40320-60-3Relevant articles and documents
A convenient method for the preparation of 3-azetidinylidene acetic acid
Vuilhorgne, Marc,Commercon, Alain,Mignani, Serge
, p. 605 - 606 (1999)
A facile route to novel 3-azetidinylidene acetic acid from commercially available epichlorohydrin is described.
ISOXAZOLE CARBOXAMIDE COMPOUNDS AND USES THEREOF
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Page/Page column 68-69, (2020/04/25)
A compound of Formula (I) or or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating hearing loss or balance disorder: Formula (I) wherein R1 and Y are as defined herein.
Preparation method of tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5]nonane-2-formate
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Paragraph 0006; 0013, (2019/12/25)
The invention relates to a preparation method of tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5]nonane-2-formate, and mainly solves the technical problem that no proper industrial synthesis methodexists at present. The product is synthesized by six steps, and the preparation method comprises the steps: a first step, a compound 1 is subjected to Swern oxidation reaction to generate a compound 2; a second step, a compound 3 is obtained through a Horner-Wadsworth-Emmons reaction; a third step, a compound 4 is obtained through Michael addition; a fourth step, a compound 5 is obtained through reduction of the compound 4 with lithium tetrahydroaluminum; a fifth step, the compound 5 is dehydrated and retained with a ring to obtain a compound 6 under the action of sodium hydrogen; and a sixthstep, hydrogenation is preformed to remove a protective group, and then a protective group is added to obtain the target compound 7. The obtained compound is a useful intermediate or product for synthesis of many drugs.
Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7
Swain, Nigel. A.,Batchelor, Dave,Beaudoin, Serge,Bechle, Bruce M.,Bradley, Paul A.,Brown, Alan D.,Brown, Bruce,Butcher, Ken J.,Butt, Richard P.,Chapman, Mark L.,Denton, Stephen,Ellis, David,Galan, Sebastien R. G.,Gaulier, Steven M.,Greener, Ben S.,De Groot, Marcel J.,Glossop, Mel S.,Gurrell, Ian K.,Hannam, Jo,Johnson, Matthew S.,Lin, Zhixin,Markworth, Christopher J.,Marron, Brian E.,Millan, David S.,Nakagawa, Shoko,Pike, Andy,Printzenhoff, David,Rawson, David J.,Ransley, Sarah J.,Reister, Steven M.,Sasaki, Kosuke,Storer, R. Ian,Stupple, Paul A.,West, Christopher W.
supporting information, p. 7029 - 7042 (2017/09/07)
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.
1-diphenylmethylazetidine-3-ketone synthesis process method
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Paragraph 0013; 0014-0015, (2017/07/22)
The invention discloses a 1-diphenylmethylazetidine-3-ketone synthesis process method, which comprises: using 1-diphenylmethyl-3-hydroxy azetidine as a raw material, dissolving in DMSO, adding triethylamine, cooling to a temperature of 0-10 DEGC, adding pyridine sulfur trioxide in batches, carrying out a stirring reaction for 2 h at a room temperature, detecting the reaction through TLC until the reaction is completely performed, slowly adding ice water, completely stirring, adding ethyl acetate, extracting three times, combining the three collected organic phases, washing three times with 1/3 volume of saturated edible salt water, drying with anhydrous sodium sulfate, filtering, carrying out pressure reducing organic solvent removing on the filtrate to obtain a residual oil-like material, adding petroleum ether having the volume 5 times the volume of the residual oil-like material, beating, precipitating a yellow solid, filtering, and collecting the solid to obtain the 1-diphenylmethylazetidine-3-ketone. According to the present invention, compared to the traditional swern oxidation, the method of the present invention has advantages of simple operation and less feeding variety; compared to the final product purification methods in the similar literatures in the prior art, the method of the present invention is simple and is suitable for enlargement production; and the process method has advantages of low solvent consumption, emission reducing, and cost saving.
BRUTON'S TYROSINE KINASE INHIBITORS
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Page/Page column 83; 84, (2014/05/24)
Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (BTK). Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the BTK inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions. (Formula I)
Novel carboxamide-based allosteric MEK inhibitors: Discovery and optimization efforts toward XL518 (GDC-0973)
Rice, Kenneth D.,Aay, Naing,Anand, Neel K.,Blazey, Charles M.,Bowles, Owen J.,Bussenius, Joerg,Costanzo, Simona,Curtis, Jeffry K.,Defina, Steven C.,Dubenko, Larisa,Engst, Stefan,Joshi, Anagha A.,Kennedy, Abigail R.,Kim, Angie I.,Koltun, Elena S.,Lougheed, Julie C.,Manalo, Jean-Claire L.,Martini, Jean-Francois,Nuss, John M.,Peto, Csaba J.,Tsang, Tsze H.,Yu, Peiwen,Johnston, Stuart
supporting information; experimental part, p. 416 - 421 (2012/06/30)
The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S) -piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.
Process development of a novel azetidinyl ketolide antibiotic
Li, Bryan,Magee, Thomas V.,Buzon, Richard A.,Widlicka, Daniel W.,Bill, Dave R.,Brandt, Thomas,Cao, Xiaoping,Coutant, Michael,Dou, Haijian,Granskog, Karl,Flanagan, Mark E.,Hayward, Cheryl M.,Li, Bin,Liu, Fengwei,Liu, Wei,Nguyen, Thuy-Trinh,Raggon, Jeffrey W.,Rose, Peter,Rainville, Joseph,Reilly, Usa Datta,Shen, Yue,Sun, Jianmin,Wilcox, Glenn E.
scheme or table, p. 788 - 797 (2012/08/27)
Process development and the multikilogram synthesis of a novel azetidinyl ketolide antibiotic is described. Starting with clarithromycin, the eight-step synthesis features several telescoped operations and direct isolations, which results in a significant improvement in throughput and a major reduction in solvent usage and waste stream volume over the first scale-up campaign. Particular highlights of this effort include the development of an efficient synthesis of 3-hydroxy-1,5-naphthyridine-4-carbaldehyde via a Skraup process and engineering a robust final API synthesis. We also discovered a crystalline monotosylate salt that addressed significant formulation and degradation issues experienced when using the noncrystalline freebase.
NOVEL HETEROCYCLIC ACRYLAMIDES AND THEIR USE AS PHARMACEUTICALS
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Page/Page column 151, (2011/06/19)
The invention relates to novel heterocyclic acrylamide compounds (I), to the preparation of the compounds and intermediates used therein, to the use of the compounds as antibacterial medicaments and pharmaceutical compositions containing the compounds.
AMINO-HETEROCYCLIC COMPOUNDS
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Page/Page column 38, (2010/08/07)
The invention provides PDE9-inhibiting compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, A, and n are as defined herein. Pharmaceutical compositions containing the compounds of Formula I, and uses thereof in treating neurodegenerative and cognitive disorders, such as Alzheimer's disease and schizophrenia, are also provided.
