- Aminimides as potential CNS acting agents. I. Design, synthesis, and receptor binding of 4′-aryl aminimide analogues of clozapine as prospective novel antipsychotics
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A series of substituted 1-[4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)- 1-methylhexahydropyrazin-1-ium]-1-aminimide derivatives were designed on the basis of the physicochemical properties of the aminimide functional group and synthesized as potential antipsychotic agents for the treatment of schizophrenia. The target compounds were readily prepared in two steps from clozapine (8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine) and involved N-acylation of a common hydrazinium salt intermediate by an acyl chloride or activated ester in the presence of a strong base. The aminimides were tested for in vitro activity at the dopamine D4 and serotonin 5-HT2A receptors and were found to possess modest affinity for both receptor systems. CSIRO 2007.
- Capuano, Ben,Crosby, Ian T.,Lloyd, Edward J.,Neve, Juliette E.,Taylor, David A.
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Read Online
- NOVEL and IMPROVED SYNTHESIS OF ANTIPSYCHOTIC DRUG
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The present invention relates to novel as well as improved process for the preparation of Clozapine of Formula I which involves anti-narcotic and highly cost effective raw materials.
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- Palladium-catalysed regioselective: N -arylation of anthranilamides: A tandem route for dibenzodiazepinone synthesis
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A palladium-catalyzed domino approach to the synthesis of 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepinones from 2-aminobenzamides and 1,2-dihaloarenes has been developed. Our strategy integrating double N-arylations (inter- and intra-molecular) of 2-aminobenzamides with 1,2-dihaloarenes under palladium-catalyzed conditions is clearly distinct from the current literature available for the synthesis of dibenzodiazepinones. Unlike a previous report described for regioselective N-arylation of 2-aminobenzamide at the amine group, our mechanistic studies support the regioselective N-arylation of 2-aminobenzamide occurring first primarily at the amide group. The translational application of our protocol may be demonstrated in the synthesis of a marketed drug, clozapine.
- Laha, Joydev K.,Manral, Neelam,Hunjan, Mandeep Kaur
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p. 7339 - 7343
(2019/05/24)
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- Direct Reductive Cyclocondensation of the Nitro Group with the Amido Group: Key Role of the Iminophosphorane Intermediate in the Synthesis of 1,4-Dibenzodiazepine Derivatives
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A class of dialkylamino-substituted dibenzodiazepines and their hetero analogues was synthesized by the intramolecular aza-Wittig condensation of the amido group with iminophosphoranes. The one-pot, two-step procedure includes reductive synthesis of the intermediate iminophosphoranes from the corresponding nitroamides and tributylphosphine.
- Tryniszewski, Micha?,Bujok, Robert,Cmoch, Piotr,Gańczarczyk, Roman,Kulszewicz-Bajer, Irena,Wróbel, Zbigniew
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p. 2277 - 2286
(2019/05/16)
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- Applications of TiCl3 as a Diagnostic Reagent for the Detection of Nitro- and N-Oxide-Containing Compounds as Potentially Mutagenic Impurities Using Ultrahigh-Performance Liquid Chromatography Coupled with High-Resolution Mass Spectrometry
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The ICH has strict guidelines for limiting the presence of potentially mutagenic impurities (PMIs) in marketed drugs. Therefore, it is important to fully characterize and quantitate all possible PMIs that could arise during the process of synthesizing and developing a drug. Two important and prevalent examples of PMIs are compounds containing N-oxide and nitro functional groups. TiCl3 derivatization is an established method for determining the presence or absence of N-oxide metabolites by reduction to the corresponding amine. In this study, we demonstrate a novel application of TiCl3 reduction combined with high-resolution UHPLC/HRMS to analyze PMIs. The results indicate that a variety of N-oxide- and nitro-containing compounds can be readily characterized by this facile platform method. In addition, we show that this chemical derivatization method can be utilized to enhance the ionization of nitro-containing compounds for LC/MS analysis.
- Yang, Rong-Sheng,Beard, Adam,Sheng, Huaming,Zhang, Li-Kang,Helmy, Roy
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- The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs
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Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand-receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure-activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10000-fold selectivity for hM3Dq over hM3.
- Chen, Xin,Choo, Hyunah,Huang, Xi-Ping,Yang, Xiaobao,Stone, Orrin,Roth, Bryan L.,Jin, Jian
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p. 476 - 484
(2015/03/30)
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- Synthesis and oxidant properties of phase 1 benzepine N-oxides of common antipsychotic drugs
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There is increasing evidence that cell constituents are oxidized by widely used antipsychotic drugs but until now the underlying chemistry has remained unclear. It is well known that such drugs readily undergo N-oxidation as a first key metabolic step. To gain insight into the problem, the tertiary phase 1 N-oxides of clozapine, olanzapine, quetiapine, and zotepine were synthesized, together with the N,S-dioxides of quetiapine and zotepine. These N-oxides were then subjected to well-established chemical transformations to test their oxidant properties in group VIII transition-metal-catalyzed reactions. In the osmium tetroxide catalyzed dihydroxylation of styrene or cinnamyl alcohol and in the tetrapropylammonium perruthenate catalyzed oxidation of cinnamyl alcohol, the benzepine N-oxides could be used as replacements for the standard oxidant, N-methylmorpholine N-oxide (NMO) with varying degrees of efficiency. From a chemical point of view, clozapine N-oxide displayed a comparable oxidation power to NMO, characterizing the benzepines as oxygen carriers. Moreover, quetiapine was found to be an excellent double oxygen acceptor, undergoing initial N-oxidation and subsequent S-oxidation. It is therefore worthwhile considering whether oxidative damage to the human body might be related to the potential redox properties of common antipsychotic drugs. Georg Thieme Verlag Stuttgart ? New York.
- Koerber, Jochen,Loeffler, Stefan,Schollmeyer, Dieter,Nubbemeyer, Udo
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p. 2875 - 2887
(2013/10/22)
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- DIBENZO[b,e][1,4]DIAZEPINE MODULATORS OF DOPAMINE RECEPTORS, SEROTONIN RECEPTORS, ADRENERGIC RECEPTORS, ACETYLCHOLINE RECEPTORS, AND/OR HISTAMINE RECEPTORS
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The present invention relates to new dibenzo[b,e][1,4]diazepine modulators of dopamine receptors, serotonin receptors, adrenergic receptors, acetylcholine receptors, and/or histamine receptors, pharmaceutical compositions thereof, and methods of use thereof.
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- Bifunctional solid catalysts for chemoselective hydrogenation-cyclisation- amination cascade reactions of relevance for the synthesis of pharmaceuticals
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The benzodiazepines olanzapine and clozapine are nowadays manufactured by a three-step process with a final yield below 50%. An approach to environmentally-friendly intensive processes consists in the development of multifunctional solid catalyst able to catalyze multistep reactions. Here, a bifunctional metal-acid solid catalyst has been prepared and is able to carry out hydrogenation-cyclisation-amination reactions in a cascade process. The catalytic system is illustrated for the synthesis of these important antipsychotics, being an alternative for the current industrial process that requires three steps batch reactions, using mineral acids and bases, and stoichiometric amounts of SnCl2.
- Leyva-Pérez, Antonio,Cabrero-Antonino, Jose R.,Corma, Avelino
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supporting information; experimental part
p. 8203 - 8209
(2010/11/05)
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- AMINO SUBSTITUTED DIARYL[A,D]CYCLOHEPTENE ANALOGS AS MUSCARINIC AGONISTS AND METHODS OF TREATMENT OF NEUROPSYCHIATRIC DISORDERS
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Disclosed herein are analogs of clozapine and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof; methods of synthesizing the analogs; and methods of using the analogs for treating neuorpsychiatric disorders. In some embodiments, the analogs are amino substituted diaryl[a,d]cycloheptenes.
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(2008/06/13)
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- Compositions and methods for the administration psychotropic drugs which modulate body weight
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Embodiments of the invention describe compositions and methods for the administration of fast disintegrating atypical antipsychotics, metabolites of atypical antipsychotics, and antidepressants which reduce weight in patients previously taking conventional formulation of atypical antipsychotics and antidepressants. In a preferred embodiment said fast dissolving atypical antipsychotic is FAZACLO. In another preferred embodiment said fast dissolving metabolite of an atypical antipsychotic is desmethyl clozapine. In another preferred embodiment said fast dissolving antidepressant is paroxetine.
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Page/Page column 13
(2008/06/13)
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- Hydrazides of clozapine: A new class of D1 dopamine receptor subtype selective antagonists
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Acylated and aroylated hydrazinoclozapines are highly potent dopamine D1 antagonists that show remarkable selectivity over other dopamine receptors. The most potent compound in this series is the 2,6-dimethoxybenzhydrazide 33 with a D1 Ki of 1.6 nM and 212-fold selectivity over D2 receptor.
- Sasikumar,Burnett,Zhang,Smith-Torhan,Fawzi,Lachowicz
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p. 4543 - 4547
(2007/10/03)
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- Combination treatment for anxiety, depression, obsessive compulsive disorder and psychosis
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The present invention relates to a method of treating depression, obsessive compulsive disorder and psychosis in a mammal, including a human, by administering to the mammal an atypical antipsychotic in combination with an antidepressant agent with improvement in efficiency. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, an atypical antipsychotic, and an SRI.
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- THE OCULAR HYPOTENSIVE ACTIVE COMPOSITIONS
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The present invention is related to the ocular hypotensive active compositions, which comprise clozapine or sulpiride and pharmaceutically acceptable excipients. The ocular preparations of the invention have ocular hypotensive effect (10P). They are new drugs in the therapy of glaucoma which can be easily prepared, and are so safe in clinical practice that no side-effect has been found.
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- Hypotensive intraocular pressure activity of clozapine and sulpiride
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This invention introduces a novel anti-glaucoma solution which comprises of Clozapine or Sulpiride and a pharmaceutical vehicle. This is the first time all the above agents have been prepared in ophthalmologic solutions, which will be able to decrease the IOP in animals.
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- Process for making 11-piperazino-diazepines, oxazepines, thiazepines and azepines
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This invention concerns a novel process for the preparation of 6-piperazinyl derivatives of morphantridine and corresponding ring-substituted and hereto analogues thereof, comprising reacting a compound of the formula: SPC1 Wherein A is benzene or thiophene, and X is --CH2 -- or a hetero atom or group, with a complex comprising titanium, zirconium, hafnium or vanadium and a corresponding piperazinyl derivative. The end products are in general known and useful as neuroleptics.
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