135729-56-5Relevant articles and documents
Total synthesis of the 5-HT3 receptor antagonist palonosetron
Kowalczyk, Bruce A.,Dvorak, Charles A.
, p. 816 - 818 (1996)
A short and efficient synthetic route to the 5-HT3 receptor antagonists 1 and 2 (palonosetron) was developed. The novel adjustment of the oxidation states at the necessary centers of imide 7 was accomplished by hydrogenation, selective sodium borohydride reduction, and dehydration to yield 1. The sodium borohydride reduction of imide 8 was selective for the C-3 carbonyl versus the C-1 carbonyl next to the aromatic ring to give the hydroxy compound 9. It was essential to keep the sodium borohydride reduction free of oxygen, or diols 10a and 10b were formed as significant byproducts.
Synthesis and Pharmacological Evaluation of [11C]Granisetron and [18F]Fluoropalonosetron as PET Probes for 5-HT3 Receptor Imaging
Mu, Linjing,Müller Herde, Adrienne,Rüefli, Pascal M.,Sladojevich, Filippo,Milicevic Sephton, Selena,Kr?mer, Stefanie D.,Thompson, Andrew J.,Schibli, Roger,Ametamey, Simon M.,Lochner, Martin
, p. 1552 - 1564 (2016/11/29)
Serotonin-gated ionotropic 5-HT3 receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT3 receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril) and palonosetron (Aloxi), belong to a family of drugs (the "setrons") that are well established for clinical use. To enable us to better understand the actions of these drugs in vivo, we report the synthesis of 8-fluoropalonosetron (15) that has a binding affinity (Ki = 0.26 ± 0.05 nM) similar to the parent drug (Ki = 0.21 ± 0.03 nM). We radiolabeled 15 by nucleophilic 18F-fluorination of an unsymmetrical diaryliodonium palonosetron precursor and achieved the radiosynthesis of 1-(methyl-11C)-N-granisetron ([11C]2) through N-alkylation with [11C]CH3I, respectively. Both compounds [18F]15 (chemical and radiochemical purity >95%, specific activity 41 GBq/μmol) and [11C]2 (chemical and radiochemical purity ≥99%, specific activity 170 GBq/μmol) were evaluated for their utility as positron emission tomography (PET) probes. Using mouse and rat brain slices, in vitro autoradiography with both [18F]15 and [11C]2 revealed a heterogeneous and displaceable binding in cortical and hippocampal regions that are known to express 5-HT3 receptors at significant levels. Subsequent PET experiments suggested that [18F]15 and [11C]2 are of limited utility for the PET imaging of brain 5-HT3 receptors in vivo.
Process for the Preparation of Substantially Pure Palonosetron and its Acid Salts
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Page/Page column 5, (2011/02/18)
This invention relates to an improved and scalable process for the preparation of substantially pure palonosetron and its acid addition salts, in particular hydrochloride (I) which comprises of, (a) converting intermediate (IIa) as such or as its freebase (II) to a crude mixture of diastereomeric palonosetrons (VIII) or (VIIIa) contaminated with varying amounts of unconverted intermediate (II) or (IIa) via hydrogenation under pressure with an appropriately chosen hydrogenation catalyst in an suitable organic solvent.(b) making the resulting crude mixture of diastereomeric palonosetrons (VIII) or (VIIIa) contaminated with varying amounts of unconverted intermediate (II) or (IIa) substantially free from (II) or (IIa) via halogenation reaction.(c) Finally, converting the resulting diastereomeric palonosetron (VIII) or its hydrochloride (VIIIa) substantially free from intermediate (II) or (IIa) to the desired palonosetron hydrochloride (I) in substantially pure form via selective crystallization from a suitable single or mixture of organic solvents.
Total synthesis of RS-42358 and analogs using lateral lithiation
Kowalczyk, Bruce A.
, p. 1113 - 1116 (2007/10/03)
A short synthesis of the 5-HT3 receptor antagonist RS-42358 was developed based on the condensation of lactone 2 with S-3- aminoquinuclidine. The position 2 analogs of RS-42358 were made by condensing various primary amines with lactone 2. The key step in the synthesis of lactone 2 was lateral lithiation of diethyl amide 7 using n-BuLi in THF.
Processes for preparing 2-(1-azabicyclo[2.2.2]oct-3-yl)-1H-benz[de] isoquinolin-1-one derivatives and intermediates useful therein
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, (2008/06/13)
This invention relates to processes for preparing 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one, particularly 2-(1-azabicyclo[2.2.2]oct-3S-yl)-2, 3,3aS,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one, and to intermediates useful in such processes.
Tricyclic 5-HT3 receptor antagonists
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, (2008/06/13)
The present invention is directed to 5-HT 3 receptor antagonist compounds of formula I: STR1 in which the dashed line denotes an optional double bond;n is 1, 2 or 3;p is 0, 1, 2 or 3;q is 0, 1 or 2;each R 1 is independently selected from halogen, hydroxy, lower alkoxy, lower alkyl, nitro, amino, amino carbonyl, (lower alkyl)amino, di(lower alkyl)amino, and (lower alkanoyl)amino;each R 2 is lower alkyl; andR 3 is a group selected from Formulae (a), (b), (c) and (d): STR2 in which u is 0 or 1;z is 1, 2 or 3; andR 4 is C 1-7 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-2 alkyl, or a group (CH 2) t R 5 where t is 1 or 2 and R 5 is thienyl, pyrrolyl, or furyl, each optionally further substituted by one or two substituents selected from C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C 1-4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C 1-4 alkyl optionally substituted by hydroxy, C 1-4 alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy; and the pharmaceutically acceptable salts, individual isomers, mixtures of isomers, processes for preparation, compositions, and methods of use thereof.
2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists
Clark,Miller,Berger,Repke,Weinhardt,Kowalczyk,Eglen,Bonhaus,Lee,Michel,Smith,Wong
, p. 2645 - 2657 (2007/10/02)
Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series,2-(quinuclidin-3-yl)tetrahydropyrido[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridge
