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Jia-lu Luo - One of the best experts on this subject based on the ideXlab platform.
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N-Cyclohexyl-5H,7H-13,15-dimethyl-9-nitro-5-oxophenanthrido[4,4a,5-bc][1,4]benzOxazepine-7-carboxamide
Acta Crystallographica Section E Structure Reports Online, 2009Co-Authors: Jia-lu LuoAbstract:In the title compound, C29H27N3O5, a dibenz[b,f][1,4]Oxazepine Derivative, the cyclohexane ring adopts a chair conformation, the Oxazepine seven-membered ring has a twist-boat conformation, and the piperidin-2-one ring assumes a flattened boat conformation. Intermolecular N—H⋯O hydrogen bonding between imino and nitro groups links two molecules into a centrosymmetric dimer.
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N-Cyclo-hexyl-5H,7H-13,15-dimethyl-9-nitro-5-oxophenanthrido[4,4a,5-bc][1,4]benzOxazepine-7-carboxamide.
Acta crystallographica. Section E Structure reports online, 2009Co-Authors: Jia-lu LuoAbstract:In the title compound, C(29)H(27)N(3)O(5), a dibenz[b,f][1,4]Oxazepine Derivative, the cyclo-hexane ring adopts a chair conformation, the Oxazepine seven-membered ring has a twist-boat conformation, and the piperidin-2-one ring assumes a flattened boat conformation. Inter-molecular N-H⋯O hydrogen bonding between imino and nitro groups links two mol-ecules into a centrosymmetric dimer.
Andrea Strasser - One of the best experts on this subject based on the ideXlab platform.
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dibenzo b f 1 4 Oxazepines and dibenzo b e oxepines influence of the chlorine substitution pattern on the pharmacology at the h1r h4r 5 ht2ar and other selected gpcrs
Pharmacological Research, 2016Co-Authors: Franziska Naporra, Susanne Gobleder, Julia Spindler, Michael Bodensteiner, Gunther Bernhardt, Harald Hübner, Peter Gmeiner, Hans-joachim Wittmann, Andrea StrasserAbstract:Abstract Inspired by VUF6884 (7-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[ b,f ][1,4]Oxazepine), reported as a dual H 1 /H 4 receptor ligand (p K i : 8.11 (human H 1 R (hH 1 R)), 7.55 (human H 4 R (hH 4 R))), four known and 28 new Oxazepine and related oxepine Derivatives were synthesised and pharmacologically characterized at histamine receptors and selected aminergic GPCRs. In contrast to the Oxazepine series, within the oxepine series, the new compounds showed high affinity to the hH 1 R (p K i : 6.8–8.7), but no or moderate affinity to the hH 4 R (p K i : ≤ 5.3). For one oxepine Derivative (1-(2-Chloro-6,11-dihydrodibenzo[ b , e ]oxepin-11-yl)-4-methylpiperazine), the enantiomers were separated and the R -enantiomer was identified as the eutomer at the hH 1 R (p K i : 8.83 ( R ), 7.63 ( S )) and the guinea-pig H 1 R (gpH 1 R) (p K i : 8.82 ( R ), 7.41 ( S )). Molecular dynamic studies suggest that the tricyclic core of the compounds is bound in a similar mode into the binding pocket, as described for doxepine in the hH 1 R crystal structure. Moreover, docking studies of all oxepine Derivatives at the hH 1 R indicate that the oxygen and the position of the chlorine in the tricyclic core determines, if the R - or the S -enantiomer is the eutomer. For some of the Oxazepines and oxepines the affinity to other aminergic GPCRs is in the same range as to hH 1 R or hH 4 R, thus, those compounds have to be classified as dirty drugs. However, one Oxazepine Derivative (3,7-Dichloro-11-(4-methylpiperazin-1-yl)dibenzo[ b,f ][1,4]Oxazepine was identified as dual hH 1 /h5-HT 2A receptor ligand (p K i : 9.23 (hH 1 R), 8.74 (h5-HT 2A R), ≤7 at other analysed GPCRs), whereas one oxepine Derivative (1-(3,8-Dichloro-6,11-dihydrodibenzo[ b,e ]oxepin-11-yl)-4-methylpiperazine) was identified as selective hH 1 R antagonist (p K i : 8.44 (hH 1 R), ≤6.7 at other analyzed GPCRs). Thus, the pharmacological results suggest that the Oxazepine/oxepine moiety and additionally the chlorine substitution pattern toggles receptor selectivity and specificity.
Franziska Naporra - One of the best experts on this subject based on the ideXlab platform.
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dibenzo b f 1 4 Oxazepines and dibenzo b e oxepines influence of the chlorine substitution pattern on the pharmacology at the h1r h4r 5 ht2ar and other selected gpcrs
Pharmacological Research, 2016Co-Authors: Franziska Naporra, Susanne Gobleder, Julia Spindler, Michael Bodensteiner, Gunther Bernhardt, Harald Hübner, Peter Gmeiner, Hans-joachim Wittmann, Andrea StrasserAbstract:Abstract Inspired by VUF6884 (7-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[ b,f ][1,4]Oxazepine), reported as a dual H 1 /H 4 receptor ligand (p K i : 8.11 (human H 1 R (hH 1 R)), 7.55 (human H 4 R (hH 4 R))), four known and 28 new Oxazepine and related oxepine Derivatives were synthesised and pharmacologically characterized at histamine receptors and selected aminergic GPCRs. In contrast to the Oxazepine series, within the oxepine series, the new compounds showed high affinity to the hH 1 R (p K i : 6.8–8.7), but no or moderate affinity to the hH 4 R (p K i : ≤ 5.3). For one oxepine Derivative (1-(2-Chloro-6,11-dihydrodibenzo[ b , e ]oxepin-11-yl)-4-methylpiperazine), the enantiomers were separated and the R -enantiomer was identified as the eutomer at the hH 1 R (p K i : 8.83 ( R ), 7.63 ( S )) and the guinea-pig H 1 R (gpH 1 R) (p K i : 8.82 ( R ), 7.41 ( S )). Molecular dynamic studies suggest that the tricyclic core of the compounds is bound in a similar mode into the binding pocket, as described for doxepine in the hH 1 R crystal structure. Moreover, docking studies of all oxepine Derivatives at the hH 1 R indicate that the oxygen and the position of the chlorine in the tricyclic core determines, if the R - or the S -enantiomer is the eutomer. For some of the Oxazepines and oxepines the affinity to other aminergic GPCRs is in the same range as to hH 1 R or hH 4 R, thus, those compounds have to be classified as dirty drugs. However, one Oxazepine Derivative (3,7-Dichloro-11-(4-methylpiperazin-1-yl)dibenzo[ b,f ][1,4]Oxazepine was identified as dual hH 1 /h5-HT 2A receptor ligand (p K i : 9.23 (hH 1 R), 8.74 (h5-HT 2A R), ≤7 at other analysed GPCRs), whereas one oxepine Derivative (1-(3,8-Dichloro-6,11-dihydrodibenzo[ b,e ]oxepin-11-yl)-4-methylpiperazine) was identified as selective hH 1 R antagonist (p K i : 8.44 (hH 1 R), ≤6.7 at other analyzed GPCRs). Thus, the pharmacological results suggest that the Oxazepine/oxepine moiety and additionally the chlorine substitution pattern toggles receptor selectivity and specificity.
Leroy B. Townsend - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of 1-Hydroxy-10-methyl-pyrimido [1, 6-C][1, 3]oxazine and the Oxazepine Derivative, Structural Mimicry of Anti-Constrained Acyclic Thymidine
Nucleosides and Nucleotides, 1996Co-Authors: Ling-yih Hsu, Dean S. Wise, John C. Drach, Leroy B. TownsendAbstract:Abstract A number of pyrimido[1, 6-c][1, 3]oxazine and -Oxazepine Derivatives, mimicry analogs of anti-constrained acyclic thymidine, have been prepared via treatment of lithiated 5, 6-dimethyl-2, 4-dimethoxypyrimidine with benzylchloromethyl ether or oxiran to furnish 2, 4-dimethoxy-6-(1-benzyloxyethyl)-S-methylpyrimidine (2) and 2, 4-dimethoxy-6-(1-hydroxypropyl)-5-methylpyrimidine (8), respectively. Debenzylation of 2 afforded 2, 4-dimethoxy-6-(1-hydroxyethyl)-5-methylpyrimidine (3). Chloromethylation of 3 and 8 with paraformaldehyde and gaseous hydrogen chloride produced reactive chloromethyl ether intermediates which were converted to the cyclized products 9-methyl-(1H, 2H, 4H, 7H)-pyrimido[1, 6-c][1, 3]-oxazine (5) and -Oxazepine (9)-6, 8-dione, respectively. By using selenium dioxide, allylic oxidation of 5 and 9 afforded the target compounds, a racemic mixture of (±)1-hydroxy-9-methyl-(1H, 2H, 4H, 7H)-pyrimido[1, 6-c][1, 3]-oxazine (6) and -Oxazepine (10)-6, 8-dione, respectively. Compounds 5, 6, ...
Geczy J. - One of the best experts on this subject based on the ideXlab platform.
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Electrooxidation Potential as a Tool in the Early Screening for New Safer Clozapine-Like Analogues
2001Co-Authors: Mouthys-mickalad Ange, Damas Jacques, Kauffmann J. M., Petit C., Bruhwyler J., Liao Y., Wikstrom H., Delarge J., Deby-dupont G., Geczy J.Abstract:The chemical modification of clozapine (1) has permitted the finding of new analogues, e.g., olanzapine (2), quetiapine (3), 5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzOxazepine fumarate (9), with a clinical or psychopharmacological profile similar to that of clozapine. However, when developing new Derivatives, the designers are discouraged by the development of clozapine-induced agranulocytosis. Different researchers have raised the role played by the oxidizability of the molecule in such a deleterious effect. In the present paper, we examined the oxidation profile (direct scavenging abilities, efficacy in inhibiting lipid peroxidation, and electrooxidation potential) of newly developed methoxy and trifluoromethylsulfonyloxy analogues related to clozapine, some of them being described as putative antipsychotic. The Oxazepine Derivative 7, unlike the other diazepine Derivatives (6, 10--12), was not readily oxidized. Using a statistical predictive model for hematotoxicity previously described, 7 was found in the cluster of potentially nontoxic compounds while diazepine Derivatives 6 and 10-12 were classified as potentially toxic compounds. Among these original compounds, 7, which presents a preclinical clozapine-like profile and a low sensitivity to oxidation, could be a promising antipsychotic candidate with low side effects. Considering the tricyclic Derivatives examined so far, some elements of structure-oxidation relationship (SOR) might be pointed out. Regarding the nature of the tricyclic ring substituent, from the most to the least sensitive to oxidation, the sequence was as follows: HO > Cl > CH(3)O > CF(3)SO(2)O. The nature of the tricyclic ring influenced also the sensitivity to oxidation; the diazepine moiety appeared to be the most reactive ring compared to oxa- and thiazepine congeners. These parameters could be advantageously integrated in the early design of new safer clozapine-like analogues.Peer reviewe
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Electrooxidation Potential as a Tool in the Early Screening for New Safer Clozapine-Like Analogues
'American Chemical Society (ACS)', 2001Co-Authors: Mouthys-mickalad Ange, Damas Jacques, Kauffmann J. M., Petit C., Bruhwyler J., Liao Y., Wikstrom H., Delarge J., Deby-dupont G., Geczy J.Abstract:peer reviewedaudience: researcher, professional, studentThe chemical modification of clozapine (1) has permitted the finding of new analogues, e.g., olanzapine (2), quetiapine (3), 5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzOxazepine fumarate (9), with a clinical or psychopharmacological profile similar to that of clozapine. However, when developing new Derivatives, the designers are discouraged by the development of clozapine-induced agranulocytosis. Different researchers have raised the role played by the oxidizability of the molecule in such a deleterious effect. In the present paper, we examined the oxidation profile (direct scavenging abilities, efficacy in inhibiting lipid peroxidation, and electrooxidation potential) of newly developed methoxy and trifluoromethylsulfonyloxy analogues related to clozapine, some of them being described as putative antipsychotic. The Oxazepine Derivative 7, unlike the other diazepine Derivatives (6, 10--12), was not readily oxidized. Using a statistical predictive model for hematotoxicity previously described, 7 was found in the cluster of potentially nontoxic compounds while diazepine Derivatives 6 and 10-12 were classified as potentially toxic compounds. Among these original compounds, 7, which presents a preclinical clozapine-like profile and a low sensitivity to oxidation, could be a promising antipsychotic candidate with low side effects. Considering the tricyclic Derivatives examined so far, some elements of structure-oxidation relationship (SOR) might be pointed out. Regarding the nature of the tricyclic ring substituent, from the most to the least sensitive to oxidation, the sequence was as follows: HO > Cl > CH(3)O > CF(3)SO(2)O. The nature of the tricyclic ring influenced also the sensitivity to oxidation; the diazepine moiety appeared to be the most reactive ring compared to oxa- and thiazepine congeners. These parameters could be advantageously integrated in the early design of new safer clozapine-like analogues
