- Pivaloylcodeine, a new codeine derivative, for the inhibition of morphine glucuronidation. An in vitro study in the rat
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We have previously found that phenanthrenic opioids, including codeine, modulate morphine glucuronidation in the rat. Here codeine and five of its derivatives were compared in their effects on the synthesis of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) from morphine by rat liver microsomal preparations, and by primary cultures of rat hepatocytes previously incubated for 72 h with either codeine or its derivatives. Acetylcodeine and pivaloylcodeine shared the capability of the parent compound of inhibiting the synthesis of M3G by liver microsomes through a noncompetitive mechanism of action. Their IC50 were 3.25, 2.27, and 4.32 μM, respectively. Dihydrocodeine, acetyldihydrocodeine, and lauroylcodeine were ineffective. In all the experimental circumstances M6G was undetectable in the incubation medium. In primary hepatocyte cultures codeine only inhibited M3G formation, but with a lower efficacy than that observed with microsomes (IC 50 20.91 vs 4.32 μM). Preliminary results show that at micromolar concentrations codeine derivatives exhibit a low rate of affinity for μ opiate receptors. In conclusion, acetyl and pivaloyl derivatives of codeine noncompetitively inhibit liver glucuronidation of morphine interacting with microsomes. This study further strengths the notion that phenanthrenic opioids can modulate morphine glucuronidation independently from their effects on μ opiate receptors.
- Antonilli, Letizia,Togna, Anna Rita,Sabatini, Giovanna,Venditti, Alessandro,Guarcini, Laura,Togna, Giuseppina I.,Nicoletti, Rosario,Sanasi, Filomena,Bianco, Armandodoriano,Nencini, Paolo
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Read Online
- Synthesis of 1-fluoro-substituted codeine derivatives
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Syntheses of new N-demethyl-N-substituted analogues (propyl, allyl) of 1-fluorocodeine and their 7,8-dihydro derivatives were described starting from codeine. 1-Fluoronorcodeine and 1-fluorodihydronorcodeine were prepared by N-demethylation with α-chloroethyl chloroformate from the corresponding 6-O-acetyl protected derivatives. 3-O-Demethylation of 1-fluorocodeine and 1-fluorodihydrocodeine with boron tribromide resulted in 1-fluoromorphine and 1-fluorodihydromorphine respectively. 1-Fluorodihydromorphine was acetylated to 3,6-di-O-acetyl-1-fluorodihydromorphine. 8-Fluoroapocodeine and N-propyl-8-fluoroapocodeine were synthesized from the appropriate 1-fluorocodeine derivatives by acid-catalyzed rearrangement.
- Hosztafi, Sándor,Marton, János
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p. 973 - 982
(2016/05/19)
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- A two-step one-pot radiosynthesis of the potent dopamine D 2/D3 agonist PET radioligand [11C]MNPA
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(R)-(-)-2-[11C]Methoxy-N-n-propylnorapomorphine ([ 11C]MNPA ([11C]2)) is an agonist radioligand of interest for imaging D2/ D3 receptors in vivo. Here we sought to develop an improved radiosynthesis of this radioligand. Reference 2 was synthesized in nine steps with an overall yield of about 5%, starting from codeine. Trimethylsilyldiazomethane proved to be a practical improvement in comparison to diazomethane in the penultimate methylation step. A protected precursor for radiolabeling ((R)-(-)-2-hydroxy-10,11-acetonide-N-n- propylnoraporphine, 4) was prepared from (R)-(-)-2-hydroxy-N-n- propylnorapomorphine (1) in 30% yield. [11C]2 was prepared from 4 via a two-step one-pot radiosynthesis. The first step, methylation of 4 with [ 11C]methyl triflate, occurred in quantitative radiochemical yield. The second step, deprotection of the catechol moiety with HCl and heat, yielded 60-90% of [11C]2 giving an overall incorporation yield from [ 11C]methyl triflate of 60-90%. In a typical run more than 1 GBq of [11C]2, was produced from carbon-11 generated from a 10-min proton irradiation (16 MeV; 35 μA) of nitrogen-hydrogen target gas. The radiochemical purity of [11C]2 was > 99% and specific radioactivity at the time of injection was 901±342 GBq/μmol (n = 10). The total synthesis time was 35-38 min from the end of radionuclide production. The identity of [11C]2 was confirmed by comparing its LC-MS/MS spectrum with those of reference 2 and (R)-(-)-10-methoxy-2,11-dihydroxy-N-n- propylnoraporphine. Copyright
- Steiger,Finnema,Raus,Schou,Nakao,Suzuki,Pike,Wikstroem,Halldin
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experimental part
p. 158 - 165
(2010/06/20)
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- METHODS FOR MAKING 3-O-PROTECTED MORPHINONES AND 3-O-PROTECTED MORPHINONE DIENOL CARBOXYLATES
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Disclosed are methods for making aldehydes and ketones comprising allowing the corresponding primary or secondary alcohol to react in the presence of trichoroisocyanuric acid, a compound of formula R1SR2 and a base. In one embodiment, the alcohol is a compound of formula (I) wherein R3 is a protecting group. Also disclosed are methods for making 3-O-protected morphine dienol carboxylates comprising allowing a compound of formula (I) to oxidize in the presence of a chlorine-containing compound and a compound of formula R1SR2; and allowing the product of the oxidation step to react with an acylating agent.
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Page/Page column 33-34
(2008/06/13)
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- Preparation of 14-hydroxynormorphinones from normorphinone dienol acylates
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The invention provides processes for the conversion of normorphinone and its derivatives, which can be synthesized from morphine, to the corresponding 14-hydroxynormorphinone and its derivatives including oxycodone, oxymorphone, noroxymorphone and naltrexone. Noroxymorphone is a key intermediate for the production of important narcotic analgesics and antagonists. The invention also provides certain novel intermediates.
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- N-Cubylmethyl substituted morphinoids as novel narcotic antagonists
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N-Cubylmethylnormorphine (1) and N-cubylmethylnoroxymorphone (2) have been synthesized and found to be more potent ligands at the μ and κ opioid receptors than morphine and oxymorphone respectively. In the guinea-pig ileum preparation, compounds 1 and 2 were characterized as opioid μ antagonists (Ke=68 and 16 nM, respectively). Compound 2 also showed effective κ-antagonism (Ke=22 nM). The narcotic antagonism activity of 1 has been confirmed by in vivo assays.
- Cheng, Chen-Yu,Hsin, Ling-Wei,Lin, Yen-Pin,Tao, Pao-Luh,Jong, Ting-Ting
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- ON THE GIF OXIDATION OF ALICYCLIC TERTIARY AMINES
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Oxidation of various tertiary amines by the GifIV system based on iron catalyst associated with a reductant (zinc) and molecular oxigen, led to a mixture of the keto-derivatives and the corresponding lactams.Steric hindrance and electron withdrawing substituents exert a deactivating effect on the oxidation.
- Barton, D.H.R,Boivin, J.,Gaudin D.,Jankowski, K.
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p. 1381 - 1382
(2007/10/02)
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- Selective Aminolysis of Benzoates and Acetates of α-Hydroxy Acids and Phenols with Benzylamine and Butan-1-amine
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Benzoates and acetates of α-hydroxy acids and phenols undergo facile aminolysis on treating with benzylamine or butan-1-amine in benzene at room temperature.Under the same conditions acetates and benzoates of alcohols are unaffected.
- Bell, Kevin H.
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p. 1723 - 1735
(2007/10/02)
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- Claisen Reactions on Codeins. 8-Alkyl-8,14-dihydro-6-demethoxythebaines and -oripavines
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Claisen Eschenmoser reaction of 1a leads to 2a, which is transformed to 2c, e, and f by especially adopted reduction conditions.Reduction of 2i with LiAlH4 gives 2g.Catalytic hydrogenation of 2 results in ether bridge opening and formation of 4.Reaction of 2e with 4 N HCl yields the cyclic phenol 7a.Orthoester Claisen rearrangement of 1a leads to orthoacetate 10 and 11.Claisen Eschenmoser reaction on codeine isomers 1b and 12c gives the amides 12a and 1f.
- Fleischhacker, Wilhelm,Richter, Bernd
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p. 3866 - 3880
(2007/10/02)
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