- Extractive spectrophotometric methods for the determination of doxepin hydrochloride in pharmaceutical preparations using titanium (IV) and iron (III) thiocyanate complexes
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Two simple, precise, and accurate extractive spectrophotometric methods have been developed for the determination of doxepin hydrochloride in pharmaceutical preparations. The methods are based on the formation of ion association complexes of doxepin with
- Misiuk, Wieslawa
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Read Online
- Preparation method of benzyl aryl ether and application of benzyl aryl ether in synthesis
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and, 6-dihydrodibenzo [11 - b] oxazepine e -11 - ketone compounds are synthesized through a one-step reaction of benzaldehyde compounds and phenolic compounds through one-step reaction. The benzyl aryl ether and 6 and 11 -dihydrodibenzo [b, e] oxazepine -11 - ketone compound respectively have a chemical structure formula shown in a formula I and II. The invention discloses a synthesis method of the compound. Benzaldehyde compound After completion of the reaction, I, 6-dihydrodibenzo [11 - b] oxazepine e ketone compound -11 - can be synthesized through an oxidation or hydrolysis step and a ring closing step after the reaction is complete II.
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- A New Antagonist of Caenorhabditis elegans Glutamate-Activated Chloride Channels With Anthelmintic Activity
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Nematode parasitosis causes significant mortality and morbidity in humans and considerable losses in livestock and domestic animals. The acquisition of resistance to current anthelmintic drugs has prompted the search for new compounds for which the free-living nematode Caenorhabditis elegans has emerged as a valuable platform. We have previously synthetized a small library of oxygenated tricyclic compounds and determined that dibenzo[b,e]oxepin-11(6H)-one (doxepinone) inhibits C. elegans motility. Because doxepinone shows potential anthelmintic activity, we explored its behavioral effects and deciphered its target site and mechanism of action on C. elegans. Doxepinone reduces swimming rate, induces paralysis, and decreases the rate of pharyngeal pumping required for feeding, indicating a marked anthelmintic activity. To identify the main drug targets, we performed an in vivo screening of selected strains carrying mutations in Cys-loop receptors involved in worm locomotion for determining resistance to doxepinone effects. A mutant strain that lacks subunit genes of the invertebrate glutamate-gated chloride channels (GluCl), which are targets of the widely used antiparasitic ivermectin (IVM), is resistant to doxepinone effects. To unravel the molecular mechanism, we measured whole-cell currents from GluClα1/β receptors expressed in mammalian cells. Glutamate elicits macroscopic currents whereas no responses are elicited by doxepinone, indicating that it is not an agonist of GluCls. Preincubation of the cell with doxepinone produces a statistically significant decrease of the decay time constant and net charge of glutamate-elicited currents, indicating that it inhibits GluCls, which contrasts to IVM molecular actions. Thus, we identify doxepinone as an attractive scaffold with promising anthelmintic activity and propose the inhibition of GluCls as a potential anthelmintic mechanism of action.
- Bouzat, Cecilia,Castro, María Julia,Faraoni, María Belén,Gerbino, Darío,Turani, Ornella
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- Synthesis of dibenzocycloketones by acyl radical cyclization from aromatic carboxylic acids using methylene blue as a photocatalyst
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An efficient intramolecular radical cyclization reaction via photoredox catalysis was developed for the synthesis of dibenzocycloketone derivatives using methylene blue as a photosensitizer. This strategy could be widely used to synthesize large heterocycles due to the unique reactivity of phosphoranyl radicals formed by a polar/SET crossover between an aromatic carboxylic acid and a phosphine radical cation. Attractive features of this process include generation of an acyl radical by an inexpensive and metal-free photocatalyst, which effectively undergoes a cyclization process.
- Jiang, Hongshuo,Mao, Guijie,Wu, Hongfeng,An, Qi,Zuo, Minghui,Guo, Weihao,Xu, Chunzhao,Sun, Zhizhong,Chu, Wenyi
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supporting information
p. 5368 - 5373
(2019/10/11)
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- Iron(II) promoted direct synthesis of dibenzo[b,e]oxepin-11(6H)-one derivatives with biological activity. A short synthesis of doxepin
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A novel and efficient synthesis of dibenzo[b,e]oxepin-11(6H)-ones by direct intramolecular ortho-acylation from readily available 2-(phenoxymethyl)benzoic acids was developed. The method takes advantage of a newly developed cooperative system consisting of sustainable FeCl2 and Cl2CHOCH3 as the key components. This methodology is compatible with a wide variety of functional groups in good to excellent yields and high regioselectivity. The synthetic application of new protocol was extended to the synthesis of known tricyclic drug doxepin as well as a small library of oxepin based derivatives. For the first time, the obtained dibenzo[b,e]oxepinone derivatives were evaluated for their biological activities on the free-living nematode Caenorhabditis elegans as an effective and cost-efficient model system for anthelmintic discovery.
- Scoccia, Jimena,Castro, M. Julia,Faraoni, M. Belén,Bouzat, Cecilia,Martín, Víctor S.,Gerbino, Darío C.
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p. 2913 - 2922
(2017/04/26)
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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 0719
(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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- Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material
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The present invention discloses a method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as a raw material. In the method, o-halogen methyl methyl benzoate which is wide in source is used as a starting raw material, and sulfasalazine is obtained through substitution, hydrolysis, cyclization, nucleophilic addition, elimination reaction, nucleophilic substitution and neutralization reaction. The method comprises: during a nucleophilic substitution reaction obtained in the seventh step, using an organic lithium compound in an ether solution, so that the organic lithium compound and dimethylamine form an ammonium lithium salt (the formula is as shown in the description); then conducting an alkylation reaction on the ammonium lithium salt and a halide to improve the yield of tertiary amine, thereby ensuring the yield and purity of doxepin hydrochloride.
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- Synthetic method of doxepin hydrochloride adopting o-halogen methyl benzoate as raw material
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The invention discloses a synthetic method of doxepin hydrochloride adopting o-halogen methyl benzoate as a raw material. The synthetic method comprises: taking the o-methyl benzoate wide in source as a starting raw material, and sequentially carrying out benzyl halogenations, substitution, hydrolysis, cyclization, nucleophilic addition, nucleophilic substitution and neutralization to obtain salazosulfapyridine. In the nucleophilic substitution step of step 7, an organic lithium compound is dissolved in an ether solvent, so that the organic lithium compound and dimethylamine react to form an ammonium lithium salt (see the description), then the ammonium lithium salt is subjected to alkylation reaction with a halogen compound, the yield of the tertiary ammonium is increased, and the yield and purity of the final doxepin hydrochloride can be guaranteed.
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- A to phthaldialdehyde as the raw material to synthesize method of doxepin hydrochloride (by machine translation)
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This invention discloses in a to phthaldialdehyde as the raw material to synthesize method of doxepin hydrochloride. The method comprises in a wide range of sources phthaldialdehyde as the starting material, reaction by sequentially connie Zha Luo, intramolecular esterification, substituted, cyclized, nucleophilic addition, elimination reactions, nucleophilic substitution, pro-nuclear substituted, and in the reaction, to obtain liu Danhuang pyridine. In section 8 step in the nucleophilic substitution reaction steps, yu Mi using organic lithium compound in the solvent, so that the organic compound forming ammonium lithium salt with dimethylamine , Then this ammonium lithium salt for carrying out the alkylation reaction with halo, improve the yield of the addition, the ultimate so as to guarantee the yield and purity of doxepin hydrochloride. Phthaldialdehyde cheap, so as to reduce the production cost. (by machine translation)
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- A Parham cyclization approach to diaryl-fused seven-membered ring heterocyclic ketones
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Aryl-fused seven membered heterocyclic frameworks appear in a variety of pharmaceutically pertinent compounds. However, only a very few methods for their preparation have been described. This work describes a novel synthesis route to diaryl-fused seven membered heterocyclic ketones through the generation of functionalized aryllithiums by bromine-lithium exchange, followed by intramolecular cyclization onto an electrophilic nitrile functional group. The resulting N-lithioimine can then be hydrolyzed to the desired ketone, generally in good yields. The order of addition of n-butyllithium is crucial to the process with inverse addition proving to mitigate side product formation and increase yields.
- Farrokh, John,Campos, Catherine,Hunt, David A.
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p. 5245 - 5247
(2015/08/19)
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- PROCESS FOR THE PREPARATION OF PHARMACEUTICAL INTERMEDIATES
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Process for the preparation of intermediates that are useful in the synthesis of active pharmaceutical ingredients (API), in particular active in the central nervous system.
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Paragraph 0035; 0036; 0037; 0038
(2014/10/29)
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- Process for the preparation of pharmaceutical intermediates
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Process for the preparation of dibenzo[b,e]oxe-/thiepin-11-(6H9-one compounds that are useful intermediates in the synthesis of known tricycli antidepressants Doxepin and Dothiepin respectively.
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Paragraph 0031-0033
(2014/10/28)
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- Doxepin analogs and methods of use thereof
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The invention relates to novel antihistamines and methods of modulating sleep by administering a doxepin analog or a pharmaceutically effective salt thereof.
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Page/Page column 48; 56; 57
(2008/06/13)
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- Investigation of the solvent enclathration potentials of 5-phenyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol and related seven-membered ring alcohols
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Four previously reported tricyclic alcohols containing seven-membered central B-rings, 5-phenyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol, 5-phenyl-5H-dibenzo[a,d]cyclohepten-5-ol, 11-phenyl-6,11-dihydrodibenzo[b,e] oxepin-11-ol and 11-phenyl-6,11-dihydrodibenzo[b,e]thiepin-11-ol have been synthesized and their solvent enclathration (inclusion) properties investigated and compared by using 1H-NMR and differential scanning calorimetry (DSC). The presence of an oxygen or a sulphur atom, respectively, in the B-ring of the latter two compounds had a detrimental effect on the solvent enclathration properties of the host compounds as compared to those containing an ethane or ethylene bridge. This suggests that, although enclathration is highly dependent on the hydrogen bonding ability of the host, rigidity of the structure plays a crucial role in the formation and stability of these complexes.
- Taljaard, Benjamin,Barton, Benita,McCleland, Cedric W.
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- Synthesis and biological activity of 11-[4-(cinnamyl)-1-piperazinyl]-6,11-dihydrodibenz[b,e]oxepin derivatives, potential agents for the treatment of cerebrovascular disorders
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A series of 11-[4-(cinnamyl)-1-piperazinyl]-6,11-dihydrodibenz[b,e]oxepins and related compounds were synthesized and evaluated for their protective activities against complete ischemia, normobaric hypoxia, lipidperoxidation and convulsion. Structure-activity relationship studies of this series led to the finding of (E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-yl)-4-(3-phenyl-2-prop enyl)piperazine dimaleate (50), AJ-3941 with the most appropriate property for combined pharmacological activities. Compound 50 also shows an inhibitory effect against cerebral edema as well when orally given to rats.
- Kurokawa,Sato,Masuda,Yoshida,Ochi,Zushi,Fujiwara,Naruto,Uno,Matsumoto
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p. 2564 - 2573
(2007/10/02)
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- SYNTHESIS OF DOTHIEPIN AND DOXEPIN BY GRIGNARD REACTIONS IN TOLUENE
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The tricyclic antidepressant agents 11-(3-N,N-dimethylaminopropylidene)-6H,11H-dibenzo--thiepin hydrochloride (Dothiepin) and 11-(3-N,N-dimethylaminopropylidene)-6H,11H-dibenzo-oxepin hydrochloride (Doxepin) have been prepared in good yield by Grignard reactions in toluene.
- Jalander, Lars,Oksanen, Lasse,Taehtinen, Johanna
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p. 3349 - 3352
(2007/10/02)
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