- The application of a specific morphinan template to the synthesis of galanthamine
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(–)-Galanthamine (4) was synthesized from naltrexone (1) in 18 steps with 3% total yield by overcoming many specific side reactions derived from the 4,5-epoxymorphinan skeleton. The key features are cleavage of the D-ring by the Hofmann elimination and the following the one-pot C9–C10 and C9–14 bond cleavages concomitant with the C9 removal by the OsO4–NaIO4 combination reaction. Then, the treatment with zinc powder in acetic acid led to not only removal of the 2,2,2-trichloroethoxycarbonyl (Troc) group, but also reductive amination of the resulting imine to give the desired 7-membered ring.
- Yamamoto, Naoshi,Okada, Takahiro,Harada, Yukimasa,Kutsumura, Noriki,Imaide, Satomi,Saitoh, Tsuyoshi,Fujii, Hideaki,Nagase, Hiroshi
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- Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies
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Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX1R) (Ki = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 with improvement of the antagonist activity (OX1R, Ki = 1.36 nM; OX2R, not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in water, attenuated the physical dependence of morphine. Furthermore, all of the active nalfurafine derivatives in this study had almost no activity for OX2R, which led to high OX1R selectivity. These results suggest that nalfurafine derivatives could be a useful series of lead compounds to develop highly selective OX1R antagonists.
- Nagase, Hiroshi,Yamamoto, Naoshi,Yata, Masahiro,Ohrui, Sayaka,Okada, Takahiro,Saitoh, Tsuyoshi,Kutsumura, Noriki,Nagumo, Yasuyuki,Irukayama-Tomobe, Yoko,Ishikawa, Yukiko,Ogawa, Yasuhiro,Hirayama, Shigeto,Kuroda, Daisuke,Watanabe, Yurie,Gouda, Hiroaki,Yanagisawa, Masashi
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- Transformation of naltrexone into mesembrane and investigation of the binding properties of its intermediate derivatives to opioid receptors
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We transformed naltrexone (5) with the morphinan skeleton into mesembrane (4) belonging to the Sceletium alkaloids via key intermediate 6, characterized by a cis-fused hydroindole skeleton with a suspended phenyl ring fixed by an epoxy bridge. We then investigated the binding affinities of 4 and the key intermediate 6 derivatives to the opioid receptors. Among the tested compounds, 15′, with a cis-fused hydroindole core, bound to the three opioid receptor types with strong to moderate affinities. The observed differences of binding affinities among the tested compounds were reasonably explained by the conformational analyses of the compounds. The structure-activity relationship (SAR) of the tested compounds like 15′ with the hydroindole structure was completely different from the reported SAR of morphinan derivatives with the hydroisoquinoline skeleton. Compound 15′ with a structure that differs from the morphinans represents a useful fundamental skeleton with a novel chemotype that may contribute to the development of new opioid ligands.
- Konoura, Kazuya,Fujii, Hideaki,Imaide, Satomi,Gouda, Hiroaki,Hirayama, Shigeto,Hirono, Shuichi,Nagase, Hiroshi
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- Novel Baeyer–Villiger-type oxidation of 4,5-epoxymorphinan derivatives
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A novel molecular oxygen-mediated Baeyer–Villiger-type oxidation specific to the morphinan skeleton has been discovered. The reaction of a ketone bearing a bicyclo[2.2.2]octenone skeleton with KOH (pellet) in refluxing tBuOH under an oxygen atmosphere (balloon) afforded unexpected cyclopropanecarboxylic acid and ketolactone derivatives. The reactive sites (carboxylic acid and ester) in those products are oriented over the C-ring in the morphinan skeleton, and thus such morphinan compounds would be useful intermediates to design ideal κ opioid receptor agonists.
- Hino, Tsubasa,Kutsumura, Noriki,Saitoh, Tsuyoshi,Yamamoto, Naoshi,Nagumo, Yasuyuki,Mogi, Yuzo,Watanabe, Yoshikazu,Nagase, Hiroshi
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- Rapid access to morphinones: removal of 4,5-ether bridge with Pd-catalyzed triflate reduction
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A new synthetic method for the removal of the 4,5-bridged ether moiety of several opioids has been developed. This process offers a faster, simpler synthetic route to obtain the morphinone scaffold in high yields without the need for protection of the ketone moiety.
- Hupp, Christopher D.,Neumeyer, John L.
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- Effects of N-substituents on the functional activities of naltrindole derivatives for the δ opioid receptor: Synthesis and evaluation of sulfonamide derivatives
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We have recently reported that N-alkyl and N-acyl naltrindole (NTI) derivatives showed activities for the δ opioid receptor (DOR) ranging widely from full inverse agonists to full agonists. We newly designed sulfonamide-type NTI derivatives in order to in
- Iwamatsu, Chiharu,Hayakawa, Daichi,Kono, Tomomi,Honjo, Ayaka,Ishizaki, Saki,Hirayama, Shigeto,Gouda, Hiroaki,Fujii, Hideaki
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- Syntheses and receptor-binding studies of derivatives of the opioid antagonist naltrexone
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Naltrexone (1), which is a member of the group of competitive opioid antagonists, shows a strong affinity for μ-receptors and its derivatives have been notable as novel receptor anatgonists. In this paper, the preparation of several naltrexone derivatives is described; these were used to investigate the role of the oxygenated functional groups in facilitating binding to a series of the opioid receptors. The derivatives showed affinity for opioid μ-receptors which was similar to that of naltrexone, but these compounds, which had masked hydroxyl functional groups, displayed a moderate activity. These results suggest that every oxygenated functional group in naltrexone (1) plays an important role in binding to the opioid receptor.
- Uwai, Koji,Uchiyama, Hiroko,Sakurada, Shinobu,Kabuto, Chizuko,Takeshita, Mitsuhiro
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- Binding of norbinaltorphimine (norBNI) congeners to wild-type and mutant mu and kappa opioid receptors: Molecular recognition loci for the pharmacophore and address components of kappa antagonists
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Molecular modifications of both the kappa opioid antagonist norbinaltorphimine (norBNI, 1) and the kappa receptor have provided evidence that the selectivity of this ligand is conferred through ionic interaction if its N17' protonated amine group (an 'address') with a nonconserved acidic residue (Glu297) on the kappa receptor. In the present study, we have examined the effect of structural modifications on the affinity of norBNI analogues for wild-type and mutant kappa and mu opioid receptors expressed in COS-7 cells. Compounds 2, 3, and 7, which have an antagonist pharmacophore and basic N17' group in common with norBNI, retained high affinity for the wild-type kappa but exhibited greatly reduced affinity for mutant kappa receptors (E297K and E297A). Modification of the phenolic or N-substituent groups of the antagonist pharmacophore (4 and 5) or removal of basicity at the address N17' center (6) led to greatly reduced affinity for the wild-type and mutant receptors. The reduced affinity upon modification of the kappa receptor is consistent with the ionic interaction of the protonated N17' group of kappa antagonists (1-3, 7) with the carboxylate group of E297 at the top of TM6. This was supported by the greatly enhanced affinity of compounds 1-3 for the mutant mu receptor (K303E), as compared to the wild-type mu receptor, given that residue K303 occupies a position equivalent to that of E297 in the kappa receptor. In view of the high degree of homology of the seven TM domains of the kappa and mu opioid receptors, it is suggested that the antagonist pharmacophore is bound within this highly conserved region of the kappa or mutant mu receptor and that an anionic residue at the top of TM6 (E297 or K303E, respectively) provides additional binding affinity.
- Larson, Dennis L.,Jones, Robert M.,Hjorth, Siv A.,Schwartz, Thue W.,Portoghese, Philip S.
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- Asymmetric synthesis of (-)-naltrexone
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(-)-Naltrexone, an opioid antagonist used extensively for the management of drug abuse, is derived from naturally occurring opioids. Herein, we report the first asymmetric synthesis of (-)-naltrexone that does not proceed through thebaine. The synthesis starts with simple, achiral precursors with catalytic enantioselective Sharpless dihydroxylation employed to introduce the stereogenic centers. A Rh(i)-catalyzed C-H alkenylation and torquoselective electrocyclization cascade provides the hexahydro isoquinoline bicyclic framework that serves as the precursor to the morphinan core. The acidic conditions used for Grewe cyclization not only provide the morphinan framework, but also cause a hydride shift resulting in the introduction of the C-6 oxo functionality present in (-)-naltrexone. The C-14 hydroxyl group is installed by an efficient two-step sequence of Pd-mediated ketone to enone dehydrogenation followed by C-H allylic oxidation using Cu(ii) and O2, a method that has not previously been reported either for the synthesis or semi-synthesis of opioids. The longest linear sequence is 17 steps, and because the stereogenic centers in the product rely on Sharpless asymmetric dihydroxylation, the route could be used to access either enantiomer of the natural product, which have disparate biological activities. The route also may be applicable to the preparation of opioid derivatives that could not be easily prepared from the more fully elaborated and densely functionalized opioid natural products that have traditionally served as the starting inputs.
- Dongbang, Sun,Pedersen, Blaine,Ellman, Jonathan A.
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p. 535 - 541
(2019/01/10)
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- NONCRUSHABLE PILL FORMULATIIONS
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Non-crushable pill formulations and methods of using the formulations are disclosed. A non- crushable pill formulation for preventing unintended use of a drug, comprising a polymer, the polymer forming a polymer backbone of the complex; cross-linkers, the
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Paragraph 00362-00364
(2018/07/29)
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- Substituted Morphinans and the Use Thereof
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The application is directed to compounds of Formula I: and pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3, R4a, and R4b are defined as set forth in the specification. The invention is also directed to use of compounds of Formula I to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain.
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Paragraph 0656
(2014/07/08)
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- 7,8-Cyclicmorphinan Analogs
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The application is directed to compounds of Formula I-A and pharmaceutically acceptable salts and solvates thereof, wherein Cy, R1a-R3a, R4a, and R4b are defined as set forth in the specification. The invention is also directed to use of compounds of Formula I-A to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain.
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Paragraph 0361-0363
(2014/07/08)
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- Investigation of structure, vibrational and NMR spectra of oxycodone and naltrexone: A combined experimental and theoretical study
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In this work, two important opioid antagonists, naltrexone and oxycodone, were prepared from thebaine and were characterized by IR, 1H NMR and 13C NMR spectroscopy. Moreover, computational NMR and IR parameters were obtained using density functional theory (DFT) at B3LYP/6-311++G* * level of theory. Complete NMR and vibrational assignment were carried out using the observed and calculated spectra. The IR frequencies and NMR chemical shifts, determined experimentally, were compared with those obtained theoretically from DFT calculations, showed good agreements. The RMS errors observed between experimental and calculated data for the IR absorptions are 85 and 105 cm-1, for the 1H NMR peaks are 0.87 and 0.17 ppm and for those of 13C NMR are 5.6 and 5.3 ppm, respectively for naltrexone and oxycodone.
- Tavakol, Hossein,Esfandyari, Maryam,Taheri, Salman,Heydari, Akbar
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p. 574 - 582
(2011/07/31)
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- Synthesis of (-)-homogalanthamine from naltrexone
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Acetylcholinesterase inhibitor (-)-homogalanthamine 3 was synthesized from μ opioid antagonist naltrexone (2) in 16% total yield. The synthesis features Grob fragmentation as a key reaction, which was especially accelerated in the presence of 15-crown-5.
- Yamamoto, Naoshi,Fujii, Hideaki,Imaide, Satomi,Hirayama, Shigeto,Nemoto, Toru,Inokoshi, Junji,Tomoda, Hiroshi,Nagase, Hiroshi
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scheme or table
p. 2257 - 2260
(2011/06/11)
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- Novel synthesis of a 1,3,5-trioxazatriquinane skeleton using a nitrogen clamp
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(Chemical Equation Presente) An α-hydroxyaldehyde derived from naltrexone was converted to an oxazoline dimer with ammonium chloride and sodium acetate in MeOH under reflux. The resulting dimer was treated with dl-camphorsulfonic acid in CHCl3 to give the trimer. The method for trimer synthesis was also applied to general α-hydroxyaldehydes to afford trimers in good yield.
- Nagase, Hiroshi,Watanabe, Akio,Harada, Masaya,Nakajima, Mayumi,Hasebe, Ko,Mochizuki, Hidenori,Yoza, Kenji,Fujii, Hideaki
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supporting information; experimental part
p. 539 - 542
(2009/09/25)
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- Mixed k/μ opioid receptor agonists: The 6β-naltrexamines
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Ligands from the naltrexamine series have consistently demonstrated agonist activity at κ opioid receptors (KOR), with varying activity at the μ opioid receptor (MOR). Various 6β-cinnamoylamino derivatives were made with the aim of generating ligands with
- Cami-Kobeci, Gerta,Neal, Adrian P.,Bradbury, Faye A.,Purington, Lauren C.,Aceto, Mario D.,Harris, Louis S.,Lewis, John W.,Traynor, John R.,Husbands, Stephen M.
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body text
p. 1546 - 1552
(2010/01/07)
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- Synthesis of a novel 4,6′-epoxymorphinan derivative and a highly strained novel conjugated ketone
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A modification of the 4,5-epoxymorphinan skeleton of naltrexone was carried out to improve the potency and the selectivity of the ligand for an opioid receptor subtype. As one of the modified structures, we newly designed and synthesized a novel 7-membere
- Nemoto, Toru,Fujii, Hideaki,Sato, Noriko,Nagase, Hiroshi
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p. 7413 - 7417
(2008/03/13)
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- A new useful conversion method of naltrexone to 14-deoxynaltrexone
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A novel synthetic method of 14-deoxynaltrexone (2), a μ-opioid receptor antagonist possessing a new message-structural part of opioid ligands, was established. Naltrexone methyl ether (5) was first converted to its acetal (24), followed by dehydration with thionyl chloride in pyridine to afford 8,14-dehydroderivative (26) of 24. The resulting unsaturated compound (26) was reduced with PtO2 under hydrogen to give saturated compound (27), which was then acid-hydrolyzed to afford the desired 14-deoxynaltrexone (23) (3-O-methyl of 2) without degradation of the naltrexone skeleton. The total yield from naltrexone (1) to 23 was 86%. Finally, 23 was demethylated to give 14-deoxynaltrexone (2) in 85% yield. This method provides a useful reaction route to give various important intermediates as a message part to synthesize selectives ligands for the opioid receptor subtypes.
- Osa, Yumiko,Ida, Yoshihiro,Yano, Yumiko,Furuhata, Kimio,Nagase, Hiroshi
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p. 271 - 282
(2008/02/10)
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- 4-HYDROXYBENZOMORPHANS
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4-Hydroxybenzomorphans containing carboxamide or thiocarboxamide at the 3-position are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications.
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Page/Page column 21
(2010/11/30)
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- Synthesis and opioid receptor binding properties of 17- cyclopropylmethyl-6,7-dehydro-3,14-dihydroxy-4,5α-epoxy-6,7:4',5'- pyrimidinomorphinans
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A class of opioid receptor active derivatives of naltrexone has been synthesized using a common enaminone intermediate. The intermediate used in the synthesis is prepared from N,N-dimethylformamide dimethyl acetal and naltrexone and can be isolated and characterized. The derivatives have heterocyclic groups fused to the 6,7-positions of the morphinan system and all were synthesized in high yield. All compounds were very high affinity, nonselective antagonists for the opioid receptors.
- Xu, Wei,Huang, Liang-Fu,Bauer, Ludwig,Bhargava, Hemendra N.,Dunn III, William J.
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p. 389 - 407
(2007/10/03)
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- A New Reagent for the Selective, High-Yield N-Dealkylation of Tertiary Amines: Improved Syntheses of Naltrexone and Nalbuphine
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Secondary amine hydrochlorides are obtained in high yield by reaction of tertiary amines with α-chloroethyl chloroformate followed by warming the intermediate carbamate in methanol.
- Olofson, R. A.,Martz, Jonathan T.,Senet, Jean-Pierre,Piteau, Marc,Malfroot, Thierry
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p. 2081 - 2082
(2007/10/02)
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- N-dealkylation of N-alkyl-14-hydroxymorphinans and derivatives thereof
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There is provided a novel, high yield, method of dealkylating N-alkylated 14-hydroxymorphinans and derivatives thereof including, inter alia, oxymorphone and oycodone. There are thus provided, inter alia, more efficient routes for the formation of naloxone, naltrexone, and nalbuphine. In the principal step of the process, the dealkylation using certain oxycarbonyl halides (or haloformates) is carried out on the N-alkyl-14-acyloxy-morphinan which it is desired to dealkylate.
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- N-alkyl-14-hydroxymorphinans and derivatives
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There is provided a novel and high yield procedure for transforming acid salts of 14-alkanoyloxymorphinans and derivatives thereof into the corresponding N-alkyl-14-hydroxymorphinans wherein the alkyl moiety on the nitrogen contains the same number of carbon atoms as that previously in the 14-alkanoyl moiety. In the process of the present invention, the acid is neutralized to the free base, the alkanoyl moiety at the 14-oxy then spontaneously shifts to the nitrogen and is subsequently reduced to the corresponding alkyl moiety. O-dealkylation at C-3, where an alkoxy group is originally present, is carried out in the usual manner. There is also provided a readily produced and readily disassociated adduct of the corresponding 14-hydroxy-N-alkanoyl morphinan-6-alkylene ketal with benzene, tetrahydrofuran, and the like.
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