- Parallel modification of tropane alkaloids
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Various tropane alkaloids have been prepared by structural modification of the readily available natural product, scopolamine 1. Reaction of isocyanates with 6,7-dehydrotropine 5 provided a number of urethanes 6a-e. Reductive amination of tropinone 7 and subsequent reaction with isocyanates provided ureas 9a-f. Mitsunobu inversion of the C-3 alcohol of tropine 10 afforded the epimeric ester 11.
- Aberle, Nicholas S.,Ganesan,Lambert, John N.,Saubern, Simon,Smith, Reg
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- FLUOROPHENYL SUBSTITUTED MUSCARINIC RECEPTOR LIGANDS WITH SELECTIVITY FOR M3 OVER M2
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The present invention relates to fluorophenyl substituted muscarinic receptor ligands with selectivity for M3 over M2 and to the use of these compounds in the treatment of various diseases such as asthma, chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD) and urinary incontinence.
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Page/Page column 36
(2019/06/23)
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- Total Synthesis of (±)-Scopolamine: Challenges of the Tropane Ring
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Scopolamine was synthesized using 6,7-dehydrotropine as a key intermediate. Rhodium-catalyzed [4 + 3] cycloaddition chemistry and a modified Robinson-Sch?pf reaction were each independently evaluated for their utility in constructing the tropane core. Both synthetic approaches gave comparable overall yields.
- Nocquet, Pierre-Antoine,Opatz, Till
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p. 1156 - 1164
(2016/03/05)
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- 3-Aryloxy-8-aza-bicyclo[3.2.1]]oct-6-ene derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
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This invention relates to novel 8-aza-bicyclo[3.2.1]oct-6-ene derivatives useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.
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Page/Page column 7
(2009/02/11)
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- NOVEL CHROMEN-2-ONE DERIVATIVES AND THEIR USE AS MONOAMINE NEUROTRANSMITTER RE-UPTAKE INHIBITORS
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This invention relates to novel chromen-2-one derivatives of formula (I) useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention. Formula (I) wherein Q represents a chromen-2-one group; which chromen-2-one group is optionally substituted with one or more substituents independently selected from the group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl; R1 represents hydrogen or alkyl; which alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl; and R2 and R3 together form -(CH2)-(CH2)- or -(CH)=(CH)-.
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Page/Page column 19
(2008/06/13)
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- Synthesis and radiolabelling of ipratropium and tiotropium for use as PET ligands in the study of inhaled drug deposition
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Ipratropium bromide [(1R,3r,5S,8r,2′RS)-3-(3′-hydroxy-2′- phenylpropionyloxy)-8-isopropyl-8-methyl-8-aza-bicyclo[3.2.1]octan-8-ium bromide] and tiotropium bromide [(1R,2R,4S,5S,7s)-7-[2′-hydroxy-2′, 2′-di(thiophen2″-yl)acetoxy]-9,9-dimethyl-9-aza-3-oxatricyclo[3.3.1. 02,4]nonan-9-ium bromide] are inhaled drugs used in the treatment of chronic obstructive pulmonary disease (COPD) and asthma. Tertiary amine precursors have been synthesized and radiolabelled with carbon-11 by N-alkylation with [11C]CH3I. The [11C] ipratropium and [11C]tiotropium positron emission tomography (PET) ligands are obtained with high radiochemical purity, in 0.3 and 0.5% non-decay corrected yields based on [11C]CO2 at end-of-synthesis and specific activities of 11 and 18 GBq μ mol-1, respectively, calculated at end-of-synthesis. These PET radioligands can be used in the study of inhaled drug deposition. CSIRO 2006.
- Issa, Fatiah,Kassiou, Michael,Chan, Hak-Kim,McLeod, Malcolm D.
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- Synthesis and nicotinic receptor activity of a hydroxylated tropane
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(±)-3α-Hydroxy homoepibatidine 4 has been synthesized from the alkaloid scopolamine 5 and its properties as a nicotinic agonist assessed. While still binding strongly, the compound showed reduced agonist potency for the α4β2 nAChR compared with the parent compound epibatidine 1. Compound 4 also displayed generally similar binding and selectivity profiles at α4β2, α 2β4, α3β4, and α4β4 nAChR subtypes to those for nicotine.
- Bremner, John B.,Godfrey, Colette A.,Jensen, Anders A.,Smith, Reginald J.
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p. 271 - 273
(2007/10/03)
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- Synthesis of scopin acetate and 6,7-didehydrohyoscyamin. Intramolecular phenylsulfenylation of a nonactivated methylene group of ethyl N-demethyl-3-O-(phenylthio)tropine-N-carboxylate
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The synthesis of scopin acetate (6b) and 6,7-didehydrohyoscyamine (17) was achieved by using tropine (5) as the starting compound. Formal (phenylthio)-radical transfer to the nonactivated 6-position of ethyl N-demethyl-3-O-(phenylthio)tropine-N-carboxylate (9) by irradiation in the presence of hexabutyldistannane is a key step of this synthetic approach, involving ethyl 6,7-didehydro-N-demethyltropine-N-carboxylate (15) as a synthetic intermediate (Schemes 3 and 5). The reaction of 9 with tributylstannane in the presence of ethyl acrylate, as a radicophilic olefin, involves Michael-type alkylation at C(6) of the tropine skeleton affording ethyl N-demethyl-N-(ethoxycarbonyl)tropine-6-propanoate (18) (Scheme 6).
- Petrovi?, Goran B.,Sai?i?, Radomir N.,?ekovi?, ?ivorad M.
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p. 3179 - 3186
(2007/10/03)
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- Industrial process for preparing tropenol
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The invention relates to a new industrially useable process for preparing tropenol, optionally in the form of the acid addition salts thereof.
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- Synthesis of acetyl scopine. Intramolecular reactions of N-carbethoxy nortropine-3α-benzene-sulfenate
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The synthesis of acetyl scopine using tropine as a starting compound was achieved. Free radical phenylthio group transfer to the 6-position, in the reaction of N-carbethoxy nortropine-3α-benzenesulfenate with hexabutylditin, is a key step of this synthetic approach to scopine. The reaction of N- carbethoxy nortropine-benzenesulfenate with tributyltin hydride in the presence of a radicophilic olefin involves Michael type alkylation at the 6- position of tropine skeleton affording 6-(2-carbethoxyethyl)-N-carbethoxy nortropine in 31% yield.
- Petrovi?, Goran,Sai?i?, Radomir N.,?ekovi?, ?ivorad
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p. 635 - 637
(2007/10/03)
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- A Meisenheimer rearrangement approach to bridgehead hydroxylated tropane alkaloid derivatives
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Thermolysis of 3-t-butyldimethylsiloxy-8-methyl-8-azabicyclo[3.2.1]oct-6-ene N-oxide (11) and (12) in butyronitrile gave 3-t-butyldimethylsiloxy-9-methyl-8-oxa-9-azabicyclo[3.2.2]non-6-ene (13) which upon reductive N-O ring cleavage, hydrogenation, oxidation and deprotection yielded the 3-hydroxy analogue 8-methyl-8-azabicyclo[3.2.1]octane-1,3-diol (6a ? 6b) of the tropane alkaloid physoperuvine.
- Bremner, John B.,Smith, Reginald J.,Tarrant, Gregory J.
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