- 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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Paragraph 0230; 0231
(2018/03/25)
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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 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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- 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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- 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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- 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 12
(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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- Remarkable solvent effect in Barton-Zard pyrrole synthesis: application in an efficient one-step synthesis of pyrrole derivatives
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A unique solvent effect encountered in the Barton-Zard pyrrole synthesis was exploited to develop an efficient synthesis of pyrrole-2-esters. The chemistry was extended to a one-pot synthesis of pyrrole-2,4-dicarboxylates.
- Bhattacharya, Apurba,Cherukuri, Sankara,Plata, Robert Erik,Patel, Nitinchandra,Tamez Jr., Victoriano,Grosso, John A.,Peddicord, Michael,Palaniswamy, Venkatapuram A.
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p. 5481 - 5484
(2007/10/03)
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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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- Copper- or phosphine-catalyzed reaction of alkynes with isocyanides. Regioselective synthesis of substituted pyrroles controlled by the catalyst
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The copper-catalyzed reaction of isocyanides (CNCH2EWG 1) 1 with electron-deficient alkynes (RC=CEWG2) 2 gave the 2,4-di-EWG-substituted pyrroles 3 selectively, whereas the phosphine-catalyzed reaction of 1 with 2 afforded
- Kamijo, Shin,Kanazawa, Chikashi,Yamamoto, Yoshinori
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p. 9260 - 9266
(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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- Flash vacuum pyrolysis of N-alkenylbenzotriazoles and N-alkenylisoxazolones
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The flash vacuum pyrolysis of 1-(2-ethoxycarbonylethenyl)benzotriazole has been reinvestigated, and the processes leading to the formation of ethyl indole-3-carboxylate and 2-ethoxyquinolin-4(1H)-one elucidated. Similar pathways are followed in the flash vacuum pyrolysis of the corresponding benzisoxazolone. Some N-ethenylisoxazolones have been pyrolysed to form pyrroles, but rearrangement of the intermediate carbenes may be observed. Photolysis of the isoxazolones gives carbenes that may be captured by solvent or give pyrroles. CSIRO 2000.
- Cox, Matthew,Heidarizadeh, Fariba,Pragei, Rolf H.
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p. 665 - 671
(2007/10/03)
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- Transformations of alkyl 2-(2,2-disubstituted-ethenyl)amino-3- dimethylaminoprop-2-enoates: Synthesis of alkyl 3,4-disubstituted- and alkyl 1-acyl-3,4-disubstituted pyrrole-2-carboxylates
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Alkyl 3,4-disubstituted pyrrole-2-carboxylates were obtained by cyclization of alkyl-2(2,2-disubstituted-ethenyl)amino-3- (dimethylamino)prop-2-enoates in acidic media, while in the presence of acyl chlorides alkyl 1-acyl-3,4-disubstituted pyrrol-2-carbox
- Selic, Lovro,Stanovnik, Branko
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p. 479 - 482
(2007/10/03)
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- The total synthesis of chlorophyll a
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The total synthesis of chlorophyll a starting from Knorr's pyrrole (1) is described with full experimental detail. Forty six stages are involved to reach the target molecule, chlorin e6 trimethyl ester (46), from which the preparation of chlorophyll a has already been described. The four pyrroles which are required for rings A, B, C and D are elaborated largely by known reactions, although with considerable improvements. These pyrroles are manipulated to give two dipyrrin derivatives: a left-hand component (26, comprising rings A and D) and a right-hand component (the thioaldehyde 31, comprising rings B and C). These are brought together in a carefully controlled, stepwise, condensation to give a single porphyrin product (35) in 50% yield. This synthesis of an unsymmetrically-substituted porphyrin bearing an electron-withdrawing substituent and a meso-substituent is seen as a very considerable advance, both in conceptual and practical terms, over earlier approaches. During the course of the closure of the macrocycle, intermediates which exemplify a new group of dihydroporphyrins, the phlorins (e.g. 34), are recognised. Eleven steps remain. The porphyrin (35) is shown to undergo dehydrogenation (again via a phlorin intermediate) on brief treatment with acetic acid in air to give the meso-crylic acid derivative (36), which in acetic acid under nitrogen at 110° slowly reaches equilibrium with the purpurin (37). The introduction of the reactive vinyl group at C-3 has been delayed until this point in the synthesis. Photo-oxygenation of the product, the vinylpurpurin (38), cleaves the cyclopenteno-ring giving the methoxalylpurpurin (39). A reverse Claisen reaction now generates the methoxylactone, rac-isopurpurin 5 methyl ester (40), the first substance in this synthetic series which can be compared with a sample (albeit optically active) derived from natural chlorophyll a. rac-Isopurpurin 5 methyl ester (40) is hydrolysed to the lactol, chlorin 5 (41), which is resolved (diastereoisomeric salts with quinine). The less soluble salt gives synthetic act-chlorin 5, identical with a sample of natural provenance. Diazomethane treatment of the free acid (42) yields purpurin 5 dimethyl ester (43), again identical with the naturally-derived compound. Treatment with hydrogen cyanide in triethylamine leads to the cyanolactone (44), reductive cleavage and methylation of which give the chlorin e6 nitrile (45). Methanolysis of this furnishes synthetic crystalline chlorin e6 trimethyl ester (46), identical (mp, mixed mp, electronic spectrum, infra red spectrum) with a naturally-derived sample, so completing the total synthesis.
- Woodward, Robert Burns,Ayer, William A.,Beaton, John M.,Bickelhaupt, Friedrich,Bonnett, Raymond,Buchschacher, Paul,Closs, Gerhard L.,Dutler, Hans,Hannah, John,Hauck, Fred P.,Ito, Sho,Langemann, Albert,Le Goff, Eugene,Leimgruber, Willy,Lwowski, Walter,Sauer, Juergen,Valenta, Zdenek,Volz, Heinrich
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p. 7599 - 7659
(2007/10/02)
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- Photochemical Heterocyclization of Functionalized Dienamines
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A series of functionalized dienamines were prepared by base-catalyzed isomerisation of N-vinylaziridines.Photochemical cyclization of these N-substituted dienamines yielded predominantly pyrroline derivatives.
- Gelas-Mialhe, Yvonne,Mabiala, Gaston,Vessiere, Roger
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p. 5395 - 5400
(2007/10/02)
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- ELECTROPHILIC HETEROAROMATIC SUBSTITUTIONS. IX. BEHAVIOUR OF HALOGENOPYRROLES TOWARDS HYDROGEN HALIDES IN DIVERSE SOLVENTS
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The reactions of a series of α- and β-bromo and-chloropyrroles with hydrogen halides have been investigated both in aprotic and protic solvents in order to establish the true nature of the processes.Proto dehalogenation (reductive dehalogenation) has only been observed in position α in aprotic solvents able to scavenge the elemental halogen (or mixed halogen) formed, whereas halogen exchange reactions are the prevailing processes under protic conditions.Contrary to previous statements, halogen exchange can occur in both directions (Cl--->Br and Br--->Cl) and has been observed only in α position.
- Giuliano, Francesco,Penna, Marina,Sleiter, Giancarlo
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p. 589 - 594
(2007/10/02)
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