaromatic rings. While some potency loss was observed in the 6-membered heteroaromatic series (IC50 = 1 nM for pyridine-linked 4 vs 0.5 nM for phenyl-linked (±)-1), several inhibitors showed a significantly decreased shift in the bone resorption functional assay (10-fold for pyridine 4 vs 53-fold for (-)-1). Though this shift was not reduced in the 5-membered heteroaromatic series, potency against Cat K was significantly improved for thiazole 9 (IC50 = 0.2 nM) as was the pharmacokinetic profile of N-methyl pyrazole 10 over our lead compound (-)-1.
- Robichaud, Joel,Bayly, Christopher I.,Black, W. Cameron,Desmarais, Sylvie,Leger, Serge,Masse, Frederic,McKay, Daniel J.,Oballa, Renata M.,Paquet, Julie,Percival, M. David,Truchon, Jean-Francois,Wesolowski, Gregg,Crane, Sheldon N.
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p. 3146 - 3151
(2008/02/05)
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- The expedient access to bromo-pyridine carbaldehyde scaffolds using gem-dibromomethyl intermediates
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A simple, efficient, and general two-step synthesis to bromo-pyridine carbaldehyde scaffolds is described. This direct route involves sequential reactions employing the dibromination of bromo-picolines followed by hydrolysis using an aqueous solution of calcium carbonate. Bromo-pyridine carbaldehyde scaffolds 1-7 were obtained in good overall yield. Bromo-dibromomethyl-pyridine intermediates have been isolated and characterized.
- Mandal, Ashis Baran,Augustine, John Kallikat,Quattropani, Anna,Bombrun, Agnes
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p. 6033 - 6036
(2007/10/03)
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- Fused pyridine derivatives
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The present provides a condensed pyridine compound (I) represented by the following formula: (wherein, R2represents ring A represents benzene ring, pyridine ring, thiophene ring or furan ring; and B represents its pharmaceutically acceptable salt or hydrates thereof, which is a clinically useful medicament having a serotonin antagonism, in particular, that for treating, ameliorating or preventing spastic paralysis or central muscle relaxants for ameliorating myotonia.
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- Pyridine radicals in synthesis. Part 3: Cyclopentannulation of pyridine via the 3-pyridyl radical and a formal synthesis of (±)-oxerine
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The allylation and propargylation of 3-bromo-4-formylpyridine under zinc-mediated Barbier conditions is described. The homoallylic alcohols produced are cyclised via the derived 3-pyridyl radical to give cyclopentannulated pyridines. One of these bicyclic compounds is converted into an advanced intermediate in a previous synthesis of the monoterpene alkaloid (±)-oxerine. (C) 2000 Elsevier Science Ltd.
- Jones, Keith,Fiumana, Andrea,Escudero-Hernandez, Maria L.
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p. 397 - 406
(2007/10/03)
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- General synthetic method for naphthyridines and their N-oxides containing isoquinolinic nitrogen
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Substituted naphthyridines containing isoquinolinic nitrogen were synthesized by the reaction of o-ethynylpyridinecarbaldehydes with ammonia. The synthesis of their N-oxides was also achieved by a basic cyclization reaction of the same pyridine derivatives via the corresponding oximes.
- Numata, Atsushi,Kondo, Yoshinori,Sakamoto, Takao
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p. 306 - 311
(2007/10/03)
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- Substituted aryl and heteroaryl compounds as E-type prostaglandin antagonists
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This invention relates to substituted and unsubstituted ???(aryl- and heteroaryl-) alkyl-, alkyloxy-, alkylthio-, oxo-, thio-, and alkylamino!- heteroaryl and aryl!- alkylamino-, aminoalkyl-, alkyloxy-, and alkylthio!- aryl and heteroaryl compounds of the formula STR1 and pharmaceutically acceptable salts thereof, which are useful as antagonists of the pain enhancing effects of E-type prostaglandins, to processes for the preparation of such compounds, to pharmaceutical compositions comprising such compounds, and to methods for treating pain comprising the administration of such compounds.
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