- Synthesis of indole-4-carboxaldehydes and 4-Acetylindole from N-alkyl-5-aminoisoquinolinium salts
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N-Alkyl-5-aminoisoquinolinium salts (8a-d) are converted into indole-4-carboxaldehydes (1a-c) on heating in a two phase alkyl acetate-water system containing an excess of a 2:1 sodium bisulfite-sodium sulfite mixture, 4-Acetylindole 1e is prepared in the same way from 1-methyl-2-cyanomethylisoquinolinium bromide 8f.
- Muchowski
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- Palladium-catalyzed external-CO-free reductive carbonylation of aryl sulfonates
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Pd-catalyzed reductive carbonylation of aryl sulfonates using N-formylsaccharin as a carbon monoxide (CO) surrogate was developed. This external-CO-free carbonylation provides a safe and practical access to aldehydes from phenol derivatives. The reaction has a broad substrate scope, rendering it an attractive method for synthesizing aldehydes.
- Konishi, Hideyuki,Kumon, Minoru,Yamaguchi, Miyuki,Manabe, Kei
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- Dopamine receptor ligands. Part 18: Modification of the structural skeleton of indolobenzazecine-type dopamine receptor antagonists
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On the basis of the D1/5-selective dopamine antagonist LE 300 (1), an indolo[3,2-f]benzazecine derivative, we changed the annulation pattern of the heterocycles. The target compounds represent novel heterocyclic ring systems. The most constrained indolo[4,3a,3-ef]benzazecine 2 was inactive, but the indolo[4,3a,3-fg]benzazacycloundecene 3 showed antagonistic properties (functional Ca2+ assay) with nanomolar affinities (radioligand binding) for all dopamine receptor subtypes, whereas the indolo[2,3-f] benzazecine 4 displayed a selectivity profile similar to 3 but with decreased affinities.
- Robaa, Dina,Enzensperger, Christoph,El Din Abul Azm, Shams,El Khawass, El Sayeda,El Sayed, Ola,Lehmann, Jochen
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supporting information; experimental part
p. 2646 - 2650
(2010/08/19)
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- THERAPEUTIC AGENTS, AND METHODS OF MAKING AND USING THE SAME
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In part, the present invention is directed to antibacterial compounds
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Page/Page column 161-162
(2010/11/27)
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- Novel 4-phenyl substituted tetrahydroisoquinolines and therapeutic use thereof
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The present invention relates to a method of treating disorders including cognition impairment, generalized anxiety disorder, acute stress disorder, social phobia, simple phobias, pre-menstrual dysphoric disorder, social anxiety disorder, major depressive
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Page/Page column 20
(2010/11/08)
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- Glucagon antagonists/inverse agonists
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Non-peptide compounds comprising a central hydrazide motif and methods for the synthesis thereof are disclosed. The compounds act to antagonize the action of the glucagon peptide hormone.
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- Optimization of alkylidene hydrazide based human glucagon receptor antagonists. Discovery of the highly potent and orally available 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1h-indol-4ylmethylene]hydrazide
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Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-cyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure - metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC50 = 2.3 nM, KB = 760 pM) and of the isolated rat receptor (IC50 = 430 pM, KB = 380 pM). Glucagonstimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (Ki = 14 nM). This compound was orally available in dogs (Fpo = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.
- Madsen, Peter,Ling, Anthony,Plewe, Michael,Sams, Christian K.,Knudsen, Lotte B.,Sidelmann, Ulla G.,Ynddal, Lars,Brand, Christian L.,Andersen, Birgitte,Murphy, Douglas,Teng, Min,Truesdale, Larry,Kiel, Dan,May, John,Kuki, Atsuo,Shi, Shenghua,Johnson, Michael D.,Teston, Kimberly Ann,Feng, Jun,Lakis, James,Anderes, Kenna,Gregor, Vlad,Lau, Jesper
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p. 5755 - 5775
(2007/10/03)
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- Novel 4-phenyl substituted tetrahydroiso quinolines therapeutic use thereof
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Compounds are provided that, by way of their selective neurotransmitter binding useful for the treatment of various neurological and psychological disorders, e.g., ADHD. Such compounds are 4-phenyl substituted tetrahydroisoquinolines having the Formula IA, IB, IIA, IIB, IIIA or IIIC as set forth herein.
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- Thiazolidinedione derivatives, method for preparing the derivatives and pharmaceutical compositions containing same
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A thiazolidinedione derivative represented by the following general formula (I): STR1 ?wherein the dotted line represents a single bond or a double bond, the thiazolidinedione ring residue is linked to either of 2-, 3-, 4-, 5- and 6-positions on the indole ring and R represents a group selected from the group consisting of hydrogen atom and alkyl, alkenyl, alkynyl, phenyl, aralkyl, heterocycloalkyl, arylsulfonyl and arylaminocarbonyl groups! or a pharmaceutically acceptable salt thereof exhibits excellent effects of reducing the blood sugar level and of reducing the lipid concentration in blood and is accordingly useful as a therapeutic agent for treating diabates mellitus. These derivatives and pharmaceutically acceptable salt thereof are almost free of any side effect.
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- Azepinoindole derivatives with high affinity for brain dopamine and serotonin receptors
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We synthesized 20 and 21 as conformationally constrained analogues of the dopamine receptor antagonist SKF-83742, as well as analogues 6-9, 16, and 18-22. Although 20 and 21 were inactive, 7, 9, and 19 showed strong binding to D-1, D-2, S-2, and α-1 receptors, as well as antipsychotic activity in vivo.
- Maryanoff, Bruce E.,McComsey, David F.,Martin, Gregory E.,Shank, Richard P.
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p. 983 - 988
(2007/10/03)
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- Palladium-catalyzed reactions in aqueous media. An efficient removal of allyloxycarbonyl protecting group from oxygen and nitrogen
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The Allyloxycarbonyl (Alloc) moiety can be removed smoothly and selectively in good yield (70-99%) from allylic esters, carbamates and carbonates by aqueous Pd (0) catalyzed allyl transfer to diethylamine as the accepting nucleophile. The method has been successfully used for deprotection of a wide range of secondary amines.
- Genet, Jean Pierre,Blart, Errol,Savignac, Monique,Lemeune, Stephane,Paris, Jean-Marc
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p. 4189 - 4192
(2007/10/02)
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- Intramolecular Cycloadditions: Synthesis of 1-Methylene-2,3,3a,4,5,9b-hexahydro-1H-benzindenes and an unsuccessful approach to Ergot Alkaloids
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1-(1-Hydroxy-2-trimethylsilylmethylprop-2-enyl)-2-(4-substituted-but-3-enyl)-4-methoxybenzenes, prepared by a short synthesis, underwent intramolecular cycloadditions to produce the title indenes.An analogous intramolecular cycloaddition was attempte
- Collins, Michael P.,Drew, Michael G. B.,Mann, John,Finch, Harry
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p. 3211 - 3218
(2007/10/02)
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- SYNTHESIS OF 4-ACYLINDOLES VIA 2-(2-PHENYLSULFINYLVINYL)PYRROLE.
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4-Acylindoles are readily obtained by the cycloaddition of 1-triisopropylsilyl-trans-2-(2-phenylsulfinylvinyl)pyrolle with electron deficient acetylenes followed by N-desilylation of the cycloadducts with fluoride ion.
- Muchowski, Joseph M.,Scheller, Markus E.
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p. 3453 - 3456
(2007/10/02)
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- A CONVENIENT SYNTHETIC APPROACH TO 4-SUBSTITUTED INDOLES
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A simple and practical synthetic method for 4-halogenoindoles, 4-indolecarbaldehyde, 4-cyanoindole, and 4-methoxycarbonylindole is elaborated.
- Yamada, Fumio,Somei, Masanori
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p. 1173 - 1176
(2007/10/02)
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- SHORT STEP SYNTHESIS OF 4-FORMYLINDOLE AND DERIVATIVES FROM 4-OXO-4,5,6,7-TETRAHYDROINDOLE
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The reaction of 4-oxo-4,5,6,7-tetrahydroindole with umpolung anions provides a new short efficient procedure for the synthesis of 4-formylindole derivatives.
- Hatanaka, Naoto,Watanabe, Nobuko,Matsumoto, Masakatsu
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p. 1987 - 1996
(2007/10/02)
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- Metal-Halogen Exchange of Bromoindoles. A Route to Substituted Indoles
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The 4-, 5-, 6-, and 7-bromoindoles, conveniently synthesized by the Batcho-Leimgruber process, serve as efficient precursors to regiochemically pure lithiated indoles.Metal-halogen exchange was most effective if potassium hydride was used first to remove the acidic indole NH, and tert-butyllithium was used then to effect metal-halogen exchange.The resulting indolyl organometallic reagents react with a variety of electrophiles to give regioisomerically pure acylated indoles.
- Moyer, Mikel P.,Shiurba, John F.,Rapoport, Henry
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p. 5106 - 5110
(2007/10/02)
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- Some Observations on the Formation of 1-Hydroxyindoles in the Leimgruber-Batcho Indole Synthesis
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The factors influencing the formation of 1-hydroxyindoles in the catalytic hydrogenation of β-dimethylamino-2-nitrostyrenes (Leimgruber-Batcho indole synthesis) have been investigated.Significant amounts of 1-hydroxyindoles were obtained only when the β-dimethylamino-2-nitrostyrene was substituted with an electron-withdrawing group at the 5 or 6 position.The proportion of 1-hydroxyindole formed relative to the normal indole product was found to increase as both the amount of catalyst and hydrogen pressure were decreased.
- Clark, Robin D.,Repke, David B.
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p. 121 - 125
(2007/10/02)
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- TOTAL SYNTHESES OF CLAVINE ALKALOIDS BY AN INTRAMOLECULAR NITRONE-OLEFIN CYCLOADDITION REACTION
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The racemic ergot alkaloids chanoclavine I (1) and 6,7-secoagroclavine (4) have been synthesized stereoselectively from indole-4-carboxaldehyde (7) in overall yields of 14 and 13 percent, respectively.Further syntheses of isochanoclavine I (2), paliclavine (5) and costaclavine (6), via the same isoxazolidine 18 are described.The key step 16-->18 (Scheme 4) involves a transient nitrone 17 which undergoes a kinetically controlled, regio- and stereoselective intramolecular cycloaddition to a 1,2-disubstituted olefinic bond.
- Oppolzer, W.,Grayson, J. I.,Wegmann, H.,Urrea, M.
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p. 3695 - 3706
(2007/10/02)
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- SYNTHESES OF 4-ALKYLINDOLES FROM 2-METHYL-5-NITROISOQUINOLINIUM IODIDE
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4-aminomethylindole was prepared economically on a large scale from 2-methyl-5-nitrosoisoquinolinium iodide.Subsequent alkaline hydrolysis afforded 4-methylaminomethylindole.Starting from these two compounds, various 3,4-di- and 4-subst
- Somei, Masanori,Karasawa, Yoshio,Kaneko, Chikara
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p. 813 - 816
(2007/10/02)
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