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Curt Wentrup - One of the best experts on this subject based on the ideXlab platform.
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1H-1,3-Diazepines and Ketenimines from Cyanotetrazolopyridines*
Australian Journal of Chemistry, 2008Co-Authors: Chris Addicott, Curt WentrupAbstract:Cyano-substituted tetrazolo[1,5-a]pyridines/2-azidopyridines 8T and 15T undergo thermal ring opening to the azides 8A and 15A. Solution photolysis causes nitrogen elimination and ring expansion to 1,3-diazacyclohepta-1,2,4,6-tetraenes 10 and 17, which react with alcohols to afford 2-alkoxy-1H-1,3-Diazepines, with secondary amines to 2-dialkylamino-5H-1,3-Diazepines, and with water to 1,3-diazepin-2-ones (12–14, 19, 21). Argon matrix photolysis of the azides affords the diazacycloheptatetraenes 10 and 17 as principal products together with ring-opened dicyanovinylketenimines 11 and 18. The matrix-isolated species were identified on the basis of comparison of the infrared spectra with those calculated at the B3LYP/6–31+G* level.
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1H-1,3-Diazepines, 5H-1,3-Diazepines, 1,3-diazepinones, and 2,4-diazabicyclo[3.2.0]heptenes.
Organic & biomolecular chemistry, 2004Co-Authors: Ales Reisinger, Paul V. Bernhardt, Rainer Koch, Curt WentrupAbstract:Tetrazolo[1,5-a]pyridines/2-azidopyridines 1 undergo photochemical nitrogen elimination and ring expansion to 1,3-diazacyclohepta-1,2,4,6-tetraenes 3, which react with alcohols to afford 2-alkoxy-1H-1,3-Diazepines 4 (5), with secondary amines to 2-dialkylamino-5H-1,3-Diazepines 16, sometimes via isolable 2-dialkylamino-1H-1,3-Diazepines 15, and with water to 1,3-diazepin-2-ones 19. The latter are also obtained by elimination of isobutene or propene from 2-tert-butoxy- or 2-isopropoxy-1H-1,3-Diazepines 4 or 5. 1,3-Diazepin-2-one 22B and 1,3-diazepin-4-one 24 were obtained from hydrolysis of the corresponding 4-chloroDiazepines. Diazepinones 19 undergo photochemical ring closure to diazabicycloheptenones 25 in high yields. The 2-alkoxy-1H-1,3-Diazepines 4 and 5 interconvert by rapid proton exchange between positions N1 and N3. The free energies of activation for the proton exchange were measured by the Forsen–Hoffman method as ΔG‡298 = 16.2 ± 0.6 kcal mol−1 as an average for 4a–c in CD2Cl2, acetone-d6, and methanol-d4, and 14.1 ± 0.6 kcal mol−1 for 4c in acetone/D2O. The structures of 2-methoxy-5,6-bis(trifluoromethyl)-1H-1,3-Diazepine 4k, 1,2-dihydro-4-diethylamino-5H-1,3-diazepin-2-one 22bB, and diazabicycloheptanone 26 were determined by X-ray crystallography. The former represents the first reported X-ray crystal structure of any monocyclic N-unsubstituted 1H-azepine.
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Synthesis of 1,3-Diazepines and ring contraction to cyanopyrroles.
Organic & biomolecular chemistry, 2003Co-Authors: Ales Reisinger, Paul V. Bernhardt, Curt WentrupAbstract:Several tetrazolo[1,5-a]pyridines/2-azidopyridines undergo photochemical nitrogen elimination and ring expansion to 1,3-diazacyclohepta-1,2,4,6-tetraenes (7,10,13,16,19,22) as well as ring cleavage to cyanovinylketenimines (8,17,20b) in low temperature Ar matrices. 6,8-Dichlorotetrazolo[1,5-a]pyridine/2-azido-3,5-dichloropridine 6 undergoes ready exchange of the chlorine in position 8 (3) with ROH/RONa. 8-Chloro-6-trifluoromethyltetrazolo[1,5-a]pyridine 15 undergoes solvolysis of the CF3 group to afford 8-chloro-6-methoxycarbonyltetrazolo[1,5-a]pyridine 18. Several tetrazolopyridines/2-azidopyridines afford 1H- or 5H-1,3-Diazepines in good yields on photolysis in the presence of alcohols or amines (11,14,23,25). 5-Chlorotetrazolo[1,5-a]pyridines/2-azido-6-chloropyridines 21 and 38 undergo a rearrangement to 1H- and 3H-3-cyanopyrroles 27 and 45, respectively. The mechanism of this rearrangement was investigated by 15N-labelling and takes place via transient 1,3-Diazepines. The structures of 6,8-dichloro-tetrazolo[1,5-a]pyridine 6T, 6-chloro-8-ethoxytetrazolo[1,5-a]pyridine 9Tb, dipyrrolylmethane 28, and 2-isopropoxy-4-dimethylamino-5H-1,3-Diazepine 25b were determined by X-ray crystallography. In the latter case, this represents the first reported X-ray crystal structure of a 5H-1,3-Diazepine.
Francois Huet - One of the best experts on this subject based on the ideXlab platform.
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highly peri regio and diastereoselective 1 3 dipolar cycloaddition of mesitonitrile oxide to 1 7 dimethyl 2 3 dihydro 1h 1 4 Diazepines unexpected one step formation of a new triheterocyclic framework
New Journal of Chemistry, 2001Co-Authors: A Baouid, J.-p. Lavergne, Said Elhazazi, A Hasnaoui, Philippe Compain, Francois HuetAbstract:We report here an efficient one-step synthesis of new [1,2,4]oxadiazolo[4,5-d][1,4]Diazepines and [1,2,4]oxadiazolo[4,5-d][1,4]-Diazepine-8-spiro-5′-isoxazolines by way of highly peri-, regio- and diastereoselective 1,3-dipolar cycloadditions of mesitonitrile oxide to 1,7-dimethyl-2,3-dihydro-1H-1,4-Diazepines. The structures were elucidated by spectral methods and X-ray crystallographic analysis. The regiochemistry of the cycloaddition is dictated by frontier orbital interactions.
Lorenzo Tei - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of 6-Substituted 6-Nitroperhydro-1,4-Diazepines via Novel Tandem Retro-Henry and Mannich/Michael Reactions
2016Co-Authors: Jonathan Martinelli, Giuseppe Gugliotta, Lorenzo TeiAbstract:N,N′-Dibenzyl-6-hydroxymethyl-6-nitroperhydro-1,4-Diazepine was converted into a nitronate via retro-Henry reaction, followed by either Michael reaction with several acrylic derivatives or Mannich reaction with different amines, thus leading to 6-substituted 6-nitroperhydro-1,4-Diazepines. The tandem retro-Henry/Mannich reaction was also carried out using benzylamine as base, solvent, and reagent at the same time. Selective hydrogenation of the nitro group and complete hydrogenolysis were also successfully achieved
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synthesis of 6 substituted 6 nitroperhydro 1 4 Diazepines via novel tandem retro henry and mannich michael reactions
Organic Letters, 2012Co-Authors: Jonathan Martinelli, Giuseppe Gugliotta, Lorenzo TeiAbstract:N,N′-Dibenzyl-6-hydroxymethyl-6-nitroperhydro-1,4-Diazepine was converted into a nitronate via retro-Henry reaction, followed by either Michael reaction with several acrylic derivatives or Mannich reaction with different amines, thus leading to 6-substituted 6-nitroperhydro-1,4-Diazepines. The tandem retro-Henry/Mannich reaction was also carried out using benzylamine as base, solvent, and reagent at the same time. Selective hydrogenation of the nitro group and complete hydrogenolysis were also successfully achieved.
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A New, Easy Access to the 6-Aminoperhydro-1,4-Diazepine Scaffold under Ultrasound and Microwave Irradiation
Synthesis, 2008Co-Authors: Alessandro Barge, Silvia Fuzerova, Dharita J. Upadhyaya, Davide Garella, Silvio Aime, Lorenzo Tei, Giancarlo CravottoAbstract:A novel, efficient, and rapid synthesis of the 6-amino-perhydro-1,4-Diazepine scaffold is reported. It was promoted by microwave or sequential ultrasound/microwave irradiation under solvent-free conditions or in solution. Protected ethylenediamine derivatives and N-Boc-serinol dimesylate underwent rapid cyclization to give 6-aminoperhydro-1,4-Diazepine derivatives in excellent yields and with high selectivity, whereas the same reaction failed or gave negligible yields under conventional heating. Cesium or potassium ions catalyzed the ring closure by coordinating the sulfon-amide groups. All relevant work reported to date in the literature mostly concern about the syntheses of either 1 H-tetrahydro-1,4-Diazepine-2,5-dione or substituted 1,4-benzoDiazepines, while the few published procedures for the preparation of 6-aminoperhydro-1,4-Diazepines involved several steps, required long reaction times and afforded low yields. By the present method, access to 6-aminoperhydro-1,4-Diazepines becomes much easier and faster.
Shiro Kato - One of the best experts on this subject based on the ideXlab platform.
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synthesis and structure activity relationships of 4 amino 5 chloro n 1 4 dialkylhexahydro 1 4 diazepin 6 yl 2 methoxybenzamide derivatives novel and potent serotonin 5 ht3 and dopamine d2 receptors dual antagonist
Chemical & Pharmaceutical Bulletin, 2002Co-Authors: Yoshimi Hirokawa, Naoyuki Yoshida, Hiroshi Harada, Takashi Yoshikawa, Shiro KatoAbstract:In search of a dopamine D2 and serotonin 5-HT3 receptors dual antagonist as a potential broad antiemetic agent, a number of benzamides were prepared from 4-amino-5-chloro-2-methoxybenzoic acid derivatives and 6-amino-1,4-dialkylhexahydro-1,4-Diazepines and evaluated for their binding affinity for the dopamine D2 and the serotonin 5-HT3 receptors using rat brain synaptic and rat cortical membranes, respectively. From the results of both in vitro receptor binding and in vivo biological assays for the dopamine D2 receptor, 1-ethyl-4-methylhexahydro-1,4-Diazepine ring was selected as an optimum amine moiety. Introduction of one methyl group on the nitrogen atom at the 4-position and/or modification of the substituent at the 5-position of the 4-amino-5-chloro-2-methoxybenzoyl moiety caused a marked increase in the dopamine D2 receptor binding affinity along with a potent 5-HT3 receptor binding affinity. Among the compounds, 5-chloro-N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)-2-methoxy-4-methylaminobenzamide (82), 5-bromo (110), and 5-iodo (112) analogues exhibited a much higher affinity for the dopamine D2 receptor than that of metoclopramide (IC50=17.5—61.0 nM vs. 483 nM). In particular, 82 showed a potent antagonistic activity for both receptors in vivo tests. Optical resolution of the racemate 82 brought about a dramatic change in the pharmacological profile with the (R)-enantiomer exhibiting a strong affinity for both the dopamine D2 and the 5-HT3 receptors, while the corresponding (S)-enantiomer had a potent and selective serotonin 5-HT3 receptor binding affinity.
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Nitrogen‐containing heteroalicycles with serotonin receptor binding affinity: Development of gastroprokinetic and antiemetic agents
Medicinal Research Reviews, 1999Co-Authors: Shiro Kato, Iwao Fujiwara, Naoyuki YoshidaAbstract:To obtain gastroprokinetic agents with more potent and selective activity than metoclopramide and cisapride, a series of N-(4-benzyl-2-morpholinylmethyl)benzamides were designed and prepared. Their synthesis and structure-activity relationships were described. As a result, mosapride was selected as a promising candidate for potent gastroprokinetic activity with selective 5-HT4 receptor agonistic activity. As an extension to this project, the novel benzamide and the carboxamide derivatives having 1-benzyl-4-methylhexahydro-1,4-Diazepine ring in the amine moiety were prepared and evaluated for 5-HT3 receptor antagonistic activity. DAT-582 was identified as an antiemetic agent in cancer chemotherapy. The asymmetric synthesis of DAT-582 and the SAR studies were briefly reviewed. In further modifications of the N-(1-benzyl-4-methylhexahydro-1,4-diazepin-6-yl)benzamides, the novel nicotinamides with 1-ethyl-4-methylhexahydro-1,4-diazepin ring were found to have potent 5-HT3 and dopamine D2 and D3 receptor antagonistic activities and to show weak central nervous system depression and extrapyramidal syndrome. After extensive SARs, AS-8112 was selected as a broad antiemetic agent.
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development of potent serotonin 3 5 ht3 receptor antagonists ii structure activity relationships of n 1 benzyl 4 methylhexahydro 1h 1 4 diazepin 6 yl carboxamides
Chemical & Pharmaceutical Bulletin, 1995Co-Authors: Hiroshi Harada, Iwao Fujiwara, Naoyuki Yoshida, Yoshimi Hirokawa, Toshiya Morie, Hideo Terauchi, Shiro KatoAbstract:Our studies on 4-amino-5-chloro-2-ethoxybenzamides led to the discovery that the N-(1, 4-dimethylhexahydro-1H-1, 4-diazepin-6-yl)benzamide 9 and the 1-benzyl-4-methylhexahydro-1H-1, 4-Diazepine analogue 10 are potent serotonin-3 (5-HT3) receptor antagonists. Structure-activity relationship (SAR) studies on the influence of the aromatic nucleus of 9 and 10 upon inhibition of the von Bezold-Jarisch reflex in rats are described. Heteroaromatic rings such as pyrrole, thiophene, furan, pyridine, pyridazine, 1, 2-benzisoxazole, indole, quinoline, and isoquinoline rings showed weak 5-HT3 receptor antagonistic activity. Within this series, use of the 1H-indazole ring as an aromatic moiety led to a substantial increase of the acitivity; the 1H-indazolylcarboxamides 54, 57, 97, and 102 showed potent 5-HT3 receptor antagonistic activity. The optimal compound identified via extensive SAR studies was N-(1-benzyl-4-methylhexahydro-1H-1, 4-diazepin-6-yl)-1H-indazole-3-carboxamide (54), whose effect was superior to that of the corresponding benzamide 10 and essentially equipotent to those of ondansetron (1) and granisetron (4).
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development of potent serotonin 3 5 ht3 receptor antagonists i structure activity relationships of 2 alkoxy 4 amino 5 chlorobenzamide derivatives
Chemical & Pharmaceutical Bulletin, 1995Co-Authors: Hiroshi Harada, Yoshimi Hirokawa, Naoyuki Yoshida, Toshiya Morie, Shiro KatoAbstract:A new series of 2-alkoxy-4-amino-5-chlorobenzamide derivatives bearing five- to seven-membered heteroalicyclic rings in the amine moiety was synthesized and evaluated for serotonin-3 (5-HT 3 ) receptor antagonistic activity by assaying the ability to antagonize the von Bezold-Jarisch reflex in rats. The five- to seven-membered heteroalicycles comprise pyrrolidine, morpholine, 1,4-thiazine, piperidine, piperazine, 1,4-oxazepine, 1,4-thiazepine, azepine, and 1,4-Diazepine rings. Among them, some benzamide derivatives having a 1,4-Diazepine ring showed a potent 5-HT 3 receptor antagonistic activity. In particular, 4-amino-5-chloro-N-(1,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)-2-ethoxybenzamide (96) and the 1-benzyl-4-methylhexahydro-1H-1,4-Diazepine analogue 103 showed potent 5-HT 3 receptor antagonistic activity without 5-HT 4 receptor binding affinity.
Nicolas Masurier - One of the best experts on this subject based on the ideXlab platform.
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Selective C-Acylation of 2-Aminoimidazo[1,2-a]pyridine: Application to the Synthesis of Imidazopyridine-Fused [1,3]Diazepinones
2016Co-Authors: Nicolas Masurier, Roberta Aruta, Vincent Gaumet, Séverine Denoyelle, Emmanuel Moreau, Vincent Lisowski, Jean Martinez, Ludovic T. MaillardAbstract:A series of 20 optically pure 3,4-dihydro-5H-pyrido[1′,2′:1,2]imidazo[4,5-d][1,3]diazepin-5-ones which form a new family of azaheterocycle-fused [1,3]Diazepines were synthesized in four steps with 17–66% overall yields. The key step consists of a selective C-acylation reaction of easily accessible 2-aminoimidazo[1,2-a]pyridine at C-3
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synthesis and reactivity of pyrrolo 3 2 d 1 3 oxazine 2 4 dione access to new pyrrolo 3 2 e 1 4 Diazepine 2 5 diones
Tetrahedron, 2014Co-Authors: Jeandaniel Malcor, Nicolas Masurier, Jean Martinez, Ludovic T Maillard, Yann Brouillette, Julien Graffion, Kim Spielmann, Vincent LisowskiAbstract:Abstract A convenient synthesis of pyrrolo[3,2- d ][1,3]oxazine-2,4-dione 4 is described and its reactivity towards various nucleophiles studied. The regioselective ring opening of anhydride 4 or its N -alkylated analog 25 in the presence of alanine or proline afforded, respectively, imidazolidinedione 22 and N -protected pyrrolo[3,2- e ][1,4]Diazepines 30 and 31 in a one-pot process. In a last part of this study, an alternative route to produce a library of eight non protected pyrrolo[3,2- e ][1,4]Diazepine-2,5-diones 35a – h is described to overcome the limited reactivity of anhydride 4 .
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Imidazopyridine-fused [1,3]-diazepinones: Synthesis and antiproliferative activity.
European Journal of Medicinal Chemistry, 2014Co-Authors: Audrey Gallud, Vincent Lisowski, Jean Martinez, Ophélie Vaillant, Ludovic T Maillard, Dominique P Arama, Joëlle Dubois, Marie Maynadier, Marcel Garcia, Nicolas MasurierAbstract:: A series of 15 pyrido-imidazo-1,3-diazepin-5-ones and pyrido-1,3-Diazepine-2,5-diones were synthesized and their anticancer activities were evaluated. Among tested compounds on a cell lines panel, compound 6a presents the best growth inhibition activity on 21 cell lines with a cytotoxic effect on MDA-MB-435 melanoma cells. This compound led to deep cell morphological changes and revealed to be an inhibitor of the Hepatocyte progenitor kinase-like kinase (HGK), which is known to be implicated in the migration, adhesion and invasion of various tumor cells.