2243-58-5Relevant academic research and scientific papers
Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors
Haffner, Curt D.,Charnley, Adam K.,Aquino, Christopher J.,Casillas, Linda,Convery, Máire A.,Cox, Julie A.,Elban, Mark A.,Goodwin, Nicole C.,Gough, Peter J.,Haile, Pamela A.,Hughes, Terry V.,Knapp-Reed, Beth,Kreatsoulas, Constantine,Lakdawala, Ami S.,Li, Huijie,Lian, Yiqian,Lipshutz, David,Mehlmann, John F.,Ouellette, Michael,Romano, Joseph,Shewchuk, Lisa,Shu, Arthur,Votta, Bartholomew J.,Zhou, Huiqiang,Bertin, John,Marquis, Robert W.
supporting information, p. 1518 - 1523 (2019/10/19)
Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.
A 10 - bromo - 7H - benzo [c] carbazole preparation method (by machine translation)
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Paragraph 0091; 0095, (2019/10/17)
The invention discloses a 10 - bromo - 7 H - benzo [c] carbazole preparation method, comprises the following raw materials: 2 - naphthol: 260 g; hydrazine hydrate (80%): 520 g; water: 500 g; toluene: 750 ml; concentrated hydrochloric acid: 100 ml; 2 - naphthylhydrazine hydrochloride: 164 g; methanol: 968 ml; cyclohexanone: 91 g; cold methanol: 250 ml; 5, 6, 7, 8 - tetrahydro - 3, 4 - benzo-carbazole: 98.3 g; toluene: 700 ml; DDQ: 201.9 g; ethanol: 200 ml; benzo [c] carbazole: 65.1 g; dichloromethane: 600 ml; NBS: 54 g; toluene: 450 ml; activated carbon: 3 g; four reaction bottle: several, specific reaction steps are: (1). 2 - naphthol and 2 times weight of hydrazine hydrate (80%), reflux reaction 20 h, after processing by the dilute hydrochloric acid, to obtain 2 - naphthylhydrazine hydrochloride. The invention pollution is small, low cost, high yield, use of cheap and easily obtained raw materials, through the four-step reaction, to obtain the target compound, the total yield of products is relatively high; simple process operation, little three-waste discharge, is suitable for the large-scale production. (by machine translation)
Synthesis of Aryl Hydrazines via CuI/BMPO Catalyzed Cross-Coupling of Aryl Halides with Hydrazine Hydrate in Water
Kumar, Siripuram Vijay,Ma, Dawei
supporting information, p. 1003 - 1006 (2018/09/20)
The N,N’-bis(2,6-dimethylphenyl)oxalamide was discovered as a powerful ligand for Cu-catalyzed cross-coupling of aryl halides with hydrazine hydrate, leading to the formation of a variety of aryl hydrazines at 80 oC in water under the assistance of K3PO4 and 4 mol% cetyltrimethylammonium bromide from aryl bromides and aryl iodides. Good to excellent yields were observed in most cases.
Asymmetric catalysis on the nanoscale: The organocatalytic approach to helicenes
Koetzner, Lisa,Webber, Matthew J.,Martinez, Alberto,Defusco, Claudia,List, Benjamin
supporting information, p. 5202 - 5205 (2014/05/20)
The first asymmetric organocatalytic synthesis of helicenes is reported. A novel SPINOL-derived phosphoric acid, bearing extended π-substituents, catalyzes the asymmetric synthesis of helicenes through an enantioselective Fischer indole reaction. A variety of azahelicenes and diazahelicenes could be obtained with good to excellent yields and enantioselectivities. Twisting indoles: A novel chiral Bronsted acid, specifically designed for long-range control on a nanoscale, catalyzes the asymmetric synthesis of azahelicenes through a Fischer indolization. The method has the advantage of starting from simple achiral starting materials, which can be modified by changing the protecting group (R2) or the terminal substituents (R1, R3). The products can be further oxidized to polyaromatic systems.
Pyrazole compounds as sigma receptor inhibitors
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Page/Page column 12; 17-18, (2012/01/03)
The invention refers to compounds of general formula (I) having pharmacological activity towards the sigma receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use for the treatment and or prophylaxis of a disease in which the sigma receptor is involved.
Pyrazole urea-based inhibitors of p38 MAP kinase: From lead compound to clinical candidate
Regan, John,Moss, Neil,Pargellis, Chris,Pav, Sue,Proto, Alfred,Swinamer, Alan,Tong, Liang,Torcellini, Carol,Breitfelder, Steffen,Cirillo, Pier,Gilmore, Thomas,Graham, Anne G.,Hickey, Eugene,Klaus, Bernhard,Madwed, Jeffrey,Moriak, Monica
, p. 2994 - 3008 (2007/10/03)
We report on a series of N-pyrazole, N′-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5′-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure-activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.
Design of peptidomimetic δ opioid receptor antagonists using the message-address concept
Portoghese,Sultana,Takemori
, p. 1714 - 1720 (2007/10/02)
Highly selective nonpeptide ligands with potent δ opioid receptor antagonist activity have been developed using the message-address concept. This approach envisaged the δ opioid receptor to contain two major recognition subsites; a message subsite which recognizes the pharmacophore, and an address subsite that is unique for the δ receptor type and confers selectivity. The message and address components of the δ-selective enkephalins were postulated to be Tyr1 and Phe4, respectively, with Gly2-Gly3 functioning as a spacer. The message component of the target compounds in this study was derived from naltrexone and related structures. An indole system was fused to the C ring of naltrexone as a mimic of the address component. The benzene moiety of indole was viewed as the δ address component, mimicking the phenyl group of Phe4, and the pyrrole portion was used as a rigid spacer. Members of the series (1-23) were evaluated for opioid antagonist activity on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Naltrindole (NTI, 1) was the most potent member of the series, with K(e) values of ~0.1 nM at δ receptors. The antagonism by NTI was ~220- and 350-fold greater at δ than at μ and κ opioid receptors. The binding of NTI and selected members of the series to guinea pig brain membranes was qualitatively consistent with their pharmacologic antagonist activity profiles in the MVD and GPI, but the K(i) values were not in the same rank order. The selectivity of NTI arises mainly as a consequence of increased affinity at δ receptors. Thus, the K(e) and K(i) values of NTI were 1/530 and 1/90 that of the δ antagonist enkephalin analogue, ICI 174864. In contrast to NTI, ICI174864 derives its selectivity through greatly decreased recognition at μ and κ receptors. The implications of the high affinity and selectivity of NTI as a consequence of its conformational rigidity are discussed. It is suggested that any attempt to model a receptor-bound conformation of an opioid peptide should consider affinity and potency at multiple receptor sites rather than selectivity alone.
