- Method for preparing vanonitinib and analogue intermediate thereof through electro-reduction
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The invention relates to an electroreduction preparation method of 2-amino-5-methoxybenzoic acid derivatives represented by a formula I shown in the specification. A preparation reaction is shown in the specification, wherein n is selected from 1, 2 or 3;
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Paragraph 0078-0085
(2021/03/18)
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- Structure–activity relationship study of novel quinazoline-based 1,6-naphthyridinones as MET inhibitors with potent antitumor efficacy
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As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinaz
- Zhuo, Lin-Sheng,Wu, Feng-Xu,Wang, Ming-Shu,Xu, Hong-Chuang,Yang, Fan-Peng,Tian, Yan-Guang,Zhao, Xing-E.,Ming, Zhi-Hui,Zhu, Xiao-Lei,Hao, Ge-Fei,Huang, Wei
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- Histone lysine methyltransferase structure activity relationships that allow for segregation of G9a inhibition and anti-Plasmodium activity
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Plasmodium falciparum HKMTs (PfHKMTs) play a key role in controlling Plasmodium gene expression and represent exciting new anti-malarial epigenetic targets. Using an inhibitor series derived from the diaminoquinazoline HKMT inhibitory chemotype, we have previously identified compounds with highly promising antimalarial activity, including irreversible asexual cycle blood stage-independent cytotoxic activity at nM concentrations, oral efficacy in in vivo models of disease, and the unprecedented ability to reactivate dormant liver stage parasites (hypnozoites). However, future development of this series will need to address host versus parasite selectivity, where inhibitory activity against human G9a is removed from the lead compounds, while maintaining potent anti-Plasmodium activity. Herein, we report an extensive study of the SAR of this series against both G9a and P. falciparum. We have identified key SAR features which demonstrate that high parasite vs. G9a selectivity can be achieved by selecting appropriate substituents at position 2, 4 and 7 of the quinazoline ring. We have also, in turn, discovered that potent G9a inhibitors can be identified by employing a 6-carbon 'Nle mimic' at position 7. Together, this data suggests that while broadly similar, the G9a and potential PfHKMT target(s) binding pockets and/or binding modes of the diaminoquinazoline analogues exhibit clear and exploitable differences. Based on this, we believe this scaffold to have clear potential for development into a novel anti-malarial therapeutic.
- Sundriyal, Sandeep,Chen, Patty B.,Lubin, Alexandra S.,Lueg, Gregor A.,Li, Fengling,White, Andrew J. P.,Malmquist, Nicholas A.,Vedadi, Masoud,Scherf, Artur,Fuchter, Matthew J.
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p. 1069 - 1092
(2017/07/12)
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- Design and discovery of 4-anilinoquinazoline-urea derivatives as dual TK inhibitors of EGFR and VEGFR-2
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EGFR and VEGFR-2 are involved in pathological disorders and the progression of different kinds of tumors, the combined blockade of EGFR and VEGFR signaling pathways appears to be an attractive approach to cancer therapy. In this work, a series of 4-anilinoquinazoline derivatives containing substituted diaryl urea or glycine methyl ester moiety were designed and identified as EGFR and VEGFR-2 dual inhibitors. Compounds 19i, 19j and 19l exhibited the most potent inhibitory activities against EGFR (IC50?=?1?nM, 78?nM and 51?nM, respectively) and VEGFR-2 (IC50?=?79?nM, 14?nM and 14?nM, respectively), they showed good antiproliferative activities as well. Molecular docking established the interaction of 19i with the DFG-out conformation of VEGFR-2, suggesting that they might be type II kinase inhibitors.
- Zhang, Hai-Qi,Gong, Fei-Hu,Ye, Ji-Qing,Zhang, Chi,Yue, Xiao-Hong,Li, Chuan-Gui,Xu, Yun-Gen,Sun, Li-Ping
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p. 245 - 254
(2016/10/03)
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- Identification and Structure–Activity Relationship Studies of Small-Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1
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The methyllysine reader protein Spindlin1 has been implicated in the tumorigenesis of several types of cancer and may be an attractive novel therapeutic target. Small-molecule inhibitors of Spindlin1 should be valuable as chemical probes as well as potential new therapeutics. We applied an iterative virtual screening campaign, encompassing structure- and ligand-based approaches, to identify potential Spindlin1 inhibitors from databases of commercially available compounds. Our in silico studies coupled with in vitro testing were successful in identifying novel Spindlin1 inhibitors. Several 4-aminoquinazoline and quinazolinethione derivatives were among the active hit compounds, which indicated that these scaffolds represent promising lead structures for the development of Spindlin1 inhibitors. Subsequent lead optimization studies were hence carried out, and numerous derivatives of both lead scaffolds were synthesized. This resulted in the discovery of novel inhibitors of Spindlin1 and helped explore the structure–activity relationships of these inhibitor series.
- Robaa, Dina,Wagner, Tobias,Luise, Chiara,Carlino, Luca,McMillan, Joel,Flaig, Ralf,Schüle, Roland,Jung, Manfred,Sippl, Wolfgang
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p. 2327 - 2338
(2016/10/24)
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- Epidermal growth factor receptor tyrosine kinase inhibitors MPGF and MPGH with anti-tumor activity and preparation method and application thereof
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The invention discloses epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) MPGF and MPGH with the anti-tumor activity and a preparation method and application thereof. By optimizing and improving the chemical structure of PD153035, brand-new EGFR TKIs are obtained and named as MPGF (shown in the formula I) and MPGH (shown in the formula II). Research shows that the synthesized EGFR TKI-MPGF and EGFR TKI-MPGH can effectively inhibit tumor cell proliferation and has a stronger proliferation inhibition effect on mutational EGFR lung cancer cell line PC-9 compared with the PD153035, and therefore the EGFR TKI-MPGF and the EGFR TKI-MPGH can serve as anti-tumor agents to be applied in clinic. In addition, the invention discloses the method for preparing the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) MPGF and MPGH with the anti-tumor activity. By means of the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) MPGF and MPGH with the anti-tumor activity and the preparation method and application thereof, an effective technological means is provided for tumor treatment, especially for treatment of the non-small cell lung cancer.
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- Condensation of anthranilic acids with pyridines to furnish pyridoquinazolones via pyridine dearomatization
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The unprecedented carbodiimide-mediated condensation between pyridines and anthranilic acids via pyridine dearomatization at room temperature has been developed to provide a straightforward approach to pyridoquinazolones. The value of this approach has further been demonstrated by its application to one-step, gram-scale syntheses of a series of pyridoquinazolone-based natural products and their analogues from readily available starting materials.
- Yang, Yajun,Zhu, Cuiju,Zhang, Min,Huang, Shijun,Lin, Jingjing,Pan, Xiandao,Su, Weiping
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supporting information
p. 12869 - 12872
(2016/11/06)
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- 4-substituted anilinoquinazoline derivatives, and preparation method and application thereof
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The invention discloses novel 4-substituted anilinoquinazoline derivatives or pharmaceutically acceptable salts thereof, or polymorphic substances, solvates or stereomers of the 4-substituted anilinoquinazoline derivatives, and a preparation method and application thereof. The 4-substituted anilinoquinazoline compounds have favorable inhibition activities for EGFR and VEGFR-2 in a biological test and have obvious effects in an in-vitro anti-human tumor cell proliferation activity test.
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-
Paragraph 0058; 0059
(2017/01/31)
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- THERAPEUTIC COMPOUNDS AND USES THEREOF
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Described herein are compounds of Formula (I) or Formula (VI), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Also provided are particles (e.g., nanoparticles) comprising compounds of Formula (I) or Formula (VI) and pharmaceutical compositions thereof that are mucus penetrating. Methods of using the compounds or pharmaceutical compositions thereof for treating diseases are also provided.
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- Synthesis of 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)- quinazoline
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The preparation of the novel isomeric 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)-quinazoline was achieved using a six-step process. An alternate method to the 7-propargyloxy derivative and analogous 7-propargyloxy containing compounds is als
- Pham, Helen Trinh,Hanson, Robert N.,Olmsted, Sandra L.,Kozhushnyan, Anton,Visentin, Adam,Weglinsky, Paul J.,Massero, Chris,Bailey, Kristen
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p. 1053 - 1056
(2011/03/22)
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- 4-Quinazolinyloxy-diaryl ureas as novel BRAFV600E inhibitors
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Aryl phenyl ureas with a 4-quinazolinoxy substituent at the meta-position of the phenyl ring are potent inhibitors of mutant and wild type BRAF kinase. Compound 7 (1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy) phenyl)urea hydrochloride) exhibits good pharmacokinetic properties in rat and mouse and is efficacious in a mouse tumor xenograft model following oral dosing.
- Holladay, Mark W.,Campbell, Brian T.,Rowbottom, Martin W.,Chao, Qi,Sprankle, Kelly G.,Lai, Andiliy G.,Abraham, Sunny,Setti, Eduardo,Faraoni, Raffaella,Tran, Lan,Armstrong, Robert C.,Gunawardane, Ruwanthi N.,Gardner, Michael F.,Cramer, Merryl D.,Gitnick, Dana,Ator, Mark A.,Dorsey, Bruce D.,Ruggeri, Bruce R.,Williams, Michael,Bhagwat, Shripad S.,James, Joyce
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scheme or table
p. 5342 - 5346
(2011/10/09)
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- STEROIDAL ANTI-HORMONE HYBRIDS
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Disclosed are novel compounds and compositions for inhibition of androgen and estrogen receptor signaling, methods for inhibiting androgen signaling, methods for inhibiting estrogen signaling, methods for inhibiting the interaction between a co-regulatory protein and an androgen or estrogen receptor, and methods for treating cancer.
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Page/Page column 53
(2010/08/08)
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- PROCESS FOR PRODUCING AROMATIC AMINE HAVING ARALKYLOXY OR HETEROARALKYLOXY GROUP
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There is provided a process for producing an aromatic amine compound having an aralkyloxy or heteroaralkyloxy group, in which an aromatic nitro compound having an aralkyloxy or heteroaralkyloxy group is reacted with hydrogen under mild conditions in accordance with a simple procedure while preventing the removal of aralkyl or heteroaralkyl group and keeping stable the other substituents on the aryl group or heteroaryl group so that the substituent does not take part in the reaction, to selectively reduce only the nitro group. The present invention is directed to a process for producing an aromatic amine compound which comprises reacting an aromatic nitro compound represented by the general formula (1): wherein Ar represents an aryl group or heteroaryl group which may have a substituent, and Z represents a divalent aromatic group which may have a substituent, with hydrogen in the presence of a metal catalyst to obtain an aromatic amine compound represented by the general formula (2): wherein Ar and Z have the meaning as defined above.
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Page/Page column 6-7
(2009/12/07)
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- VEGFR INHIBITORS CONTAINING A ZINC BINDING MOIETY
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The present invention relates to VEGFR inhibitors and their use in the treatment of cell proliferative diseases such as cancer. The said derivatives may further act as HDAC inhibitors.
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Page/Page column 26-27
(2009/04/24)
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- One-pot microwave-assisted selective azido reduction/tandem cyclization in condensed and solid phase with nickel boride
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An efficient and inexpensive method using microwave-assisted irradiation with Ni2B for the syntheses of aromatic amines, pyrrolobenzodiazepines as well as pyrroloquinazolinones was developed. This protocol was applied in the tandem resin-cleavage, azido reduction, and cyclization of compounds 3 and 5 that afforded substituted pyrrolo[2,1-c][1,4] benzodiazepines 4 and 6 in a one-pot manner. The microwave-assisted irradiation reactions enhanced yields with very short reaction times in contrast to the conventional thermal reactions. Georg Thieme Verlag Stuttgart.
- Shankaraiah, Nagula,Markandeya, Nagula,Espinoza-Moraga, Marlene,Arancibia, Claudia,Kamal, Ahmed,Santos, Leonardo Silva
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experimental part
p. 2163 - 2170
(2009/12/31)
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- Chemoselective aromatic azido reduction with concomitant aliphatic azide employing Al/Gd Triflates/Nal and ESI-MS mechanistic studies
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Aluminium and gadolinium inflates catalyze the chemoselective reduction of aromatic azides to the corresponding amines in combination with sodium iodide. This mild chemoselective method has been applied to the synthesis of various aryl amines, C2azido-substituted pyrrolo[2,1-c]-[1,4]benzodiazepines, and fused[2,1b]quinazolinones by an intramolecular azido reduction tandem cyclization reaction. Interestingly, this methodology selectively reduces aryl azides with enhanced yields and proceeds in shorter reaction times than previous strategies. The mechanistic aspects have been investigated and the intermediates associated with this selective transformation have been intercepted and characterized by online monitoring of the reaction by ESI-MS.
- Kamal, Ahmed,Markandeya, Nagula,Shankaraiah, Nagula,Ratna Reddy,Prabhakar,Sanjeeva Reddy,Eberlin, Marcos N.,Santos, Leonardo Silva
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experimental part
p. 7215 - 7224
(2010/03/05)
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- BENZO[C][2,7]NAPHTHYRIDINE DERIVATIVES, AND THEIR USE AS KINASE INHIBITORS
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The present invention relates to Benzo[c] [2,7] naph thy ri dine Derivatives of formula (I), compositions comprising an effective amount of a Benzo[c] [2,7]naphthyridine Derivative, methods for treating or preventing a proliferative disorder or an autoimmune disease, comprising administering to a subject in need thereof an effective amount of a Benzo[c] [2,7]naphthyridine Derivative, methods for modulating PDK-I activity, PKA activity, Akt activity, S6K activity, or PKC activity, comprising administering to a subject in need thereof an effective amount of a Benzo[c] [2,7] naphthyridine Derivative. The invention also relates to processes for preparing a Benzo[c] [2,7] naphthyridine Derivative.
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- An efficient selective reduction of aromatic azides to amines employing BF3·OEt2/NaI: Synthesis of pyrrolobenzodiazepines
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A selective and facile method for the reduction of aromatic azides to amines by employing borontrifluoride diethyl etherate and sodium iodide. This methodology has been applied towards the preparation of biologically important imine-containing pyrrolobenzodiazepines and their dilactams through intramolecular reductive-cyclization process. In this protocol the reagent systems are amenable for the generation of solution-phase combinatorial synthesis. Georg Thieme Verlag Stuttgart.
- Kamal, Ahmed,Shankaraiah,Markandeya,Reddy, Ch. Sanjeeva
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experimental part
p. 1297 - 1300
(2009/04/06)
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- Methods of synthesizing radiolabeled 3-cyano[14C]quinolines
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The present invention is directed to radiolabeled 3-cyanoquinolines of the formula: and methods of synthesizing the same, wherein G1, G2 R1, R4, Z, X, and n are as defined herein. The present invention is also directed to a radiolabeled intermediate compounds of formula (VII): wherein PG, G1, R1, R4, R10, and R11 are as defined herein, and synthesis of the same.
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Page/Page column 14-15
(2010/11/28)
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- QUINOLINE AND QUINOXALINE DERIVATIVES AS INHIBITORS OF KINASE ENZYMATIC ACTIVITY
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Compounds of formula (IA) or (IB), are inhibitors of aurora kinase activity: Formula (IA), (IB) wherein -L1Y1-[CH2]z- is a linker radical wherein Y1, L1 and z are as defined in the claims; R6 is C1-C4alkoxy, hydrogen or halo; W represents a bond, -CH2-, -O-, -S-, -S(=O)2-, or -NR5- where R5 is hydrogen or C1-C4 alkyl; Q is =N-, =CH- or =C(X1)- wherein X1 is cyano, cyclopropyl or halo; linker radicals L2 are as defined in the claims; R is a radical of formula (X) or (Y): wherein R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group; R4 is hydrogen; or optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, heteroaryl, heteroaryl(C1-C6 alkyl)-, -(C=O)R3, -(C=O)OR3, or -(C=O)NR3 wherein R3 is hydrogen or optionally substituted (C1-C6)alkyl, C3-C7 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, heteroaryl, or heteroaryl(C1-C6 alkyl)-; R41 is hydrogen or optionally substituted C1-C6 alkyl; and D is a monocyclic heterocyclic ring of 5 or 6 ring atoms.
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- Selective reduction of aromatic azides in solution/solid-phase and resin cleavage by employing BF3·OEt2/EtSH. Preparation of DC-81
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An efficient method for the reduction of aromatic azides in both solution and solid-phase has been developed by employing BF3·OEt2/EtSH. This report also describes resin cleavage employing this reagent system. Further, this protocol has been utilized for the solution as well as the solid-phase synthesis of pyrrolo[2,1-c][1,4]benzodiazepines, including the naturally occurring antibiotic DC-81 and fused [2,1-b]quinazolinones.
- Kamal, Ahmed,Shankaraiah,Reddy, K. Laxma,Devaiah
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p. 4253 - 4257
(2007/10/03)
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- A novel route to pyrrolo[2,1-c][1,4]benzodiazepin-5-ones. Formal total synthesis of (±)-DC-81
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(formula presented) Compounds 3a and 3b were synthesized from N-allylisatoic anhydrides 5a and 5b in six and seven steps, respectively. Synthesis of 3b constitutes a formal total synthesis of (±)-DC-81.
- Wang, Tiansheng,Lui, Alfred S.,Cloudsdale, Ian S.
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p. 1835 - 1837
(2008/02/11)
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- Lewis Acid-Mediated Selective Removal of N-tert-Butoxycarbonyl Protective Group (t-Boc)
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A simple and efficient method for the selective cleavage of N-Boc protective groups from amines employing Lewis acid aluminum chloride, is described.The scope of this procedure is explored for the deprotection of a variety of amines including amino acid derivatives. - Keywords: aluminum chloride; t-Boc carbamates; selective cleavage
- Bose, D. Subhas,Lakshminarayana, V.
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- An efficient and highly selective cleavage of N-tert- butoxycarbonyl group under microwave irradiation
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A simple and high yielding method for the cleavage of t-Boc carbamates is described which occurs under mild and solvent-free conditions using microwave irradiation.
- Bose, D. Subhas,Lakshmiriarayana
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p. 5631 - 5634
(2007/10/03)
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