- An efficient electrophilic N-amination utilizing in situ generated chloramine under phase transfer conditions
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An efficient, one-pot, phase transfer N-amination technology was developed. The protocol utilizes chloramine, an inexpensive and safe electrophilic aminating agent potentially viable for commercial manufacturing.
- Bhattacharya, Apurba,Patel, Nitin C.,Plata, Robert Erik,Peddicord, Michael,Ye, Qingmei,Parlanti, Luca,Palaniswamy, Venkatapuram A.,Grosso, John A.
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Read Online
- SUBSTITUTED PYRROLO TRIAZINE CARBOXAMIDE DERIVATIVES AS PROSTAGLANDIN EP3 RECEPTOR ANTAGONISTS
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The invention relates to substituted pyrrole triazine carboxamide derivatives of formula (I) and to processes for their preparation, and also /to their use for preparing medicaments for the treatment and/ or prophylaxis of diseases, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and diabetes, and also urogenital and ophthalmic disorders.
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Page/Page column 90
(2021/05/21)
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- TYROSINE KINASE INHIBITOR AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
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The present invention relates to a tyrosine kinase inhibitor and a pharmaceutical composition comprising same. The tyrosine kinase inhibitor of the present invention has the structures as shown in the following formula (I) or (II):
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- Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2
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c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ± 0.1 nM and 5.0 ± 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ± 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ± 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.
- Shi, Wei,Qiang, Hao,Huang, Dandan,Bi, Xinzhou,Huang, Wenlong,Qian, Hai
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p. 814 - 831
(2018/09/29)
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- Development of a practical synthesis of a p38 kinase inhibitor via a safe and robust amination
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The development of a practical synthesis for a p38 kinase inhibitor is described. The key advances include an improved route to the key intermediate, a substituted pyrrole, and a subsequent animation utilizing O-(4-nitrobenzoyl)- hydroxylamine, which provides a safe, scalable, and robust amination method. The new protocol was successfully demonstrated to generate 1.6 kg of API in seven steps and 26% overall yield.
- Shi, Zhongping,Kiau, Susanne,Lobben, Paul,Hynes Jr., John,Wu, Hong,Parlanti, Luca,Discordia, Robert,Doubleday, Wendel W.,Leftheris, Katerina,Dyckman, Alaric J.,Wrobleski, Stephen T.,Dambalas, Konstantinos,Tummala, Srinivas,Leung, Simon,Lo, Ehrlic
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p. 1618 - 1625
(2013/02/23)
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- Development of a practical synthesis of a functionalized pyrrolo[2,1-f][1,2,4]triazine nucleus
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Functionalized pyrrolotriazine 1b is a key heterocyclic building block in the synthesis of BMS-690514, a potent anticancer agent. Described herein are our development activities that led to the efficient preparation of 1b on a large scale. The key transformations include a selective C-alkylation of an oxalacetate salt with a hydrazonyl bromide to form a 2-hydrazonoethyl-3- oxosuccinate, followed by cyclodehydration to an aminopyrrole. Subsequent deprotection and condensation with formamidine afforded the pyrrolotriazine scaffold. Further elaboration of this core provided the desired pyrrolotriazinyl amine.
- Zheng, Bin,Conlon, David A.,Corbett, R. Michael,Chau, Melissa,Hsieh, Dau-Ming,Yeboah, Agnes,Hsieh, Daniel,Mueslehiddinoglu, Jale,Gallagher, William P.,Simon, Jeffrey N.,Burt, Justin
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p. 1846 - 1853
(2013/01/15)
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- Design, synthesis, and anti-inflammatory properties of orally active 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38α mitogen-activated protein kinase inhibitors
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A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1-f][1,2,4] triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1-f][1,2,4]tria
- Hynes Jr., John,Dyckman, Alaric J.,Lin, Shuqun,Wrobleski, Stephen T.,Wu, Hong,Gillooly, Kathleen M.,Kanner, Steven B.,Lonial, Herinder,Loo, Derek,McIntyre, Kim W.,Pitt, Sidney,Ding, Ren Shen,Shuster, David J.,Yang, XiaoXia,Zhang, Rosemary,Behnia, Kamelia,Zhang, Hongjian,Marathe, Punit H.,Doweyko, Arthur M.,Tokarski, John S.,Sack, John S.,Pokross, Matthew,Kiefer, Susan E.,Newitt, John A.,Barrish, Joel C.,Dodd, John,Schieven, Gary L.,Leftheris, Katerina
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- Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38α MAP kinase inhibitors
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A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38α MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class o
- Wrobleski, Stephen T.,Lin, Shuqun,Hynes Jr., John,Wu, Hong,Pitt, Sidney,Shen, Ding Ren,Zhang, Rosemary,Gillooly, Kathleen M.,Shuster, David J.,McIntyre, Kim W.,Doweyko, Arthur M.,Kish, Kevin F.,Tredup, Jeffrey A.,Duke, Gerald J.,Sack, John S.,McKinnon, Murray,Dodd, John,Barrish, Joel C.,Schieven, Gary L.,Leftheris, Katerina
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p. 2739 - 2744
(2008/12/21)
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- Amination of heterocyclic compounds with O-benzoylhydroxylamine derivatives
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The N-amination of heterocyclic compounds 1a - k with O- benzoylhydroxylamine derivatives 5 was developed and demonstrated to be a superior alternative to existing N-amination methods. A structure - reactivity relationship study was performed on variously
- Parlanti, Luca,Discordia, Robert P.,Hynes Jr., John,Miller, Michael M.,O'Grady, Harold R.,Shi, Zhongping
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p. 3821 - 3824
(2008/02/12)
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- Methods for the preparation of pyrrolotriazine compounds
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A method for preparing a compound having the formula: including the steps of: (a) cyclizing a compound of formula II: to form a compound of formula I: (b) deprotecting the nitrogen atom of the compound of formula I by amination or hydrogenation to form compound III.
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Page/Page column 13-14
(2008/06/13)
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- Pyrrolopyridazine MEK inhibitors
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The synthesis and SAR of a series of pyrrolopyridazine MEK inhibitors are reported. Optimal activity was achieved by incorporation of a 4-phenoxyaniline substituent at C4 and an acylated amine at C6.
- Chen, Zhong,Kim, Soong-Hoon,Barbosa, Stephanie A.,Huynh, Tram,Tortolani, David R.,Leavitt, Kenneth J.,Wei, Donna D.,Manne, Veeraswamy,Ricca, Carolyn S.,Gullo-Brown, Johnni,Poss, Michael A.,Vaccaro, Wayne,Salvati, Mark E.
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p. 628 - 632
(2007/10/03)
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- Process for preparing salts of 4-[[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide and novel stable forms produced therein
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Processes are provided for selectively preparing novel stable crystalline salt forms, selectively and consistently, namely, preparing Form N-1 of the methanesulfonic acid salt, and Form N-1 and Form N-4 of the hydrochloric acid salt of the p38 kinase inhibitor 4-[[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide. The processes preferably employ solvent systems including formic acid/acetone and formic acid/methylethyl ketone which produce crystals having suitable flow properties and desired particle size, and solvents such as N,N-dimethylformamide and N,N-dimethylacetamide may be employed as well. Novel Form N-1 crystals of the Form N-1 and Form N-4 crystals of the hydrochloride salt and Form N-1 crystals of the methanesulfonic acid salt of the above free base, pharmaceutical compositions containing such novel forms and a method of treating p38 kinase associated conditions, including rheumatoid arthritis are also provided.
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Page/Page column 20
(2010/11/24)
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- Method for preparing pyrrolotriazine compounds
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A method for aminating pyrrole derivatives and for preparing pyrrolotriazine compounds having the formula V,
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Page/Page column 7
(2008/06/13)
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- Method for preparing pyrrolotriazine compounds via in situ amination of pyrroles
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A method for aminating pyrrole derivatives via in situ generated chloramines and for preparing pyrrolotriazine compounds having the formula III,
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Page/Page column 6
(2008/06/13)
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- New dual inhibitors of EGFR and HER2 protein tyrosine kinases
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A novel series of dual EGFR and HER2 inhibitors based on the pyrrolo[2,1-f][1,2,4]triazine nucleus is described. A general route toward their synthesis, which enables functionalization at multiple sites, has been developed. Biological evaluation in enzyma
- Fink, Brian E.,Vite, Gregory D.,Mastalerz, Harold,Kadow, John F.,Kim, Soong-Hoon,Leavitt, Kenneth J.,Du, Karen,Crews, Donald,Mitt, Toomas,Wong, Tai W.,Hunt, John T.,Vyas, Dolatrai M.,Tokarski, John S.
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p. 4774 - 4779
(2007/10/03)
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- Pyrrolopyridazine compounds and methods of use thereof for the treatment of proliferative disorders
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Disclosed are pyrrolopyridazine compounds, methods of preparing such compounds, and their use for the treatment of proliferative, inflammatory, and other disorders.
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- N-Amination of Pyrrole and Indole Heterocycles with Monochloramine (N H2Cl)
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A survey of several electrophilic ammonia reagents for the N-amination of indole- and pyrrole-containing heterocycles revealed that monochloramine (NH2Cl) is an excellent reagent for this transformation. Pyrroles and indoles containing a variety of substitution were aminated on nitrogen with isolated yields ranging from 45% to 97%.
- Hynes Jr., John,Doubleday, Wendel W.,Dyckman, Alaric J.,Godfrey Jr., Jollie D.,Grosso, John A.,Kiau, Susanne,Leftheris, Katerina
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p. 1368 - 1371
(2007/10/03)
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