- Synthesis of 3-Benzazepines by Metal-Free Oxidative C–H Bond Functionalization–Ring Expansion Tandem Reaction
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A metal-free synthesis of biologically important benzazepines is achieved through a single synthetic operation involving an oxidative C–H bond functionalization and ring expansion with diazomethanes as key reagent. This represents a new, strong methodology for the straightforward construction of the seven-ring N-heterocyclic structures under mild conditions using a 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) oxoammonium salt as oxidant. Moderate to good yields are achieved from simple, readily available tetrahydroisoquinolines, and this methodology has been further successfully applied for the synthesis of the 3-benzazepine drug Lorcaserin. A possible mechanistic pathway for the ring expansion step, comprising the extrusion of nitrogen in a concerted asynchronic process, is proposed based on both mechanistic proof and density function theory (DFT) calculations. (Figure presented.).
- Gini, Andrea,Bamberger, Julia,Luis-Barrera, Javier,Zurro, Mercedes,Mas-Ballesté, Rubén,Alemán, José,Manche?o, Olga García
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supporting information
p. 4049 - 4056
(2016/12/30)
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- Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5- tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity
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The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [3H]phosphoinositol turnover: 5-HT 2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
- Smith, Brian M.,Smith, Jeffrey M.,Tsai, James H.,Schultz, Jeffrey A.,Gilson, Charles A.,Estrada, Scott A.,Chen, Rita R.,Park, Douglas M.,Prieto, Emily B.,Gallardo, Charlemagne S.,Sengupta, Dipanjan,Dosa, Peter I.,Covel, Jon A.,Ren, Albert,Webb, Robert R.,Beeley, Nigel R. A.,Martin, Michael,Morgan, Michael,Espitia, Stephen,Saldana, Hazel R.,Bjenning, Christina,Whelan, Kevin T.,Grottick, Andrew J.,Menzaghi, Frederique,Thomsen, William J.
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p. 305 - 313
(2008/09/19)
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- Discovery and SAR of new benzazepines as potent and selective 5-HT 2C receptor agonists for the treatment of obesity
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We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT2C receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT2C, h5-HT2A or h5-HT2B receptors. Several compounds are shown to be potent and selective 5-HT 2C receptor agonists, which decrease food intake in a rat feeding model.
- Smith, Brian M.,Smith, Jeffrey M.,Tsai, James H.,Schultz, Jeffrey A.,Gilson, Charles A.,Estrada, Scott A.,Chen, Rita R.,Park, Douglas M.,Prieto, Emily B.,Gallardo, Charlemagne S.,Sengupta, Dipanjan,Thomsen, William J.,Saldana, Hazel R.,Whelan, Kevin T.,Menzaghi, Frederique,Webb, Robert R.,Beeley, Nigel R.A.
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p. 1467 - 1470
(2007/10/03)
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- BENZAZEPINE DERIVATIVES AND METHODS OF PROPHYLAXIS OR TREATMENT OF 5HT2C RECEPTOR ASSOCIATED DISEASES
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The present invention relates to substituted-2,3,4,5-tetrahydro-3-benzazepine derivatives that are modulators of the 5HT2C receptor. Accordingly, compounds of the present invention are useful for the prophylaxis or treatment of 5HT2C receptor associated diseases, conditions or disorders, such as, obesity and related disorders.
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Page/Page column 43
(2008/06/13)
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- BENZAZEPINE DERIVATIVES AND METHODS OF PROPHYLAXIS OR TREATMENT OF 5HT2C RECEPTOR ASSOCIATED DISEASES
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The present invention relates to substituted-2,3,4,5-tetrahydro-3-benzazepine derivatives that are modulators of the 5HT2C receptor. Accordingly, compounds of the present invention are useful for the prophylaxis treatment of 5HT2C receptor associated diseases, conditions or disorders, such as, obesity and related disorders.
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Page/Page column 34
(2008/06/13)
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