- An Alternative Approach to the Hydrated Imidazoline Ring Expansion (HIRE) of Diarene-Fused [1.4]Oxazepines
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A four-step approach to the “hydrated imidazoline ring expansion” (HIRE) is presented. In most cases, the ring expansion was the sole process. However, for the first time, an alternative course of the hydrated imidazoline evolution was discovered which gave N-aminoethyl derivatives. These can, in principle, be converted into the target HIRE products under sufficiently forcing conditions. The approach offers improved flexibility with respect to the peripheral substituents and is also applicable to the synthesis of eleven-membered lactams. We observed that the latter can exist in two stable isomeric forms due to lactam–amide bond isomerization. The latter finding further demonstrates the value of medium-sized rings as multiple-conformer probes for biological target interrogation.
- Grintsevich, Sergey,Sapegin, Alexander,Reutskaya, Elena,Peintner, Stefan,Erdélyi, Máté,Krasavin, Mikhail
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p. 5664 - 5676
(2020/07/21)
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- Design of Conjugated Molecules Presenting Short-Wavelength Luminescence by Utilizing Heavier Atoms of the Same Element Group
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The introduction of heavy atoms into conjugated molecules often induces a redshift in the emission spectra. Conversely, we report here a blueshifting effect in the absorption and emission bands of a conjugated organic dye by employing a heavier atom from the same element group. Boron complexes having oxygen- and sulfur-bridged structures in the ligand moiety were synthesized, and their optical properties were compared. Significant optical bands in the absorption and luminescence spectra of the sulfur-bridged complex were observed in a shorter wavelength region than those of the oxygen-bridged complex. Theoretical calculations suggest that replacement of the bridging atom by a heavier one should reduce molecular planarity because of the larger atom size. As a result, the degree of electronic conjugation decreases, and this is followed by a blueshift in the optical bands. Finally, a blue-emissive crystal is demonstrated.
- Yamaguchi, Madoka,Tanaka, Kazuo,Chujo, Yoshiki
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supporting information
p. 1342 - 1347
(2018/04/30)
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- Methods for Treating Cognitive Disorders Using Inhibitors of Histone Deacetylase
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This disclosure relates to compounds for the inhibition of histone deacetylase and treatment of a cognitive disorder or deficit. More particularly, the disclosure provides for compounds of formula (I) wherein Q, J, L and Z are as defined in the specification.
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Paragraph 0399
(2017/01/23)
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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
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Inspired by VUF6884 (7-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine), reported as a dual H1/H4 receptor ligand (pKi: 8.11 (human H1R (hH1R)), 7.55 (human H4R (hH4R))), 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 hH1R (pKi: 6.8–8.7), but no or moderate affinity to the hH4R (pKi: ≤ 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 hH1R (pKi: 8.83 (R), 7.63 (S)) and the guinea-pig H1R (gpH1R) (pKi: 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 hH1R crystal structure. Moreover, docking studies of all oxepine derivatives at the hH1R 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 hH1R or hH4R, 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 hH1/h5-HT2A receptor ligand (pKi: 9.23 (hH1R), 8.74 (h5-HT2AR), ≤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 hH1R antagonist (pKi: 8.44 (hH1R), ≤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.
- Naporra, Franziska,Gobleder, Susanne,Wittmann, Hans-Joachim,Spindler, Julia,Bodensteiner, Michael,Bernhardt, Günther,Hübner, Harald,Gmeiner, Peter,Elz, Sigurd,Strasser, Andrea
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p. 610 - 625
(2016/10/12)
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- INHIBITORS OF HISTONE DEACETYLASE
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Compounds which are histone deacetylase inhibitors and their use in treating various disorders, including Alzheimer's Disease.
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Page/Page column 60
(2010/01/29)
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- INHIBITORS OF HISTONE DEACETYLASE
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This invention relates to compounds for the inhibition of histone deacetylase. More particularly, the inven- tion provides for compounds of formula (I) wherein (B), Q, J, L and Z are as defined in the specification
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Page/Page column 133
(2008/12/07)
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- Synthesis and evaluation of antipsychotic activity of 11-(4-aryl-1- piperazinyl)-dibenz [b, f][1,4] oxazepines and their 8-chloro analogues
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Atypical drugs reduce positive and negative symptoms of schizophrenia, without inducing EPS, but they exert other undesirable side effects. We have gone for synthesis of novel derivatives of Loxapine which are devoid of catalepsy and have decreased metabolic demethylation which is the prominent factor for bioavailability of the drug. While doing so we have also been successful in retaining the antipsychotic activity of the drug. Condensation of 8,11-dichlorodibenzoxazepine and 11-chlorodibenzoxazepine with 1-aryl piperazines was carried to give 8-chloro-11-(4-aryl-1-piperazinyl)-dibenz[b,f] [1,4]oxazepines and 11-(4-aryl-1-piperazinyl)-dibenz[b,f][1,4]oxazepines respectively. These derivatives were found as active as Clozapine.
- Wagh,Patil,Jain,Harak,Wagh
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p. 165 - 172
(2008/02/12)
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- IRON CATALYZED CROSS-COUPLING REACTIONS OF IMIDOYL DERIVATIVES
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Disclosed is a process for preparing a compound of formula A - N=C(D)(B), from a compound of formula A-N=C(E)(B) and a compound of formula D-M using an iron catalyst, where the process has is represented by Equation (I).
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Page/Page column 21; 57
(2010/11/27)
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- Iron-catalyzed cross-coupling of imidoyl chlorides with Grignard reagents
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A general, high yielding rapid iron-catalyzed cross-coupling reaction between Grignard reagents and imidoyl chlorides is described. These reactions are typically completed within 5 min, resulting in high yields of 71-96% using 5% iron catalyst in a THF-NM
- Ottesen, Lars K.,Ek, Fredrik,Olsson, Roger
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p. 1771 - 1773
(2007/10/03)
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- Characterization of the histamine H4 receptor binding site. Part 1. Synthesis and pharmacological evaluation of dibenzodiazepine derivatives
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A series of dibenzodiazepine derivatives was synthesized to probe the binding site of the recently discovered histamine H4 receptor (H 4R). Optimization of the lead structure clozapine (2) resulted in (E)-7-chloro-11(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine (7j), a potent H4R agonist (H4R, pK, = 7.6). Pharmacological data suggests that the series of nonimidazole compounds can be used to describe the orthosteric binding site of the H4R because both 2 and 7j displace [3H]histamine in a competitive manner. Furthermore, it is demonstrated that the effects of 7j are competitively antagonized by the selective H4R antagonist JNJ 7777120 (1), indicating considerable overlap of their binding sites. On the basis of the derived structure-activity relationships and additional pharmacological results, a pharmacophore model was constructed, which will be the premise for the design of novel H4R ligands.
- Smits, Rogier A.,Lim, Herman D.,Stegink, Bart,Bakker, Remko A.,De Esch, Iwan J. P.,Leurs, Rob
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p. 4512 - 4516
(2007/10/03)
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- Loxapine analogs and methods of use thereof
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The invention relates to novel compounds and methods of using them for modulating sleep.
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Page/Page column 75-76
(2008/06/13)
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- Behavioral approach to nondyskinetic dopamine antagonists: Identification of Seroquel
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A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-Potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-Induced climbing and antagonism of apomorphine-Induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-Sensitized Cebus monkeys. Initial examination of a few close cogeners of I enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-Hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-Substituted analogues of 6-(piperazin-1-yl)-11H-Dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]-thiazepines and -Oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]-piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-Substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.
- Warawa,Migler,Ohnmacht,Needles,Gatos,McLaren,Nelson,Kirkland
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p. 372 - 389
(2007/10/03)
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- 2-(Substituted phenyl)-dibenz[b,f][1,2,4]triazolo-[4,3-d][1,4]oxazepin or thiazepin-3(2H)-ones
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Compounds of the following formula STR1 wherein W is O or S; and X, Y and Z are independently selected from hydrogen, fluorine, bromine, chlorine, trifluoromethyl, lower alkyl and lower alkoxy; are disclosed. These compounds are useful as antiinflammatory
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